![Examples of area under the LDL-C versus age curves. Each color represents a different patient population plotting cumulative low-density lipoprotein cholesterol (LDL-C) years versus age and the average onset of atherosclerotic cardiovascular disease (ASCVD) (black dashed horizontal line). Individuals with genetically determined severe hypercholesterolemia from birth (e.g., familial hypercholesterolemia [FH]) have the largest area under the curve at any given age (red dashed vertical line) and steepest slope of LDL-C versus age. Thus, they experience the earliest onset of ASCVD. Individuals with moderate hypercholesterolemia starting in the teenage years secondary to genetics and/or suboptimal lifestyle habits are at risk for relatively early ASCVD due to a lengthy cumulative exposure to LDL-C. Those with modest hypercholesterolemia from adulthood, often due to suboptimal lifestyle habits, generally develop ASCVD later than the other 2 groups. Individuals genetically endowed with low LDL-C from birth have a markedly reduced risk of developing ASCVD. (Figure and legend reproduced from Shapiro and Bhatt with permission [208]).](https://www.researchgate.net/publication/362536650/figure/fig1/AS:11431281085485858@1663777743634/Examples-of-area-under-the-LDL-C-versus-age-curves-Each-color-represents-a-different_Q320.jpg)
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2666-6677/© 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
State-of-the-Art Review
There is urgent need to treat atherosclerotic cardiovascular disease risk
earlier, more intensively, and with greater precision: A review of current
practice and recommendations for improved effectiveness
Michael E. Makover
a
, Michael D. Shapiro
b
, Peter P. Toth
c
,
d
,
*
a
New York University Grossman School of Medicine, New York, NY, USA
b
Division of Cardiology, Wake Forest University Baptist Medical Center, Winston Salem, NC, USA
c
Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA
d
CGH Medical Center, 101 East Miller Road, Sterling, Illinois
GRAPHICAL ABSTRACT
ARTICLE INFO
Keywords:
Atherosclerosis
Cholesterol
Coronary artery disease
Dementia
Lipoproteins
Myocardial infarction
Prevention
Stroke
ABSTRACT
Atherosclerotic cardiovascular disease (ASCVD) is epidemic throughout the world and is etiologic for such acute
cardiovascular events as myocardial infarction, ischemic stroke, unstable angina, and death. ASCVD also impacts
risk for dementia, chronic kidney disease peripheral arterial disease and mobility, impaired sexual response, and
a host of other visceral impairments that adversely impact the quality and rate of progression of aging. The
relationship between low-density lipoprotein cholesterol (LDL-C) and risk for ASCVD is one of the most highly
established and investigated issues in the entirety of modern medicine. Elevated LDL-C is a necessary condition
for atherogenesis induction. Basic scientic investigation, prospective longitudinal cohorts, and randomized
clinical trials have all validated this association. Yet despite the enormous number of clinical trials which support
the need for reducing the burden of atherogenic lipoprotein in blood, the percentage of high and very high-risk
patients who achieve risk stratied LDL-C target reductions is low and has remained low for the last thirty years.
Abbreviations: ASCVD, Atherosclerotic cardiovascular disease; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; CAD, coronary artery dis-
ease; HMG CoA, 3-hydroxymethyl-3-methylglutaryl coenzyme A; RCT, Randomized controlled trial; CHD, Coronary Heart Disease; HDL-C, High-density lipoprotein
cholesterol; NMR, Nuclear Magnetic Resonance; PCSK9, Proprotein convertase subtilisin:kexin type 9; apoB, apolipoprotein B; VLDL, Very low-density lipoprotein;
IDL, Intermediate-density lipoprotein; LLT, Lipid-lowering therapy; NFT, Neurobrillary tangle; MCI, Mild cognitive impairment; PAV, Percent Atheroma Volume;
FCT, Fibrous Cap Thickness; LCBI, Lipid core burden index; CAC, Coronary artery calcium; CCTA, Coronary computed tomographic angiography; PAD, Peripheral
Arterial Disease; NPV, Negative predictive value; FH, Familial hypercholesterolemia.
* Corresponding author.
E-mail address: Ptoth1@jhmi.edu (P.P. Toth).
Contents lists available at ScienceDirect
American Journal of Preventive Cardiology
journal homepage: www.journals.elsevier.com/american-journal-of-preventive-cardiology
https://doi.org/10.1016/j.ajpc.2022.100371
Received 11 March 2022; Received in revised form 10 July 2022; Accepted 5 August 2022
American Journal of Preventive Cardiology 12 (2022) 100371
2
Atherosclerosis is a preventable disease. As clinicians, the time has come for us to take primordial and primary
prevention more serously. Despite a plethora of therapeutic approaches, the large majority of patients at risk for
ASCVD are poorly or inadequately treated, leaving them vulnerable to disease progression, acute cardiovascular
events, and poor aging due to loss of function in multiple visceral organs. Herein we discuss the need to greatly
intensify efforts to reduce risk, decrease disease burden, and provide more comprehensive and earlier risk
assessment to optimally prevent ASCVD and its complications. Evidence is presented to support that treatment
should aim for far lower goals in cholesterol management, should take into account many more factors than
commonly employed today and should begin signicantly earlier in life.
1. Introduction
Atherosclerosis is the leading cause of disease, disability, and death
in the United States and globally [1,2]. Current medical practice has
made progress, but agonizingly slowly considering the millions of peo-
ple still adversely aficted by atherosclerotic complications despite use
of current treatments. This review examines how new approaches can
signicantly reduce the human cost of atherosclerosis. In light of the
continued high rate of atherosclerotic disease, what seems needed is
what Martin Luther King, Jr. called “the erce urgency of now” [3]. An
entire paradigm shift is required such that preventive efforts are
embraced much earlier in life, as discussed later in the paper. We
propose that preventing and controlling atherosclerosis, the greatest
killer of both men and women, be the top priority of medical care in the
United States.
While there has been a signicant reduction in heart attack and
stroke [4,5], large numbers of Americans still sustain myocardial and
cerebral infarctions and other complications of atherosclerotic cardio-
vascular disease (ASCVD) [6,7] Despite the wealth of evidence and the
availability of effective preventive interventions, declines in ASCVD hit
a nadir, and in fact, cardiovascular mortality has been on the rise over
the last decade in both men and women in the US [8]. and throughout
the world [2] Even though modern technology has helped more victims
of acute cardiovascular events survive, signicant numbers of patients
who survive due to stents and other interventions in the immediate
acute phase nevertheless often experience long-term disability, rein-
farction, and death secondary to inadequate treatment [9,10].
Atherosclerosis causes or contributes to many other diseases be-
sides coronary artery disease. Success cannot be claimed until they are
equally addressed and reduced.
Current practices are certainly not eliminating atherosclerotic dis-
ease. Atherosclerotic disease is preventable since its drivers of risk are
largely modiable (e.g., hyperlipidemia, hypertension, diabetes, ciga-
rette smoking, sedentary lifestyle, obesity). A more intensive, more
precise approach applied earlier than is current practice is delineated in
this paper, which will also explain why doing so has a higher likelihood
of signicantly reducing the total burden of atherosclerotic disease.
Delay and inadequate care leave patients at heightened risk for ASCVD-
related events and complications and all of the many other manifesta-
tions of atherosclerosis. Guidelines and risk assessment tools used to
prevent events and other complications of atherosclerosis need to have
high treatment and prediction success rates. Unfortunately, that has not
been the case in many instances.
Multiple studies have shown that the guidelines would not have
recommended treatment for at least half of patients who subsequently
suffered proven myocardial infarctions, including those with MI’s
under age 50, those from a high-risk population (India) and those over
age 65 [11–14]. A better approach is required and justied.
2. Not just coronary artery disease and stroke
Current practice focuses essentially on preventing acute events from
coronary artery disease (CAD), but atherosclerosis affects many other
arterial beds [15–17] in ways that develop slowly over many years.
Atherosclerosis causes disability and death from its contributions to:
•Disabling consequences of cerebral vascular accidents and cerebral
ischemia
•Dementia
•Peripheral arterial disease
•Heart failure
•Renal artery stenosis
•Carotid artery stenosis and embolization
•Kidney failure
•Hypertension
•Aortic disease
•Mesenteric artery disease
•Erectile dysfunction
•Frailty
•Poor aging [18–21]
These can take so long to manifest that they are ignored in ran-
domized controlled trials (RCTs). Assuming that just reducing acute
events will also prevent long-term consequences of atherosclerosis is
unwarranted by current evidence and has not been adequately studied.
These slower to develop manifestations of atherosclerotic disease should
also be prioritized and equal efforts should be made to prevent them.
2.1. Low-density lipoprotein cholesterol and ASCVD
The most important atherosclerosis treatment breakthrough
occurred in 1987 when the FDA approved lovastatin, the rst 3-hydrox-
ymethyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor
[22]. One year later the National Cholesterol Education Program pub-
lished the rst guidelines for clinicians to prevent myocardial infarctions
by reducing cholesterol levels [23,24]. While many countries have
developed their own national guidelines, most follow a similar premise –
intensity of preventive efforts should match the individual’s estimated
global ASCVD risk [25–28]. While various national guideline recom-
mendations are largely overlapping, important differences exist. Sources
of variation are primarily related to two issues:
•Risk and principal drivers of ASCVD differ in different racial and
ethnic groups.
•Different guideline committees around the globe evaluate the same
evidence and yet reach very different conclusions as to what the
evidence means and what recommendations it supports.
2.2. Limits of guidelines
Cardioprevention guidelines are intended to provide physicians with
a single consensus point of view, providing algorithms, calculators and
tables based on pooled cohorts for quick reference, and establishing
evidence-based standards. However, most guidelines have important
limitations, among which are inadequate personalization of care; slow
incorporation of new knowledge; and relatively conservative treatment
strategies. Moreover, many are lengthy and complex, making them
inaccessible to many practitioners, who have multiple guidelines with
which they need to be facile [29].
M.E. Makover et al.
American Journal of Preventive Cardiology 12 (2022) 100371
3
2.3. Slow adoption of optimal medical treatment
Physicians in clinical practice tend to be slow in adopting new ap-
proaches and in changing how they care for patients (i.e., “clinical
inertia”) [30–32]. Partly that is due to the time pressures in modern
medicine and partly due to the conservative nature of physicians to
avoid changes until the evidence demonstrates that a newer strategy is
clearly superior. Most cholesterol and prevention guidelines prioritize
the evaluation and treatment of hypercholesterolemia. The evidence
supporting this approach is incontrovertible, yet the majority of patients
with dyslipidemia are under-treated [33,34]. Even among treated
high-risk patients, 50% of such individuals discontinue their statin
therapy within 6 months and by 5 years only 20% remain adherent to it
[35]. There are likely multiple reasons: socioeconomic factors; media
attacks on statins [36]; shortened visits in modern medical practice; lack
of understanding of what specic drugs do to prevent events and pre-
serve health on the part of patients; and tolerability issues, among
others. It might also be that many practicing physicians have yet to
recognize that preventing atherosclerosis is the most impactful action
they can take. If so, that lack of urgency can be communicated to pa-
tients. Whatever the reason, premature discontinuation of
lipid-lowering therapy is associated with a rapid rise in risk for ASCVD
events [37,38]. Among high-risk patients, statin titration occurs infre-
quently in patients not meeting their risk-stratied Low-Density Lipo-
protein Cholesterol (LDL-C) goals [39]. Despite widespread availability
of adjuvant therapies that can dramatically increase LDL-C goal attain-
ment rates, these are vastly and conspicuously underutilized [40].
Acute events occurring despite what appears to be optimal medical
treatment are attributed to ‘residual cardiovascular risk’ [41–43]. The
clinical goal in patient management should be to lower the remaining
total burden of disease to an extremely low level. Moreover, the concept
of residual risk, as it is typically formulated, does not consider the risk of
non-acute events. This review will explore how treating earlier in the
course of atherosclerosis, treating more intensively and more precisely,
and individualizing care can help accomplish that goal.
Interest in the relationship between hypercholesterolemia and
atherosclerosis rst took root in 1913 when Anichkow rst fed rabbits
cholesterol and saw atherosclerosis develop in a mammal that never
develops it in the wild [44,45]. Scientic advances now provide a more
granular and extensive understanding of atherogenesis, though there is
still much more to learn. There has been exponential growth in scientic
tools and methods that have accelerated our understanding of the
complex mechanisms that result in atherosclerosis and its consequences
[46–57]. Atherosclerosis begins as lipid deposition in the intima of ar-
teries, widening the intimal space, then progresses to a plaque, then to
an unstable, vulnerable plaque, and then (subsequent to loss of plaque
integrity) to thrombosis inside the artery. The earlier that sequence can
be halted, the fewer occlusive thrombi there will be, and the fewer
complications of atherosclerosis that can result. There is a highly so-
phisticated toolbox to recognize atherosclerosis early [15], to measure it
and its causes precisely, and to use that information coupled with
evidence-based preventive interventions (therapeutic lifestyle changes
and medications) to arrest its progression. If LDL-C can be kept very low
from birth, atherosclerosis will not occur. Where that early prevention is
not possible to institute, even larger plaques can potentially be
controlled in nearly every case if treated intensively enough – doing so
would likely prevent most of the thrombi that lead to acute cardiovas-
cular events or more or larger plaques, as long as treatment is not
delayed for too long nor inadequately applied.
2.4. Atherosclerosis represents a clinical paradox: it is potentially the
most preventable or treatable chronic disease, yet it remains the greatest
cause of disability and death throughout the world. This does not have to
be the case
There has been compelling and convincing justication for some
time that an approach that includes keeping plasma atherogenic lipo-
proteins low from early in life will greatly reduce risk for ASCVD. As
detailed by Ference et al. “initiating lipid-lowering therapy after a person
has already been exposed to a cumulative burden of 6250 mg-years of LDL by
age 50 years means that person has very likely already developed a large
atherosclerotic plaque burden … lowering LDL after this cumulative exposure
to LDL should reduce the risk of cardiovascular events, but this person will
remain at relatively high “residual” risk of experiencing an acute cardio-
vascular event because one of the underlying plaques can still disrupt to cause
an acute coronary syndrome … [that] may explain much of the high residual
risk of cardiovascular events observed among people enrolled in lipid-
lowering randomized trials” [58].
2.5. Normal LDL-C is 20–40 mg/dL
Humans were never meant to harbor the low-density lipoprotein
cholesterol (LDL-C) levels that are now commonplace. In one series of
147 full-term neonates, the average LDL-C was 20 ±10 mg/dL [59]
Despite the extraordinary rate of development and need for myelination,
even neonates need very little LDL-C [60–63]. The fact that animals,
non-human primates, and humans who maintain low cholesterol levels
from early in life have very little atherosclerosis all suggest that a
‘normal’ non-atherogenic LDL-C level is 20–40 mg/dl. That is of course
difcult to achieve in a modern society and, as described herein, is not
necessary for most people.
Based on the log-linear relationship of LDL-C to the hazard ratio for
an acute ASCVD event, the LDL-C level where no excess risk occurs is
approximately 38 mg/dL or 1 mmol/L [64] (Fig. 1). This value is
consistent with the LDL-C levels observed among hunter-gatherer pop-
ulations [65,66]. In the Framingham Study, the average LDL-C of a man
presenting with an Acute Coronary Syndrome (ACS) is approximately
150 mg/dL [67]. In the Cooper Center Longitudinal Study, even when
LDL-C at baseline was <100 mg/dL, there was a continuous rise in risk
for Coronary Heart Disease (CHD) mortality over a mean follow-up time
of 26.5 yrs [68,69] Hence, it is crucial that exposure to atherogenic li-
poproteins be dramatically reduced early and over the long-term.
3. Despite many recommendations, early treatment has not
become common practice
There are practical tools available to recognize atherosclerosis very
early, to assess lipids more accurately, and to uncover and treat ancillary
risk factors. These concepts and tools allow precision management of
atherosclerosis, but they are employed too little and too late in many
cases. Current approaches using algorithms and calculators are based on
generalized data rather than precisely individualized to each patient
[29,70–72].
Fig. 1. Log-linear relationship between LDL-C levels and relative risk for CHD.
Reproduced with permission from Grundy et al. [64].
M.E. Makover et al.
American Journal of Preventive Cardiology 12 (2022) 100371
4
3.1. The art of medicine
As important and vital as the science is, the practice of medicine is
the art of medicine, which means to apply the scientic evidence to each
individual tailored to unique needs [72]. Confounding factors are
rigorously excluded from RCTs, but humans contain them in multitudes
unique to each person [72]. RCTs test hypotheses about specic in-
terventions, but they do not tell physicians how to treat a person [73]. As
Virgil Brown noted, “Just as evidence is not the law, evidence is not the
art of medicine. Considering evidence provides for inductive reasoning,
but this requires deductive considerations to actually apply evidence in
the most effective ways” [74].
3.2. The rationale for keeping LDL-C at very low levels
Our understanding of atherosclerosis, its molecular pathways [18,
75], genetic inuences [76–78], inammatory mechanisms [79–82],
interaction of comorbidities [83], and the role of lifestyle [84,85] and
the environment [86,87], have expanded rapidly [46,88]. There is now
a powerful therapeutic armamentarium to lower cholesterol, stabilize
the arterial wall, and prevent the plaques and thrombi that incur
considerable acute, progressive and chronic injury [89,90]. Anti-in-
ammatory treatments have proven benecial and are being rened,
and new medications are likely coming to the clinical setting [91–93].
Vaccines against targets etiologic for atherosclerosis are being explored
[94]. Current medicines are already remarkably effective and it will be
ever more likely to completely halt progression of atherosclerosis before
harm is done in most cases, and sooner than current common practice
patterns accomplish. Even before these new treatments come to fruition,
we propose that there are enough tools to nearly eliminate “residual
risk.”
3.3. A childhood disease
Atherosclerosis begins in earliest childhood, sometimes even during
gestation, presenting as yellow streaks in arterial walls [95–98]. It is a
chronic disease: absent intervention, it slowly progresses throughout
life, unevenly, sometimes rapidly [16], but inevitably worsening over
time [18,99–104]. It has been shown that the progression can be halted,
and even reversed to some degree with depletion of the lipid core, if
plaque is not extensively brotic or calcied [18,105,106]. Previously
believed to just be part of normal aging, atherosclerosis is actually a
pediatric disease that progresses into adulthood [107–111]. Advanced
disease recognized in very young people was observed in young men
killed in Korea and Vietnam, as well as victims of trauma as young as
20–25 years of age [112]. Those fatty streak lesions in early childhood
are usually the sites of more advanced lesions later in life [113]. Mothers
who are not overweight, diabetic, hypertensive or hypercholesterolemic
in pregnancy and have otherwise healthy lifestyles are less likely to have
children with hyperlipidemia [82]. Childhood risk factors have been
shown to predict future clinical atherosclerotic disease by midlife [114].
Atherosclerosis would likely be far less common if from birth everyone
maintained a healthy weight and diet and avoided toxic habits and
environmental exposures. Unfortunately, such goals have proven very
difcult to achieve in modern society and the success rates of lifestyle
improvement are low at any age [85,115,116].
3.4. Atherosclerosis is not inevitable
Mammals, primates, those living indigenous lives away from ‘mod-
ern civilization’ , and those with mutations that cause extremely low
LDL-C from birth [117] develop little or no signicant atherosclerosis
[118]. The fact that animals, non-human primates, and humans who
maintain low cholesterol levels from early in life have very little
atherosclerosis all support the conclusion that a ‘normal’
non-atherogenic LDL-C level is below 38 mg/dl, as noted previously.
Other than those with genetically low LDL, what those with little or no
atherosclerosis have in common from birth are: [1] low intake of satu-
rated fats, salt, and sugars and other rened carbohydrates, [2] pri-
marily plant-based diets, [3] absence of harmful substance abuse and
less polluted environments, and [4] physically active, non-sedentary
lives. The Tsimane tribe of Bolivia, for example, live unexposed to
‘developed’ life and are essentially free of atherosclerotic disease [119].
The mean LDL-C and HDL-C in the Tsimane people are at 90 mg/dL and
39.5 mg/dL, respectively [120]. People with the least risk factors fare
much better [121], but unfortunately the vast majority have one or
many major risk factors. In 2010, 47% of Americans had one or more of
uncontrolled high blood pressure, uncontrolled high levels of LDL-C, or
were current smokers [122,123]. When you add in those with other
risks, as noted in Table 3, the percentage would be much higher
(Table 4).
Interventions to improve lifestyle in Americans usually have low
success rates or are often inadequate to fully control risk even with
excellent adherence. Medications are important adjuncts and can
signicantly attenuate the impact of poor lifestyle, environmental
pollution and genetics if begun early and intensively. Even under condi-
tions of adverse genetics, toxic environmental exposures, and comor-
bidities, most atherosclerosis can be slowed signicantly or completely
halted if also treated early and intensively.
3.5. Cells do not need LDL-C
Cholesterol is essential for modulating cell membrane uidity, cell
transporters, and intracellular signaling systems, and is a precursor to
myelin, bile salts, Vitamin D, steroid hormones (corticosteroids, sex
hormones, mineralocorticoids), and establishes impermeability of the
skin. All somatic cells, including astrocytes and oligodendrocytes in the
brain, make cholesterol through the same pathway that the liver utilizes,
and can obtain some from High-Density Lipoprotein (HDL) [57,124,
125]. Even when LDL-C is extremely low, there is no impairment of
cellular cholesterol production and utilization within the brain because
the brain produces its own pool of cholesterol [126], as do all cells in the
body. No tissues depend on cholesterol transfer from LDL-C (the ovaries,
testes, and adrenals produce cholesterol de novo or import it via SR-B1
receptors from HDL particles). Currently, common practice considers an
LDL-C of 100 mg/dl as acceptable, but atherosclerosis exists even below
an LDL-C of 55 mg/dl and even lower [127].
3.6. The primary role of lipoproteins is excretion of excess cholesterol
While apolipoproteins play the dual role of distributing triglyceride
and cholesterol to systemic tissues, their primary role is to facilitate
excretion of cholesterol from the bloodstream and the body [128].
Atherosclerosis occurs when those mechanisms are inadequate and lead
to excess circulating cholesterol that is deposited in the intimal space of
medium to large arteries by transcytosis of LDL particles and athero-
genic apo B remnants [18,129]. Atherogenic apolipoprotein B (ApoB)
lipoproteins include LDL, Very Low-Density Lipoprotein (VLDL), and
Intermediate-Density Lipoprotein (IDL). These lipoproteins are toxic
because they deliver sterols, oxysterols, oxidized phospholipids, and
toxic lipids (e.g., oxidized fatty acids) into the arterial vasculature and
potentiate inammation, a primary driving force of atherogenesis [130].
Thus the initiating event for atherosclerosis is the deposition of
lipids into the intimal space beyond what that space can hold, as noted
by Tabas et al. [131], Williams et al. [132] and Boren and Williams
[133].
•If there is no such lipid deposition, then there will be little or no inam-
mation in the endothelium and intimal space. Keeping LDL-C very low will
accomplish that.
•If there is no inammation, then there will be no atherogenesis.
M.E. Makover et al.
American Journal of Preventive Cardiology 12 (2022) 100371
5
•If no atherosclerosis, there are no complications and much better vigor
and longer aging.
As Sniderman et al. said, “After all, if disease in the wall is pre-
vented, there will be no events to predict” [134].
Brown and Goldstein demonstrated in 1974 that there is a receptor
feedback-controlled limit to cholesterol deposition of about 25 mg/dL
and that the LDL receptor is critical to understanding atherosclerosis
[46,75,135]. Any cholesterol in excess of that generates an inamma-
tory response in the intima and endothelium, mediated by the immune
system, in which monocytes migrate into the intimal space and trans-
form into resident macrophages [136]. A cascade of immunological
reactions follows thereafter, mediated by interleukins, cytokines, oxy-
gen free radicals, and growth factors produced by T helper cells, mast
cells, neutrophils, and platelets [,[137]. This causes or contributes to
arterial consequences in the entire body, not just the coronary arteries:
•Brain (dementia, including Alzheimer’s disease) [19,138–148].
•Heart (adverse forms of structural remodeling, heart failure, brosis,
arrhythmias including atrial brillation and malignant ventricular
arrhythmias).
•Kidney (renal artery stenosis, chronic kidney disease).
•Arteries in the lower extremities (peripheral arterial disease).
•Pudendal artery (erectile dysfunction).
•Mesenteric arteries (mesenteric ischemia).
•Aorta (aneurysms) and aortic valve (calcic aortic stenosis).
The accumulated effect can be any combination of reduced cognition
or dementia, weakness and fatigue, dyspnea, frailty, vital organ failure,
poor aging and premature mortality. These peripheral but critical
manifestations of atherosclerosis are devastating and common, yet
difcult to capture in RCT’s. As Kuller has noted, “The incubation period
for the development of brain pathology, i.e., amyloid plaques and
neurobrillary tangles (NFTs), for example, to cognitive decline, mild
cognitive impairment (MCI) and dementia is very long, perhaps as
much as 20 years or more. Both the longitudinal studies and especially
the clinical trials may not have been followed long enough to see a
benecial effect” [149].
LIMITS OF RCTs
The relative brevity of RCTs is likely one of the reasons that current
practice is directed essentially only against limited acute events, mainly
in people who already have advanced disease that would manifest
within the time frame and the number of subjects. In addition, few
primary prevention studies are powered enough to detect effects on
mortality, even from infarctions. Preventing heart attacks and strokes
seems extremely likely to also reduce mortality over the longer term. As
Kostapanos and Elisaf note, “no long-term placebo-controlled primary
prevention statin trials are available, nor is there a current ethical
basis for designing one” [150]. Statin trials are not powered to detect
reductions in mortality but reducing acute events and long-term con-
sequences seems essential to reducing mortality as well.
3.7. Low-enough LDL-C prevents atherosclerosis
If LDL-C in blood is kept very low routinely – under 85 mg/dL for life,
or correspondingly low by other measures discussed below, including
LDL particle number by nuclear magnetic resonance (NMR) spectros-
copy, ApoB or non-HDL-C (total cholesterol-HDL cholesterol), athero-
sclerosis seems unlikely to occur to any clinically meaningful degree.
Hypertension, diabetes, and some inammatory conditions cause
inammation and damage to the endothelium, but if ApoB containing
lipoproteins are kept low relatively early in life, as low as at birth, they
will likely have far less pathophysiologic impact. Peter Libby [18] noted
that “If the entire population maintained LDL concentrations akin to
those of a neonate (or to those of adults of most other animal species),
atherosclerosis might well be an orphan disease” [18]. Based on the
preponderance of evidence, it seems best to set LDL-C goals below 40
mg/dl (1 mmol/dl), or even lower for even higher risk. This is also
consistent with current recommendations from the European Society of
Cardiology/European Atherosclerosis Society guidelines for the man-
agement of dyslipidemia [151]. However, that would likely be chal-
lenging to achieve widely, but as will be shown in this review, in those
with no enhancing risk factors, keeping LDL-C below at most 85 mg/dl
from birth throughout life would likely delay onset of complications
until age 100. This has been derived from experience with those with a
heterozygous deciency in PCSK9. For those with additional risk factors
or more advanced atherosclerosis, keeping LDL-C below 38 mg/dl
(depending on severity) would also likely maintain good health until
very late in life.
3.8. Co-factors are also extremely important
There are many factors that damage the endothelium, contribute to
atherosclerosis in other ways and activate the immune system, such as
insulin resistance [152,153], hypertension [154–156], smoking [157,
158], immunological disease and inammation elsewhere in the body
[82,159], clonal hematopoiesis of indeterminate potential (CHIP)
[160–163], neutrophil extracellular traps [164,165–167], environ-
mental pollutants [86,87,168], Non-alcoholic Fatty Liver Disease
(NAFLD) [169], and many others (Table 3). Good control of those should
help preserve healthy arteries. This is a ripe area for research, as it seems
likely that controlling atherosclerosis very early and intensively will
minimize the impact of these factors. Because such early studies might
not be feasible due to needed length and power, extrapolating from
known information would strongly suggest that early and intensive
treatment would preclude the adverse consequences of many co-factors
participating in the progression of atherosclerosis. If LDL-C is kept out
of the intimal space, there will be no atherosclerosis to be a cofactor
for.
Triglycerides have long been of concern, but there is now growing
recognition of their importance in atherogenesis [170–173]. Higher
triglyceride levels displace cholesterol in lipoprotein particles leading to
smaller, more atherogenic particles [172–176]. As noted, the greater the
number of ApoB containing lipoprotein particles there are in circulation,
the higher the likelihood they will penetrate the intimal space, be
oxidized and initiate a chronic maladaptive inammatory response.
3.9. The lower the better
Many studies have conrmed that the lower the LDL-C, the lower the
risk and the fewer complications of atherosclerosis, with no evidence of
any clinically signicant harm no matter how low the LDL-C level [177,
178]. Logarithmic scales including many historical trials of
lipid-lowering show a direct relationship of disease level with lower
LDL-C level achieved [179–182]. The Cholesterol Treatment Trialists
[177], the Justication for the Use of Statin in Prevention: An Inter-
vention Trial Evaluating Rosuvastatin (JUPITER) study [183,184], and
the Further Cardiovascular Outcomes Research With PCSK9 Inhibition
in Subjects With Elevated Risk (FOURIER) [185] and ODYSSEY Out-
comes: Evaluation of Cardiovascular Outcomes After an Acute Coronary
Syndrome During Treatment With Alirocumab [186] demonstrated that
even for patients with LDL-C below 70–100 mg/dl, further reduction in
LDL-C improved outcomes in several clinical scenarios. It seems logical
that the same would be even more effective before advanced athero-
sclerosis has developed. These trials showed that for every 1 mmol/L
(38.67 mg/dl) reduction in LDL-C, the rate of adverse events is reduced
by about 22% [187].
FOURIER and ODYSSEY made clear that no matter how low LDL-C,
even below 20 mg/dl, there was no greater incidence of adverse events
than from placebo. As cognitive effects of very low LDL-C have been of
theoretical concern, the Evaluating PCSK9 Binding antiBody Inuence
oN coGnitive HeAlth in High cardiovascUlar Risk Subjects
M.E. Makover et al.
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(EBBINGHAUS) Trial examined neurocognitive function using the
Cambridge Neuropsychological Test Automated Battery (CANTAB)
battery of tests and found no difference between baseline and end of
study. Even when ultra-low LDL-C was achieved (<10 mg/dL), no
between-group differences could be discerned. In a subsequent analysis
of questionnaires lled out by Ebbinghaus participants, the study found
no evidence of neurocognitive harm between the start and end of the
study [188].
3.10. Mendelian randomization also very convincingly shows that the
lower the LDL-C, the less atherosclerosis and the fewer the resulting
ASCVD-related events [189]
Some recommend that percent reduction in LDL-C is most important,
particularly at low levels of LDL-C [190,191]. Other studies, such as
FOURIER and the Mendelian randomization studies previously refer-
enced, show that the level of LDL-C is highly determinative, not just the
percentage reduction. That is consistent with our understanding of the
pathophysiology of atherosclerosis, in which the fewer LDL particles
that enter the intimal space, the less inammation and its consequences
that will occur and the lower the loading with cholesterol that macro-
phages will undergo. Were it true that the degree of reduction is all that
matters, then it would imply that a patient with Familial Hypercholes-
terolemia [192] with an LDL-C of 500 mg/dl would no longer be at risk if
treatment reduced the LDL-C fty-percent to 250 mg/dL. Those patients
would certainly still be at greater risk than if their LDL could be reduced
to very low levels with treatment and, if needed, LDL apheresis [193].
3.11. LDL-C is a vascular toxin
Fortunately, mainstream lipid-lowering therapies (LLT) are remark-
ably safe [126,194]. The low incidence of side effects is dwarfed by the
events protected and the lives saved, for a very positive benet/risk ratio
[195]. Consistent with this, in the world of cardiovascular disease pre-
vention, “it is vital that we rid the system of its most potent toxin:
LDL-C, a metabolite responsible for the death and disability of more
people than any other known product of human physiology” [31].
Is it reasonable to view LDL-C as a vascular toxin? Yes. LDL particles
represent the end-product of lipoprotein metabolism. LDL particles have
two routes for removal: (1) clearance by hepatic LDL receptors, or (2)
uptake into the intimal space and scavenged by macrophages [196]. LDL
particles induce endothelial dysfunction, and promote the development
of a pro-oxidative, pro-inammatory, prothrombotic phenotype along
the arterial wall. Mendelian randomization studies are quite consistent
when it comes to LDL: the higher the serum level, irrespective of genetic
polymorphism, the higher the risk for ASCVD [197]. The opposite of this
is also true: the lower the level of LDL-C, the lower the risk. This is
consistent with the principles of toxicology.
3.12. Treating early is far more effective than starting treatment after
disease develops
No reasonable clinician would wait for kidney damage or a cere-
brovascular event before treating hypertension, delay managing hy-
perglycemia until kidney failure or retinal hemorrhage, hold off on an
antibiotic for pneumonia or cellulitis or let joints deteriorate before
treating rheumatoid arthritis. In contrast, addressing hypercholester-
olemia is frequently delayed until after a cardiovascular event occurs.
Brown and Goldstein noted that the discovery of proprotein con-
vertase subtilisin: kexin type 9 (PCSK9) made clear a vital lesson that
many leading lipidologists had been proposing for a long time: the
earlier LDL-C is kept very low, the lower the burden of atherosclerosis
that will develop. They compared the reduction in risk in those born
with PCSK9 deciency to those who were treated in later life with a
statin in a ve-year trial [117]. They calculated that in both cases LDL-C
was 40 mg/dl lower than if either no treatment or no PCSK9 mutation.
Table 1 shows a comparison based on their paper [198].
They concluded: “Early intervention may well put an end to the epidemic
of coronary heart disease that ravaged Western populations in the 20th
century.”
As early as 1996 they had said, “If we wait for susceptible individuals to
develop symptoms before deciding to treat, the earliest symptom is often
sudden death” [199]. Others in the forefront of atherosclerosis research
and conceptualization have said the same [113,134].
3.13. The pathogenesis of atherosclerosis explains why early and lower
are better
This corresponds mechanistically to the rapidly developing under-
standing of the pathogenesis of atherosclerosis. It is an inammatory
disease. The more it progresses, the more intense the immunological
reaction becomes, which sensitizes circulating immune cells and causes
signicant changes in the endothelium. As an atheroma develops, it is
likely that the process will eventually become at least somewhat inde-
pendent of additional LDL-C inltration of the intima, resulting in
resistance to treatment. If initially the immunological atherosclerotic
process can be prevented or halted by keeping the inux of LDL-C very
low, then it seems unlikely that a self-propagating immunologic reaction
would become irreversible. Inadequately controlled inammation is
posited as part of the reason for residual risk, and it certainly plays a
dening role in advanced atherosclerosis. However, if atherosclerosis is
halted very early on, it is unlikely that inammation would continue and
therefore would not frustrate efforts to prevent atherosclerotic compli-
cations. The evidence of the protective effect of maintaining very low
LDL-C from very early on seems to support this concept. In the unfor-
tunately much more common case, where opportunity for early life
intervention does not exist, then counteracting inammation and
dramatically lowering the circulation of ApoB lipoproteins should stop
the process and even allow regression, which has been shown where
there is adequate intensity of treatment [132,200–204].
Many things, such as systemic or localized inammation (autoim-
mune diseases, periodontal disease, others), hypertension, diabetes and
more, can damage the endothelium in ways that might induce an im-
mune reaction [205,206]. Managing the immune component of
atherosclerosis is vital, though currently specic tools to do so are
limited [207]. In any case, if LDL-C is kept very low very early on, that
would mute the effect of inammation on the arterial lining because
there would not be the cholesterol to initiate the immune response and
induce foam cell formation and an atheroma to develop and then
progress to plaques and formation of overlying thrombi. When Reverse
Cholesterol Transport (RCT) is intact, as in most people, then foam cells
and atheromas already in place should be reduced and stabilized by
achieving very low cholesterol levels.
3.14. The trajectory of disease can be altered if treated early
Studies show that the trajectory of developing atherosclerotic plaque
to acute events can be altered (Fig. 2). The lower and the earlier LDL-C is
reduced, the larger the rightward shift along the clinical event horizon,
and the more delayed the onset of clinically apparent disease will be
[208]. Horton et al. calculated that the degree of atherosclerosis
Table 1
Effect of low lifelong LDL-C (from birth due to genetic causes) versus from ve
years of treatment.
LDL level
reduction
By Duration of
reduction
Reduction in
events
40 mg/dl
reduction
Statin treatment in a trial 5 years 23%
40 mg/dl
reduction
Loss of function
mutation in PCSK9
From birth 88%
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American Journal of Preventive Cardiology 12 (2022) 100371
7
progression relates to level of apo B lipoproteins times the duration of
the exposure of the intima to LDL-C. In their seminal paper on PCSK9
they noted that a useful measure would be the total accumulation of
LDL-C over time (g/dl LDL-C x years of exposure) [209]. They drew
Kaplan-Meier curves estimating that for each level of LDL-C over time
there was a predictable age range at which the curve would cross the
threshold where acute coronary events became more likely. The
threshold for homozygous FH was under age 15 years (some need cor-
onary bypass graft surgery by age 6); early thirties for heterozygous FH;
mid-sixties for average Americans (calculated from National Health and
Nutrition Education Survey III); above ninety years for PCSK9 hetero-
zygous for loss of function. Thresholds were judged fteen years lower
for males and those with cofactors like hypertension, diabetes, and
smoking and ten years higher for females with no cofactors. Early
treatment extends the time before events become more likely. Subse-
quent studies strongly substantiated this nding [58,210–212].
Steinberg and Grundy concluded that current guidelines are too
conservative. The evidence for the value of early intervention is so
strong, even in the thirty-year age group, they said, that it misses the
opportunity to reduce the toll of CHD. They identied the core principles
of LDL-C reduction as “the lower the better,” and “the earlier the
better” [213]. They also argued that an RCT would be prohibitively
prolonged and would require unaffordable numbers of subjects [213]. In
addition, they noted that, because the evidence is so compelling, an RCT
is unnecessary, just as it is obvious smoking is harmful even though that
has never been ‘proven’ by an RCT (nor have parachutes been shown by
an RCT to be benecial after jumping out of an airplane [214]). Ference
and colleagues state, “such a trial may not be logistically feasible
because it would take several decades to complete and because
adherence to the allocated treatment over such a prolonged follow-up
period would be difcult to maintain. As a result, such a trial is un-
likely ever to be conducted” [58].
Log linear plots of results of lipid-lowering trials all show that the
lower the LDL-C, the lower the risk down to the lowest LDL-C levels [64],
]. In the analysis by Beokholdt et al., the relationship between CV events
and attained LDL-C on a statin is linear between 25 and 200 mg/dL
[215]. Similarly, in the FOURIER trial, investigators observed a mono-
tonic relationship between attained LDL-C on lipid-lowering therapy
with a statin and evolocumab and CV risk all the way down to <10
mg/dL without an increase in adverse events [216].
3.15. Lifestyle modication is benecial but seldom successful
If LDL-C can be kept very low early by lifestyle alone, it would likely
produce great benet, but further signicant lifestyle change is unlikely
for the vast majority of Americans (of whom 73.6% percent are over-
weight or obese [217] and over 34 million still smoke [218]), beyond
what has been achieved to this point. Society can do both – work toward
a healthier national lifestyle and treat those at risk.
The accumulating evidence that it is not just level of cholesterol, but
duration of elevation above healthy levels, would suggest that now is the
time to reconsider current approaches in this regard. Further delay in
early management of atherosclerosis would continue to expose a large
population of younger people to later risk that could have been pre-
vented and would burden society with the cost, loss of productivity, and
the human tragedy of unnecessary disease. Yet despite strong evidence
and repeated calls by leaders in the eld to treat much earlier, early
intervention has not been adopted and likely few practitioners are
aware of the rationale for this approach.
3.16. Adequate treatment can signicantly reverse atherosclerosis
The Vascular Effects of Alirocumab in Acute MI-Patients (PACMAN-
AMI) trial [204] showed conclusively that atheroma can regress.
Changes in Percent Atheroma Volume (PAV), Lipid Core Burden Index
(LCBI) and Fibrous Cap Thickness (FCT) were biphasic and improved
with larger benecial changes observed as LDL-C fell below 50 mg/dl
when participants were treated with either statin monotherapy or with a
statin and alirocumab.
3.17. The rationale for assessing risk more precisely
Controlling atherosclerosis as early and effectively as possible,
preferably far earlier than in current practice, requires early identi-
cation of intimal changes, precise measurement of lipid levels, and
recognition of all the comorbidities and risk factors listed in Table 3. As
noted, atherosclerosis begins as lipid streaks in the intima, but eventu-
ally widens the intimal space to a degree that is measurable by a variety
of techniques.
3.18. Advantages of coronary artery calcium scoring
Coronary Artery Calcium Scoring (CAC) is now widely recommended
as a means of detecting early atherosclerosis [191,219].
•It is not operator-dependent.
•Is inexpensive.
•Is easy to do and interpret.
•Has a rich body of studies supporting it.
Fig. 2. Examples of area under the LDL-C versus age curves.
Each color represents a different patient population plotting cumula-
tive low-density lipoprotein cholesterol (LDL-C) years versus age and
the average onset of atherosclerotic cardiovascular disease (ASCVD)
(black dashed horizontal line). Individuals with genetically deter-
mined severe hypercholesterolemia from birth (e.g., familial hyper-
cholesterolemia [FH]) have the largest area under the curve at any
given age (red dashed vertical line) and steepest slope of LDL-C versus
age. Thus, they experience the earliest onset of ASCVD. Individuals
with moderate hypercholesterolemia starting in the teenage years
secondary to genetics and/or suboptimal lifestyle habits are at risk for
relatively early ASCVD due to a lengthy cumulative exposure to LDL-C.
Those with modest hypercholesterolemia from adulthood, often due to
suboptimal lifestyle habits, generally develop ASCVD later than the
other 2 groups. Individuals genetically endowed with low LDL-C from
birth have a markedly reduced risk of developing ASCVD. (Figure and
legend reproduced from Shapiro and Bhatt with permission [208]).
M.E. Makover et al.
American Journal of Preventive Cardiology 12 (2022) 100371
8
•A positive CAC score (>0) is highly predictive of increased ASCVD
risk.
•CAC 0 has a Negative Predictive Value (NPV) of 99% for acute events
over the following ten years.
However, for those with no CAC but a high-risk prole (particularly
those with diabetes, history of smoking, or family history of premature
ASCVD), who often have considerable non-calcied plaque, coronary CT
angiography (CCTA) may be indicated [220,221] and treatment begun.
3.18.1. Limits of CAC
As with all tests, CAC has its limitations:
•Plaque calcication is a late event and thus does not accomplish
early, pre-plaque detection (the goal being to prevent any plaque
from forming in the rst place)
•Non-calcied plaque is just as likely to cause intraarterial thrombi
and is shown to be signicantly present in patients with CAC scores
of 0 [222–226].
•Calcication usually continues to deposit even when atherosclerosis
stabilizes, thus making serial CAC of less value.
•It is calibrated for age 40 years and above.
•As a screening tool, it would entail exposing large numbers of people
to radiation
•Preventive cardiology has begun looking ahead to lifetime risk rather
than the ten years for CAC and most risk calculators [28,29].
3.18.2. Risk is lifetime, not just a decade and people are living longer with
better life expectancy
While it is good that a calcium score of zero makes an acute event less
likely in the subsequent decade, looking beyond ten years and consid-
ering that atherosclerosis can have effects on other organ systems be-
sides the coronary arteries, it seems worthwhile instituting earlier
prevention in even those with CAC 0 who have a high-risk prole, as
outlined in this review.
3.18.3. There is compelling evidence and signicant agreement, as reviewed
above, that
•Atherosclerosis begins early in childhood as LDL-C exceeds 20–40
mg/dl, and then progresses unless therapeutic intervention is
instituted.
•Atherosclerosis is essentially universal in the United States and
developed countries.
•Powerful evidence shows that the earlier treatment is begun, the
more successful it will be.
•Atherosclerosis burdens the young [227–229], middle-aged and old.
•LDL-C is the initial and primary driver of atherosclerosis. The lower
the LDL-C that is achieved, and the earlier, the lower the likelihood
of atherosclerosis progression and the greater the chance of stabili-
zation or regression.
•There is no apparent clinically signicant harm (no signal for neu-
rocognitive impairment/dementia, hemorrhagic stroke, increase in
neoplasms, risk for demyelination, etc.) from lowering LDL to even
the very lowest levels (<10 mg/dL) [230,231].
•Statins and other LLT are remarkably safe and the few adverse effects
that occur affect far fewer people than the many lives saved, an
extremely favorable benet/risk ratio [195,232–234].
•Other manifestations of atherosclerosis are as dangerous as coronary
artery disease and stroke but are mostly unaddressed in prevention.
They are not reected in current risk assessments. The new paradigm
would incorporate preserving all vital functions that atherosclerosis
can degrade, which early, intensive treatment would likely
accomplish.
•Detailed individualization of treatment is preferable to generic tools.
•As valuable as randomized controlled trials are, they are not the only
form of valid evidence and they have important limitations, as dis-
cussed above. When RCTs are not feasible or adequate to answer
important needs, such as diseases that take very long times to
develop, that should not prevent establishing important goals and
approaches when there is ample other evidence demonstrating their
value.
•Considering the considerable ‘residual risk’ and the high potential of
reducing it with precise, early, intensive treatment, it seems urgent
that new approaches as described herein be adopted to reduce that
toll. As numerous references noted above have said, if treatment
were to begin early and intensively, atherosclerosis could become so
rare as to be an ‘orphan disease’ in all who followed the advice.
3.19. Early and intensive precision prevention can be cost effective
The downside of early detection and management of atherosclerosis
is that so many more Americans would require treatment. Can we afford
to take care of them all? A better question would be: can we afford not
to? The American Heart Association estimated current direct and indi-
rect costs of cardiovascular disease in 2021 and projected to 2035 if
trends continue [235], listed in Table 2. Indirect costs are major con-
tributors to cost of atherosclerosis, even with only ASCVD events being
assessed [236].
Dementia currently costs the United States $305 billion [237], also
likely to at least double by 2035 if the trends noted above apply. Since
the US population is aging rapidly, an even faster increase in costs for
dementia seem likely. Not included in these numbers are the costs of all
the other manifestations of atherosclerosis and the effect on vigor of
aging. Correcting disparities in healthcare would also bring considerable
savings [238]. If the projections are fullled, within thirteen years US
expense for these diseases will well exceed $1 trillion. The cost of the
early, precise, and intensive treatment of atherosclerosis as reviewed
above would likely cost a fraction of that, especially when early detec-
tion means beginning management at a stage that would be much more
effective and less costly. There would be huge savings from prevented
acute events, procedures and long-term complications [239]. Increased
productivity and reduced presenteeism from chronic atherosclerotic
disease would also bring considerable cost savings.
The cost effectiveness of generic statins has been reported . The study
of screening and treating FH in the very young also showed cost-
effectiveness [240–242]. At current costs (The Medical Letter,
September 23, 2019), rosuvastatin costs the pharmacy $144 per year.
Ezetimibe $444 per year. Giving both would cost $588 per year. There
were about 100 million Americans ages 20–44 in the 2020 census. If
20% qualied for treatment under the recommendations in this paper
and half of those agreed to treatment, that would cost about $6 billion
per year for the cost of the two drugs, which would be about 0.14% of US
healthcare expenditures of around $4.3 trillion in 2021. Even counting
the costs of laboratory testing and doctors’ visits it would still be a tiny
percentage. While a more detailed accounting is beyond the scope of this
paper, early treatment appears to be cost effective, as has been judged by
multiple analyses [243–245].
Table 2
Direct and indirect costs of specic atherosclerotic disease current and projected
to 2035, adapted from AHA report [235].
Condition Current total of direct and
indirect costs (in billions of
dollars)
Projected 2035 total costs
(in billions of dollars)
Hypertension 110 221
CHD 188 366
Congestive Heart
Failure
29 64
Stroke 67 143
Totals 394 794
M.E. Makover et al.
American Journal of Preventive Cardiology 12 (2022) 100371
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Table 3
Factors to consider in assessing risk of atherosclerosis and individualizing
treatment.
Factor Details of increased risk
Presence of plaque in any vascular bed Either non-calcied as seen on ultrasound
or other modalities and/or calcied
plaque seen in aorta, peripheral arteries
or by CAC. Plaque is a sign of advanced
atherosclerosis. Calcied plaque is an
even later nding. Thickening Intimal-
media is also of concern and is the earliest
sign.
Insulin resistance, diabetes, metabolic
syndrome*
Adiposopathy [261), insulin resistance,
prediabetes, diabetes, metabolic
syndrome [253], excess visceral fat.
Hemoglobin A1C predicts subclinical
atherosclerosis [254].
Hypertension* Essential, secondary, or primary
aldosteronism [154] Blood pressure is
safest at or below 120/70 mm Hg at any
age [255–258]
Elevated Lipoprotein (a) [259–264]* Levels >75 Nmol/L [265–269] Elevated
levels are likely as common as 20% of the
population. A major contributor to
ASCVD and calcic aortic stenosis. Also
increases risk of stroke in children [263,
270]. Measurement in nmol/L is
preferable to mg/dl.
Familial Hypercholesterolemia [271]* Heterozygous FH is the most common
monogenic condition, affecting between 1
in 200–300 Americans, and as frequent as
1 in 24 of those with ASCVD [272].
Elevated hsCRP [273] or GlycA
[274–276]*
Indicators of active inammation.
However, hsCRP can be lower at times
despite even advanced atherosclerosis with
plaque (probably due to temporary inactivity
of inammation). A normal hsCRP does not
negate the risks of other important factors, as
inammation activity can wax and wane.
High Sensitivity CRP >1.0 mg/dl denotes
even higher risk.
LDL-C,
non-HDL-C, ApoB*
LDL-C of 20–40 mg/dl seems to be the
healthy level for humans from birth on,
but impractical to achieve in developed
societies. Apolipoproteins are the primary
cause of atherosclerosis [277]. ApoB and
non-HDL-C can help rene atherogenic
particle levels.
Triglycerides* Shaik and Rosenson [278–281] Risk
begins to increase above 100 mg/dl [282]
Post-prandial surge important as well.
Remnant Cholesterol Remnant cholesterol (approximation) =
Total cholesterol – HDL-C – LDL-C.
Levels above 10 mg/dl indicate risk
[283].
Apolipoprotein B levels and non-HDL
Cholesterol also include atherogenic
remnants and are likely more predictive
than LDL-C alone.
Age** Risk increases with age (age is the most
determinative factor in risk calculators).
Even over age 75 years, treatment is
effective, safe and appropriate [284–289]
Family history* Early ASCVD, diabetes , hypertension
[290] all increase risk for descendants
[291–296]
Obesity, visceral fat Major cause of metabolic syndrome and
atherosclerosis, even when at rst
‘metabolically healthy’ [252,297–301].
Chronic kidney disease* CKD and atherosclerosis each increases
risk and pathology of the other
[302–305]
Non-alcoholic fatty liver disease Closely related to atherosclerosis and
contributory to it [169].
Other co-morbidities Hypo- or hyperthyroidism [306], gout
[307], sleep apnea [308], gut
microbiome (theoretical) [309],
Table 3 (continued )
Factor Details of increased risk
Cushing’s syndrome [310], many others.
The microbiome is not currently
actionable.
Some medications Some increase LDL (Corticosteroids
[311], Androgenic steroids [312],
Progestogens, Thiazide diuretics,
Beta-blockers, Retinoic acid derivatives,
Oral estrogens [313]). Chronic
corticosteroids increase risks even at low
doses. Many others [314].
Substance use* Tobacco [315,316], marijuana
[317–319], alcohol [320], cocaine [321]
Autoimmune disease* Rheumatoid arthritis [322,323], Systemic
Lupus Erythematosus [324], psoriasis and
psoriatic arthritis [325,326], ankylosing
spondylitis [327], scleroderma [328],
inammatory bowel disease [329],
probably others
immunological disease and
inammation elsewhere in the body
[82,159]; clonal hematopoiesis of
indeterminate potential (CHIP)
[160–163]; neutrophil extracellular
traps [164–167]
These are not yet readily actionable and
further research is needed.
Genetic factors and social determinants
of health
Knowledge and applicability are
developing rapidly, already useful for FH
and some other genetic variants
[330–334]
Race/ethnicity (All people are complex
genetic mixtures, but some genetic
factors are alerted by ethnicity in
some cases. While of course not
universal or denitive, Race/
ethnicity can signal risk requiring
deeper evaluation)*
South Asian (much higher risk of
atherosclerosis, high Lipoprotein (a) and
diabetes and at early ages) [280,
335–341], African American
(hypertension, renal disease); Non-white
Hispanic (diabetes, obesity, CAD); many
others. Some of Asian heritage have lower
risk. Ethnicity affects incidence of
biomarkers [342]
Other lab parameters Elevated Microalbumin/creatine ratio
[343,344], even in children [104].
High uric acid [345,346], low vitamin D
[347], periodontitis [383], elevated
ceramides [348] and others [384] are
associated with increased risk of
atherosclerosis, though causation remains
to be fully determined and thus treatment
not yet justied just to reduce risk of
atherosclerosis. Their presence implies
increased risk even if causation not
proven. Thus, a high uric acid would raise
concern but lowering uric acid just for
that reason is not indicated.
Testosterone deciency and treatment Reasonable evidence that hypogonadism
increases risk of atherosclerosis, less
certain if treatment affects risk. Excess
testosterone treatment probably increases
risk. Must use replacement therapy
carefully [349].
Female reproductive* Premature menopause, high cholesterol
in pregnancy (cholesterol usually
increases in pregnancy and in
menopause), preeclampsia, eclampsia,
gestational diabetes mellitus and
polycystic ovary syndrome all increase
risk [350–352]
Social factors* Socioeconomic status [353];
discrimination [238,354] and nancial
barriers to access to healthcare [355].
Culture, beliefs, life views, etc. that affect
use of medical science. Lack of belief in
science. Desire for ‘natural’ approach.
Poor compliance and long-term
adherence [356,357]. Unjustied fear of
LLT medications [36]
Mental health [358] Depression (associated and possibly
causal [359]), stress [360], anxiety or
anger syndromes [361].
(continued on next page)
M.E. Makover et al.
American Journal of Preventive Cardiology 12 (2022) 100371
10
3.20. Lack of informed consent
Guidelines recommend physicians engage in Shared Decision Mak-
ing with patients, which we unequivocally endorse, as it respects patient
autonomy and dignity. Currently, patients are only informed of one
approach to manage their atherosclerosis and prevent complications.
True informed consent and Shared Decision Making ethically requires
that patients be informed about all well-founded approaches, such as the
differences from current guidelines reviewed here and urged by many of
the leading gures in preventive cardiology and lipidology for decades.
3.21. Summary of specic recommendations
Based on all the above, we make the following recommendations:
•Principles:
○ Atherosclerosis is by far the greatest cause of disease, disability,
death and cost. It should be the number one priority of the
healthcare system.
○ Risk is proportional to the level of LDL-C and the duration of the
exposure and increased by enhancing factors.
■ Thus, the earlier elevated LDL-C is lowered, the better.
○ That means screening at the earliest age possible.
○ Each patient should be evaluated thoroughly and individually for
all factors that contribute to risk (Table 3).
○ The optimal LDL-C appears to be the level present at birth (20–40
mg/dl).
■ That is probably not necessary for everyone nor likely practical
to attain widely.
○ We recommend:
•Progression of atherosclerosis seems unlikely when all these
conditions are met:
•LDL-C in all previous years never exceeds 85 mg/dl
•Non-HDL-C is below 100 mg/dl
•There are no signicant enhancing factors
•The patient is t and follows a healthy lifestyle (such as the
AHA Seven Healthy Habits)
•Medications would not be indicated for these patients unless
they develop plaque, but of course continued healthy lifestyle is
vital.
•These patients should be evaluated yearly to estimate risk if and
when it develops.
•Treatment to reduce or at least halt progression of intimal changes
is indicated when one or a combination of the following exists:
•Patients have LDL-C consistently greater than 100 mg/dl or non-
HDL-C >110 mg/dl.
•Plaque
•Signicant enhancing factors
•Established ASCVD.
•Studies have shown that reversal of plaque begins when LDL-C falls
below approximately 60–80 mg/dl and treatment is begun before
signicant scarring and calcication occurs [246–248].
•That should also make new intimal thickening, plaque and
intraarterial thrombi much less likely, if blood pressure and all
other factors are well controlled.
•Thus, getting LDL-C below 40 mg/dl seems the most effective goal
for patients in the category of more advanced atherosclerosis.
•Very advanced disease or very high risk would benet from
lowering LDL-C <20 mg/dl.
•There are now excellent, safe treatments to achieve these goals in
most patients.
Table 3 (continued )
Factor Details of increased risk
Some anti-psychotic medications increase
atherosclerotic risk [314].
Lifestyle [362]* Atherogenic diet (highly processed food,
high salt and simple carbohydrates,
poorly balanced nutrition) [363–366];
saturated fat [367–370];
trimethylamine-N-oxide (TMAO) [371,
372].
Inadequate aerobic and resistance
exercise [373,374].
Excess sedentary time independent of
exercise [375–377].
Mediterranean diet [378], vegan diet
[379,380], DASH Diet [102] are proven
much healthier and less atherogenic.
Overweight, obesity and (most
important) excess visceral fat.
Environment Air pollution [86,381] contributes to
atherosclerosis risk, as do excess noise
[381–384] and chemical pollution [87,
168]
Acute respiratory syndrome-
coronavirus-2 (SARS-CoV-2)
This virus causes signicant endothelial
changes in many arteries. This causes
immediate cardiac pathology in some
patients, even in mild cases. Whether it
will have long-term consequences
remains to be seen, but all COVID patients
should be carefully monitored for the
development of cardiac problems over
time and for accelerated atherosclerosis.
(Some of these, designated with *, are partly or wholly addressed in the 2019
AHA guidelines, as contributors or risk enhancers, but often partially or at higher
thresholds than recommended in this paper. Age (**) is a major determinant of
the AHA risk calculator).
Table 4
Factors not included in risk calculators.
Patient A Patient B
Required by calculator
Age 40 40
Gender Male Male
Race Non-African
American
Non-African
American
Smoker No No
Treated for diabetes No No
Treated for Hypertension No No
Total Cholesterol (mg/dl) 175 220
HDL cholesterol (mg/dl) 55 55
Systolic blood pressure (mmHg) 110 110
Diastolic blood pressure (mmHg) 70 70
Not included in calculator Patient A Patient B
Fasting Triglycerides (mg/dl) 80 210
LDL-C (mg/dl) 75 150
LDL-P (Nmol/L) 800 2300
Strong family history of ASCVD No Yes
Hemoglobin A1C (%) 5.4 6.3
Waist circumference (inches) 35 42
Lipoprotein (a) (mg/dl) 70 250
AHA/ACC Risk Score by calculator
(% ten-year risk) 0.6% 0.9%
Consider two hypothetical male non-African-American patients, each 40 years
old and their AHA Risk Calculator scores as follows (Patient B has a common
prole) (Table 4). The latest guidelines recommend taking ancillary factors into
account, as for Patient B, but with a risk score below 1%, most calculator users would
be unlikely to recommend treatment for Patient B, yet he appears at very high risk of
an acute event in the relatively near future, as well as slow-developing manifestations
of atherosclerosis. Changing only the age for Patient B to 60 years in the AHA Risk
Calculator means a Risk Score of only 6.8%, still below the treatment threshold of
7.5%.
Every decade of delay in treatment could mean risk of an acute event, damage to other
organs, poor aging and ever greater physiological resistance to treatment once nally
begun.
Treating Patient B at age 40 or younger would likely prevent premature morbidity and
mortality and would be signicantly easier, safer and more effective.
M.E. Makover et al.
American Journal of Preventive Cardiology 12 (2022) 100371
11
•As duration of arterial exposure to excess cholesterol is the other
primary determinant, the earlier and faster those lower levels are
achieved, the better.
•It requires only six weeks to see the effect of most medication
changes, so physicians can act quickly to ensure getting patients to
goal as soon as possible to reduce continued exposure of the
vascular bed to excess cholesterol.
•It is very important to identify all enhancing factors and to do all
possible to correct as many as are amenable to improvement.
•The presence of plaque on imaging should spur even more careful
management.
•If atherosclerosis can be recognized and controlled from an early
age, residual risk could be virtually eliminated, and the “epidemic
of vascular disease” ended.
•Most patients are encountered later in life.
•If they have had lifelong low LDL-C, no plaque and no risk factors,
as noted, observe only.
•If they have more advanced signs, as noted above (LDL-C consis-
tently greater than 100 mg/dl or non-HDL-C >110 mg/dl, plaque,
signicant enhancing factors, and/or established ASCVD), then
treatment to goal <40 mg/dl.
•If they have more severe disease – any one or more of many sig-
nicant risk factors, major plaque, high CAC, history of ASCVD
events or other complications of atherosclerosis (Mild Cognitive
Impairment, PAD, etc.), then LDL-C goal should be <20 mg/dl.
•In all cases, it is critical to manage all controllable enhancing
factors.
•Screening should begin as early as possible
•Whenever a patient is rst encountered
•Screening from birth would have even better results, as follows:
•In the rst year: test Lipoprotein (a) and LDL-C (high Lipoprotein
(a) increases the risk of stroke in children and FH needs to be
treated very early, depending on severity).
•Within eight years, do a full lipid panel.
•If it indicates Familial Hypercholesterolemia not previously
detected, treat immediately in cooperation with the pediatri-
cian and follow closely. (Note discovery of FH should always
be accompanied by cascade screening of blood relatives)
•Other than FH, if there are no signicant enhancing factors
and LDL-C is below 85 mg/dl, improved lifestyle is likely all
that is needed. Regular follow-up is important to detect
changes.
•If there are signicant enhancing factors (Table 3), consider
lifestyle management for six months. If no improvement in
lifestyle, weight, lipids and other factors, statin and ezetimibe
might be needed from age eight on.
•Currently statins are used sparingly in children and only for
FH. Those studies show LLT to be effective and safe begin-
ning as early as age 8 and for over 20 years. It seems unlikely
to expect a different safety prole in children with dyslipi-
demia short of full FH [249–251].
•Children deemed at very high risk can be considered for
treatment even at an early age depending on individual
cases and clinical judgment.
•When a person enters care by age 13 on:
•If there is evidence that LDL-C has not exceeded 85–100 mg/dl
previously and there are no signicant enhancing factors,
continue to observe yearly and encourage healthy lifestyle.
•When there is intimal thickening or plaque or enhancing factors
that cannot rst be reversed by lifestyle change, then more
aggressive efforts can be considered.
•Plaque can be surprisingly present in even young adults, some-
times without obvious causes.
•Few between 20–50 years old would be rated eligible for
treatment by current guidelines but many would benet from
early intervention.
•Screening for plaque can be useful to detect those cases at an
early stage.
•Carotid Intimal-medial Thickness (CIMT) by 2D B-mode ul-
trasound, if it can be done reliably, detects atherosclerosis at
the earliest stage. However, it is very operator dependent and
is useful only where dedicated technique can be carefully
controlled.
•3D carotid plaque burden by ultrasound is more reliable and
can follow plaque development serially.
•Any presence of arterial plaque in the aorta, femoral artery,
etc., signies plaque and advanced atherosclerosis.
•If risk is much higher, then CT angiography and, if necessary,
MRA (Magnetic Resonance Angiography) can be considered.
•CAC is calibrated only for those over 40 years of age.
•The goal for LDL-C when plaque is present is at least <38 mg/dl
(plus control of all enhancing factors).
•Those at higher risk (longstanding high cholesterol, major pla-
que, prior events and/or major enhancing factors), will in most
cases require lowering LDL-C to below 20 mg/dl, as in the PCSK9
trials.
•Considerations in female patients
•Pregnancy, complications of pregnancy, menopause, Polycystic
Ovary Disease and other such factors unique to women tend to
elevate cholesterol to high levels and increase risk later in life.
While the cholesterol elevations might be of shorter duration,
the risk is still considerable even in women with no other risk
factors.
•Treatment would be indicated immediately after pregnancy,
breastfeeding and future pregnancy are no longer issues.
3.22. Summary
Concern for costs tend to dominate discussions of public policy, but
the human suffering from disease, disability, and death caused by
atherosclerosis is overwhelming and far more important. As Brown and
Goldstein said, it is time to end the epidemic and, as Peter Libby said,
demote atherosclerosis from the leading killer to a rare disease. We
should do the same for all the other atherosclerotic-driven diseases.
Assessing precisely, beginning very early, and achieving intensive
goals has been shown to be efcacious, safe and cost effective. With the
urging of so many leaders in the eld for so long and the compelling
evidence laid out in this review, the question remains: what is the pro-
fession waiting for? There is that erce urgency of now: every day of
delay means more people losing arterial health, with all the tragic
consequences that result. We have the means; do we have the will?
CRediT authorship contribution statement
Michael E. Makover: Conceptualization, Writing – original draft,
Writing – review & editing. Michael D. Shapiro: Conceptualization,
Writing – review & editing. Peter P. Toth: Conceptualization, Writing –
review & editing.
Declaration of Competing Interest
Michael Makover: None. Michael Shapiro: Dr Shapiro has partici-
pated in the Scientic Advisory Boards for Amgen, Esperion, Novartis,
and Novo Nordisk. Peter P. Toth: Dr. Toth is a member of the speakers
bureau for Amarin, Amgen, Esperion, and Novo-Nordisk; he is a
consultant to Amarin, Kowa, Merck, Novartis, and Resverlogix.
Acknowledgments
Makover wishes to dedicate this paper to the late Michael Schloss, of
New York University, a colleague who was a pioneer of many of the
concepts discussed.
M.E. Makover et al.
American Journal of Preventive Cardiology 12 (2022) 100371
12
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