Premature atherosclerosis: A review of current literature

Alexander R. Neifert, MD,a David Su, MD,b Cassius Iyad Ochoa Chaar, MD,a and Bauer E. Sumpio, MD, PhD,a
New Haven, CT

ABSTRACT
Background: The global burden of atherosclerotic disease continues to rise and is becoming increasingly prevalent in a
distinct subgroup of individuals, who present with clinical manifestations of premature atherosclerosis (PreAS) before the
age of 50. Disease in this subgroup can have a disproportionately large impact on disease-associated loss of quality-
adjusted life-years and societal productivity. Although there is significant overlap with traditional atherosclerotic risk
factors, risk factors and genetic syndromes for patients with PreAS have not been reported on collectively. To close this
gap, the aim of this review was to summarize our current state of knowledge of PreAS.
Methods: A comprehensive review of the literature was conducted to examine the evidence of known risk factors,
genetic predispositions, diagnostics, and interventions pertaining to PreAS.
Results: In recent decades, clinical manifestations of atherosclerotic disease, such as myocardial infarction, peripheral
arterial disease, and cerebral vascular disease, have increased in frequency in patients aged <50 years, while decreasing in
the traditional population. Nontraditional risk factors for PreAS are explored including human immunodeficiency virus
infection, highly active antiretroviral therapy, chemotherapy, radiation, lifestyle, diet, the metabolic syndrome, recrea-
tional substance use, preeclampsia, and inflammatory and autoimmune conditions. Hereditary disorders are discussed in
three main categories: clotting abnormalities, lipid derangements, and vessel disorders. Various approaches for clinical
diagnosis and laboratory evaluation are assessed along with interventions specific to patients with PreAS.
Conclusions: The reviewed literature reinforces the importance of a personalized approach to PreAS, given the wide
variation of unique risk factors and genetic predispositions that can lead to premature atherosclerotic disease. (JVS-Vascular
Insights 2023;1:100013.)
Keywords: Premature atherosclerosis; Genetics; Risk factors

Atherosclerosis (AS) and its clinical manifestations are a atherosclerotic associated pathology diagnosed before
major cause of global morbidity and mortality. In the the age of 50 to 55 years and accounts for approximately
westernized world, AS accounts for 50% of all deaths, 10% of patients with AS symptoms.2
but there has been a globalization of AS with a growing Although there is some overlap, many patients with
number of countries approaching a similar disease PreAS have unique predisposing risk factors and clinical
burden.1 The clinical consequences of AS involve all presentations than those with traditional atherosclerotic
vascular beds and result in coronary artery disease (TradAS).3 Unfortunately, characterization of this group
(CAD), peripheral arterial disease (PAD), and cerebral and understanding best management practices is scat-
vascular disease (CVD). tered and relatively sparse. Furthermore, current risk pre-
There is now increasing awareness for a distinct sub- diction tools may fail to properly assess risk in the
class of AS occurring in patients significantly younger younger population.4 Although there has been signifi-
than the typical age group at risk for atherosclerotic cant improvement in mortality and morbidity for tradi-
disease. Premature AS (PreAS) has been referred to by tional patient populations, younger patient groups have
various names, but it is typically defined as shown unchanged or even increasing mortality rates for
the sequela of atherosclerotic disease.2,4,5 With a near
From the Division of Vascular and Endovascular Surgery,a and the Division of doubling of global cardiovascular disease cases since
General Surgery,b Department of Surgery, Yale University School of Medicine. 1990, and its disproportionate impact on disability-
Author conflict of interest: none. adjusted life-years, it is crucial to better understand
Correspondence: Bauer E. Sumpio, MD, PhD, Professor of Surgery (Vascular) and
PreAS. We review the underlying genetic predispositions
of Radiology and Biomedical Imaging and of Medicine (Cardiology),
Boardman Building, 330 Cedar Street, New Haven, CT 06510 (e-mail: bauer.
for PreAS and provide a suitable algorithm for workup of
sumpio@yale.edu). patients who present with PreAS.
The editors and reviewers of this article have no relevant financial relationships to
disclose per the Journal policy that requires reviewers to decline review of any COMPARISON OF TRADAS WITH PREAS
manuscript for which they may have a conflict of interest.
The development of atherosclerotic disease in patients
2949-9127
Copyright Ó 2023 by the Society for Vascular Surgery. Published by Elsevier Inc.
with TradAS and PreAS is thought to share the same
This is an open access article under the CC BY-NC-ND license (http:// mechanistic pathway. This insidious process involves
creativecommons.org/licenses/by-nc-nd/4.0/). macrophage infiltration, lipid accumulation, and prolifer-
https://doi.org/10.1016/j.jvsvi.2023.100013 ation of surrounding smooth muscle cells (Fig 1, A and B).

1
2 Neifert et al JVS-Vascular Insights
2023

Traditional risk factors include nonmodifiable factors present in 43%, the mean age was 42.0 6 4.2 years, and
such as age, family history, and sex, in addition to the 76% were current or past smokers.11
modifiable risk factors of smoking, diabetes, hyperten-
sion, dyslipidemia, obesity, and chronic kidney disease.
NONTRADITIONAL RISK FACTORS ASSOCIATED
TradAS and PreAS can affect all vascular beds, but
WITH PreAS
commonly present with clinical symptoms associated
Although there is significant overlap in the risk factors
with PAD, CAD, and CVD (Fig 2).
with TradAS, PreAS has been associated with multiple
Myocardial infarction. Myocardial infarction (MI) is additional and unique risk factors. These include human
common manifestation of atherosclerotic cardiovascular immunodeficiency virus (HIV) infection, highly active an-
disease (ASCVD). A study by Beller et al6 demonstrated a tiretroviral therapy (HAART), chemotherapy, radiation,
clustering of MI in the higher age groups and a broader recreational substance use, inflammatory and autoim-
spread in the younger age suggestive of divergent trends mune conditions, and metabolic syndromes (Fig 3).
in risk factors. Vikulova et al4 reported a similar trend of
HIV and HAART. HIV and HAART have been shown to
unchanged mortality rates for patients <50 years of age.
predispose to PreAS and, there is evidence that some
Women were found to have a significantly higher mor-
HAART therapies may further increase the risk of dis-
tality rate than male counterparts aged <45 years.
ease.14 Patients with HIV had an acute MI rate of 11.13
Women also underwent fewer emergent procedures
per 1000 person-years compared with 6.98 for patients
and had fewer successful revascularizations or guideline-
without HIV.14 On pathologic examination, lesions noted
based therapies relative to males in the same PreAS
in patients with HIV had characteristics more consistent
cohort.2,4
with arteritis than TradAS. Potential mechanisms iden-
In a study of the incidence of metabolic syndrome, pa-
tified included dyslipidemia, chronic inflammation,
tients age <50 represented 5% to 20% of reported acute
macrophage activation, endothelial activation, smooth
MI.7 The mean age of first acute MI in patients <50 was
muscle cell activation, and platelet damage.14 HAART
44.6 6 5.1 years and 90% of patients were men.5,7 In pa-
therapy seems to have varying degrees of impact on the
tients with TradAS, the age >50 group had an average
vascular system. However, the true incidence may be
age of 67.3 6 9.2, and 67.2% were men.7 The American
difficult to ascertain because many patients are on
Heart Association reported that the mean age of the first
multiple therapies.9 HAART impedes HIV-induced
MI was 65.6 years for men and 72.0 years for women.8
dysfunction, but extended therapy may cause chronic
Although the overall rate of MI is decreasing, it seems
endothelial dysfunction and induce smooth muscle cell
to be increasing in frequency for the population <50. It
proliferation and neointimal hyperplasia, potentially
has been suggested that the decreased morbidity in
accelerating AS in patients with HIV.14
the TradAS population is a result of timely prevention
through increased exercise, healthier diets, decreased Chemotherapy and radiation. The cancer microenvi-
smoking rates, and improved medical interventions.6 ronment and angiogenesis share multiple overlapping
Increasing young adult obesity rates, and the metabolic pathways, and certain agents, such as those that target
syndrome in pediatric and adult populations are thought vascular endothelial growth factor, may place patients
to be a likely driver of increased incidence of PreAS. at significantly elevated risk for AS. By inhibiting vascular
Furthermore, the metabolic syndrome has been shown endothelial growth factor, these agents systemically limit
to be an independent predictor of 6-year of morbidity the production of nitric oxide and prostacyclin necessary
owing to major adverse cardiac and cerebral events.9,7 for healing endothelial injury. These agents include
monoclonal antibody-based tyrosine kinase inhibitors,
PAD. PAD has a sharp age-associated increase in
small molecular tyrosine kinase inhibitors, and
prevalence. It most notably increases after age 60, with a
mammalian target of rapamycin inhibitors.15 Concurrent
>20% to 30% prevalence in those aged >80 years.10 The
radiation can cause DNA damage, oxidative stress, pre-
prevalence of severe disease requiring intervention is
mature cellular senescence, cell death, and inflamma-
greater among men than women, despite a nearly
tion, as well as injury to connexin-based gap junction,
equivalent overall prevalence of PAD in patients >50
which are all believed to further contribute to the pro-
and <50 years old.11,12 The prevalence of PAD in
gression of AS.16,17
those <50 years old is estimated between 1% and 10% in
the subpopulations with multiple high-risk factors.13 It Lifestyle and diet. Physiological stress such as depres-
has also been noted that those patients with premature sive symptoms, irregular sleep, loss of interest, and finan-
PAD seem to have greater involvement of major arteries, cial stress have been associated with increased risk of
such as the carotid and coronary arteries.14 Of the pa- cardiovascular death, nonfatal MI, or nonfatal stroke.18
tients with premature PAD, 76% have at least one tradi- Garshick et al19 explored nontraditional risk factors in
tional risk factor for PAD, the metabolic syndrome was young to middle age (youngest quartile, age 25-57) who
JVS-Vascular Insights Neifert et al 3
Volume 1, Number C

Fig 1. (A) Components of atherosclerosis (AS). (B) Typical progression of atherosclerotic disease.

had a new diagnosis of obstructive CAD. They found that rise of vaping in the young adult and pediatric pop-
the patients in this population had higher odds of per- ulations has led to significant concern that it may in-
sonal stress and financial stress, as well as a lower func- crease the risk for PreAS. Multiple mechanisms have
tional capacity. Diets were also noted to differ been proposed based on prior tobacco research; how-
significantly with the younger group, which included ever, the diversity of chemical substrates and lack of
having an increased sweetened beverage intake and a long-term data have led to significant challenges in
lower consumption of fruits, vegetables, and fish relative determining the true atherosclerotic risk. Given these
to the older quartiles.19 Modern sedentary lifestyle is also limitations, further research is still needed to characterize
a notable driver of AS because it leads to obesity and the potential role vaping may play in the development of
increased activity of inflammatory pathways. This factor PreAS.26
is often evidenced in elevated blood pressures, insulin
Pregnancy. Pregnancy and preeclampsia, although
resistance, and elevated lipid levels.20
acute events, seem to have a lasting effect in predispos-
Obesity and the metabolic syndrome. Obesity is a ing women to AS. Rates of CAD and CVD are nearly twice
negative long-term predictor in young patients with as high when compared with women who had normo-
MI; however, it seems to serve a potentially protective role tensive pregnancies. Similar to AS, there has been an as-
in patients >50 years old.7 Risk factors for obesity, such as sociation with preeclampsia and the metabolic
lack of sleep and increased screen time, are more prev- syndrome, chronic endothelial impairment, and inflam-
alent in the younger population.21 Pediatric and global mation.25 Pregnancy-associated plasma protein-A,
obesity rates have continued to rise, and there are widely screened for evaluating pregnancy for Down
ongoing discussions on how to define the metabolic syndrome, serves to cleave insulin-like growth factors.
syndrome and the impact it has on PreAS.21 However, it also seems to impact AS through multiple
mechanisms, including lipid accumulation, vascular
Recreational substance abuse. Recreational drug use
inflammation, endothelial dysfunction, vascular smooth
has also been linked to the PreAS with the use of four
muscle cell proliferation and migration, plaque stability,
or more substances creating a greater than nine-fold
and thrombus formation.27
increase in the risk of PreAS.22 Methamphetamine and
cocaine have been demonstrated to lead to increased Infection and inflammation. Chronic infections that
atherosclerotic disease burden. Interestingly, use can be have been attributed to AS include HIV, Chlamydia
correlated with a decrease in other traditional risk factors pneumoniae, Porphyromonas gingivalis, and Helico-
such as dyslipidemia and obesity.23,24 This finding sug- bacter pylori. These infections are believed to cause
gests a potential distinct mechanism relative to TradAS. chronic inflammation associated AS through interac-
Endothelin-1, released by cocaine, is believed to tions with Toll-like receptors.28 Periodontal disease has
contribute by causing vasoconstriction, increasing cal- long been associated with AS, with proposed models
cium deposition and increasing fibrinogen and Von suggesting direct activation by microbes entering the
Willebrand factor production, leading to an increased bloodstream or indirect inflammatory response path-
thrombotic risk.24,25 Further research is needed because ways.29 More recently, associations between AS and gut
polysubstance use and direct cardiotoxic and neurotoxic microbiota have been identified. It is unclear if these are
effects can confound our understanding of the true role causative or reflect more generalized conditions, such as
substance use plays in CAD, CVD, and PAD.24 The recent the metabolic syndrome. Proposed causative
4 Neifert et al JVS-Vascular Insights
2023

Fig 2. Comparison of characteristics of premature atherosclerotic cardiovascular disease (ASCVD) and traditional
ASCVD.

mechanisms have included an inflammatory response matched disease-free controls.34 Ankylosing spondylitis
model, alterations in cholesterol metabolism, and dif- and other spondylopathies have also been associated
ferences in microbiota metabolites.30 with accelerated AS. Ankylosing spondylitis had an
increased odds ratio of 2.2 for ischemic heart disease
Autoimmune disease. Chronic inflammatory states
relative to disease-free controls. When compared with
and autoimmune disorders such as systemic lupus ery-
smoking or other traditional risk factors, ankylosing
thematosus have long been identified as unique AS risk
spondylitis was a stronger predictor for the need for early
factors.31 It is thought that there is an increased rate of
vascular intervention.35
thrombotic lesions associated with an increased
atherosclerotic burden and coagulopathic state.31,32 In a GENETIC DISORDERS
study by Manzi et al,33 women aged 35 to 44 with sys- Genetic factors can influence susceptibility to ASCVD.
temic lupus erythematosus had a 50-fold increased risk Recent advances in molecular techniques have unveiled
of MI. Another example is Sjögren’s syndrome. which has numerous monogenic and polygenic conditions that are
a two-fold higher risk for stroke and MI. Interestingly, linked to an individual’s propensity for developing
even in patients without acute manifestations, the ankle- atherosclerotic disease. We discuss the hereditary disor-
brachial indexes were found to be abnormal in 20% of ders according to three main categories: clotting abnor-
patients with Sjögren’s syndrome, compared with 4% in malities, lipid derangements, and vessel disorders (Fig 4).

Fig 3. Traditional and nontraditional atherosclerotic cardiovascular disease (ASCVD) risk factors.
JVS-Vascular Insights Neifert et al 5
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Clotting disorders Homocystinuria. Homocystinuria is an inherited meta-

Hereditary coagulopathies influence one’s risk for bolic disorder in which the amino acid methionine is un-
developing early AS by either directly impacting clotting able to be metabolized owing to the deficiency of
factors (such as prothrombin or factor V) or the genera- cystathionine beta synthase or methionine synthase,
tion of autoantibodies (eg, antiphospholipids). resulting in a spectrum of disorders, including connec-
Familial prothrombin G20210A. Implicated in the tive tissue abnormalities, seizures, and intellectual
early development of CVD and CAD, prothrombin disability, as well as vascular disease.42 The effects of
G20210A mutation reflects a G-to-A substitution in the homocysteine on arteriosclerotic plaques and carotid
30 -untranslated region of prothrombin. Patients with het- artery wall hypertrophy were first suggested in a study of
erozygous prothrombin mutations make up 2% of the vascular pathology on children with inherited disorders
US population, and studies show they have an increased of homocysteine metabolism. In vitro and animal studies
risk of MI.36 When stratified by age, there was a marked suggest that homocysteine has a wide array of toxic ef-
age-related association for MI risk found in patients fects on all layers of the arterial wall, ranging from
aged <55 years. A systematic review documented an endothelial dysfunction, medial remodeling, and
elevation of prothrombin G20210A levels in patients with adventitial inflammation.42
critical limb ischemia.37 Prospective cohort studies eval- Dysfibrinogenemia. Congenital dysfibrinogenemia de-
uating the role of G20210A allele in ASCVD have yet to be scribes a group of inherited clotting disorders caused by
performed. mutations in fibrinogen genes (FGA, FGB, or FGG), in
Factor V Leiden. Factor V Leiden (FVL) is the most com- which a functionally abnormal fibrinogen is produced
mon inherited thrombophilia, found in roughly 5% of and interferes with the normal clotting process.43
Caucasians in North America. This variant renders factor Individuals with dysfibrinogenemia inherit the mutation
V insensitive to the actions of activated protein C, a nat- as an autosomal dominant trait and are often found as
ural circulating anticoagulant, resulting in hypercoagula- heterozygous carriers of missense variants, but dysfunc-
bility and risks for venous thromboembolism. Like the tional fibrinogen can also be acquired through liver dis-
prothrombin G20210A polymorphism, FVL was detected ease, multiple myeloma, disseminated intravascular
in higher frequencies in children with a parental history coagulation, or hemophagocytic lymphohistiocytosis.
of premature CAD, suggesting a genetic predisposition Clinical profiles are challenging to correlate with geno-
to AS may exist.38 One cross-sectional study showed an typic data given the phenotypic variability of the fibrin-
exponential increase in the risk of carotid AS with in- ogen disorders, ranging from bleeding to thrombosis.
creases in serum low-density lipoprotein (LDL) choles- Altered fibrin properties have been reported in cases of
terol in nondiabetic carriers of FVL.39 Although FVL is ischemic stroke and peripheral artery disease through a
expected to influence the early development of AS, plethora of variants.44 Certain gene variants exhibit
retrospective cohort studies linking the relationship have bleeding symptoms, whereas other variants manifest a
been conflicting and sparse. When FVL is paired with thrombotic phenotype and clinically present with
certain subgroups, such as young women, smokers, or recurrent thrombosis.43
those with higher serum LDL cholesterol, early stage AS is
Lipid disorders
often observed.
This section reviews several key lipid disorders and their
Antiphospholipid syndrome. Antiphospholipid syn-
impact on the early development of atherosclerotic
drome (APS) is an autoimmune disorder characterized
disease.
by hypercoagulability in the presence of antiphospholi-
Beta-thalassemia major. Beta-thalassemias are
pid antibodies (aPL), often manifesting as arterial or
inherited microcytic anemias that stem from >100 path-
venous thrombosis or as a pregnancy-related complica-
ogenic variants that result in a decrease in or absence of
tion. The exact mechanism for how this occurs is un-
one or more globin chains in the adult hemoglobin
known, but the proatherogenic properties of aPL have
structure.45 Patients with untreated thalassemia can ac-
been characterized in mouse models. The Coronary Ar-
quire severe anemia, which can result in excess iron,
tery Risk Development in Young Adults (CARDIA) study
culminating in heart failure, growth impairment, dia-
by Majka et al40 compared aPL levels and the degree of
betes, and ultimately death. Vascular disease, AS, and
coronary artery calcification measured by computed to-
CAD have emerged in the younger population amongst
mography in 2203 participants. They reported that aPL
patients with beta-thalassemia major. An Egyptian cross-
positivity in young adults is significantly increased in
sectional study found that patients with beta-
those with subclinical AS.40 Furthermore, patients with
thalassemia major aged 5 to 18 years showed elevated
APS and critical limb ischemia have a higher pooled
serum triglyceride levels, increased carotid artery intima
prevalence of lupus anticoagulant antibodies than those
media thickness, and atherogenic index of plasma when
without critical limb ischemia or PAD, suggesting a po-
compared with healthy controls.45
tential link between PAD and APS.41
6 Neifert et al JVS-Vascular Insights
2023

Fig 4. Known genetic disorders associated with increased atherosclerosis (AS) risk.

Familial hypercholesterolemia. Familial combined hy- Familial defective APOB. Familial defective APOB
percholesterolemia (FCHC), also known as autosomal (FDB) is a rare form of FCHC characterized by elevated
dominant hypercholesterolemia, is characterized by an LDL cholesterol levels and caused by APOB mutations.50
increase in LDL cholesterol levels that can be associated Typically, the APOB gene is constitutively expressed and
with a variety of genetic mutations, including LDL recep- regulated by post-translational degradation pathways of
tor gene (LDLR), apolipoprotein B-100 (APOB) gene, or apoB-100. Mutations in APOB decrease the binding af-
proprotein convertase subtilisin/kexin type 9.46 finity between apoB-100 and LDLR, resulting in hyper-
Although atherosclerotic disease may affect cerebrovas- cholesterolemia and CAD. In fact, several APOB variants
cular and peripheral artery territories, CAD is the most can raise plasma LDL cholesterol by #70 mg/dL.51
frequent location in patients with familial hypercholes- Although FDB has a milder clinical phenotype
terolemia.47 Accumulations of LDL cholesterol levels can compared with other forms of FCHC, it has been asso-
accelerate the onset of AS; therefore, patients with FCHC ciated with adverse clinical outcomes, such as increased
with markedly elevated levels of cholesterol can exhibit coronary artery calcification and early onset MI in addi-
atherosclerotic disease as early as the first decade of life, tion to several cases of early onset PAD. Population
especially in the homozygous form.46,48 studies estimate that FDB affects 1 in every 1000 people
Heterozygous FCHC affects approximately 1 in 500 peo- in the United States. However, certain populations
ple, with a higher prevalence in certain subpopulations including the Swiss, Amish, Polish, and Han Chinese
including Quebecois, Lebanese, and Dutch South Afri- reportedly have a higher prevalence.
kaner. If untreated, approximately one-half of male pa- Familial hypertriglyceridemia. Familial hypertriglyceri-
tients develop CAD by age 50 years. However, with the demia (FHTG), also known as type IV familial dyslipide-
advent of statin therapy, CAD-associated mortality mia, is an autosomal dominant disorder characterized
decreased 100-fold in the age group of 20 to 40 years by the overproduction of very low-density lipoproteins
and four-fold in the 40- to 59-year age group.49 Ischemic (VLDL). Individuals with the monogenic form of FHTG are
stroke mortality among treated patients with heterozy- likely to have deficiencies in lipoprotein lipase, which
gous FCHC was not different from the general popula- leads to an inability to hydrolyze triglycerides within the
tion, according to a study of a large prospective UK VLDL core.50 However, most cases are thought to be
registry. Although not as common, FCHC can also in- polygenic and strongly influenced by environmental
crease the risks of PAD and chronic kidney disease.49 factors. Although no studies have shown a direct corre-
Autosomal recessive hypercholesterolemia. Auto- lation between monogenic FHTG and preAS, hyper-
somal recessive hypercholesterolemia (ARH) is caused triglyceridemia is seen in other preAS-linked genetic
by LDLRAP1 loss-of-function mutations, producing a disorders such as FCHC or dyslipidemia in patients with
truncated protein that results in a similar but less severe type 2 diabetes mellitus.52 Notwithstanding, there is
clinical phenotype as homozygous familial hypercholes- substantial evidence that hypertriglyceridemia is inde-
terolemia. ARH is exceedingly rare, occurring in <1 in pendently associated with CAD after adjusting for many
every 1,000,000 people, and onset can vary widely from traditional risk factors.
1 to 46 years. Furthermore, the clinical phenotype is less Hyperlipoproteinemia type III. Hyperlipoproteinemia
severe than that of FCHC. A survey of Sardinian patients type III (HLP), also known as familial dysbetalipoproteine-
with ARH reported variable ranges of LDL cholesterol mia, is a highly atherogenic disorder, caused by dysfunc-
levels and presence of CAD (44%). Aortic valve stenosis tional genetic variants or absence of apolipoprotein E
and aortic root disease were observed later in life.49 (apoE), which leads to the accumulation of remnants of
JVS-Vascular Insights Neifert et al 7
Volume 1, Number C

triglyceride-rich lipoproteins, VLDL, and chylomicrons. ASCVD.57 Exome sequencing performed in a group of
Although typically a recessive disorder, 10% of familial HLP kindreds with early AS identified a mutation in the
is inherited via autosomal dominance, and premature gene CYP27 A, which encodes the sterol-27-hydroxylase
CAD risk is 5 to 10 times higher for individuals with HLP involved in cholesterol synthesis and is implicated in
than the general population. This patient population is the pathogenesis of cerebrotendinous xanthomatosis,
also at an increased risk of triglyceride-induced pancrea- which often accompanies early onset AS.58 Other muta-
titis,44 peripheral vascular disease, and palmar tions, such as ST6GALNAC5 gene observed in an Iranian
xanthomas.53 pedigree, may also play a causal role in premature
Multiple studies have demonstrated the cardiovascular CAD. This gene encodes for sialyltransferase, which trans-
impact on the pediatric population. One study showed fers a sialic acid residue to glycoproteins or glycolipids.
HLP had a 10-fold increased risk for premature CAD inde- Werner syndrome. Werner syndrome is an uncommon
pendent of other risk factors. The impact of different ge- autosomal recessive disorder characterized by early onset
netic polymorphisms of apoE on premature CAD has aging and frequently associated with osteoporosis, dia-
also been explored, although the association remains betes mellitus, and AS.59 Most individuals presenting
controversial. One meta-analysis showed that the with Werner syndrome have a mutation in the WRN gene,
APOE2 allele increased the risk of premature CAD which encodes for a RecQ helicase, a DNA unwinding
among Asians, whereas it demonstrated protective ef- protein critical in maintaining chromosomal stability. The
fects in the Caucasian population.53 Individuals with the most common causes of mortality in Werner syndrome
APOE4 allele were more likely to have premature CAD, are premature atherosclerotic complications and cancer.
as well as coronary heart disease and stroke. Interestingly, AS in Werner syndrome develops more
Sitosterolemia. Sitosterolemia, also known as phytoster- extensively in the arterioles as compared with general
olemia, is a rare autosomal recessive disorder of lipid population and is usually symptomatic after puberty.59
metabolism caused by ABCG5 or ABCG8 mutations. It is Treating these patients with 3-hydroxy-3-methyl-glutaryl-
associated with tendon xanthomas, hemolytic anemias, coenzyme A reductase inhibitors (statins) or peroxisome
arthralgias, and premature atherosclerotic disease. Individ- proliferator-activated receptor (PPAR) agonists have been
uals with sitosterolemia are found to have elevated shown to improve prognosis.
plasma concentrations of plant sterols owing to intestinal Familial partial lipodystrophy. Familial partial lipodys-
hyperabsorption and low bile excretion.54 Significant trophy (FPLD) is a very rare congenital syndrome charac-
phenotypic heterogeneity exists among patients with terized by variable loss of adiposity and is associated with
sitosterolemia. PreAS leading to sudden cardiac death has metabolic complications as well as cardiomyopathy,
been noted as early as 5 to 18 years of age, whereas other congestive heart failure, and premature AS.51 Six types
patients show none of the classic signs of sitosterolemia. of FPLD have been defined thus far, each with different
Furthermore, premature coronary heart disease may genetic mutations (LMNA, PPARG, AKT2, PLIN1, CIDEC,
develop in individuals with normal levels of cholesterol. and LIPE). The most common form is type 2 FPLD ,which
Autosomal-dominant CAD. Although CAD is conven- is due to mutations in the LMNA gene. A large majority of
tionally a multifaceted interplay between genetic and patients with type 2 FPLD had hypertriglyceridemia, hy-
environmental factors, autosomal dominant CAD is a percholesterolemia, and high-density cholesterol levels
very rare but highly penetrated disorder with a mono- of <40 mg/dL, with female patients incurring a higher
genic effect and autosomal dominant inheritance risk of atherosclerotic cardiovascular complications.60
pattern.55 Three potential causal genes have emerged in
recent years: myocyte-specific enhancer factor 2A Vessel abnormalities
(MEF2A), LDL receptor-related protein 6 (LRP6), and cyto- Several congenital disorders that are known to alter the
chrome P450 family 27 subfamily A member 1 (CYP27A1). vessel architecture. At times rare, evidence is emerging
In 2003, Wang et al56 identified a large family with a these patients may be predisposed to premature AS.
deletion in exon 11 of MEF2A gene. Most family members Williams syndrome. Williams syndrome, also known as
developed acute MI, and four underwent coronary artery Williams-Beuren syndrome, is a multisystem disorder
bypass surgery. MEF2A is a gene that encodes a tran- resulting in complications in the cardiovascular, con-
scription factor that regulates vasculogenesis. nective tissue, and central nervous systems. It is caused
In 2007, Mani et al57 studied a separate family with a by de novo hemizygous deletions of approximately 28
high prevalence for premature CAD, revealing the causal genes from chromosome 7, including a gene that en-
variant to be the gene LRP6. LRP6 functions as a co- codes the protein elastin. The lack of elastin leads to
receptor with Frizzle proteins in Wnt signaling, which is vascular smooth muscle cell proliferation and sub-
a signal transduction pathway that regulates cell func- endothelial migration, resulting in vascular occlusion.
tion, migration, and embryonic development. In vitro This process is linked to the early development of car-
functional studies show substantial attenuations in Wnt diovascular anomalies, such as supravalvular aortic ste-
signaling, linking LRP6 gene defects to CAD and nosis and severe peripheral pulmonary artery stenosis.61
8 Neifert et al JVS-Vascular Insights
2023

Pseudoxanthoma elasticum. Pseudoxanthoma elasti-

cum (PXE), also known as Groenblad-Strandberg syn-
drome, is a rare disorder characterized by elastic fiber
fragmentation and calcification in various soft tissues
including the skin, eyes, and arterial media. The under-
lying defect causing the PXE disease has been identified
as a mutation on the gene ABCC6 (ATP-binding cassette
subfamily C member 6), which encodes an ATP-binding
efflux transporter, typically expressed in the liver and the
kidney. Histological studies have found aggregates of
pleomorphic elastic structures in the medial layer of ar-
teries. PXE is usually diagnosed in the second or third Fig 5. Standard laboratory evaluation for atherosclerotic
decades of life after the cutaneous and retinal findings cardiovascular disease (ACSVD) and additional laboratory
become more evident. Other vascular complications workup for premature ASCVD. BG, blood glucose; BNP,
include brain infarction, intracranial hemorrhage, and brain natriuretic peptide; HgbA1c, hemoglobin A1c; HDL,
peripheral vascular disease.62 high-density lipoprotein; LDL, low-density lipoprotein; LPA,
lipoprotein (a) FH, familial hypercholesterolemia; LDLR,
Hutchison-Gilford progeria. Hutchinson-Gilford proge- low-density lipoprotein receptor gene.
ria is a rare congenital disorder classically caused by a
point mutation in the LMNA gene and resulting in ubiq-
uitous expression of progerin. Affected children develop levels of personal and financial stress, which seem to
early signs of premature aging and cardiovascular dis- correlate with PreAS risk in particular. Increasing global
ease, often leading to death from MI or stroke at a obesity rates with varying regional associated rates of
mean age of 14.6 years. Using murine models, one study atherosclerotic disease suggest there are also underlying
showed that progerin accumulates in the endothelial genetic predispositions, which remain poorly
cells of the artery, leading to stiffness of the nuclear lam- understood.65
ina and consequently mechanical stress and fibrosis. For young patients with PreAS, common laboratory
Hamczyk et al63 noted that in LMNA knock-in mice workup includes metabolic evaluation with particular
progerin expression promotes loss of vascular smooth attention to lipids, coagulation factors, blood glucose,
muscle cells and collagen deposition, accelerating and homocysteine. Routine laboratory studies typically
atherosclerotic disease in the absence of elevated include an LDL cholesterol, high-density lipoprotein
cholesterol.63 cholesterol, triglycerides, total cholesterol, fatty acids
(Omega-3 and Omega 6), homocysteine, hemoglobin
IDENTIFICATION AND LABORATORY WORKUP A1c, and fasting blood glucose. It should be emphasized
The identification of developing atherosclerotic disease that not all of these tests are indicated to be obtained on
is not limited to symptomatology or advanced imaging all patients with PreAS. The listed tests should be per-
modalities. The ankle-brachial index is an invaluable formed as appropriate to the clinical scenario. For pa-
screening tool to detect symptomatic and asymptom- tients with a history suggestive of inflammatory disease,
atic PAD, including PreAS that, when combined with his- the workup should include an apolipoprotein panel,
tory and screening questionnaires, may have an Apo B, lipoprotein (a), and inflammatory markers such
important role in initiating medical management and as C-reactive protein and erythrocyte sedimentation
risk factor modification. Ultrasound measurement of ca- rate. If these initial diagnostics are positive, further
rotid intima-media thickness has been shown to be an workup with tests such as antinuclear antibody, Coombs
independent predictor of vascular events in test, and disease-appropriate antibody testing can help
patients <50 years of age, but is not used widely.64 Addi- to evaluate for potential disease-specific immunologic
tional screening tools, such as flow-mediated dilatation, therapies when evidence of inflammatory disease is pre-
may serve a role in the evaluation of PreAS; however, sent. When initial laboratory work or history supports a
further studies are needed to better identify differentiate rare genetic pathology such as a 9p21 genotype test or
pathologic premature changes relative to typical age- family hypercholesteremia, tests such as a 9p21 genotype
related changes. test and family hypercholesteremia panel (LDLR, ApoB,
An important first step in treatment and prevention is and proprotein convertase subtilisin/kexin type) may be
identifying which patients are at risk for premature AS. indicated (Fig 5).
A common screening tool is the seven American Heart Beyond understanding the underlying causation, evalu-
Association screening risk factors; however, there remain ations should also work to evaluate the current level of
notable limitations.19 Tully et al65 proposed a modified disease burden. The history and physical examination
screening protocol to address some of these limitations will guide further workup, but the general evaluation
that included dietary intake, functional capacity, and for PreAS mirrors those of TradAS, including ankle-
JVS-Vascular Insights Neifert et al 9
Volume 1, Number C

brachial indexes, pulse volume recordings, duplex ultra- and a high-dose statin. Patients with other disorders
sound examination, cardiac and peripheral vascular such as sitosterolemia may benefit from more targeted
studies, and additional imaging studies. interventions such as ezetimibe and a low sterol diet.
Similarly, patients with Werner syndrome can benefit
THERAPIES AND INTERVENTIONS from statins, bisphosphonates, and oral diabetic agents.
Current pharmacological interventions primarily serve Lonafarnib, a farnesyltransferase inhibitor that helps to
as risk reduction and symptom management agents; prevent the buildup of defective progerin, is recommen-
however, preclinical work suggests that future pharma- ded for patients with Hutchinson-Gilford progeria. Simi-
ceutical agents may enable disease regression.66 For larly, genetics also may dictate the timing and type of
PreAS, many of the tenants of TradAS management still vascular intervention. Examples include patients with
are relevant. Efforts should be made to identify and con- Williams syndrome who may benefit from proactive
trol modifiable risk factors, including smoking cessation, intervention to address smooth muscle wall thickening,
glycemic control, blood pressure control, and weight or those patients with sitosterolemia who may benefit
management. Exercise has been shown to decrease from partial ileal bypass surgery.
the risk of the sequelae of AS. This outcome is believed An interdisciplinary team is particularly important in
to be due to decreased inflammation, oxidative stress, managing PreAS to direct pharmacological agents and
and normalization of endothelial regulation. Supervised interventions. This team often includes vascular sur-
exercise programs have continued to show symptom geons, podiatrists, endocrinologists, infection disease
improvement in claudication, with high- intensity pro- specialists, social workers, addiction medicine, dieticians,
grams showing superiority to low-intensity therapies.67 and exercise physiologists.
Preventative pharmacological agents can prevent the
sequelae of AS and include antiplatelet therapy, statins, CONCLUSIONS
and anticoagulation. Medications such as cilostazol and PreAS remains a poorly defined clinical entity, owing in
chelation therapy can aid in improving symptom man- part to the heterogenicity of potential contributing risk
agement for claudication. Nitroglycerine serves a similar factors. In the setting of an increasing global disease
symptom mitigating role for angina in some patient burden and evidence demonstrating divergence from
populations. patients with tradAS, it is important continue efforts to
Patients with autoimmune disease warrant careful better understand this subgroup. By the nature of
evaluation for appropriate antiplatelet, anticoagulation, impacting patients at a younger age, successful identifi-
and statin therapies.68 Disease-modifying medications cation and intervention have the potential to have a
typically serve a role in reducing the disease-associated greater impact on individuals quality-adjusted life-years
atherosclerotic risk. Beyond patients with chronic inflam- and associated health systems costs. For these reasons,
matory disease, there has also been some evidence to we believe that preAS warrants continued research ef-
suggest that the inflammatory pathway may represent forts and attention to clinical management, despite
a general therapeutic target in preventing and treating remaining a relatively small subgroup of the overall
AS. A randomized trial by Ridker et al68 found signifi- ASCVD population.
cantly lower rates of recurrent cardiovascular disease in
patients placed on canakinumab, a therapeutic mono-
clonal antibody targeting IL-1b at 3 months. This finding AUTHOR CONTRIBUTIONS
was independent of lipid-lowering therapy. However, a Conception and design: AN, DS, BS
predictable increased rate of infection was observed.68 Analysis and interpretation: CIOC, BS
There has already been notable progress in addressing Data collection: AN, DS
premature AS in the HIV positive patient population Writing the article: AN, DS, CIOC, BS
receiving HAART. Klein et al69 reporting a convergence Critical revision of the article: AN, DS, CIOC, BS
of risk in their database, which they had previously iden- Final approval of the article: AN, DS, CIOC, BS
tified a 40% to 80% higher risk of cardiovascular disease Statistical analysis: Not applicable
in patients with HIV. This risk reduction was attributed to Obtained funding: Not applicable
a greater awareness and use of antiretroviral agents with Overall responsibility: BS
a lower cardiovascular risk profile, increased effort to AN and DS contributed equally to this article and share
address general cardiovascular disease, and a growing co-first authorship.
treated ART population.69
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