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HOMOCYSTEINE AS A CARDIOVASCULAR RISK FACTOR
Marcelo Flavio G Jardim Filho1
Abstract: This article aims to review the evidence on the relationship between homocysteine and
cardiovascular disease (CVD), as well as the possible mechanisms involved and therapeutic strategies
to reduce homocysteine levels. Homocysteine is an amino acid that can accumulate in the blood for
various reasons, such as enzymatic defects, nutritional deciencies, or changes in liver or kidney
function. Hyperhomocysteinemia is considered an independent risk factor for CVD as it aects the
vascular endothelium, promotes LDL oxidation, and stimulates thrombosis. The article presents a meta-
analysis of clinical and experimental studies that investigated the association between homocysteine
and CVD, the mechanisms by which homocysteine can cause vascular damage, and ways to treat
hyperhomocysteinemia, mainly through supplementation with B vitamins. The article concludes that
homocysteine is both a marker and a causal factor of CVD, and that reducing its levels can prevent or
slow the progression of the disease.
Keywords: Cardiovascular Diseases; Homocysteine; Diseases; Markers.
INTRODUCTION
Among the numerous markers that have been investigated in the literature to assess the
probability of developing cardiovascular disease (CVD) ( Habib, et al; 2023), homocysteine stands
out as one of the independent, non-traditional and debatable risk factors for arterial disease. coronary
disease (Hankey, Eikelboom, 1999). Homocysteine is an amino acid formed from the conversion
1 Cardiologist, Specialist in Cardiology by the SBC, Specialist in Arterial Hypertension Certicate
by the Brazilian Society of Hypertension, Major Doctor of the Military Police of RJ, Doctor on duty at
the Coronary Care Unit at the Salgado Filho Municipal Hospital, municipal public servant
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of methionine to cysteine (Faeh, et al., 2006). Signicant elevations in homocysteine levels can be
observed in patients with defects or mutations in the metabolic enzymes involved in this process, such
as cystathionine β-synthase and 5,10-methylenetetrahydrofolate reductase (MTHFR) (Faeh, et al.,
2006). Homocysteine elevations are found in individuals with vitamin B12 or folic acid deciencies,
although these changes can be modied (Veeranna, et al., 2011). Other factors that may result in
hyperhomocysteinemia include methotrexate overdose/toxicity or impaired liver or kidney function
(Hankey, Eikelboom, 1999).
The main concern with high levels of circulating homocysteine is its impact on the endothelial
cells lining blood vessels. Homocysteine also interferes with the oxidation of low-density lipoproteins
and has prothrombotic properties (Baszczuk, Kopczyński, 2014). It is known that many patients with
CVD have high levels of non-traditional risk factors, including homocysteine (Shenoy, et al., 2014).
Atherosclerotic cardiovascular diseases (ASCVD) increasingly aect young individuals
around the world (Ichikawa, et al., 2023). This is a situation with a major impact on public health, as
people with ASCVD may lose the ability to work and have greater health expenses throughout their
lives.
Some traditional and well-established risk factors for CVD are smoking, diabetes,
hyperlipidemia, hypertension, metabolic syndrome, prothrombotic states, and chronic inammation
(Hankey, Eikelboom, 1999). Smoking is a modiable risk factor that increases the likelihood of
peripheral arterial disease and abdominal aortic aneurysm by ve times, and two to three times the
likelihood of CVD, stroke and sudden cardiac death (Shenoy, et al., 2014). However, the presence of
multiple traditional and non-traditional risk factors may generate inconsistent results on the association
between homocysteine and CVD.
The purpose of this systematic review is to synthesize the available evidence on the role of
homocysteine in ASCVD in young adults and children. These ndings will allow us to identify which
pathological conditions, patient characteristics, medications/interventions and biomarkers inuence
homocysteine levels and, consequently, the risk of CVD. These ndings may be applied in clinical
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practice to guide appropriate management based on homocysteine levels obtained in laboratory tests.
METHODOLOGY
Search strategy
This review was performed in accordance with the Preferred Reporting Items for Systematic
Reviews and Meta-Analysis (PRISMA) guidelines (Figure 1). The article selection period was from
2013 to 2023. The databases searched were PubMed and SciELO.
The search strategy involved the use of specic keywords in combination with the conjunctions
“OR” and “AND”. These keywords included “coronary artery disease,” “coronary heart disease,”
“coronary heart disease,” “vascular disease,” “atherosclerosis,” “arteriosclerosis,” and “homocysteine.”
In the second phase, two independent reviewers examined the search results; Initially, they reviewed
the titles and abstracts and excluded any studies that were not relevant.
Abstracts that were related to our topic were considered for a full review. The full texts of all
pertinent articles and those requiring further study were then obtained and rechecked against eligibility
criteria. A total of 2,596 studies were screened. After pre-screening and removing all duplicates,
572 studies were eliminated from the total of 2,596. Titles and abstracts were then reviewed by two
independent investigators to include only those studies relevant to the topic of interest. At this stage,
around 1,983 studies were excluded. All remaining 41 studies were carefully reviewed for inclusion
criteria and there were 6 studies that did not meet them. Finally, 35 studies were included in the nal
analysis of the systematic review. Details are mentioned in Figure 1 which shows the ow diagram of
the entire article selection process as per PRISMA guidelines.
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Inclusion and exclusion criteria
Inclusion criteria were studies that included homocysteine as a cause of premature myocardial
infarction or coronary artery disease for patients under 45 years of age, regardless of gender. Case-
control, cohort and cross-sectional studies of human subjects published in English were included.
Exclusion criteria were studies published before January 2013 and after 2023. Conference
abstracts, review articles, research theses, editorials, commentaries, opinions, views, case reports and
systematic reviews were all excluded. Duplicates and retracted articles that did not meet the inclusion
criteria were automatically ltered.
Figure 1: Identication of studies via databases and records
Source: The author (2024)
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Statistical analysis
This meta-analysis was performed using the online software Med Calc
(https://metaanalysis.com/?gad_source=1&gclid=CjwKCAjwpsBhAiEiwALwsVYfV_
ad8v_1RmprKd2OLar30QYPJFQSqehl9HHuLmxYVnpPgYclzFhoCb9wQAvD_BwE). The mean
dierence (MD) was calculated for studies that used exactly the same methods and measurement units
for homocysteine as a CVD biomarker. We also compared the standardized mean dierence (SMD)
for selected studies that used dierent methods and units of measurement for similar outcomes. Of
these, 15 studies were included in the meta-analysis. Data analyzes were conducted with I2 statistics
to detect heterogeneity and meta-regression analysis was done to nd the source of heterogeneity.
When I2 values were <50%, we used the xed eects model; otherwise, the random eects model
was used.
RESULTS
The studies analyzed consisted of 11 cross-sectional studies (Ijaz, et al., 2015, Karim, et
al., 2015, Prajapati, et al., 2015, Islam, et al., 2016, Kaur, et al., 2016, Chaudhary , et al., 2017, Qin, et
al., 2017, Li, et al., 2021, Sun, et al., 2021, Teng, et al., 2022), 3 cohort studies (Pac-Kozuchowska, et
al., 2018, Raeld, et al., 2018, Monasso, et al., 2021), 3 randomized controlled trials (Cerbone, et al.,
2016, Fruzzetti, et al., 2016, Momeni1comma, et al., 2019 ) and 18 case-control studies (Islam, et al.,
2015, Jain, et al., 2015, Kouzehgaran, et al., 2015, Ramkaran, et al., 2015, Iqbal, et al., 2016, İşgüven,
et al., 2016, Lai, et al., 2017, Rallidis, et al., 2017, Gupta, et al., 2018, Vishwajeet, et al., 2018, Nedelcu,
et al., 2021, Ra, et al. ., 2021). Most studies found a positive association between homocysteine
levels and carotid intima-media thickness (IMT-C). Homocysteine levels were higher in younger
individuals (<40 years) and correlated with increased IMT-C. Lifestyle factors such as obesity and
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smoking also inuence homocysteine levels. The most investigated gene in relation to homocysteine
was the Methylenetetrahydrofolate reductase (MTHFR) gene and its variants. Other genes were
evaluated, but only mutations in the MTHFR gene showed signicant changes in homocysteine levels.
Homocysteine levels decreased with the use of medications such as oral contraceptives, L-thyroxine
and antidiabetics.
The descriptive data of the studies collected are presented in Table I, according to gender,
countries, interventional procedures, observational ndings and association with homocysteine. Of
the 33 studies that showed a signicant association of homocysteine with outcomes, 15 studies (Islam,
et al., 2015, Jain, et al., 2015, Karim, et al., 2015, Iqbal, et al., 2016, Islam, et al., 2016, Lai, et al.,
2017, Qin, et al., 2017, Rallidis, et al., 2017, Shah, et al., 2018, Gupta, et al., 2018, Pac-Kozuchowska,
et al., 2018, Raeld, et al., 2018, Teng, et al., 2022) were selected for the meta-analysis with similar
outcomes. Figure 2 shows the geographic distribution of studies around the world. Figure 3 shows the
meta-analysis with full xed-eects models and random-eects models. The eect size was estimated
from the DMP values. Heterogeneity tests indicated an I2 value of 97.98% with condence intervals
for I2 of 97.44-98.41 (p<0.001).
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Figure 2 : Geographic Distribution
Table 1 Descriptive data of the studies collected
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DISCUSSION
Homocysteine has a high correlation with atherosclerotic cardiovascular disease (ASCVD)
in young and overweight patients. Furthermore, the relationship of homocysteine with smoking,
genetic polymorphism, specic hormonal and kidney disorders, nutritional deciencies (vitamin B12
and folic acid) and the use of specic medications are among the other recurring ndings. The data
extracted from the compiled studies and the results produced in this systematic review provided a
sucient summary of the current literature related to homocysteine levels associated with premature
cardiovascular disease.
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Figure 3 : Forest plots of studies selected for meta-analysis with homocysteine as a biomarker for
CVD
Genetic Role
From the studies collected, it was observed that homocysteine levels are inuenced by several
genetic associations. A randomized clinical trial was conducted to determine the inuence of the
MTHFR gene on the size of carotid intima-media thickness (IMT-C) in female patients with rheumatoid
arthritis (Marini, et al., 2008). This gene is located on chromosome 1, at locus 1p36.3, and acts as a
catalyst in the irreversible reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate.
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The latter acts as a methyl group donor in the synthesis of methionine from homocysteine.
The results showed a signicant increase in both IMT-C and homocysteine levels in 280
female patients. This raises the question whether people with MTHFR polymorphism are naturally
predisposed to higher levels of homocysteine and, consequently, carotid intima-media thickness.
This depends on the nature of the enzyme variant and its prevalence. For example, folate-correctable
variants can be counterbalanced by increasing intake of folic acid supplements ( Agodi, et al., 2011).
An investigation into the prevalence of MTHFR variants in the population of Tamil Nadu in
southern India showed that MTHFR A1298C was more widespread than MTHFR C677T. It should be
noted that of the 72 Tamilians tested, 52 had acute myocardial infarction (AMI), suggesting that the
rst variant may be more involved in the pathogenesis of CVD (Abd El-Aziz, Mohamed, 2017). Just
having a gene polymorphism alone is not enough to guarantee premature CVD, as other factors need
to be considered in addition to an increase in homocysteine.
To illustrate this, the same gene was studied again in a dierent study (Iqbal, et al., 2016)
that analyzed a population of Pakistani patients with AMI. In addition to MTHFR C677T and
MTHFR A1298C, polymorphisms of methionine synthase and cystathionine-beta-synthase were also
considered. The research results showed that both patients with AMI and healthy controls (both with
MTHFR polymorphism) had elevated homocysteine levels (23±17.2 and 23±13.4 mmol/l, respectively)
above the normal limit (15 mmol /l), while the other two genes did not signicantly alter homocysteine
levels.
Despite these ndings, there was no signicant association of the MTHFR polymorphism
with an increased risk of premature myocardial infarction in the Pakistani population (Iqbal, et al.,
2016). Another study (Gupta, et al., 2018) examined how the Apolipoprotein (ApoE) polymorphism,
along with other biochemical risk factors, such as homocysteine, would be associated with very young
patients presenting with AMI.
Both ApoE and homocysteine were not signicantly altered in these young patients, while
other factors such as ApoA1 and HCL-C were signicantly reduced, but only compared to healthy
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controls and not to older patients presenting with acute AMI (Gupta, et al., 2018). From these results,
it can be seen that elevated homocysteine is not an absolute outcome, even with polymorphism in
related genes.
Essential Micronutrients
In addition to genes, nutrients play a substantial role in inuencing homocysteine levels
and IMT-C sizes. One study (Celik, Celik; 2018) examined the relationship between vitamin B12
levels and EMI-C size. All patients with vitamin B12 deciency had not only higher EMI-C but also
elevated homocysteine levels. This may be attributed to decreased autonomic function. As B12 is
essential for the maintenance of nerve function, a deciency would be expected to impair sympathetic
and parasympathetic activity, which in turn aects the cardiovascular system (Celik, Celik; 2018).
Another study (Monasso, et al., 2021) also emphasized how deciency of circulating vitamin
B12 during fetal life can aect EMI-C in school-age children. This was a prospective cohort study that
followed 3,826 children from early pregnancy to school age. Considering the normal levels of vitamin
B12 and folate circulating during pregnancy (>145 pmol/L and >8 nmol/L, respectively), low levels of
the former were associated with increased EMI-C, while low levels of the latter were associated with
decrease in EMI-C.
Interestingly, homocysteine levels did not signicantly relate to carotid intimal thickness,
except in a standard deviation score, which showed that a high level in a blood sample taken from
the umbilical cord was associated with lower IMT-C, but this was an exception (Monasso, et al.,
2021). This may have been due to the extremely young age of the sample or the suppressive eect
of vitamin B12 on homocysteine, which is why the eects of the latter were masked by the former.
This is exemplied in another study, which showed how homocysteine was inversely proportional
to both vitamin B12 and folic acid. Furthermore, homocysteine increased with age and would not be
signicantly high in children (Henry, et al., 2012).
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Thyroid Hormone
Hormones can also interact with homocysteine. The eects of thyroxine on homocysteine
were investigated in one study ( Cerbone, et al., 2016); a total of 39 children with subclinical
hypothyroidism were treated with L-thyroxine for more than 2 years, and several parameters were
compared before and after the intervention. Weight-to-height ratio, triglyceride levels, atherogenic
index, and homocysteine decreased signicantly after therapy, while high-density lipoprotein
(HDL-C) levels increased. Although the underlying reason has not been claried, a separate study
(İşgüven, et al., 2016) sought to determine the eects of thyroid autoimmunity (TA) in euthyroid girls
diagnosed with Hashimoto’s thyroiditis. The outcome was a measure of IMT-C and several other
CVD risk factors, including homocysteine.
Here, the ndings are contradictory to the previously mentioned study (Cerbone, et al., 2016).
When comparing the diseased and control groups, there was not much dierence in the following
parameters: thyroid hormone levels, insulin levels, homocysteine levels and Homeostasis Model
Assessment for Insulin Resistance (HOMA-IR). However, regardless of thyroid function, all patients
showed increased IMT-C compared to the control group. It was concluded that TA was more related
to chronic inammation that caused endothelial dysfunction and not to the elevation of any specic
marker of cardiovascular risk (İşgüven, et al., 2016). It appears that only particular hormonal diseases
are associated with homocysteine, but this needs further investigation.
Female Reproductive System
Polycystic ovary syndrome (PCOS) is another hormonal disease known to be associated with
vascular changes, such as increased intima-media thickness, increased arterial stiness and endothelial
dysfunction. This is also reected by the elevation of certain surrogate markers of cardiovascular risk,
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of which homocysteine is one of the main factors. An intervention to examine how administering
metformin tablets (under the trade name Formaet, manufactured by Mylan MV Canonsburg, USA)
to patients with PCOS would aect cardiovascular risk factors. The drug was administered at a dose
of 850 mg per day for 6 months. Metformin signicantly reduced only insulin, blood pressure, high-
sensitivity C-reactive protein (Hs-CRP) and plasminogen activator inhibitor-1 levels. On the other
hand, it can lead to elevated homocysteine levels, but to a lesser extent. Because many other risk
factors have been suppressed, a slight increase in homocysteine should not be considered to place
the patient at greater risk for cardiovascular events (20). But if metformin could indirectly aect
homocysteine, can the same be said about other antidiabetic medications? One paper found that
rosiglitazone (GSK plc, Brentford, UK) had a suppressive eect on homocysteine, and another found
that sulfonylureas did not signicantly alter homocysteine ( Sullivan, et al., 2011). Whether these
medications are preferred to metformin in CVD prevention is a question beyond the scope of this
systematic review.
Endogenous female hormones are known to alter homocysteine levels. Therefore, it is
expected that oral contraceptive pills may also inuence homocysteine and lipid levels and indirectly
aect CVD risk, but the literature presents contradictory results, so it has not been conrmed which
nding is more valid. A study (Momeni1comma, et al., 2019) conducted in Iran compared the use
of oral contraceptives (OC) among 100 women with normal menstrual cycles over a period of 3-6
months. In the group that used OCs for at least 24 to 36 months, higher levels of homocysteine,
low-density lipoprotein (LDL), cholesterol, triglycerides, and systolic blood pressure were recorded.
There was a signicant dierence between this group and the other groups according to the Tukey
test, especially for homocysteine (Momeni1comma, et al., 2019). This should in no way be taken as
evidence for the active use of OCPs as part of therapy for patients with CVD. Instead, it should be
based on clinical judgment and other factors related to the patient’s health status.
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Kidney Pathologies
One study (Do Val., et al., 2019) sought to evaluate the association between left ventricular
mass z-score and IMT-C with other risk factors. This study particularly looked at children and
adolescents with end-stage kidney disease and compared them with healthy controls. Multivariate
analysis revealed that left ventricular mass z-score was related to age, duration of dialysis, systolic
blood pressure, serum hemoglobin levels, and HDL levels, while IMT-C was related to systolic blood
pressure.
It is unclear why homocysteine was not signicantly related to the aforementioned
outcomes, especially considering that patients with chronic kidney disease typically present with
hyperhomocysteinemia (Do Val., et al., 2019).
These ndings were reinforced by another study (Aksu, et al., 2019), in which kidney
disease in the sampled population was nephrotic syndrome. As it was already established that serum
asymmetric dimethylarginine (ADMA) may be an independent risk factor for CVD (due to its ability
to inhibit nitric oxide production), the study attempted to nd any signicant link between it and
atherosclerotic risk factors. in children. As in the previous study (Do Val., et al., 2019), homocysteine
was not found to be dierent between groups, nor was it associated with ADMA or EMI-C.
It can be deduced that kidney pathologies may interfere with the expected ndings, but
this needs to be elucidated in future studies (Aksu, et al., 2019). One kidney disease that has been
found to correlate with elevated homocysteine levels is autosomal dominant polycystic kidney disease
(ADPKD). It is a known fact that ADPKD can cause increased cardiovascular mortality, but the
literature has not claried the exact underlying pathogenesis, which is why a study (Lai, et al., 2017)
was conducted to identify early and non-invasive markers of CVD in patients with ADPKD.
Study results revealed elevated homocysteine levels in addition to HOMA-IR, serum uric
acid, renal resistance index, and left ventricular mass index. However, there was no signicant increase
in EMI-C (Lai, et al., 2017). Just as only certain hormonal diseases aect homocysteine or CVD risk
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or both, the same appears to be observed in kidney diseases. This actually suggests that the dynamics
involved between homocysteine, CVD and other risk factors/diseases may be more complex than
estimated.
Age Factor
By analyzing the various risk factors including homocysteine and coronary plaque
morphology by comparing young and elderly Indian patients with coronary artery disease below
and above 40 years. Using computed tomography angiography, it was found that young patients had
more pronounced features of positive remodeling, punctate calcication, and noncalcied plaques
compared with older patients.
In addition, all patients with stable coronary angina had only a single vessel involved, whereas
patients with acute coronary syndrome had multiple vessel involvement. The most commonly involved
area was the proximal segment of the left anterior descending artery.
All young patients with acute coronary syndrome (ACS) had homocysteine levels greater
than 15 μmol/L, but the dierence between the two groups was not signicant (Chaudhary, et al.,
2017). This pattern of young patients being more predisposed to CVD due to hyperhomocysteinemia
is evident throughout the literature collected. A leading lipoprotein factor related to premature CVD
is lipoprotein(a), which is predominantly genetically inherited. In addition to the pro-inammatory
state, it is also related to the presence and severity of CVD (Habib, et al., 2013).
Gastrointestinal and Food Related
Among the diseases that predispose a patient, these seem to follow random patterns. But
perhaps this simply reects the paucity of knowledge we have about homocysteine itself, and this
forms an incentive for even more in-depth research aimed at elucidating the intricacies of the amino
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acid in the human body.
For the intima-media thickness of the superior carotid, the one that surrounds the
gastrointestinal tract, ulcerative colitis (UC) is a signicant example. Findings from a study (Jain, et
al., 2015) on 60 patients with UC showed that not only IMT-C was signicantly increased, but also
homocysteine, HOMA-IR and insulin were signicantly higher (p<0 .05). Furthermore, a signicant
correlation was observed between EMI-C and homocysteine, homocysteine and HOMA-IR levels (
Jain, et al., 2015).
CONCLUSION
This systematic review study synthesized the evidence available in the literature on
the relationship between serum homocysteine levels and the risk of early cardiovascular disease.
Homocysteine is an intermediate in methionine metabolism, which can exert atherogenic,
thrombogenic, hypertensive, cardiotoxic and neurotoxic eects, depending on its concentration and
associated pathophysiological conditions.
Hyperhomocysteinemia is determined by genetic factors, such as the polymorphism of
the enzyme methylenetetrahydrofolate reductase (MTHFR), and by environmental factors, such as
smoking, obesity, diabetes, dyslipidemia, B vitamin deciency, hypothyroidism, chronic renal failure
and some inammatory and autoimmune diseases.
Carotid intima-media thickness (IMT-C) is a marker of subclinical atherosclerosis, which
reects vascular damage and the risk of cardiovascular events, such as myocardial infarction and
stroke. IMT-C is correlated with homocysteine levels and other cardiovascular risk factors and can
be reduced by pharmacological and non-pharmacological interventions that modulate homocysteine
metabolism.
Therefore, the assessment of IMT-C and homocysteine can contribute to the diagnosis,
prevention, treatment and prognosis of cardiovascular diseases in young and adult individuals, healthy
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or with comorbidities that aect homocysteine homeostasis and vascular function.
REFERENCE
ABD EL-AZIZ, TA; MOHAMED, RH Inuence of MTHFR C677T gene polymorphism in the de-
velopment of cardiovascular disease in Egyptian patients with rheumatoid arthritis. Gene , vol. 610,
p. 127-132, 2017.
AGODI, A.; BARCHITTA, M.; VALENTI, G.; MARZAGALLI, R.; FRONTINI, V.; MARCHESE,
AE Increase in the prevalence of the MTHFR 677 TT polymorphism in women born since 1959: po-
tential implications for folate requirements. Eur J Clin Nutr , vol. 65, p. 1302-1308, 2011.
BASZCZUK, A.; KOPCZYŃSKI, Z. Hyperhomocysteinemia u chorych at schorzenia układu krąże-
nia [ Hyperhomocysteinemia in patients with cardiovascular disease]. Postepy Hig Med Dosw (On-
line) , v. 68, p. 579-589, 2014.
CELIK, SF; CELIK, E. Subclinical atherosclerosis and impaired cardiac autonomic control in pedia-
tric patients with Vitamin B12 deciency. Niger J Clin Practice , vol. 21, p. 1012-1016, 2018.
CERBONE, M.; CAPALBO, D.; WASNIEWSKA, M.; ALFANO, S.; MATTACE RASO, G.; OLI-
VIERO, U.; CITTADINI, A.; DE LUCA, F.; SALERNO, M. Eects of L-thyroxine treatment on ear-
ly markers of atherosclerotic disease in children with subclinical hypothyroidism. Eur J Endocrinol ,
v. 175, p. 11-19, 2016.
CHAUDHARY, R.; CHAUHAN, A.; SINGHAL, M.; BAGGA, S. Risk factor proling and study of
atherosclerotic coronary plaque burden and morphology with coronary computed tomography angio-
graphy in coronary artery disease among young Indians. Int J Cardiol , vol. 240, p. 452-457, 2017.
FAEH, D.; CHIOLERO, A.; PACCAUD, F. Homocysteine as a risk factor for cardiovascular disease:
should we (still) worry about? Swiss Med Wkly , v. 136, p. 745-756, 2006.
FRUZZETTI, F.; GHIADONI, L.; VIRDIS, A.; DE NEGRI, F.; PERINI, D.; BUCCI, F.; GIANNA-
RELLI, C.; GADDUCCI, A.; TADDEI, S. Adolescents with Classical Polycystic Ovary Syndrome
131
ISSN: 2763-5724 / Vol. 04 - n 03 - ano 2024
Have Changes in the Surrogate Markers of Cardiovascular Disease but Not in the Endothelial Func-
tion. The Possible Benets of Metformin. J Pediatr Teenager Gynecol , vol. 29, p. 489-495, 2016.
GUPTA, MD; GIRISH, MP; SARKAR, PG; GUPTA, A.; KATEGARI, A.; BANSAL, A.; SAIJPAUL,
R.; BATRA, V.; RAIN, M.; TYAGI, S.; PASHA, Q. Role of ApoE gene polymorphism and noncon-
ventional biochemical risk factors among very young individuals (aged less than 35 years) presenting
with acute myocardial infarction. Indian Heart J , vol. 70, p. S146-S156, 2018.
HANKEY, G.J.; EIKELBOOM, JW Homocysteine and vascular disease. Lancet , vol. 354, p. 407-
413, 1999.
HENRY, OR; BENGHUZZI, H.; TAYLOR Jr, HA; TUCCI, M.; BUTLER, K.; JONES, L. Suppres-
sion of homocysteine levels by vitamin B12 and folates: age and gender dependence in the Jackson
Heart Study. Am J Med Sci , vol. 344, p. 110-115, 2012.
ICHIKAWA, K.; SUSARLA, S.; BUDOFF, MJ The use of coronary artery calcium scoring in young
adults. J Cardiovasc Comput Tomogr , vol. 15, S1934-5925(23)00117-X, 2023.
IJAZ, A.; ZAMIR, S.; SATTAR, A.; JAN, R.; ALI, S.; WAZIR, F. Homocysteine levels in younger
patients with coronary artery disease in Pakistan. Gomal J Med Sci , vol. 13, p. 202-206, 2015.
IQBAL, MP; IQBAL, K.; TAREEN, AK; PARVEEN, S.; MEHBOOBALI, N.; HAIDER, G.; IQBAL,
SP Polymorphisms in MTHFR, MS and CBS genes and premature acute myocardial infarction in a
Pakistani population. Pak J Pharm Sci , vol. 29, p. 1901-1906, 2016.
İŞGÜVEN, P.; GÜNDÜZ, Y.; KILIÇ, M. Eects of Thyroid Autoimmunity on Early Atherosclerosis
in Euthyroid Girls with Hashimoto’s Thyroiditis. J Clin Res Pediatr Endocrinol , v. 8, p. 150-156,
2016.
ISLAM, KN; CHOWDHURY, AW; KHANDAKER, AH; SABAH, KM; AMIN, MG; KABIR, SR;
SALEH, MA Comparison of Dierent Risk Factors and Coronary Angiographic Prole in Younger
and Older Patients with Ischeamic Heart Disease. Cardiovasc J , v. 8, p. 23-29, 2015.
ISLAM, K.; CHOWDHURY, A.; KHONDOKER, A.; HAQUE, M.; SABAH, K.; AMIN, M.; KA-
BIR, S.; SALEH, M. Eect of Serum Homocysteine on Coronary Artery Disease in Younger and
132
ISSN: 2763-5724 / Vol. 04 - n 03 - ano 2024
Older Ischaemic Heart Disease Patients. Cardiovasc J , v. 25, p. 138-142, 2016.
KARIM, MA; MAJUMDER, AA; ISLAM, KQ; ALAM, MB; PAUL, ML; ISLAM, MS; CHOW-
DHURY, KN; ISLAM, SM Risk factors and in-hospital outcome of acute ST segment elevation myo-
cardial infarction in young Bangladeshi adults. BMC Cardiovasc Disord , v. 15, p. 73, 2015.
KAUR, R.; DAS, R.; AHLUWALIA, J.; KUMAR, RM; TALWAR, KK Genetic polymorphisms, Bio-
chemical Factors, and Conventional Risk Factors in Young and Elderly North Indian Patients With
Acute Myocardial Infarction. Clin Appl Thromb Hemost , vol. 22, p. 178-183, 2016.
KOUZEHGARAN, S.; VAKILI, R.; NEMATY, M.; SAFARIAN, M.; GHAYOUR-MOBARHAN,
M.; KHAJEDALUEE, M. Comparison of Novel Coronary Artery Disease Risk Factors between Obe-
se and Normal Adolescent. Iran J Med Sci , vol. 40, p. 322-327, 2015.
LI, XR; ZUO, HJ; YANG, HX; ZHANG, DF; MA, Z.; AN, ZY; SONG, XT Clinical characteristics
and prognosis of young (< 35 years) patients with acute ST-segment elevation myocardial infarction.
Zhonghua-xinxue Guan Bing Zazhi , vol. 49, p. 1124-1129, 2021.
MARINI, NJ; GIN, J.; ZIEGLE, J.; KEHO, KH; GINZINGER, D.; GILBERT, DA; RINE, J. The
prevalence of folate-remedial MTHFR enzyme variants in humans. Proc Nat Acad , v. 105, p. 8055-
8060, 2008.
MONASSO, GS; FELIX, JF; HEIL, SG; DE RIJKE, YB; GAILLARD, R.; JADDOE, VW Vitamin
B12, folate and homocysteine concentrations during pregnancy and early signs of atherosclerosis at
school-age. Clin Nutr , vol. 40, p. 5133-5140, 2021.
NEDELCU, C.; IONESCU, M.; PANDEA-STOIAN, A.; NIŢA, D.; PETCU, L.; MAZILU, L.; SU-
CEVEANU, AI; TUŢA, LA; PAREPA, IR Correlation between plasma homocysteine and rst myo-
cardial infarction in young patients: Case-control study in Constanta County, Romania. Exp Ther
Med , vol. 21, p. 101, 2021.
PAC-KOZUCHOWSKA, E.; KRAWIEC, P.; GRYWALSKA, E. Selected risk factors for atheroscle-
rosis in children and their parents with positive family history of premature cardiovascular diseases:
a prospective study. BMC Pediatr , vol. 18, p. 1-7, 2018.
133
ISSN: 2763-5724 / Vol. 04 - n 03 - ano 2024
PRAJAPATI, J.; JOSHI, H.; SAHOO, S.; VIRPARIYA, K.; PARMAR, M.; SHAH, K. AGE-Related
Dierences of Novel Atherosclerotic Risk Factors and Angiographic Prole Among Gujarati Acute
Coronary Syndrome Patients. J Clin Diagn Res , vol. 9, OC05-OC09, 2015.
QIN, G.; CHEN, Z.; SU, W.; GENG, X.; CHEN, X.; XU, X.; PAN, W. Clinical usefulness of meta-
bolic risk factors to identify young asymptomatic female adults with subclinical atherosclerosis: A
cross-sectional study. Medicine (Baltimore) , vol. 96, e6237, 2017.
RAFFIELD, L.M.; ELLIS, J.; OLSON, NC; DUAN, Q.; LI, J.; DURDA, P.; PANKRATZ, N.; KE-
ATING, B.J.; WASSEL, CL; CUSHMAN, M.; WILSON, JG Genome-wide association study of ho-
mocysteine in African Americans from the Jackson Heart Study, the Multi-Ethnic Study of Atheros-
clerosis, and the Coronary Artery Risk in Young Adults study. J Human Genet , vol. 63, p. 327-337,
2018.
RAFI, U.; AHMAD, S.; BOKHARI, SS; IQBAL, MA; ZIA, A.; KHAN, MA; ROOHI, N. Associa-
tion of Inammatory Markers/Cytokines with Cardiovascular Risk Manifestation in Patients with
Endometriosis. Mediators Inamm , v. 2021, p. 3425560, 2021.
RALLIDIS, L. S.; GIALERAKI, A.; TRIANTAFYLLIS, AS; TSIREBOLOS, G.; LIAKOS, G.;
MOUTSATSOU, P.; ILIODROMITIS, E. Characteristics and Long-Term Prognosis of Patients ≤35
Years of Age with ST Segment Elevation Myocardial Infarction and “Normal or Near Normal” Coro-
nary Arteries. Am J Cardiol , vol. 120, p. 740-746, 2017.
RAMKARAN, P.; PHULUKDAREE, A.; KHAN, S.; MOODLEY, D.; CHUTURGOON, AA Me-
thylenetetrahydrofolate reductase C677T polymorphism is associated with increased risk of coronary
artery disease in young South African Indians. Gene , vol. 571, p. 28-32, 2015.
SHAH, H.; JAN, MU; ALTAF, A.; SALAHUDIN, M. Correlation of hyperhomocysteinemia with
coronary artery disease in absence of conventional risk factors among young adults. J Saudi Heart
Assoc , vol. 30, p. 305-310, 2018.
SHENOY, V.; MEHENDALE, V.; PRABHU, K.; SHETTY, R.; RAO, P. Correlation of serum ho-
mocysteine levels with the severity of coronary artery disease. Indian J Clin Biochem , vol. 29, p.
339-344, 2014.
134
ISSN: 2763-5724 / Vol. 04 - n 03 - ano 2024
Sun, J.; HAN, W.; WU, S.; JIA, S.; YAN, Z.; GUO, Y.; ZHAO, Y.; ZHOU, Y.; LIU, X. Combined
eect of hyperhomocysteinemia and smoking on the severity of coronary artery disease in young
adults ≤ 35 years of age: a hospital-based observational study. BMC Cardiovascular Disor , v. 2, p.
1-9, 2021.
TENG, Y.; WANG, K.; FAN, X.; YANG, X. Prevalence and Risk Factors of Abnormal Carotid Artery
in Young Adults without Overt Cardiovascular Disease. Int J Gen Med , vol. 15, p. 4595-4601, 2022.
TENG, Y.; WANG, K.; FAN, X.; YANG, X. Prevalence and Risk Factors of Abnormal Carotid Artery
in Young Adults without Overt Cardiovascular Disease. Int J Gen Med , vol. 15, p. 4595-4601, 2022.
VEERANNA, V.; ZALAWADIYA, S.K.; NIRAJ, A.; PRADHAN, J.; FERENCE, B.; BURACK, RC;
JACOB, S.; AFONSO, L. Homocysteine and reclassication of cardiovascular disease risk. J Am
Coll Cardiol , vol. 58, p. 1025-1033, 2011.
VISHWAJEET, V.; JAMWAL, M.; SHARMA, P.; DAS, R.; AHLUWALIA, J.; DOGRA, RK; ROHIT,
MK Coagulation F13A1 V34L, brinogen and homocysteine versus conventional risk factors in the
pathogenesis of MI in young persons. Acta Cardiologica , v. 73, p. 328-334, 2018.
