Introduction
An elevated level of total homocysteine is known to
be associated with a higher risk for cardiovascular disease
(1). McCully was the first one to
report an association between elevated levels of homocysteine and
arterial damages (2). He reported
two cases of premature atherosclerosis and arterial thrombosis in
children with elevated levels of homocysteinemia and
homocysteinuria. He concluded that increased concentrations of
homocysteine could be responsible for premature atherosclerotic
vascular disease. These children were found to have an inborn error
in homocysteine metabolism and had extremely high levels of plasma
homocysteine. In other studies, the methylene tetrahydrofolate
reductase (MTHFR) 677T polymorphism was demonstrated to cause the
strongest modulation of total homocysteinemia of all genes
associated with homocysteine and folate metabolism (3-5).
The aim of the present study was to investigate whether the risk
for myocardial infarction (MI) is increased by elevated levels of
plasma homocysteine in patients aged less than 45 years.
Patients and methods
Our study included 28 patients ≤45 years of age who
suffered a first MI (MI group) and 33 patients matched in regards
to age, sex, and risk factors (control group). All subjects were
Romanians. Exposure items were assessed, including lifestyle
[smoking status, obesity (calculation of body mass index (BMI) and
physical activity (MET levels), medical history [diabetes mellitus
(DM), hypertension, previous cardiovascular disease (CV) and
chronic kidney disease (CKD)] and laboratory tests (serum
LDL-cholesterol). We determined the plasma levels of homocysteine
by enzymatic method, within 24 h after MI onset, respectively
within 24 h after first cardiac exam in the controls (cut-off value
15 µmol/l).
Statistical analysis
Data analysis was performed using IBM SPSS
Statistics version 23 (IBM Corp.). The procedures used included
descriptive statistics, parametric statistical tests (independent
sample t-test), non-parametric statistical tests [Chi-square test
of the association, with the evaluation of odds ratio (OR)],
adjustments for accounted variables. The significance level used in
the analysis (P-value) was 0.05.
Results
Patient frequency is depicted in Table I. Both study groups were
statistically balanced [P=0.522 >α=0.05 (one sample Chi-square
test)].
 | Table IFrequencies in the study groups. |
Table I
Frequencies in the study groups.
| Study group | Frequency | Percent | Valid percent |
|---|
| MI group | 28 | 45.9 | 45.9 |
| Controls | 33 | 54.1 | 54.1 |
Ages (mean, minimum and maximum) across the study
groups are documented in Table II.
There were no mean age differences between the two studied groups
[P=0.699 >α=0.05 (one sample Chi-square test)].
| Table IIMean, maximum and minimum age (years)
across the study groups. |
Table II
Mean, maximum and minimum age (years)
across the study groups.
| | Age (years) |
|---|
| Study group | Minimum | Maximum | Mean | SD |
|---|
| MI group | 29.00 | 45.00 | 40.0714 | 5.08395 |
| Controls | 31.00 | 45.00 | 40.5152 | 3.54543 |
There was no significant statistical difference
between sex distributions between the study groups [P=0.625
>α=0.05 (one sample Chi-square test)] (Table III).
| Table IIISex distribution of the two studied
groups. |
Table III
Sex distribution of the two studied
groups.
| | Sex |
|---|
| Study group | Male | Female |
|---|
| MI group | | |
|
Count | 19 | 9 |
|
% within
lot | 67.9% | 32.1% |
|
% of
total | 31.1% | 14.8% |
| Controls | | |
|
Count | 25 | 8 |
|
% within
lot | 75.8% | 24.2% |
|
% of
total | 41.0% | 13.1% |
We found a higher prevalence of smoking status in
the MI group [OR, 4.4; 95% confidence interval (CI)=1.417-13.666;
χ2=6.961, P=0.008) as shown in Table IV. Hypertensive subjects were 64.3%
in the MI group vs. 36.4% in the control group (Table IV), being slight significantly more
numerous (χ2=4.725, P=0.030) in the MI group (OR, 3.15;
95% CI=1.103-8.993).
| Table IVSmoking and hypertension status across
the study groups. |
Table IV
Smoking and hypertension status across
the study groups.
| | Smoking | Hypertension | |
|---|
| Study group | Yes | No | Yes | No | Total |
|---|
| MI group | | | | | |
|
Count | 22 | 6 | 18 | 10 | 28 |
|
% within
lot | 78.6% | 21.4% | 64.3% | 35.7% | 100.0% |
|
% of
total | 36.1% | 9.8% | 29.5% | 16.4% | 45.9% |
| Controls | | | | | |
|
Count | 15 | 18 | 12 | 21 | 33 |
|
% within
lot | 45.5% | 54.5% | 36.4% | 63.6% | 100.0% |
|
% of
total | 24.6% | 29.5% | 19.7% | 34.4% | 54.1% |
Obesity had a similar frequency
(χ2=0.286, P=0.593) in both study lots (OR, 0.754; 95%
CI=0.267-2.125). In addition, we found no significant differences
for LDL-cholesterol serum levels (χ2=2.382, P=0.123)
(OR, 0.427; 95% CI=0.143-1.272). Physical activity level was
sensitively equal (χ2=1.125, P=0.289) across both groups
(OR, 1.759; 95% CI=0.617-5.018) (Table
V).
| Table VObesity, serum LDL-cholesterol levels
(cut-off value 100 mg/dl) and physical activity across study
groups. |
Table V
Obesity, serum LDL-cholesterol levels
(cut-off value 100 mg/dl) and physical activity across study
groups.
| | Obesity |
LDL-cholesterol | Physical
activity | |
|---|
| Study group | Yes | No | Yes | No | Yes | No | Total |
|---|
| MI group | | | | | | | |
|
Count | 10 | 18 | 16 | 12 | 19 | 9 | 28 |
|
% within
lot | 35.7% | 64.3% | 57.1% | 42.9% | 67.9% | 32.1% | 100.0% |
|
% of
total | 16.4% | 29.5% | 26.2% | 19.7% | 31.1% | 14.8% | 45.9% |
| Control group | | | | | | | |
|
Count | 14 | 19 | 25 | 8 | 18 | 15 | 33 |
|
% within
lot | 42.4% | 57.6% | 75.8% | 24.2% | 54.5% | 45.5% | 100.0% |
|
% of
total | 23.0% | 31.1% | 41.0% | 13.1% | 29.5% | 24.6% | 54.1% |
We also studied the prevalence of high
cardiovascular risk conditions such as DM, CKD and pre-existent CV
disease in both groups. There was a significantly higher prevalence
of pre-existent cardiovascular (CV) disease in the control group
vs. the MI group (33.3 vs. 10.7%) showing a negative correlation
with the index event in the MI group (Table VI). DM (χ2=4.560,
P=0.033, OR, 3.624; 95% CI=1.073-12.235) and CKD
(χ2=6.879, P=0.009, OR, 4.286; 95% CI=1.402-13.098) were
more prevalent among subjects from the MI group (Table VI).
| Table VIPre-existent CV disease, DM and CKD
across the study groups. |
Table VI
Pre-existent CV disease, DM and CKD
across the study groups.
| | Pre-existent CV
disease | DM | CKD | |
|---|
| Study group | Yes | No | Yes | No | Yes | No | Total |
|---|
| MI group | | | | | | | |
|
Count | 3 | 25 | 11 | 17 | 15 | 13 | 28 |
|
% within
lot | 10.7% | 89.3% | 39.3% | 60.7% | 53.6% | 46.4% | 100.0% |
|
% of
total | 4.9% | 41.0% | 18.0% | 27.9% | 24.6% | 21.3% | 45.9% |
| Control group | | | | | | | |
|
Count | 11 | 22 | 5 | 28 | 7 | 26 | 33 |
|
% within
lot | 33.3% | 66.7% | 15.2% | 84.8% | 21.2% | 78.8% | 100.0% |
|
% of
total | 18.0% | 36.1% | 8.2% | 45.9% | 11.5% | 42.6% | 54.1% |
Finally, we found a significantly higher prevalence
for increased homocysteinemia (cut-off value 15 µmol/l) among
patients from the MI group (χ2=17.632, P<0.001),
showing a strong correlation between hyperhomocysteinemia and index
event in the MI group (OR, 11.822; 95% CI=3.425-40.802) (Table VII).
| Table VIIHomocysteine cut-off distribution
across the studied groups. |
Table VII
Homocysteine cut-off distribution
across the studied groups.
| | Homocysteine | |
|---|
| Study group | Yes | No | Total |
|---|
| MI group | | | |
|
Count | 19 | 9 | 28 |
|
% within
lot | 67.9% | 32.1% | 100.0% |
|
% of
total | 31.1% | 14.8% | 45.9% |
| Control group | | | |
|
Count | 5 | 28 | 33 |
|
% within
lot | 15.2% | 84.8% | 100.0% |
|
% of
total | 8.2% | 45.9% | 54.1% |
Discussion
In young patients with myocardial infarction (MI),
the evidence of atherosclerotic coronary disease is not always
discernible, which highlights a potential importance of
prothrombotic risk factors (6,7).
World-wide research regarding the role of homocysteine in favoring
ischemic heart disease (IHD) has provided controversial results.
Some studies have suggested that hyperhomocysteinemia is an
independent risk factor for IHD, especially acute ST elevation MI
(8-12),
while others revealed no association between hyperhomocysteinemia
and acute MI (13-15).
In our case-control study, we evaluated the
association between an increased level of homocysteinemia and first
MI in patients aged less than 45 years. Our results showed a
significant (P<0.001) risk for MI in patients with a high
fasting plasma homocysteine levels (OR, 11.822; 95%
CI=3.425-40.802). It was the strongest risk factor in our MI case
study group, followed by smoking (OR, 4.4; 95% CI=1.417-13.666),
chronic kidney disease (CKD) (OR, 4.286; 95% CI=1.402-13.098),
diabetes mellitus (DM) (OR, 3.624; 95% CI=1.073-12.235) and
hypertension (OR, 3.15; 95% CI=1.103-8.993). Other traditional
cardiovascular risk factors (obesity, high LDL-cholesterol levels
and sedentary lifestyle) were equal across the MI and control
groups.
Pathophysiological background of these findings is
supported by the ‘arteriosclerosis’ theory, previously expressed by
McCully (2). Significant stiffness
and damage but without lipid storages, atherosclerotic plaque and
fibrosis (similar to common atherosclerosis in older adulthood)
were the modifications in the arterial walls observed in children
with homocystinuria (16). Thus,
elevated total plasma homocysteine may lead to vascular occlusion,
either by thromboembolic events, or by arterial damage due to
endothelial dysfunction (17).
High homocysteine plasma concentration is
particularly associated with renal function impairment (18,19),
and this rationally explains the association between these two risk
factors that we found in our study. Another factor for
hyperhomocysteinemia is a common polymorphism (C677T) in
methylenetetrahydrofolate reductase (MTHFR), which induces high
thermolability of the enzyme and high susceptibility to
insufficient folate levels; ~12% of the white population is
homozygous (TT genotype) (15), and this status may be associated
with hyperhomocysteinemia especially when combined with poor folate
(and vitamin B12) intake (15,20).
Yet, reports concerning either homozygous or heterozygous subjects
did not show any association of high homocysteine plasma levels and
IHD (15,21-23).
It was demonstrated that homocysteine enhances
oxidative stress (24), and
consecutively promotes endothelial dysfunction, with altered
NO-dependent vasodilatation (25,26).
These findings may explain the association between
hyperhomocysteinemia and hypertension as risk factors in our MI
case group. Regarding coronary flow, an inverse relationship has
also been demonstrated between homocysteinemia and
endothelium-dependent blood flow, especially in young patients
(27), results that corroborate our
findings and may rationally explain it. On the other hand, the
relationship between mild hyperhomocysteinemia and IHD may be
inverse as atherosclerosis (especially in the setting of
hypertension and DM) accelerates the fall in renal function, thus
increasing plasma levels of homocysteine (28). Even if reducing very high plasma
homocysteine concentrations in patients decreases cardiovascular
risk (29), this may be due to
folate replacement, and not to the correction of
hyperhomocysteinemia itself (30,31).
In conclusion, our findings support a strong
association between elevated homocysteine plasma levels and first
MI in young patients, mainly with no previously diagnosed
cardiovascular disease, but with other significantly prevalent
cardiovascular risk factors such as smoking, CKD, hypertension, and
DM.
Acknowledgements
Not applicable.
Funding
No funding was received for this research.
Availability of data and materials
Data used in the current original study were
obtained from patient archive files, Constanţa County Emergency
Hospital, Romania. Any further information regarding the present
study is available from the corresponding author upon reasonable
request.
Authors' contributions
CN, AIS and LM designed the study and collected data
from recruited cases. DN performed the arteriographies and
angioplasties. LP, APS and LAT analyzed data and performed the
statistics. MI and IRP analysed and wrote the Results and
Discussion section including the literature review, prepared the
manuscript, translated it and managed all the correspondence for
publishing. All authors read and approved the final manuscript.
Ethics approval and consent to
participate
This non-interventional study was approved by the
local Ethics Commission of Constanța County Emergency Hospital,
Romania (no. 29/24.08.2017).
Patient consent for publication
Not applicable.
Competing interests
There are no competing interests regarding the
authors of this research.
References
|
1
|
Clarke R, Daly L, Robinson K, Naughten E,
Cahalane S, Fowler B and Graham I: Hyperhomocysteinemia: An
independent risk factor for vascular disease. N Engl J Med.
324:1149–1155. 1991.PubMed/NCBI View Article : Google Scholar
|
|
2
|
McCully KS: Vascular pathology of
homocysteinemia: Implications for the pathogenesis of
arteriosclerosis. Am J Pathol. 56:111–128. 1969.PubMed/NCBI
|
|
3
|
Frosst P, Blom HJ, Milos R, Goyette P,
Sheppard CA, Matthews RG, Boers GJ, Den Heijer M, Kluijtmans LA,
Van den Heuvel LP, et al: A candidate genetic risk factor for
vascular disease: A common mutation in methylenetetrahydrofolate
reductase. Nature Genet. 10:111–113. 1995.PubMed/NCBI View Article : Google Scholar
|
|
4
|
Sharma P, Senthilkumar RD, Brahmachari V,
Sundaramoorthy E, Mahajan A, Sharma A and Sengupta S: Mining
literature for a comprehensive pathway analysis: A case study for
retrieval of homocysteine related genes for genetic and epigenetic
studies. Lipids Health Dis. 5(1)2006.PubMed/NCBI View Article : Google Scholar
|
|
5
|
Rudreshkumar KJ, Majumdar V, Nagaraja D
and Christopher R: Relevance of plasma levels of free homocysteine
and methionine as risk predictors for ischemic stroke in the young.
Clin Nutr. 37:1715–1721. 2018.PubMed/NCBI View Article : Google Scholar
|
|
6
|
Chan MY, Andreotti F and Becker RC:
Hypercoagulable states in cardiovascular disease. Circulation.
118:2286–2297. 2008.PubMed/NCBI View Article : Google Scholar
|
|
7
|
Rossini R, Capodanno D, Lettieri C,
Musumeci G, Limbruno U, Molfese M, Spatari V, Calabria P, Romano M,
Tarantini G, et al: Long-term outcomes of patients with acute
coronary syndrome and nonobstructive coronary artery disease. Am J
Cardiol. 112:150–155. 2013.PubMed/NCBI View Article : Google Scholar
|
|
8
|
Akyürek Ö, Akbal E and Güneş F: Increase
in the risk of ST elevation myocardial infarction is associated
with homocysteine level. Arch Med Res. 45:501–506. 2014.PubMed/NCBI View Article : Google Scholar
|
|
9
|
Ma Y, Peng D, Liu C, Huang C and Luo J:
Serum high concentrations of homocysteine and low levels of folic
acid and vitamin B12 are significantly correlated with
the categories of coronary artery diseases. BMC Cardiovasc Disord.
17(37)2017.PubMed/NCBI View Article : Google Scholar
|
|
10
|
Anand SS, Yusuf S, Vuksan V, Devanesen S,
Teo KK, Montague PA, Kelemen L, Yi C, Lonn E, Gerstein H, et al:
Differences in risk factors, atherosclerosis, and cardiovascular
disease between ethnic groups in Canada: The study of health
assessment and risk in ethnic groups (SHARE). Lancet. 356:279–284.
2000.PubMed/NCBI View Article : Google Scholar
|
|
11
|
Ramesh N and Ganesan K: A study on serum
homocysteine as an independent risk factor for coronary artery
disease. IAIM. 6:75–80. 2019.
|
|
12
|
Bautista LE, Arenas IA, Penuela A and
Martinez LX: Total plasma homocysteine level and risk of
cardiovascular disease: A meta-analysis of prospective cohort
studies. J Clin Epidemiol. 55:882–887. 2002.PubMed/NCBI View Article : Google Scholar
|
|
13
|
Chen CY, Yang TC, Chang C, Lu SC and Chang
PY: Homocysteine is a bystander for ST-segment elevation myocardial
infarction: A case-control study. BMC Cardiovasc Disord.
18(33)2018.PubMed/NCBI View Article : Google Scholar
|
|
14
|
Deepa R, Velmurugan K, Saravanan G,
Karkuzhali K, Dwarakanath V and Mohan V: Absence of association
between serum homocysteine levels and coronary artery disease in
South Indian males. Indian Heart J. 53:44–47. 2001.PubMed/NCBI
|
|
15
|
Brattström L, Wilcken DE, Ohrvik J and
Brudin L: Common methylenetetrahydrofolate reductase gene mutation
leads to hyperhomocysteinemia but not to vascular disease: The
result of a meta-analysis. Circulation. 98:2520–2526.
1998.PubMed/NCBI View Article : Google Scholar
|
|
16
|
Bergheanu SC, Bodde MC and Jukema JW:
Pathophysiology and treatment of atherosclerosis: Current view and
future perspective on lipoprotein modification treatment. Neth
Heart J. 25:231–242. 2017.PubMed/NCBI View Article : Google Scholar
|
|
17
|
Brattström L and Wilcken DE: Homocysteine
and cardiovascular disease: Cause or effect? Am J Clin Nutr.
72:315–323. 2000.PubMed/NCBI View Article : Google Scholar
|
|
18
|
Arnadottir M, Hultberg B, Nilsson-Ehle P
and Thysell H: The effect of reduced glomerular filtration rate on
plasma total homocysteine concentration. Scand J Clin Lab Invest.
56:41–46. 1996.PubMed/NCBI View Article : Google Scholar
|
|
19
|
Guttormsen AB, Ueland PM, Svarstad E and
Refsum H: Kinetic basis of hyperhomocysteinemia in patients with
chronic renal failure. Kidney Int. 52:495–502. 1997.PubMed/NCBI View Article : Google Scholar
|
|
20
|
Stabler SP, Marcell PD, Podell ER, Allen
RH, Savage DG and Lindenbaum J: Elevation of total homocysteine in
the serum of patients with cobalamin or folate deficiency detected
by capillary gas chromatography-mass spectrometry. J Clin Invest.
81:466–474. 1988.PubMed/NCBI View Article : Google Scholar
|
|
21
|
Verhoef P, Rimm EB, Hunter DJ, Chen J,
Willett WC, Kelsey K and Stampfer MJ: A common mutation in the
methylenetetrahydrofolate reductase gene and risk of coronary heart
disease: Results among U.S. men. J Am Coll Cardiol. 32:353–359.
1998.PubMed/NCBI View Article : Google Scholar
|
|
22
|
Tsai MY, Welge BG, Hanson NQ, Bignell MK,
Vessey J, Schwichtenberg K, Yang F, Bullemer FE, Rasmussen R and
Graham KJ: Genetic causes of mild hyperhomocysteinemia in patients
with premature occlusive coronary artery diseases. Atherosclerosis.
143:163–170. 1999.PubMed/NCBI View Article : Google Scholar
|
|
23
|
Folsom AR, Nieto FJ, McGovern PG, Tsai MY,
Malinow MR, Eckfeldt JH, Hess DL and Davis CE: Prospective study of
coronary heart disease incidence in relation to fasting total
homocysteine, related genetic polymorphisms, and B vitamins: The
atherosclerosis risk in communities (ARIC) study. Circulation.
98:204–210. 1998.PubMed/NCBI View Article : Google Scholar
|
|
24
|
Kanani PM, Sinkey CA, Browning RL, Allaman
M, Knapp HR and Haynes WG: Role of oxidant stress in endothelial
dysfunction produced by experimental hyperhomocyst(e)inemia in
humans. Circulation. 100:1161–1168. 1999.PubMed/NCBI View Article : Google Scholar
|
|
25
|
Celermajer DS, Sorensen K, Ryalls M,
Robinson J, Thomas O, Leonard JV and Deanfield JE: Impaired
endothelial function occurs in the systemic arteries of children
with homozygous homocystinuria but not in their heterozygous
parents. J Am Coll Cardiol. 22:854–858. 1993.PubMed/NCBI View Article : Google Scholar
|
|
26
|
Bellamy MF, McDowell IF, Ramsey MW,
Brownlee M, Newcombe RG and Lewis MJ: Oral folate enhances
endothelial function in hyperhomocysteinaemic subjects. Eur J Clin
Invest. 29:659–662. 1999.PubMed/NCBI View Article : Google Scholar
|
|
27
|
Schächinger V, Britten MB, Elsner M,
Walter DH, Scharrer I and Zeiher AM: A positive family history of
premature coronary artery disease is associated with impaired
endothelium-dependent coronary blood flow regulation. Circulation.
100:1502–1508. 1999.PubMed/NCBI View Article : Google Scholar
|
|
28
|
Potter K, Hankey GJ, Green DJ, Eikelboom
JW and Arnolda LF: Homocysteine or renal impairment: Which is the
real cardiovascular risk factor? Arterioscler Thromb Vasc Biol.
28:1158–1164. 2008.PubMed/NCBI View Article : Google Scholar
|
|
29
|
Wilcken DE and Wilcken B: The natural
history of vascular disease in homocystinuria and the effects of
treatment. J Inherit Metab Dis. 20:295–300. 1997.PubMed/NCBI View Article : Google Scholar
|
|
30
|
Durga J, Bots ML, Schouten EG, Kok FJ and
Verhoef P: Low concentrations of folate, not hyperhomocysteinemia,
are associated with carotid intima-media thickness.
Atherosclerosis. 179:285–292. 2005.PubMed/NCBI View Article : Google Scholar
|
|
31
|
Brown KS, Huang Y, Lu ZY, Jian W, Blair IA
and Whitehead AS: Mild folate deficiency induces a
proatherosclerotic phenotype in endothelial cells. Atherosclerosis.
189:133–141. 2006.PubMed/NCBI View Article : Google Scholar
|
