Abstract: The goal of the present study was to analyze the relationship between homocysteinemia and cardiovascular afflictions in African patients. This prospective study was performed at the Department of Cardiology in the Campus Teaching Hospital of Lomé, from March 1 to November 30, 2008. All patients benefited from a complete cardiovascular evaluation and an assessment of blood homocysteine levels. The prevalence of hyperhomocysteinemia was 45.6%. Age (r = +0.099, p<0.0001), but not sex, was correlated with homocysteinemia. In contrast, body mass index (r = - 0.247, p<0.0001) was negatively linked to homocysteinemia. Both systolic arterial pressure (r = +0.064, p<0.0001) and diastolic arterial pressure (r = +0.148, p<0.0001) also demonstrated a correlation. Among all of the cardiovascular afflictions, the ischemic heart diseases (r = +0.153, p<0.0001) had the strongest association with homocysteinemia. The prevalence of hyperhomocysteinemia was very high among the cardiovascular patients in Togo. This hyperhomocysteinemia was correlated with high blood pressure and ischemic heart diseases, which are becoming more prevalent in this part of the world. The management of this new risk factor, which is based mainly upon its prevention, has been shown to be essential and must become a major public health issue.
INTRODUCTION
For more than three decades, hyperhomocysteinemia has been considered to be an independent risk factor for obstructive cardiovascular pathologies (Guilland et al., 2003). The numerous epidemiological and clinical studies that have been performed in the developed countries have produced contradictory results. Some of those studies (Ueland et al., 2000; Brattstrom and Wilcken, 2000) have demonstrated a relationship between moderate hyperhomocysteinemia and the thromboembolic and ischemic cardiovascular diseases (CVD) (Nevado Jr. and Imasa, 2008). Other studies, however, have shown that high homocysteine levels in populations that are free of the traditional risk factors, such as High Blood Pressure (HBP), diabetes, dyslipidemia, smoking status and obesity, did not result in an increase in the number of morbid cardiovascular events (Alfthan et al., 1994; Evans et al., 1997), suggesting that hyperhomocysteinemia can have a contributing role only in the presence of other cardiovascular risk factors. Another theory proposed that hyperhomocysteinemia that is found in CVD patients might actually be a consequence of these thromboembolic and ischemic CVDs (Guilland et al., 2003).
Currently, the measurement of blood homocysteine levels is included in the screening tests for patients who suffer from premature obstructive cardiovascular pathologies (David, 2000), particularly for those patients without any known traditional cardiovascular risk factors. Those individuals who are found to have elevated blood levels are prescribed a vitamin regimen that includes vitamins B6, B9 and B12 (Wang et al., 2007) in order to reduce homocysteine levels. However, this treatment does not reduce the risk of arisen of cardiovascular events in patients with a high cardiovascular risk (Ray et al., 2007; Ebbing et al., 2008; Imasa et al., 2009).
In the sub-Saharan African countries in general and particularly in Togo, studies in this field are rare. This study was focused on the following major aims: (1) to determine the prevalence of hyperhomocysteinemia in our patient population, (2) to evaluate the relationship between homocysteinemia and other cardiovascular risk factors and (3) to evaluate the relationship between homocysteinemia and the type of CVD.
MATERIALS AND METHODS
Study Population
This study was performed at the Department of Cardiology in the Campus University
Teaching Hospital, which is the second national reference hospital in Togo.
This prospective study included 114 cardiovascular patients of African descent
(Table 1) who were admitted or seen on an out-patient basis
between March 1, 2008 and November 30, 2008 and who were tested for the level
of homocysteine. After inclusion in the study, each patient received a questionnaire
that was used to obtain information regarding sex, age and CVD diagnosis.
The types and frequencies of CVDs in the patient population are presented in Table 1. For purposes of this study, the following criteria were used:
| • | Ischemic heart disease was defined by the presence of one of the following: angina pectoris, as characterized by chest pain during exercise that is improved by rest or trinitrin and confirmation by electrocardiogram (ECG); myocardial infarction; or diagnosis based upon typical ECG signatures |
| • | Cerebrovascular stroke was defined by the following, with the diagnosis confirmed by CT scan: transitory ischemic attack, thrombotic stroke or haemorrhagic stroke |
| • | Venous thrombo-embolic disease was defined by the association of all of the following features: clinical signs, including pain and oedema of the lower limbs, a decrease in venous blood flow and the positive identification by Doppler echography of a thrombus in a vein in the lower limbs |
| • | Obliterant chronic arteriopathy of the lower limbs was defined by a decrease in the arterial blood flow through the lower limbs, which may be associated with a plate of atheroma, as diagnosed by the Doppler echography |
| Table 1: | Distribution of patients according to CVD at inclusion |
| • | Cardiac failure was defined by clinical signs and confirmation by Doppler echocardiography. |
The Body Mass Index (BMI) was calculated for each patient. The patients were classified into three groups: obese patients, with BMI≥30 kg m-2; overweight patients, with 25 kg m-2≤BMI≤30 kg m-2 and normal weight patients, with BMI is <25 kg m-2.
A patient was considered to be hypertensive if the systolic blood pressure ≥18664.8 Pa (140 mmHg) or the diastolic blood pressure ≥11998.8 Pa (90 mmHg). The supine blood pressure in both two arms was measured by a nurse using a manual sphygmomanometer (Mancia et al., 2007). After a ten-minute rest period, the blood pressure was measured three times and the mean of the last two measurements was considered to be the patient’s blood pressure.
Measurement of Blood Homocysteine Levels
Blood samples were taking during fasting. The level of homocysteine was
measured by the immunological technique of fluorescence polarization using the
AxSYM system. Normal values ranged between 5 and 15 μmol L-1.
Hyperhomocysteinemia was defined as homocysteine levels that were greater than
15 μmol L-1 (Demuth et al., 2000)
and patients with hyperhomocysteinemia were further classified into three groups:
moderate hyperhomocysteinemia, with homocysteine levels between 16 and 30 μmol
L-1; intermediate hyperhomocysteinemia, with homocysteine levels
between 31 and 100 μmol L-1 and severe hyperhomocysteinemia,
with homocysteine levels greater than 100 μmol L-1 (Demuth
et al., 2000). The level of homocysteine was correlated with several
physical and clinical characteristics, including age, sex, BMI and type of CVD.
Data Analysis
All quantitative parameters are presented as the average±mean deviation
and all qualitative parameters are presented as the number and its corresponding
percentage. The distribution (casting) of the qualitative parameters was analyzed
by the chi square test.
For the multivariate analysis, the coefficient of correlation was calculated using Excel software v. 2003. The student’s t-test was used to verify the results (estimation of error margin), with a significance threshold of 0.05.
Associations between variables were considered to be great if the coefficient was greater than 0.5, to be average if the coefficient was between 0.5 and 0.2 and to be low if the coefficient was less than 0.2. The absence of correlation between variables was determined if the coefficient was less than 0.001.
The treatment and analyses of the data were performed using the software programs Epi-Info v. 6.04 and Microsoft Excel v. 2003.
RESULTS
Age and Sex
The study included a total of 114 patients, with 43 (37.7%) men and 71 (62.3%)
women. The sex ratio was 0.60. The average age was 53±15.5 years old
(range = 17-90 years).
The average homocysteinemia was 18.7±19.6 Fmol/l (range = 6.1-194.9 μmol L-1) statistically non significant difference between the sexes with respect to homocysteine levels (male average = 18.7±11.4 μmol L-1, female average = 18.7±23.2 μmol L-1; p = 0.995). Fifty-two (45.6%) patients had hyperhomocysteinemia and, of these, twenty-one (48.8%) were male and thirty-one (42.9%) were female (p = 0.590). Further classification revealed that
42 (36.8%) patients had moderate hyperhomocysteinemia, 9 (7.9%) had intermediate hyperhomocysteinemia and 1 (0.9%) had severe hyperhomocysteinemia. There was no significant association between age and homocysteine levels (p = 0.11) (Table 2).
Systolic and Diastolic Arterial Pressure
The average systolic blood pressure was 151.6±32.5 mmHg (range =
90-280 mmHg) and the average diastolic blood pressure was 92.3±16.5 mmHg
(range = 60-150 mmHg). Seventy seven (67.6%) patients were hypertensive (Table
3); 40 of them (51.9%) had hyperhomocysteinemia against 37 (32.2%) whose
homocysteine levels was normal.
Body Mass Index (BMI)
The average BMI was 27.4±5.3 kg m-2 (range = 16.0-50.1
kg m-2). The average homocysteinemia was 25.1±30.7 μmol
L-1 (range = 6.1 - 194.9 μmol L-1) in patients with
normal BMI, 14.8±6.1 μmol L-1 (range = 6.4-34.9 μmol
L-1) in overweight patients and 15.7±64 μmol L-1
(range = 6.5-38.6 μmol L-1) in obese patients. The average homocysteinemia
was significantly different between the three weight groups (p = 0.030). There
was statistically no significant difference in the percentage of patients with
high homocysteine levels according to the BMI classes, p = 0.41 (Table
4).
Lipid and Sugar Levels in Blood
The average total cholesterol level in blood was 2.1±0.7 g L-1
(range = 0.5 - 4.3 g L-1), with an average LDL-cholesterol level
of 1.4±0.4 g L-1 (range = 0.1 - 3.1 g L-1) and
an average HDL-cholesterol level of 0.4±0.2 g L-1 (range =
0.1 - 1.4 g L-1). The average triglyceride level in blood was 1.4±0.8
g L-1 (range = 0.4 - 4.9 g L-1).
Twenty-five (21.9%) patients were diabetics (Table 5); the average glycaemia was 1.2±0.6 g L-1(range = 0.58 - 4.57 g L-1).
| Table 2: | Homocysteinemia according to age |
| Hcy (A) = Homocysteine level in the blood | |
| Table 3: | Homocysteine level according to the blood pressure |
| Hcy (A) = Homocysteine level in the blood ; p = 0.05 | |
| Table 4: | Hyperhomocysteinemia according to BMI |
| p = 0.41 | |
| Table 5: | Homocysteine level according to the glycaemia |
| Hcy (A) = Homocysteine level in the blood; p = 0.479 | |
| Table 6: | Cardiovascular risk factors and obstructive cardiovascular pathologies correlated with homocysteinemia |
| (A) = Body mass index | |
Coefficients of Correlation
Homocysteinemia was not correlated with sex (r<0.001) but was strongly
correlated negatively with BMI and the total cholesterol levels (Table
6). Homocysteinemia is positively correlated with age and HBP, whereas it
is negatively correlated with the other cardiovascular risk factors. It was
also positively correlated with ischemic heart disease.
DISCUSSION
The homocysteine levels in blood were determined for a population of African cardiovascular patients and the levels were analyzed with respect to age, sex, BMI, blood lipid levels, blood sugar level and the type of cardiovascular disease. This study was performed in a cardiology department due to financial constraints and the fact that all hospital patients in Togo are fully responsible for paying for their own laboratory tests, which is in contrast to the systems in some developed countries, such as Belgium, in which homocysteine tests are free for CVD patients younger than 55 years (Girs and Giet, 2006). Because all our subjects were patients, these limitations could have an impact on our results, leading to potential overestimations.
The prevalence of hyperhomocysteinemia was 45.6%, which is comparable to what has been seen in other African countries. The prevalence of hyperhomocysteinemia was reported to be 56% in the West African countries (Amouzou et al., 2004) and 41% in Algeria (Hambaba et al., 2008). This high prevalence among Africans might potentially be due to the consumption of foods that have low levels of vitamins B6, B9 and B12 as well as a high proportion of individuals with the C677T polymorphism in the methylene tetrahydrofolate reductase gene (Amouzou et al., 2004). Another potentially confounding factor could be that the reagents and protocols used to measure homocysteine levels are based upon Europeans populations. Thus, a review of the available biological tests, the local diet(s) and the geographical situation will be important areas to examine further.
The observed prevalence in this study is much higher than that found in most of the studies carried out in European countries. In France, the prevalence was 7.5% among a total of 2045 military subjects (Chellak et al., 2005). The low prevalence of hyperhomocysteinemia in developed countries might be a result of the more balanced diets that can be found in these populations.
The average homocysteine levels in our study was higher than the levels found in the other studies involving African countries, with 13.5 μmol L-1 (Amouzou et al., 2004) and 14.69 μmol L-1 (Hambaba et al., 2008). The typical gap of this study was higher than the average because of the fact that the superior value of our sample was very far away from others values. Our higher average might be a result of the sample population, who were all CVD patients.
Homocysteinemia was positively correlated with age. A greater proportion of older patients had hyperhomocysteinemia than did younger patients (59% vs. 38.8 and 37.5%). These results demonstrate that homocysteinemia increases with age, which can potentially be explained by metabolic failure at advanced ages.
Homocysteinemia was not correlated with sex in this study (r<0.001), which is in contrast to the data that can be found in the literature. One potential explanation could involve the size of our patient population.
The average homocysteinemia and the prevalence of hyperhomocysteinemia were higher in normal weight patients than in overweight ones. There was a negative correlation (r = -0.247) between homocysteinemia and BMI, indicating that homocysteine levels decreased as weight increased. A similar, although lower, negative correlation (r = -0.07) was observed in a population from Great Britain (Whincup et al., 1999). One potential explanation is that overweight individuals utilize a larger amount of methionine, which is metabolized into homocysteine, during protein synthesis, thus leading to less available methionine to be converted into homocysteine.
Homocysteinemia was positively correlated with diastolic (r = +0.148; p<0.0001) and systolic (r = +0.064; p<0.0001) arterial pressures. These results are similar to those seen in other studies, although they demonstrated a stronger correlation with the diastolic arterial pressure than with the systolic. In one study (Chellak et al., 2005), the correlation coefficients for the systolic and diastolic arterial pressure were +0.063 and +0.082, respectively, which indicated that hyperhomocysteinemia causes a greater increase in diastolic arterial pressure than in systolic arterial pressure.
Homocysteinemia was negatively correlated with the four parameters of lipid analysis (Total cholesterol: r = -0.239; p<0.0001, LDL cholesterol: r = -0.235; p<0.0001, HDL cholesterol: r = -0.174; p<0.0001, triglycerides: r = -0.031; p<0.0001). It was also negatively correlated with the glycaemia. This observation is consistent with other studies. One such study (Bostom, 1999) found negative correlations between homocysteinemia and HDL cholesterol (r = -0.114) and total cholesterol (r = -0.049). These observations indicate that, as dyslipidemia becomes more severe, the levels of homocysteine become even lower.
Homocysteinemia was more strongly correlated with the ischemic cardiopathies (r = +0.153; p<0.0001) than each of the following obstructive cardiovascular diseases: venous thrombo-embolic disease (r = +0.071; p<0.0001), obliterant chronic arteriopathy of the lower limbs (r = +0.018; p<0.0001) and ischemic cerebro-vascular stroke (r = +0.006; p<0.0001). Therefore, hyperhomocysteinemia appears to be more likely associate to ischemic heart disease than any of the obstructive cardiovascular diseases.
CONCLUSION
The prevalence of hyperhomocysteinemia was very high in cardiovascular patients in Togo. This hyperhomocysteinemia is correlated to HBP and to ischemic cardiopathies, which are becoming more prevalent in this part of the world. The management of this new risk factor, which is based primarily on its prevention, has been proven to be essential and should become a major focus of public health. The prevention of hyperhomocysteinemia should include education of the population, with the objective of changing cooking habits so that foods are not overcooked and changing diet to encourage the consumption of foods that are rich in vitamins B6, B9 and B12.