|Year : 2021 | Volume
| Issue : 4 | Page : 145-153
Relations of plasma homocysteine to left ventricular geometry and functions
Obiageli Uzoamaka Agbogu-Ike1, Bilkisu Bello Maiha2, Lilian Okwubenata Okonkwo3, Mohammed Aliyu4, Albert Imhoagene Oyati1
1 Department of Medicine, Ahmadu Bello University Teaching Hospital, Zaria, Nigeria
2 Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Ahmadu Bello University, Zaria, Nigeria
3 Department of Immunology, Ahmadu Bello University Teaching Hospital, Zaria, Nigeria
4 Ahmadu Bello University Medical Centre, Zaria, Nigeria
|Date of Submission||21-Feb-2020|
|Date of Decision||24-Apr-2020|
|Date of Acceptance||08-Jul-2020|
|Date of Web Publication||11-Feb-2022|
Dr. Obiageli Uzoamaka Agbogu-Ike
Department of Medicine, Ahmadu Bello University Teaching Hospital, Zaria
Source of Support: None, Conflict of Interest: None
Background: Hyperhomocysteinemia is a risk factor for heart failure commonly in females. The study aimed at determining Hcy's association with left ventricular (LV) remodeling. Materials and Methods: A cross-sectional study evaluating the relationship of plasma Hcy to echocardiographic LV structure and function in 65 apparently healthy Nigerians (Mean age 41.87 ± 12.90 years, 52.2% females) without cardiovascular disease. Results: The mean Hcy level was 10.76 ± 2.69 μmol/L with no significant (P = 0.89) sex difference and 50.8% of the subjects had Hcy levels within the fourth quartile (hcy: 10.3–17.5 μmol/L). Plasma Hcy showed no significant (P > 0.05) relationship to LV mass (LVM), wall thickness (WT), relative WT, systolic/tissue-Doppler-derived diastolic function, and left atrial dimension in both sexes. Hyperhomocysteinemia (hcy >10.3 μmol/L) was significantly (P < 0.007) correlated to LVM indexed to height2.7 in all subjects but showed no such association in the unadjusted and adjusted binary logistic regression models. The odd of hyperhomocysteinemic patients having thicker LVM trended more toward females (odds ratio: 1.44, 95% confidence interval, 0.59–3.50) than males. Conclusion: Plasma hyperhomocysteinemia found in healthy Nigerian-Africans shows no relationship to LV remodeling, echocardiographic LV structural and functional parameters.
Keywords: Hyperhomocysteinemia_left_ventricular_gepmetry, and_functions
|How to cite this article:|
Agbogu-Ike OU, Maiha BB, Okonkwo LO, Aliyu M, Oyati AI. Relations of plasma homocysteine to left ventricular geometry and functions. Sahel Med J 2021;24:145-53
|How to cite this URL:|
Agbogu-Ike OU, Maiha BB, Okonkwo LO, Aliyu M, Oyati AI. Relations of plasma homocysteine to left ventricular geometry and functions. Sahel Med J [serial online] 2021 [cited 2023 Mar 31];24:145-53. Available from: https://www.smjonline.org/text.asp?2021/24/4/145/337486
| Introduction|| |
Plasma homocysteine (Hcy) is a risk factor for cardiovascular disease which is a public health problem associated with increased mortality and morbidity. Several studies globally have shown that, independent of other cardiovascular risk factors, mildly elevated blood Hcy levels can predispose to endothelial injury and cardiovascular diseases.,,, About 15 years ago, plasma Hcy was shown to be a risk factor for the development of heart failure especially in female subjects devoid of myocardial infarction. Hyperhomocysteinemic rats were also shown to have increased matrix metalloproteinases and cardiac fibrosis which consequently led to the left ventricular (LV) remodeling, a known precursor of heart failure., Furthermore, while some workers have reported LV dilation and wall thinning as the initial acute response to hyperhomocysteinemia in animal models, others have documented concentric hypertrophy., Hcy-induced atrial remodeling has also been reported in experimental animals.
Likewise, plasma Hcy has been shown to be a cause of LV remodeling in renal failure human subjects, large population-based study as well as hypertensive human subjects., These remodeling can consequently lead to LV diastolic and systolic dysfunction.,, There are few data and conflicting findings on the relationship of hyperhomocysteinemia to LV cardiac function and structure from studies outside of Nigeria.,, While some studies showed a positive relationship,,,, another showed a negative relationship, yet some other showed no relationship of Hcy to LV function in patients with coronary artery disease. Previous study had documented gender-related differences in relationship of Hcy to LV mass (LVM) which may partly explain the higher risk of atherosclerotic events in women with hyperhomocysteinemia when compared with men,, as LVM is also a risk factor for heart attack, arrhythmias, and sudden cardiac death.
Furthermore, Africans are known to have a low incidence of coronary artery disease, and are therefore expected to have relatively low plasma Hcy levels. Therefore, findings on the contrary, would question the etiologic role of hyperhomocysteinemia in vascular pathological mechanisms and coronary artery disease.
Plasma hyperhomocysteinemia has also been found to be prevalent in normal healthy Nigerians.,,,, However, no prior study has determined the relations of plasma Hcy to echocardiographic measures of LV structure and function in apparently healthy hyperhomocysteinemic Nigerians. Such an investigation is important to examine the hypothesis that hyperhomocysteinemia may be a risk factor for cardiovascular disease like heart failure through promotion of LV remodeling in healthy hyperhomocysteinemic patients. This study was therefore, aimed at examining the sex-specific cross-sectional relations of plasma Hcy to echocardiographic indices of LV structure (wall thickness [WT] and mass) and function (systolic and tissue Doppler-derived diastolic function and left atrial size) in the Ahmadu Bello University (ABU) Hcy survey normal healthy participants who had echocardiography done.
| Methods|| |
Study design and setting
The study was a cross-sectional study carried out over a 6 months' period. The individuals were randomly selected from willing patient escorts from the ABU Medical Centre, Zaria as well as the ABU Teaching Hospital (ABUTH), Zaria, Nigeria, in response to a community-based invitation of hypertensive patients for free medical screening exercise. Other volunteers were from hospital employees and willing staff of both hospitals. The primary study was a randomized double blind placebo controlled study done on hypertensive patients over 8 weeks. Healthy controls were also randomly selected in that study. Another substudy which was a subsect of the ABU-Hcy survey involving 120 hypertensive and 120 healthy controls (unpublished), determined the Hcy and folate levels in a sample of 65 healthy volunteers. The present study therefore sought to determine the relations of echocardiographic LV structure and function with plasma Hcy levels among 65 healthy hyperhomocysteinemic patients who had echocardiography done within 24 h of presentation.
Ethical approval/informed consent
All procedures were carried out in accordance to the amended 2013 Declaration of Helsinki. Ethical clearance was obtained from the Health Research Ethical Committee (HREC), Ministry of Health and Human Services, Kaduna, Nigeria, with HREC Reference Number: MOH/ADM/744/VOL. 1/369 and date of approval, December 28, 2015. Written informed consent for participation as well as data sharing for research purposes was obtained from all participants in the study from January 2016 to June 2016.
This was determined by the Fisher's statistical formula for sample size for descriptive studies viz.: N = Z2 pq/d2: Where N = Minimum sample size; Z = Standard deviation score at 95% = 1.96; P = Prevalence of hyperhomocysteinemia in normal healthy Nigerians equivalent to 5%;, therefore, P = 0.05; while q = Complimentary probability (1 − p) = 1–0.05 = 0.95; d: Error margin = 5%. Substituting, N = (1.96) 2 × 0.05 × 0.95/(0.05) 2 = 0.18/0.003 = 60. Hence, a minimum sample size of 60 was calculated and rounded up to 65 to take care of 5%–10% attrition rate.
Participants were included if they were healthy adult >18 years old with no history of hypertension and blood pressure <140/90 mmHg; no clinical evidence of cardiorespiratory or neurological disease (stroke/transient ischemic attack) and who had echocardiography done within 24 h of presentation.
Participants were excluded if they had renal failure (serum creatinine >3 mg/dl or >264 μmol/L or glomerular filtration rate [GFR] <60 ml/min as determined by Cockcroft-Gault equation);,,, excessive caffeine use; chronic folic acid (FA), Vitamin B12 and Vitamin B6 supplementation; history of heart failure, stroke, transient ischemic attack, heart attack, sickle cell disease or pregnancy; current tobacco and excessive alcohol intake as documented previously.,,, Individuals using drugs known to affect Hcy metabolism viz-a-viz: methotrexate, anticonvulsants, nitrous oxide, sulfadoxine-pyrimethamine, penicillamine, and contraceptives were also excluded as documented previously.,,, Current smokers, chronic alcoholics, and diabetes (determined historically and by fasting blood glucose [FBG] >7 mmol/L) were also excluded.,,,, Participants with missing echocardiographic measurements (n = 0) and who had no echocardiography done within 24 h of sample collection were excluded (n = 55). Following these exclusions, out of a total of 120 healthy volunteers, 65 individuals were included and analyzed.
Clinical and laboratory methods
The individuals underwent a standardized medical history and data collection was by well-structured interviewer-administered questionnaire done by the author alongside 4 trained assisting medical doctors. The protocol has been described in detail previously with blood pressure and body mass index (BMI) (kg/m2) determined by standard protocol.,,, Blood samples for plasma Hcy were obtained from the antecubital vein of either arm without tourniquet application and following an overnight fast.,, The blood was separated into two 5 ml aliquots and placed into labeled potassium ethylenediaminetetraacetic acid containing plastic vacutainer tubes as well as plain specimen bottles. A drop (500 Kallikrein inactivator U/ml) of aprotinin (trasylol®) had been previously added to the test tubes and these were taken to the immunology laboratory of ABUTH, Zaria within 4 h of collection in ice cubes.,, Centrifugation occurred at 1800 revolutions per minute for 20 min and plasma was separated within 1–2 h. This was divided into aliquots in cryovials and stored at −70°C in the antiretroviral laboratory of ABUTH, Zaria until assay.,, Other tests such as serum electrolyte, urea, and creatinine as well as FBG, were also determined in the Chemical pathology laboratory of the same hospital via the Chemray 120 automated clinical chemistry auto-analyzer.,,
Measurement of plasma homocysteine and plasma folate
The Human direct Hcy enzyme-linked immunosorbent assay kit (ELISA-Elabscience Biotechnology Co., Ltd., WuHan, P.R.C. with Lot No: AK0016JULI5066 and Catalog No: E-EL-HO156), was used for in vitro quantitative determination of human Hcy in plasma according to the manufacturer's manual and based on the Elisa principle as described previously.,, The coefficient of variation for this assay was <10%. The concentration of Hcy in the samples was determined by comparing the optical density (O.D) of samples to the standard curve. The upper limit for plasma Hcy was 10.3 μmol/L. The FA ELISA kit-Elabscience Biotechnology Co. Ltd., WuHan, P.R.C. with Lot No: AK0016JULI5067 and Catalog No: E-EL-0009 was used for the in vitro quantitative determination of plasma folate levels in accordance with the manufacturer's manual.,,
Participants underwent routine transthoracic echocardiography imaging using the SONOSCAPE SSI-18 two-dimensional (2-D)/three-dimensional Doppler and color flow machine with tissue Doppler facility and a 3.5 megahertz (MHz) convex probe. This was done by an experienced cardiologist (AO) at the echocardiography laboratory of ABUTH, Zaria with the subjects positioned in the left lateral decubitus position. 2-D-guided M-mode measurements of LV functions were determined at end diastole based on the American Society of Echocardiography (ASE) recommendation., Interventricular septal wall thickness (IVS), posterior LV wall thickness (PW), and LV end-diastolic diameter (LVEDD) were measured at end-diastole. From the systolic end portion of the M-mode image, the IVS diameter in systole, the LV end-systolic diameter (LVESD), and the LV posterior wall diameter in systole were determined.
Echocardiographic outcome definitions
LVWT was calculated as IVS + PW (cm) and LV relative WT (RWT) was calculated as (IVS + PW)/LVEDD (%)., Increased RWT occurred when RWT ≥0.45 with normal RWT (male and female) being ≤0.42. LVM was calculated using the Devereux and Reichek modified ASE “cube” formula, namely,, LVM (g) = 0.8 (1.04 [IVS + LVEDD + PW] 3 – [LVEDD] 3) + 0.6. LVM was indexed to the allometric power of height/growth rate of 2.7,, with normal values of 43–95 g/m2 in females and 49–115 g/m2 in males., LV hypertrophy (LVH) was determined if LVM index was ≥46 g/m2.7 in the healthy controls.,
The end systolic volume, stroke volume, ejection fraction (EF), and fractional shortening (FS) were calculated automatically by the machine using the Teicholz calculation formula. LV EF was also confirmed by visual estimation on multiple views by an experienced echocardiographer (normal LV systolic function was documented for EF ≥50% and LV systolic dysfunction for EF ≤50%)., LV FS was also calculated as (LVEDD-LVESD)/LVEDD. The left atrial diameter was also determined by placing the cursor at the tip of aortic valve on M-mode. The measurements were taken thrice and the average of the three measurements was used.
The pulse-wave tissue Doppler imaging (TDI) was performed in the apical four chamber view to acquire mitral annular velocities by pressing on the TDI and pulse wave (PW) buttons on the echocardiography machine. The sample volume was positioned at or 1 cm within the septal insertion sites of the mitral leaflets and adjusted within 5–10 mm, to cover the longitudinal excursion of the mitral annulus in both systole and diastole.,, Primary measurements included the systolic (S), early diastolic (e'), and late diastolic velocities (á). The septal mitral annulus early diastolic é velocity was used. The mitral inflow E velocity to tissue Doppler e ; (E/e') ratio was calculated manually to determine the LV filling pressure., Using the septal E/e' ratio, a ratio <8 is regarded as normal LV filling pressures whereas a ratio >15 is associated with increased diastolic filling pressures.,
Data were validated and analyzed by SPSS version 22-software (SPSS Inc., Chicago, IL, USA). The distributional properties of the study variables for the total sample and separately for men and women were examined. Plasma Hcy had a normal distribution as well as other variables. Categorical variables were presented as numbers and percentages with difference determined through Chi-square (χ2). Numerical variables were presented as mean ± standard deviation (SD). Independent Student's t-test was used to compare age, weight, height, blood pressures, BMI, GFR, packed cell volume (PCV), Hcy, and echocardiographic structure and function parameters between males and females. Pearson's Correlation was used to determine the relationship between Hcy and echocardiographic LV structure and function in males and females. Further relationships were assessed through Binary logistic Regression Analysis in the unadjusted and adjusted models. Relative Risk Assessment with Pearson's Correlation were estimated for LVM in relation to plasma Hcy which was grouped as normal if <10.3 μmol/L and hyperhomocysteinemic if >10.3 μmol/L. The level of statistical significance was assumed to be P ≤ 0.05 at 95% confidence interval (CI).
| Results|| |
Clinical and laboratory characteristics of the study participants
The mean age of the study population was 41.87 ± 12.90 years [Table 1] with no significant (P = 0.93) difference between males and females. The mean ± SD plasma Hcy was 10.76 ± 2.69 μmol/L with no significant (P = 0.89) difference between males and females. There were 50.8% of the individuals who fell within the 4th quartile of homocysteinemia [Table 1]. There was no significant (P > 0.05) difference in weight, BMI, systolic and diastolic blood pressures, FBG, GFR, and plasma folate levels between the two groups except for the difference in height and PCV (P = 0.001, respectively) with higher male values [Table 1].
The mean LVM was 159.85 ± 40.15 g with no significant (P = 0.34) difference between males and females while the LVM indexed to height2.7 was 43.18 ± 12.14 g/m2 with no significant difference between males and females (P = 0.38). There was no statistically significant (P > 0.05) difference in LV structural, functional, and tissue Doppler-derived LV diastolic filling pressure (E/e') parameters between both sexes [Table 1]. The LV internal diameter in diastole, however, was significantly (P = 0.01) higher in males than females.
|Table 1: Clinical and laboratory characteristics of the study participants|
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Relationship of plasma homocysteine levels and echocardiographic left ventricular structure and function
Plasma hyperhomocysteinemia (>10.3 μmol/L) showed no significant (P > 0.05) correlation to LVM, WT, and RWT in all individuals as well as males and females, respectively, through the Pearson's Correlation analysis [Table 2]. However, the LVM indexed to height2.7 showed significant (P = 0.007) positive correlation with hyperhomocysteinemia (>10.3 μmol/L) in all individuals with no significant (P > 0.05) gender-specific relationship. Plasma Hcy showed no significant (P > 0.05) correlation to LV FS and EF in both sexes [Table 2]. Likewise, the ratio of peak early diastolic filling of the ventricle to the atrial contraction in late diastole (E/A ratio) showed no significant (P > 0.05) correlation to hyperhomocysteinemia in both sexes. There was also no significant relationship of hyperhomocysteinemia to tissue Doppler-derived diastolic function and left atrial dimension in both subjects [Table 2].
|Table 2: Relationship between hyperhomocysteinemia (hcy>10.3 μmol/L) and echocardiographic left ventricular structure and function|
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Relationship of hyperhomocysteinemia to left ventricular mass indexed to height to Power 2.7 (LVMIHt2.7)
Further binary logistic regression analysis showed no relationship between LVMIHt2.7 in both unadjusted (odds ratio [OR], 0.42, 95% CI: 0.15–1.16; P = 0.095) and age, sex, BMI, weight, and height adjusted models (OR, 0.58, 95% CI: 0.30–1.12; P = 0.09) (Data not shown).
Relation of left ventricular mass with plasma homocysteine levels
The odd of hyperhomocysteinemic patients having thicker LVM was higher in females (OR: 1.44, 95% CI, 0.59–3.51) than males (OR: 0.94, 95% CI, 0.33–2.64) though not statistically (P = 0.55) significant [Table 3].
|Table 3: Relation of the left ventricular mass with plasma homocysteine levels|
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| Discussion|| |
This is the first Nigerian study comparing the echocardiographic LV structural and functional parameters with plasma Hcy levels in healthy hyperhomocysteinemic Nigerians with a view to determine whether high Hcy levels found in normal healthy Nigerian-Africans puts one at risk for cardiovascular diseases such as heart failure. Findings showed slightly high mean plasma Hcy levels in the normal healthy Nigerians with no gender-specific variation. This contrasts gender specific difference in Hcy levels as reported from the United States and other European countries in which mean Hcy levels was higher in males compared to females., The reason for this disparity might be the younger age group studied and the smaller sample size in this study.
There was higher mean LVM in males when compared to females which did not differ significantly (P = 0.35) but was much higher than the upper limit of normal values. However, when indexed to height,2.7 the values were well within the normal expected range as LVM indexed for height2.7 has been shown to be a more reliable index for detecting obesity-related LVH ., The finding of thick LVM in healthy controls is similar to studies which suggested that RWT, LVM and LVH are higher in the blacks compared to white subjects.,, Studies have shown that increased LVM is associated with increased risk of adverse cardiovascular events both in hospital and population based studies.,,, Therefore, the high mean LVM in the apparently normal healthy controls may be a pointer to subclinical cardiovascular disease, however, this showed no relationship to hyperhomocysteinemia, hence may not suffice. The correlation of hyperhomocysteinemia with LVM indexed to height2.7 in all individuals was only mild, with no gender-specific significant relationship and when adjusted for age, sex, BMI, weight, and height, the relationship was no longer significant; hence, other factors may explain the initial positive correlation. Some study has shown that BMI and increased abdominal obesity seems to account for most of LVM increase in normotensive individuals and consequent obesity-related LVH .
Both in experimental models and humans, hyperhomocysteinemia has been demonstrated to predispose to LVH and cardiac fibrosis while some other study showed Hcy-induced LV dilatation and wall thinning in experimental models., Hyperhomocysteinemia through vascular and nonvascular mechanisms may lead to LVH and this it does through its growth-promoting and collagen-production stimulating effects.,,,, A recent study carried out in vitro, on normotensive rats made hyperhomocysteinemic for 6 weeks via high methionine diet, with aim to induce a novel model of heart failure, showed echocardiographic left and right ventricular hypertrophy of cardiomyocytes, disarrayed myofibrils, inflammatory infiltrates, increased apoptosis, and associated activated nuclear factor-kappa B (NF-kB). NF-kB activation has proved to be pivotal in the initiation and development of atherosclerosis, ischemic heart disease, and heart failure.
Furthermore, this study showed that the odd of hyperhomocysteinemic patients having thicker LVM was higher in females than males though not statistically significant. Gender-related differences in the relationship between Hcy and cardiac remodeling and subsequent heart failure was reported in a study by Vasan et al. That study concluded that the gender difference observed in the relationship of plasma Hcy to LVH, may contribute to increased predisposition of women to developing heart failure with preserved EF Another study has shown higher risk for cardiovascular disease associated with hyperhomocysteinemia in women compared with men. The reason for the disparity between this study and previous studies may be attributed to heterogeneous nature of their study population and larger sample size in contrast to this study which is specific to apparently healthy contorls.
Furthermore, plasma Hcy levels (>10.3 μmol/L) showed no significant relationship to LVM, WT and RWT in apparently healthy men and women despite higher than normal mean values. It also showed no relationship to LV systolic function in both sexes. There was also no significant (P > 0.05) relationship of Hcy to tissue Doppler-derived diastolic function as well as left atrial dimension in males and females. On the contrary, the Framingham Offspring population-based study done on individuals without heart failure or myocardial infarction, determined the cross-sectional relations of plasma Hcy to echocardiographic LV structure and function and found homocysteine levels to be significantly positively related to LVM, WT, and RWT in women but not in men., The disparity between these two studies may be accounted for by the target population in the present study involving apparently normal controls devoid of hypertension, diabetes, or other cardiovascular risks such as smoking and alcohol intake as against the previous. Furthermore, the lack of the association of Hcy with LV structure in this study may be attributed to the younger mean age group of this study as against the fifth decade of the Framingham study., Some study has shown that postmenopausal women with lower estrogen levels may be more prone to adverse effects of Hcy on LV remodeling.
The high mean homocysteine levels in normal healthy Nigerians resident in Northern-Nigeria as well as its high prevalence of 51% (hcy >10.3 μmol/L) which has been reported previously on similar cohorts, showed it had no relationship with blood pressure in both unadjusted and adjusted models hence may not be attributable to underlying subclinical cardiovascular risk. On a further note, the echocardiographic findings of this study have confirmed that this high Hcy level and its high prevalence may not be associated with the structural changes in the heart and cardiovascular system of Nigerian-Africans.
Therefore, the slightly high normal mean hcy value may be attributed to geographic, ethnic, and racial peculiarities of blacks. It was expected also that there will be a rise in incidence of myocardial infarction in Sub-Saharan Africa on account of Westernization and epidemiologic transition, however, there is a lower incidence of coronary artery disease reported in black Africans.,,,, This may be accounted for by the unique efficiency of methionine and Hcy metabolism in blacks despite slightly high mean Hcy levels.,
Furthermore, it has been shown in the white population, that vitamin deficiencies such as folate, Vitamin B6, B12 as well as enzyme mutation in methylene tetrahydrofolate reductase enzyme may account for mild to moderate hyperhomocysteinemia., However, the contrary was the case in this study as plasma folate levels were well above normal expected range and showed no significant (P > 0.05) sex differences. Hence, suboptimal folate levels cannot account for the mildly high Hcy levels seen in this study.
A limitation of this study was the lack of assessment of other B-vitamins, but it has been reported in a recent study that vitamin B12 deficiency is rare in healthy Northern-Nigerians with folate being the major dietary determinant of Hcy metabolism.,, Further limitation, was the lack of genetic assessment for genetic mutation in enzymes involved in Hcy metabolism which may explain the reason for hyperhomocysteinemia in certain individuals despite normal vitamin status.,,, On a final note, the renal state of the subjects were within normal limits hence renal dysfunction cannot account for the high mean Hcy levels as studies have documented that hyperhomocysteinemia is associated with renal dysfunction.,,, The small sample size was also a limitation, however, studies with such or smaller small sample sizes have made valid conclusions.,,
| Conclusion|| |
In apparently healthy hyperhomocysteinemic Nigerians, plasma Hcy showed no direct relationship to LVM, WT, systolic, and tissue Doppler derived diastolic function in both sexes. LVM indexed to height2.7 showed mild positive correlation to hyperhomocysteinemia in all patients but when adjusted for covariates, was no longer associated; hence, hyperhomocysteinemia found in healthy Nigerian-Africans shows no relationship to LV remodeling, echocardiographic LV structural and functional parameters.
Further population-based studies in Nigerian-Africans are warranted to confirm these findings. Emphasis should be geared toward health education and lifestyle modifications so as to prevent or delay onset of overt cardiovascular disease in normal healthy Nigerians.
Many thanks to Emzor Pharmaceuticals Industries Ltd., and MicroNova Pharmaceuticals Nigerian Ltd., for unalloyed support. Special thanks to all willing volunteers that participated in the study.
Financial support and sponsorship
This study was supported by Micro Nova Pharmaceuticals Limited, Nigeria and Emzor Pharmaceutical Industries, Lagos, Nigeria. No specific grant for this study.
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]