Introduction and background
Hypertension is the main risk factor for cardiovascular disease (CVD) and all-cause mortality over the world [1]. Hypertension is the major cause of atherosclerosis and it has damaging effects on endothelial cells [2]. A systematic review has shown that the effect of antihypertensive drugs on reducing coronary artery disease (CAD) was about 8-14%, which is still below 20-25% for the risk of prediction of CAD attributed to blood pressure. Thus, the lowering of elevated blood pressure alone is inadequate to eliminate the wholly CAD risk in hypertensive patients [3]. These findings advocate that the link between hypertension and CAD is complex and may include other factors together with the rise in blood pressure, such as abnormal body mass index, lipid disturbance, glucose intolerance, and hyperinsulinemia, which are usually interrelated, and explore independent predictors of both CAD and hypertension. Dyslipidaemia can be assessed by traditional lipid markers; however, they have insufficient preciseness [4]. On the other hand, protein-transporting molecules like apolipoprotein B (apo B) are present in all types of atherogenic lipoproteins including low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), and intermediate-density lipoproteins (IDL), and their determination enables a more accurate estimation of atherogenicity than the traditional lipid biomarkers [5]. The risk of CAD has been proven to be predicted by apo B among normotensives, but it has not been studied widely in hypertensive patients. Previous studies indicate that ap B may be linked, via a variety of pathways, to the development of CAD in hypertensive patients. These pathways include the infiltration and retention of lipoproteins containing apo B in the arterial wall, the stimulation of endothelial dysfunction, and an increase in the severity of coronary artery stenosis [6]. The aim of this study is to explore the association between apo B and CAD among patients with hypertension. We present this article in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting checklist.
Review
Methods
A survey was done on PROSPERO to ensure the originality of the study.
Search of Literature
Search strategies on the databases PubMed, Web of Science, and Scopus were performed on September 24, 2022. The study protocol was prospectively registered at the International Prospective Register of Systematic Reviews (PROSPERO) at https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022369662. The inclusion criteria of the current study were observational case-control and cohort studies in which the primary outcome of interest has been reported, studies involving adult humans, and hypertensive and normotensive participants. The screening was restricted to publications in the English language and those published after the year 2000. Exclusion criteria were reviews, interventional, overlapping, and animal studies; grey literature; studies involving participants < 18 years old; and articles without full text. The literature search doesn’t include restrictions for gender, ethnicity, or socioeconomic status. The study was conducted in accordance with the PRISMA Statements 2020 for reporting the systematic review [7], and the PRISMA checklist is attached in the supplementary material 1. Key terms used were ((Apolipoproteins B) OR (Apolipoprotein-b)) AND (Hypertension) for PubMed search, TITLE-ABS-KEY (apolipoprotein AND b) AND (hyperten*) AND (LIMIT-TO (PUBSTAGE, "final")) AND (LIMIT-TO (DOCTYPE, "ar")) AND (LIMIT-TO (LANGUAGE, "English")) AND (LIMIT-TO (SRCTYPE, "j")) for Scopus search, and (Apolipoprotein b) and hyperten* refined by article documents and English language only for Web of Science search, search protocol explained in details in search strategy supplementary material 2. To remove duplicate papers, the resulting articles from each database were exported to the EndNote program in a separate group. After that, the duplicated articles were removed from all references section in the EndNote. Later, the articles were exported to an Excel sheet, which contained a number for each manuscript, name of the authors, year of publication, journal name, DOI, link, abstract, researcher 1 (Israa Nathir), inclusion/exclusion (which was filled as 0 or 1), reason (only for the excluded papers), then the researcher should mention the reason, researcher 2 (Fatimatuzzahra Abd Aziz), inclusion/exclusion, reason, researcher 3 (Raid D. Hashim), inclusion/exclusion, reason. Afterward, the articles were sorted alphabetically by title, and the duplicated papers were removed. The reasons for excluding the papers are mentioned in Figure 1. In the selected studies, hypertensive patients were identified by having an average of three or more readings of blood pressure, where systolic blood pressure is ≥140 mm Hg and diastolic blood pressure is ≥ 90 mm Hg for newly diagnosed patients or patients on antihypertensive drugs. Normotensive participants were identified as having an average systolic blood pressure of <140 mm Hg and a diastolic blood pressure of <90 mm Hg by three or more readings. The outcomes of CAD were identified as obstructive, non-obstructive coronary artery diseases, and spontaneous coronary artery dissection.
Figure 1
PRISMA flow diagram of the included studies in the systematic review
PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses
Selection Process
Title and abstract screening were performed by three independent researchers based on predefined criteria; discrepancies were solved by discussion between the researchers, and if the discussion didn’t solve the discrepancy, then a consult from an expert reviewer was considered (Abbas Abdulmueed Mustafa). Subsequently, full-text screening for eligibility was conducted, as all previously included papers were downloaded and those that had no available full text on the search database were excluded at once. The three independent researchers extracted data from eligible text using a standardized pilot form. Discrepancies were removed by mutual agreement or by the fourth reviewer. One study [8] was excluded during the data extraction process due to including the same baseline data of participants by the same author which was used previously in a different study included in the current systematic review [9].
Data Extraction
After full-text screening, data extraction was started for the selected studies which included the author name, year of publication, total sample size, number of participants with and without hypertension, country, study design, fasting state, period of follow-up, (age, number of males, females, smoking status, BMI, apo B, apo A, TC, TG, LDL-C, HDL-C, VLDL-C, and non HDL-C, number of participants developing diabetes mellitus, and CAD were reported for hypertensives and normotensives). The standard mean difference was executed for apo B, apo A, LDL-C, TC, TG, and HDL-C to unify the units of these variables as explained in supplementary materials 3 and 4. Data for all variables were reported from the included studies in terms of mean and standard deviation as there was no missing non-reported data.
Quality Assessment
The finally included papers were assessed for quality. The modified Newcastle-Ottawa Scale (NOS) was used for the quality assessment of observational (prospective and retrospective) studies included in the current systematic review. This quality assessment scale had three categories (parts); the selection part with 4 as a maximum score, the comparability part with 2 as a maximum score, and the exposure part with 3 as a maximum score [10]. Supplementary material 5 explains the criteria and the score of the modified NOS. The total score was calculated to consider those studies with scores of 7-9 as high quality and included in the current systematic review as explained in supplementary material 5. Studies scoring ≤ 6 were considered low-quality studies and were excluded. The robustness of the synthesized results is explained in supplementary material 6.
Results
Study Characteristics
Literature search and screening were performed according to PRISMA guidelines Figure 1. A total of 3644 publications were identified from the search database (PubMed, Scopus, and Web of Science) as explained in Figure 1. Eight hundred ninety-five duplicated papers were removed by EndNote, and then 912 duplicated papers were uninvolved by Excel. Subsequently, 1837 studies were further screened according to the title and abstract. From those, only 247 studies remained for the full-text screening, the reasons for excluding those papers were mentioned in Figure 1. The full-text screening was operated to give only nine eligible studies. After applying the modified NOS for quality assessment for the nine observational studies, three studies were excluded due to having a score of ≤ 6 as reported in supplementary material 5.
Patient Characteristics
Five studies were included in the review which contained a total of 5222 participants, 2335 were hypertensive, and 733 of them developed CAD during the study period [9,11-13]. Two studies were conducted in China, one study was accomplished in Italy, and Turkey, and multicenter in the USA. Age and gender were reported in all of the included studies, smoking status was mentioned in two studies, BMI was reported in four manuscripts, and apo B, apo A, LDL-C, TC, TG, and HDL-C were measured in the five included studies as shown in supplementary material 7.
Socio-Demographic Data
Females were the most predominant participants in one study [14]. There was no significant difference in the number of male and female participants in the remaining studies. There was a significant difference in the mean age among hypertensives compared to normotensives in four of the five selected studies where hypertensive patients have shown higher mean age except in [9]. With respect to smoking status, normotensives have shown a significantly higher prevalence compared to hypertensives in only two of the selected studies. Body mass index was significantly lower in normotensive subjects in the five selected studies. Surprisingly only in one of the selected studies, there was a significant difference in mean serum apo B [10] where it was significantly higher in hypertensive patients. Apo A was significantly higher among normotensive subjects only in one study [9]. Total cholesterol was significantly higher in hypertensive subjects [10]. In addition, hypertensive females had higher TC in comparison to normotensive females [12,13]. On the other hand, the level of TC was comparable between the groups in the remaining studies. In 4 of the 5 studies, TG was significantly higher among hypertensive participants except in [13] as well and TG was significantly higher among hypertensive females compared to normotensive females [13]. Among hypertensive females, LDL-C was significantly higher compared to normotensive females [12,13] as the results of these two studies were stratified according to sex, and it was significantly higher in hypertensive patients compared to normotensive participants [11]. There was no significant difference among groups in terms of HDL-C, only [9] showed higher HDL-C among normotensive subjects when compared to those with hypertension. In addition, one study has shown a significantly higher HDL-C in normotensive compared to hypertensive females [12]. Only one of the selected studies mentioned that the prevalence of diabetes was significantly higher among hypertensive patients [13]. Development of CAD among participants was significantly higher among the hypertensive group [12,13]. Fadl revealed no significant difference between the two groups [14]. Another study [11] did not record any CAD during the study among the normotensive group. Sechi 2001 concluded that only 60 (15.4%) of 389 hypertensive subjects had developed CAD in the study period [9]. The characteristics of each study are explained in Table 1.
Table 1
Characteristics of each study
Variables measured as mean ± standard deviation or as percentages, H: hypertensives, N: normotensives, apo B: apolipoprotein, apo A: apolipoprotein A, BMI: body mass index, LDL-C: low-density cholesterol, TC: total cholesterol, TG: triglyceride, HDL-C: high-density cholesterol, DM: diabetes mellitus, CAD: coronary artery disease.
| Name of the first author | Wang H [11] | Sechi LA [9] | Onat A [12] | Yang SH [13] | Fadl YY [14] | ||
| Year of publication | 2017 | 2001 | 2008 | 2016 | 2015 | ||
| Fasting status | Yes | yes | yes | yes | yes | ||
| Sample size | 349 | 712 | 3034 | 805 | 1045 | ||
| Patients with (H) | SDH 92 | IDH 45 | ISH 80 | 389 | 787 | 481 | 461 |
| normotensives | 132 | 323 | 1526 | 324 | 582 | ||
| Country | China | Italy | Turkey | China | Multicenter USA | ||
| Study design | Cross-sectional | Cross-sectional | prospective survey | Cross-sectional | prospective | ||
| Period of follow up | No | No | 6.6 year | No | 2 years | ||
| Age (year) of (H) | 47.54±12.29 | 43.51±10.44 | 56±(36.5-72) | 54±12 | 53.5±12.1 | 56.02±9.58 m 61.3±9.89 f | 61.7±2 |
| Age (year) of (N) | 37.5(28-46) | 52±14 | 42.6±10.4 | 53.44±11.08 m 55.08±9.99 f | 56.8±2 | ||
| Number of males (H) | 56(60.86%) | 20(44.4%) | 48(60%) | 206 | 683 | 314 | 69 |
| Number of males (N) | 73(55.3) % | 165 | 425 | 206 | 81 | ||
| Smoking (H) | 202(65.6%) | 21 | |||||
| Smoking (N) | 127(67.7%) | 26 | |||||
| BMI (H) | 27.74± 3.74 | 27.06±3.59 | 25.6(23.87-28.75) | 25.6(23.87-28.75) | 26.65±3.33m 25.59±3.56f | 28.6±0.9 | |
| BMI (N) | 25.6(23.87-28.75) | 28.9 | 24.97±3.44m 24.21±3.08f | 27.6±0.6 | |||
| Apo B (H) | 1.03(0.87-1.21) | 0.99(0.77-1.09) | 0.98(0.8-1.14) | 1.23±0.32 | 110.9m 111f | 1±0.27m 1.07±0.26f | 1.22±0.29 |
| Apo B (N) | 0.87(0.72-1) | 1.22±0.32 | 105.5m 101f | 1.03±0.31m 1.07±0.33f | 1.23±0.28 | ||
| Apo A (H) | 1.37(1.27-1.51) | 1.34(1.2-1.45) | 1.31(1.2-1.45) | 1.49±0.29 | 134.4m 147.3f | 1.31±0.26m 144±0.31f | 1.18±0.25 |
| Apo A (N) | 1.13(1.17-1.48) | 1.55±0.38 | 130.4m143.5 143.5f | 1.3±0.26m 1.46±0.28 | 1.18±0.25 | ||
| LDL-C (H) | 3.11(2.75-3.54) | 2.74(2.35-3.34) | 3(2.62-3.58) | 3.52±0.96 | 115.5M 122.3 F | 3.18±0.93M 3.4±0.91F | 3.13±0.98 |
| LDL-C (N) | 2.53(2.05-3.19) | 3.38±0.91 | 115.3M 115.6 F | 3.28±1.04M 3.66±1.26F | 3.08±0.98 | ||
| TC (H) | 5(4.52-5.75) | 4.8(4.25-5.3) | 5(4.4-5.48) | 5.38±1.11 | 191.8 M 202.5 F | 4.79±1.03M 5.04±0.94 F | 5.1±1.17 |
| TC (N) | 4.6(4-5.57) | 5.33±0.98 | 187.5 M 188.9 F | 4.83±1.11M 5.3±1.28 F | 5.13±1.11 | ||
| TG (H) | 1.89(1.37-2.89) | 1.8(1.15-3.39) | 1.7(1.03-2.3) | 1.46±0.98 | 177 M 157.5 F | 1.67(1.23,2.38) M 1.69(1.26,2.44)F | 2.16±1.27 |
| TG (N) | 1.2(0.96-1.86) | 1.29±0.58 | 147.3 M 128.7 F | 1.63(1.12,2.31) M 1.59(1.07,2.2)F | 2.36±1.37 | ||
| HDL-C (H) | 1.05(0.97-1.24) | 1(0.92-1.2) | 1.02(0.96-1.22) | 1.32±0.39 | 39.5M 46.2 F | 1.03±0.29M 1.16±0.34F | 1.04±0.31 |
| HDL-C (N) | 1.06(1-1.27) | 1.4±0.4 | 39.4 M 47.1F | 1.03±0.29M 1.23±0.41F | 1.01±0.28 | ||
| DM (H) | 13(14.13%) | 6.(13.33%) | 10(12.5%) | 27 | |||
| DM (N) | 13 | ||||||
| H with CAD | 22(23.9%1) | 8(17.78%) | 16(20%) | 60 | 192(18.1%) | 244(78%)M 102(63%)F | 89(19.3%) |
| N with (N)o CAD | 46(4.7%) | 137(66.8%)M 43(36.4%)F | 113(19.4%) | ||||
Discussion
Over the decades, factors that contributed to the development of CAD have been thoroughly studied. Hypertension and dyslipidemia were among the factors that have the highest predictive role in the development of CAD. The pathophysiological role of apo B in the development of CAD has received much more attention during the last years in an attempt to explain the higher incidence of CAD in certain populations with normal lipid profiles. Most studies have investigated this role distinctly from concurrent hypertension. Only a minority of studies have taken into consideration the plasma concentration of apo B when studying the correlation between hypertension and the development of CAD. One [12] of the 5 studies has shown significantly higher apo B concentration in hypertensive patients compared to the normotensive. In addition, it might be surprising that only 2 of the reviewed studies [12,13] have shown a significant increase in the development of CAD in hypertensive patients compared to normotensive. Of these two studies, apo B was significantly higher in hypertensive patients compared to the normotensive in only 1 study [12]. Interestingly, 2 of the reviewed studies [11] have shown a comparable percentage of occurrence of CAD in both hypertensive and normotensives concurrently with statistically insignificant differences in mean serum apo B between the two groups. These results highlight the independent impact of apo B on the development of CAD. Furthermore, even when comparing within the same hypertensive group, one of the five studies has revealed a significantly higher rate of occurrence of CVD in the subgroup with higher mean apo B concentration [9].
Three of the included studies were cross-sectional [9,11,13], and only 2 were prospective studies [12]. Three of the screened studies [15-17] were excluded due to lacking a control group of participants without hypertension although they were compatible with the required criteria. One study [8] did not account for the number of CAD in the control group and this might make the comparison difficult and might be considered a source of heterogeneity, this might be a limitation to the evidence included in the review. A further limitation that we have observed in certain studies was in the diagnosis of hypertensive subjects, which depends on three readings within 1 day and this might lead to an overestimation in the prevalence of hypertension among the selected participants. Another limitation is the use of antihypertensive therapy among certain patients included in the selected studies. The use of antihypertensive therapy had a greater impact on the outcome of CAD, consequently, this might affect our conclusion.
Although the current literature-based systematic review has provided the most comprehensive assessment of apo B and the risk of CAD among hypertensive patients, however, there was a limited number of published research that are directly studying the correlation between apo B and CAD among hypertensive patients. The exclusion of grey literature such as thesis, government publications, unpublished research, seminar journals, and conference papers which might have studies with null or negative results compared to the hypothesis of the current study might be one of the limitations for the evidence supported by this systematic review and a source of publication bias. The predictive value of apo B for CAD has already been proved [18-21] and the use of apo B as a predictor for the development of CAD should be encouraged especially for hypertensive patients due to their high risk of developing CAD. Furthermore, laboratory test for apo B is broadly available, automated, and standardized, and they can be conducted on both fresh and frozen blood specimens as well as it does not require fasting status like in other lipid profiles [22]. Two studies [10,13] revealed associations between apo B and the development of CVD in the normotensive group only and this comes in line with previous studies confirming apo B as a predictor of CVD. More research is required to confirm this relationship specifically among hypertensive populations taking into consideration the limitations mentioned earlier.
Conclusions
The risk of developing CAD is significantly increased in patients with hypertension compared to normotensive patients. The risk of developing CAD is significantly increased in patients with a higher plasma apo B concentration. The risk of developing CAD is minimized in patients with hypertension compared to normotensives when plasma apo B concentration is comparable between the two groups. The risk of the development of CAD is aggravated in hypertensive patients with higher plasma concentrations of apoB.
This systematic review highlights the independent power of apo B on the development of CVD among both hypertensive and normotensive subjects.
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