When the diagnostic performance of AT1-AA for pre-eclampsia or non-gravid hypertension subgroups was calculated independently, pooled sensitivity increased to 0.76 (95% CI 0.70–0.80) for pre-eclampsia subgroup and decreased to 0.26 (0.22–0.30) for non-gravid hypertension subgroup. Pooled specificity slightly changed: 0.86 (95% CI 0.80–0.90) for pre-eclampsia subgroup and 0.92 (95% CI 0.86–0.96) for non-gravid hypertension subgroup (Figure 6). The AUC was 0.92 (SE 0.02) in pre-eclampsia subgroup and 0.72 (SE 0.04) in non-gravid hypertension subgroup (Figure 7B and C).
The present data indicated that AT1-AA is significantly associated with hypertension, especially with pre-eclampsia. A bivariate random-effects analysis strongly suggested that AT1-AA is an indicator for poorer prognosis of patients with pre-eclampsia (summary AUC of 0.92 and a pooled estimate of 0.76 for sensitivity and 0.86 for specificity). Uncontrolled high blood pressure presents a health burden worldwide. Subjects with a history of hypertensive disorders are at increased risk of cardiovascular disease in later life.22 Usually, hypertensive patients have to rely on medicaments in their lifetime for blood pressure management. Pre-eclampsia, a pregnancy-specific hypertension that often occurs after 20 weeks of gestation,23 seems to be even more intractable due to limited drug options. Therefore, the initial cause of hypertension is an urgent need to be found. Numerous factors were reported to have association with blood pressure regulation, including wide-type of calcium/calmodulin-dependent kinase IV (CaMK4),24 platelet antigen 2 (PIA2) polymorphism,25,26 and G-protein-coupled receptor kinase 2 (GRK2) overexpression.27 These factors were considered to cause vascular impairment through regulating endothelial and vascular smooth muscle function. AT1-AA was detected in the serum of patients with hypertension or pre-eclampsia, and contributed to blood vessel injury. The definite mechanisms of AT1-AA-induced hypertension were hitherto not clear; only several possible pathways have been reported, including vasoconstrictor effect in a sustained manner,18 stimulation of vascular smooth muscle cell proliferation and up-regulation of c-fos and c-jun expression,28 causing endothelial dysfunction,8 increasing intracellular calcium,29 stimulating reactive oxygen species (ROS),30 and tissue factor expression.31 The effect of AT1-AA on aldosterone production also has been reported, but the conclusions are inconsistent. AT1-AA was present in subjects with primary aldosteronism and stimulated aldosterone production,32 but in patients with pre-eclampsia, it revealed to decrease aldosterone production.33 We have observed both increased and decreased effects of AT1-AA on aldosterone production in our previous study, and reported this effect in a time and dose-dependent manner.16 Recently, β-arrestin-1 was reported as a regulator of aldosterone synthesis via G-protein-independent signaling after AT1R or β-adrenergic receptor activation.34,35 Whether β-arrestin-1 contributes to AT1-AA-mediated aldosterone production through AT1R activation needs to be further studied. As AT1-AA can regulate vasoconstriction and aldosterone production, it is tempting to speculate that high level of AT1-AA could play a pathological role in hypertension. To our knowledge, no association study has been done between AT1-AA and hypertension by meta-analysis. The present analysis was designed to assess the clinical significance of AT1-AA in hypertensive disorder. Our data revealed that AT1-AA is significantly associated with hypertension, especially with pre-eclampsia. AT1-AA removal may be a novel therapeutic method for the high blood pressure disorders. In addition to potential risk of AT1-AA in offspring,36 we suggested that screening of AT1-AA in pre-eclampsia patients is valuable for their disease prevention and future healthcare.
To address other factors that may affect our results on the relationship between AT1-AA and hypertension pathological features, subgroup analysis was performed. Based on being pregnancy or not, the hypertensive disorders were divided into non-gravid hypertension and pre-eclampsia. Our data revealed that the heterogeneity was observed when meta-analysis was conducted in all studies (I2 = 65.6%), but it was eliminated in meta-analyses of each subgroup: pre-eclampsia (I2 = 28.5%) and non-gravid hypertension (I2 = 0.0%), and an association between AT1-AA and pre-eclampsia (OR 32.84) was much stronger than that between AT1-AA and non-gravid hypertension (OR 4.18). A summary AUC combined with a bivariate random-effects analysis also suggested AT1-AA has prognostic significance for pre-eclampsia, but not non-gravid hypertension. The reason for this state may be because of the differences of subjects between the 2 subgroups: the immune microenvironment in pregnant women is more complex than that in normal people, pre-eclamptic patients were all females aged 20 to 30 years, whereas non-gravid hypertension patients were aged approximately 50 years, and half of them were male. In addition, controls for pre-eclamptic patients were all normal pregnant women, but controls for non-gravid hypertension included both healthy male and female volunteers. A recent research demonstrated the prevalence of maternal transmission in the hypertensive subjects, and highlighted the role of X-chromosome single-nucleotide polymorphisms in this phenomenon.37 Interestingly, AT1-AA could be transmitted to offspring from mother via placenta and milk, as was previously reported.38 We infer that AT1-AA plays a pathological role in maternal high blood pressure, and also in hypertensive disorders of future generations.
Subgroup analysis was also performed by different AT1-AA measurements: ELISA, neonatal cardiomyocyte contraction assay, and 4 × NFAT-driven luciferase reporter assay. The ELISA method is based on antigen and antibody specificity,39 whereas the latter 2 are based on the biological function.13–15 Our results suggest that ELISA was efficient for AT1-AA measurement. Because of the simple procedure and repeatable result, we recommended ELISA is suitable for large sample sizes in clinic. The 4 × NFAT-driven luciferase reporter assay and the neonatal cardiomyocyte contraction assay depended on cellular status and experimental environments, so they may be less suitable for large clinical practice, but may be more suitable for mechanism research.
This study has some limitations. First, although the Begg rank correlation test and the sensitivity analysis showed no evidence for publication bias, it is inevitable since we could not include unpublished data. Therefore, the pooled OR may be potentially overestimated. Second, the publication language was limited to English and Chinese; the statistical power of our analysis may be reduced for this reason. Third, studies included in this meta-analysis are retrospective studies, and no prospective study has been published until now; this may reduce the qualities of evidence in clarifying the causal relationship between AT1-AA and high blood pressure. Fourth, the level of AT1-AA was described as “increased” or “positive,” but there was a lack of specific measuring data in these included studies. In this condition, a cut-off value of AT1-AA cannot be established. In addition, the interpretation of different observers or measurement by different methods may influence the results and this is a drawback to clinical applications.
In summary, this meta-analysis including studies revealed that AT1-AA is clearly associated with hypertension, especially pre-eclampsia. With high AUC, high sensitivity, and specificity, we strongly suggest that AT1-AA could be a valuable indicator for poorer prognosis of patients with pre-eclampsia, and could be useful in patients with hypertensive disorders for risk evaluation and making of individual treatment decision.
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