This cross-sectional study indicated that, in a hypertensive Chinese population with low levels of LDL-c, Lp(a) was identified as a significant residual risk factor for ARAS.
The result was performed in five parts. First, a univariate analysis revealed that SBP and history of PAD were positively associated with ARAS, while history of CAD was negatively correlated. Current smoking status, gender, age, BMI, and DM were not associated with ARAS. The role of SBP in ARAS can be easily understood, as this protein accelerates the progression of atherosclerosis, which directly promotes serum lipid deposition on renal artery walls. Regarding PAD, as atherosclerosis is a systemic arterial disease, the presence of PAD is inevitably accompanied by lesion formation in the renal artery. This also suggests that lipid accumulation in the peripheral and renal arteries may be homogeneous. CAD was not identified as a risk factor of ARAS in this study which was unexpected. This may be due to CAD being defined as coronary stenosis over > 70% lumen area, excluding those patients with mild to intermediate plaque lesions. Interestingly, these lesion were present even when other atherogenic risk factors we absent. In addition, we analyzed different concentrations of Lp(a) in a low LDL-c population, revealing that high-levels of Lp(a) were associated with a high incidence rate of ARAS, further supporting the hypothesis that ARAS and Lp(a) levels are related. Next, logistic analysis that adjusted for other covariates in this low LDL-c population to further confirmed the hypothesis. After controlling for current smoking, SBP, gender, age, BMI, DM, PAD, and CAD, we found that there was a significant effect of Lp(a) on ARAS in a low LDL-c population. Subsequently, in order to more intuitively demonstrate this relationship with ARAS, a concentration-prevalence fitting curve was plotted, revealing that incremental increases in Lp(a) concentration of Lp(a) initially caused increased ARAS levels, before leveling off at a certain rate. At the same time, Lp(a) concentration was divided into three tertiles in order to generate a line chart to estimate risk proportions. Finally, the distribution of Lp(a) concentrations in hypertensive patients was analyzed to distinguish between population tertiles based on ARAS risk. Thus, to our knowledge, we are the first to demonstrate an independent association between Lp(a) concentration and ARAS in a hypertensive low LDL-c population.
Pathophysiologically, the mechanisms by which Lp(a) increases CVD risk are driven by proatherogenic and prothrombotic states, including endothelial disorder, smooth muscle proliferation, foam cell formation, and local coagulation disturbances[13]. Molecularly, Lp(a) is similar to LDL-c, as it is a particle covalently bound by apoB and apo(a), which carries pathogenic LDL-c and leads to atherosclerosis[27]. However, Lp(a) is more atherogenic than LDL-c due to presence of apo(a), which can induce inflammation that is mediated by oxidized phospholipids and antifibrinolytic effects that result from inhibiting plasminogen activation[27–30]. Lp(a) shares similarities to LDL-c, which may account for the associated risk of Lp(a) leading to atherosclerosis initiation and progression in a low LDL-c environment. In this study, Lp(a) levels were significantly associated with ARAS at low LDL-c levels. One explanation for this effect is that the impact of Lp(a) is reduced at high LDL-c concentrations. Although Lp(a) has a stronger pathogenicity, LDL-c is still a significant factor in atherosclerosis progression. Together, this underscores the importance of Lp(a) in the context of low LDL-c levels and promotes further study of the related residual risks.
Clinical trials and systematic reviews over the past several decades have revealed a strong relationship between Lp(a) concentration and CVD[31–34]. For example, the JUPITER trial of low LDL-c participants demonstrated that baseline Lp(a) concentrations were associated with increased CVD risk[14]. Similar results were obtained from AIM-HIGH and LIPID trials in which participants underwent LDL-c lowering therapy[35, 36]. These data suggest that high Lp(a) levels act as a latent pathogenic factor during the development and treatment of CVD wherein common risks are treated. This study examining the relationship between ARAS and Lp(a) supports these observations, indicating that Lp(a) is a determinant for residual risk in hypertensive patients with low LDL-c levels. In the general population, LPA IS THE MAJOR GENE CONTROLLING THE LP(A) FEATURE AND EXPLAINS 70–90% of the variancE IN LP(A) LEVELS[37]. In this study, most patients had undergone primary angiographic without statin treatment, so their baseline Lp(a) levels were mostly controlled by genetics, suggesting that the study’s results are applicable to those with naturally high Lp(a) levels. This cannot be inferred across the entire population, as widespread use of statins have been demonstrated to increase Lp(a) concentrations by 10%−20% [38, 39]. Statin use may cause cholesterol to "escape" coordination with LDL-c receptors to form more Lp(a)[40], which indicates a need to monitor populations that are treated with statins.
The impact of Lp(a) on ARAS has raised and seriously questioned in previous studies, as both positive and negative results have been reported [25, 41–43]. Park et al.[41] performed renal arteriography at the time of cardiac catheterization in 270 patients and screened 28 ARAS (≥ 50% narrowing of renal artery) and 242 non-ARAS patients, concluding that Lp(a) was not associated with ARAS (median, ARAS:143 mg/l vs. non-ARAS:188 mg/l). In contrast, Scoble et al.[42] examined the lipoprotein profiles in a small number of patients with (n = 32, ≥ 30% narrowing of renal artery on angiography) or without (n = 32, matched with ARAS patients for clinical baseline features but no angiography performed) ARAS in a case-controlled study, revealing that serum Lp(a) levels were higher in the non-ARAS group (mean ± SD, ARAS:310 ± 210 mg/l vs. non-ARAS:580 ± 450 mg/l; P < 0.01). The negative relationship between ARAS and Lp(a) was explained by an Apo(a) polymorphism. Zhang et al.[25] performed a cross-sectional study of 1200 Chinese patients who underwent renal arteriography immediately after coronary angiography, and found that Lp(a) was significantly higher in patients with mild and advanced ARAS (≥ 30% narrowing of renal artery) by univariate logistic regression (percentage of high serum Lp(a), ARAS:24.2% vs. Non-ARAS:17.5%; P = 0.039). Catena et al.[43] examined 50 hypertensive patients with ARAS (in those with mild and advanced ARAS (≥ 70% narrowing of renal artery on angiography) and 58 hypertensive patients with comparable cardiovascular risk factor burden but non-ARAS (assessed by angio-MRI or angio-CT scan and/or renal angiography) in a cross-sectional study, which demonstrated that Lp(a) levels in the highest tertile had greater risk than the lowest tertile (OR:3.70; P = 0.016). Further analyzing their results, we revealed that some studies had insufficient sample sizes for analysis, while one study diagnosed ARAS by non-invasive imaging methods, which could have resulted in variability in patient assignment. In addition, few studies have taken the effect of Lp(a) at low LDL-c levels into account, resulting in studies with insufficient information to establish coherent conclusions. In this study, angiography was used to assess a 50% narrowing of renal artery in order to classify patients in either the ARAS group or non-ARAS, as opposed to non-invasive imaging, and this meets the gold standard of diagnosis. In addition, this study’s data were thoroughly and expansively collected compared to prior studies and therefore can provide higher quality evidence. It must be noted, however, that there are still some limitations to this study. First, as this study utilized cross-sectional data studies, only correlations can be inferred, rather than causality, which established the findings as a reference tool for clinical practice. Second, as the study patients needed to undergo simultaneous renal angiography and coronary angiography needs to be accurately assessed, the number of cases available to be assessed was limited. Third, patients with poor kidney function may also have proteinuria, causing the liver to produce more lipoprotein, including Lp(a) and potentially effecting serum Lp(a) levels.
Great progress has been made in understanding the role of Lp(a) in ARAS, but much remains to be explored. Patients under therapy have more clinical events of ARAS than are prevented, indicating that residual risk factors, such as Lp(a), need to be examined and taken into account. Given the potential CVD risks of Lp(a), treatment is now an urgent task. In the era of comprehensive lipid-lowering medications, there is greater importance given to reducing LDL-c levels, and, by extension, to understanding the impact of Lp(a). The 2019 European Society of Cardiology guidelines recommend measuring Lp(a) concentration at least once in each adult person’s lifetime and consider 180 mg/dL of Lp(a) to be a very high inherited level that indicates danger for ACSVD (Class IIa, Grade C)[8]. It must be noted that, currently, no known medications that directly lower Lp(a) levels have been approved for use.