Aortic dissection (AD) is a devastating aortic disease caused by an entry tear in the aortic intima or hemorrhage in the aortic media, leading to the separation of the aortic layers [1]. According to the Stanford classification, type B aortic dissection (BAD) originates distal to the ostium of the left subclavian artery [1]. With the development of thoracic endovascular aortic repair (TEVAR), the mortality rate of BAD patients has significantly reduced [2]. Nonetheless, patients can still suffer from diverse stent-graft-related complications, including endoleak, aortic dilation, retrograde type A aortic dissection (AAD) and new dissection [2]. Therefore, it is imperative to identify potential risk factors associated with aortic-related adverse events (ARAEs) in BAD patients undergoing TEVAR.

Recently published studies have found an association between simple renal cysts (SRC) and aortic dissection/aneurysm [3, 4]. However, the perioperative characteristics and long-term outcomes of BAD patients with SRC that undergo TEVAR remain unclear. In this context, a multi-center retrospective study was conducted. First of all, differences in perioperative characteristics and intraoperative details between SRC and non-SRC groups were compared. Moreover, a propensity score matching was performed to minimize selection bias. The differences in long-term outcomes between the two groups were compared in the overall and matched study populations. Finally, subgroup analysis was performed to identify which subpopulations of SRC patients sustained the highest risk of ARAEs after TEVAR.

Although previous studies indicated that SRC is a significant risk factor for BAD patients undergoing TEVAR [4], the relatively short follow-up periods and small sample size in these studies could be a source of selection and observational bias. To our best knowledge, this is the largest and most contemporary report providing comprehensive analyses of SRC-related disparities in baseline characteristics, anatomical patterns, intra-operative details and long-term outcomes of BAD patients after TEVAR.

In our study, BAD patients with SRC were significantly older than those without, consistent with the literature [13]. In comparison with the general population, patients with BAD were found to be older [14]. Clinical evidence from the international registry of acute aortic dissection (IRAD) showed that the mean age of BAD patients was 63.5 years (the mean age in our study is 57.9 years) [15]. Moreover, we found that the SRC group was significantly older than the non-SRC group (mean age, 61.1 years vs. 56.3 years; p 0.001). However, no significant interaction between age and SRC on ARAEs was found (p for interaction = 0.429, Supplementary Table 5). Our results indicated that age, although related to SRC, is not the major factor influencing aortic-related outcomes in BAD patients after TEVAR.

A significant gender imbalance was found in SRC patients in our study, with a male-to-female ratio of 4.8:1. Moreover, female patients were significantly older than male patients (62.1 $\pm$ 12.9 years vs. 57.1 $\pm$ 12.7 years, p 0.001), while the prevalence of SRC between the two groups was similar (39.8% vs. 33.4%, p = 0.175). In a study by Chung et al. [16], female patients that underwent cardiac surgery were older with larger indexed aortic sizes, with a lower prevalence of coronary disease and reduced left ventricular ejection fraction than their male counterparts. In our study, the prevalence of CAD (p = 0.174), stroke (p = 0.781), COPD (p = 0.07) and CKD (p = 0.357) was similar between the males and females, while hypertension was predominantly found in male patients (p 0.001).

In our study, a difference was found in the prevalence of hypertension between the two groups in the total population (Table 1). Consistently, previous clinical studies have shown that SRC is associated with a greater prevalence of hypertension [17]. Although we found that hypertension is not an independent predictor of ARAEs, the subgroup analysis showed that patients with SRC and hypertension led to the highest risk of rupture after TEVAR (Table 4). The attenuation of the power to detect a direct association between hypertension and ARAEs may also result from relatively small sample (n = 214) after matching. Recently, Lu et al. [4] found that lower diastolic blood pressure at admission could predict ARAEs in BAD patients after TEVAR, which emphasized the important role of hemodynamic stability in aortic remodeling. Whether hypertensive patients with SRC suffer from severer blood pressure fluctuation than that without after onset of BAD warrants further study.

Contrary to the previous belief that SRC is a benign disease, an increasing body of evidence suggests that patients with SRC experience a higher risk of long-term ARAEs after TEVAR [3, 4]. What’s more, no difference in 5-year all-cause mortality or cardiovascular events (shown in Supplementary Figs. 5,6) was found between the two groups, implying that SRC might play an exclusive role in the adverse aortic remodeling after TEVAR.

We noticed that the difference of ARAEs between the two groups was mostly accumulated in the first 2 years (Fig. 2). Therefore, a landmark analysis was performed by dividing the 5-year follow-up into the first two years and the remaining three years. Results indicated that during the first two years, patients with SRC were at a higher risk of ARAEs (HR: 1.93, 95% CI: 1.17–3.19, p = 0.009). However, for the remaining three years, the cumulative hazard ratios in the two groups were similar (HR: 1.02, 95% CI: 0.37–2.82, p = 0.97). One explanation for this trend is that the patients initially without SRC could have developed new cysts, increasing the probability of ARAEs at follow-up. Another explanation is that all patients receiving TEVAR could benefit from positive aortic remodeling in the long term, irrespective of the presence of SRC [18]. In any case, further studies should be conducted to identify the role of SRC on long-term patient outcomes.

According to current clinical and laboratory evidence, there are several possible underlying correlations between SRC and BAD.

First, both SRC and BAD are related to increased matrix metalloproteinases (MMPs). It has been established that the structural integrity of the aorta depends on the expression of extracellular matrix (ECM) proteins, which are regulated by proteolytic enzymes. Zhang et al. [19] found that MMP-1, MMP-9, and active MMP-9 levels were higher in aortic dissection tissue than control tissue. Interestingly, MMP overexpression and an elevated ratio of MMPs to tissue inhibitors of metalloproteinases (TIMPs) in aortic tissue could induce the degradation of multiple components in the ECM, making the blood vessel more vulnerable to adverse clinical events [20]. Similarly, Harada et al. [21] found massive accumulation of MMP-2 and MMP-9 in human benign cystic fluids. Obermuller et al. [22] found the upregulation of MMP-14 in a rat model of autosomal-dominant polycystic kidney disease and advocated that TIMPs are promising biomarkers for treating polycystic kidney. In summary, the imbalance of MMPs and TIMPs may persist in patients with SRC and BAD, making them susceptible to ARAEs after TEVAR.

Moreover, our study indicated that the patients with SRC had a greater aortic calcification prevalence than the non-SRC group in the total population. It has been established that multiple factors can affect arterial calcification, including calcium and phosphorus imbalances [23]. Calcium ions are key mediators that regulate inflammation, apoptosis and calcification in vascular smooth muscle cells (VSMC) [24]. Consistently, decreased calcium concentration has been documented in AD patients [25], which could be attributed to calcium loss resulting from the administration of diuretics for blood pressure control [26]. Interestingly, clinical studies demonstrated that Ca${}^{2+}$-antagonists were related to the enlargement of simple renal cysts [27]. Clinically, calcification-induced degradation presents a reduction in stiffness of the aortic wall [23]. This degradation, coupled with the significant tension caused by calcification, results in a remarkable increase in stress around the non-calcified aortic tissue, ultimately putting the aorta at high risk of rupture. Disorders of calcium metabolism and aortic calcification may lead to chronic inflammation of the arterial wall and the formation of residual thrombosis [28], consistent with our findings.

Overall, the results of our study suggested that SRC may be an independent high-risk predictor of long-term ARAEs in BAD patients after TEVAR. According to our findings, BAD patients with SRC should be followed-up by CTA at 1-month, 1-year and 2-year follow-ups and blood pressure should be closely monitored within two years after TEVAR. Annual CTA follow-up and routine blood pressure monitor should be recommended in patients with SRC, two years after TEVAR.

Due to the retrospective design of our study, it was impossible to randomly allocate the patients.

Compared with the non-SRC group, BAD patients with SRC experienced a higher risk of long-term ARAEs after TEVAR. Subgroup analysis showed that the presence of SRC and hypertension led to the highest risk of rupture after TEVAR.

All authors agreed with the publication of this study.

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

AD, aortic dissection; BAD, type B aortic dissection; SRC, simple renal cysts; TEVAR, thoracic endovascular aortic repair; AAD, type A aortic dissection; Retrograde AAD, Retrograde type A aortic dissection; ARAEs, aortic-related adverse events; PSM, propensity score matching; CAD, coronary artery disease; COPD, chronic occlusive pulmonary disease; CKD, chronic kidney disease; MMPs, matrix metalloproteinases; CTA, computed tomographic angiogram; DSA, digital subtraction angiography; IQR, interquartile range; SMD, standardized mean difference; HR, hazard ratio; CI, confidence interval; LVEF, left ventricular ejection fraction; IRAD, international registry of acute aortic dissection; ECM, extracellular matrix; TIMPs, tissue inhibitors of metalloproteinases; VSMC, vascular smooth muscle cells; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; ACEI/ARB, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker; ULP, ulcer-like projection.

HQZ—Investigation and Writing. KWZ—Writing and Data curation. GKW—Writing and Providing data. JJL—Providing data. YFP—Editing and Supervision. JZ—Writing, Review, Editing and Supervision. ZPJ—Conceptualization, Project administration. All authors read and approved the final version of the manuscript.

This retrospective study was approved by the Institutional Review Board of Shanghai Changhai Hospital (CHEC-Y2020-042, April 21, 2020). Individual informed consent was waived due to the retrospective design of the study.

Not applicable.

The study, and collection, analysis, interpretation of data, and preparation of the manuscript were supported by the source of funding as follows: the National Natural Science Foundation of China (81870366) and Science and Technology Innovation Action Plan in Shanghai (20JC1418700).

The authors declare no conflict of interest.