Several new techniques and pieces of equipment have been developed over the past 10 years to overcome to complexities inherent to the chronic total occlusion (CTO) percutaneous coronary intervention (PCI) procedure, thereby improving operative success rates [1, 2]. When successful, CTO PCI can contribute to the alleviation of patient symptoms and prolonged survival [3, 4]. However, the utility of the CTO PCI procedure is limited by the potential for serious complications that can negatively impact patient prognosis [5, 6]. In severe cases, patients may exhibit cardiac or non-cardiac complications that can contribute to the incidence of hypotension and potentially circulatory shock [7]. Despite these risks, hypotension and shock are often not included in lists of procedure-related complications in published studies [2] and scoring systems. In clinical settings, a subset of patients who experience shock do not exhibit any serious CTO PCI complications, and shock can even occur in a subset of patients who undergo successful CTO PCI treatment, necessitating the prolonged use of vasoactive drugs to maintain appropriate blood pressure. No reports to data have described this form of unexplained perioperative shock associated with the CTO PCI procedure. As such, this retrospective study was designed to survey the incidence of unexplained CTO PCI-related shock and to identify associated risk factors.

Unexplained shock is a potential CTO PCI procedural complication that has been the focus of insufficient study to date. The results of this study indicate that unexplained shock affected ~4.8% of CTO PCI patients, in addition to revealing 6 simple clinical indicators can be used to predict unexplained shock risk. This study is the first to our knowledge to have developed a model for the prediction of unexplained shock during CTO PCI, and these findings may be invaluable for future procedural planning efforts.

In a prior meta-analysis, a 3.1% pooled complication rate was reported for 18,061 cases [2], while a 2.8% complication rate was reported for 1569 hybrid CTO procedures in the PROGRESS registry [11]. The unexplained shock incidence rate for the 924 cases in this study (4.8%) was in line with the CTO complication rates reported previously [2]. This emphasizes the need for CTO operators to take this complication into consideration, given that shock-related data have not been reported for large CTO-related clinical studies such as the OPEN CTO study [12], EXPLORE study [13], and the EuroCTO study [14].

Shock is a clinical state wherein patients exhibit circulatory failure resulting in insufficient cellular oxygen utilization [15]. Shock is diagnosed based on a combination of hemodynamic, biochemical, and clinical findings [15]. Hypotension, which is common in the context of CTO PCI and can arise in response to many different factors, precedes shock [16, 17]. Certain causes of hypotension such as allergic reactions, vasovagal syndrome, guide interference with the aortic valve, or deep guide engagement can be alleviated through basic investigation and appropriate intervention [17]. Severe shock, however, is often caused by complications, and the differential diagnosis for complication-related shock is complex. Hypovolemic shock can arise due to access site complications and bleeding, while coronary complications such as donor vessel injury or perforation can exhibit a sudden and severe onset. When complication-related hypotension develops, it is vital that the underlying complications be rapidly treated to prevent progression to shock [18]. Most such complications are the result of the use of particular intraoperative procedures and techniques. Many different factors can contribute to the incidence of complications, and PROGRESS CTO complications scores offer value in the prediction of CTO PCI procedure-related complications [11]. Many patients suffering from shock, however, do not exhibit any apparent serious complications, with these cases being designated as instances of unexplained shock. Few studies to date have mentioned unexplained or complication-related shock when discussing CTO PCI-related procedural outcomes. As these two forms of shock may be driven by distinct underlying mechanisms, further efforts to differentiate between the two are warranted.

When comparing the two patient groups in this study, significant differences in base-line SBP, heart rate, BMI, and prior PCI were observed. The association between BP control and long-term PCI patient prognosis remains a matter of controversy [19]. However, prior evidence has revealed a link between lower BP at admission and in-hospital prognosis. Shiraish et al. [20] studied a population of Japanese acute MI patients undergoing PCI, and found an SBP 105 mmHg to be linked to a higher risk of in-hospital PCI patient mortality. Analyses of the INVEST study [21] supported a potential J-shaped relationship between SBP and MACE rates, while both SBP 125 mmHg on admission and heart rate $>$90 bpm are important risk factors associated with the incidence of cardiogenic shock during post-STEMI hospitalization as per the ORBI risk score [22]. Here, decreased BP and high heart rate were both significantly related to the risk of unexplained shock. Several factors may explain these findings. For one, more rapid heart rate on admission is indicative of reduced cardiac reserve [23], such that patients may be less capable of compensating for blood loss or ischemia. In addition, decreased BP on admission may be linked to impaired cardiac function and hypovolemia [24]. While lower body weight has previously been linked to an increased risk of bleeding for individuals from Asian populations [25], BMI failed to offer value in the prediction of unexplained shock in the present study cohort. This may be attributable to the fact that most blood loss in these patients was CTO PCI procedure-related, rather than complication-induced.

As CTO PCI necessitates the utilization of large sheaths and is associated with a high frequency of dual access, it is associated with a high risk of blood loss [26]. Procedure-associated blood loss may represent an important cause of unexplained shock incidence. Here, all cases exhibited a mean decrease in hemoglobin levels of ~8 g/L (140.5 $\pm$ 14.8 to 132.4 $\pm$ 16.1), and these decreases were more pronounced in the shock group (140.8 $\pm$ 14.8 to 133.2 $\pm$ 15.7). Such procedure-related blood loss is in part attributable to more frequent instrument exchanges from the Y-connector, and strategies including retrograde wire externalization further exacerbate this risk [27].

The risk of ischemia is higher for the CTO PCI procedure as compared to conventional PCI [16], in part owing to the use of additional contrast agents and a guiding catheter with a larger diameter. Certain techniques including retrograde PCI can contribute to donor artery or collateral channel ischemia [17]. While these events may not result in serious complications, they do decrease cardiac output. The extent to which these is- chemic risks are impacted following CTO opening remains to be established.

Several studies have identified severe cardiac insufficiency or low LV function (LVEF $\le$30%) as important criteria for high-risk PCI [28]. However, all patients in the present study exhibited an ejection fraction of $>$40%, potentially owing to the patient selection criteria and adequate OMT therapy employed herein.

J-CTO scores are correlated with CTO complexity, with CTOs exhibiting a J-CTO score $\ge$2 being associated with a higher risk of necessitating more complex antegrade techniques and retrograde crossing techniques [29]. Many studies have reported the retrograde approach to be predictive of procedure-related complications [6, 11, 30, 31]. While this retrograde technique is often necessary to ensure high rates of technical success, it is highly complex and associated with the potential for complications including donor vessel ischemia, donor vessel injury, or collateral injury. Moreover, the retrograde approach necessitates a longer target activated clotting time (ACT, $>$350 s), elevating the potential risk of bleeding. Minimizing the procedure duration when possible is a core tenant of the CTO PCI approach [32], but these complex techniques inevitably prolong the operation time, thereby extending the duration of bleeding and ischemia.

Overall, these findings suggest that a combination of ischemia and blood loss due to a variety of reasons can contribute to the incidence of unexplained shock among patients undergoing the CTO PCI procedure. While these patients may not experience complications in the traditional sense that are directly related to procedural success, efforts to mitigate CTO PCI-related blood loss and ischemia may protect against the incidence of unexplained shock. The risk scoring system developed herein has the potential to aid clinicians performing the CTO PCI procedure by enabling appropriate preoperative planning, arrangement, and strategy adjustment as necessary. The risk of shock for high-risk patients can be mitigated by reducing the operative duration to the greatest extent possible, employing retrograde techniques, and allowing more skilled operators to perform the procedure.

There are some limitations to this analysis. For one, this was a single-center retrospective study, and the results may thus not be representative of findings for other centers or operators. In addition, the mechanisms underlying unexplained shock were not clarified through this study, and further efforts to delineate these mechanisms may be critical to the treatment or prevention of this potentially serious clinical outcome. Moreover, these results do not offer any insight regarding long-term patient prognosis. Accordingly, we plan to perform future studies examining the mechanisms governing the incidence of unexplained shock and the long-term prognosis of these patients.

In summary, these results suggest that baseline systolic pressure, baseline heart rate, baseline hemoglobin levels, operative duration, J-CTO score, and the use of a retrograde approach can be used to predict the incidence of non-complication-related shock in patients undergoing CTO PCI procedures. These findings can be used to facilitate the preoperative evaluation of high-risk patients and corresponding strategy adjustment efforts.

ZC, YLiu, SH, YZ, YS and YLi—Data curation; ZC, WJ and HL—Formal analysis; HP, ZC—Conceptualization; ZC—Writing - original draft; JL, HP—Writing - review and editing, Resources; ALL—read and agreed to the published version of the manuscript.

Not applicable.

Not applicable.

This research was funded by National Natural Science Fund of China, grant number 81970291 and 82170344.

The authors declare no conflict of interest.