The internal carotid artery ascends to the base of the skull, traverses the petrous portion of the temporal bone, and gains entry into the cranial cavity through the foramina. And carotid artery disease typically refers to a range of conditions characterized by structural changes in the lumen of the carotid artery. The optimal management for coronary artery disease patients undergoing off-pump coronary artery bypass grafting (OPCAB), combined with carotid artery disease has been regarded as the “bottleneck” problem, requiring urgent resolution in the field of cardiac surgery (1–5). A conclusive advantage from carotid endarterectomy in mitigating stroke risks has been demonstrated for severe symptomatic carotid artery disease (6–8). However, a controversy persists regarding the management of severe asymptomatic carotid artery stenosis (ACAS) (9) and no definitive conclusions have been reached in the current guidelines for the optimal surgical management of patients with severe ACAS and coronary artery disease (CAD) (2, 10–12) (Table 1). In addition, the level of the evidence in the above guidelines is low. The root cause of the disputed conclusions for the optimal management of severe ACAS and CAD patients undergoing OPCAB, we thought that the relationship between severe ACAS and adverse 30-day postoperative outcomes, particularly the 30-day postoperative mortality in surgical patients, has not been determined by previous clinical data.

In addition, the Sequential Organ Failure Assessment (SOFA) maximum was reported to be the gold standard for the prognostic evaluation of OPCAB (13–15), and the severe multi-organ dysfunction, measured by SOFA maximum ≥11, has been confirmed to predict the 30-day postoperative mortality in patients undergoing isolated OPCAB (13). Since the independent correlation between severe ACAS and 30-day postoperative mortality in patients undergoing OPCAB cannot be explored directly, it is limited by sample size. Therefore, it is imperative to advance the study endpoint by prioritizing severe multi-organ dysfunction over the 30-day postoperative mortality as the primary endpoint of our current research.

To catch the above knowledge gap, the current research aimed to demonstrate the independent association between preoperative severe ACAS and severe multi-organ dysfunction after OPCAB, which may further indicate the relationship between severe ACAS and adverse 30-day postoperative outcomes of patients undergoing OPCAB.

The Ethics Committees of Beijing Anzhen Hospital, Capital Medical University (Beijing, China), approved the current observational research. Ethics number: 2024205x.

The baseline characteristics of the study population are shown in Table 3. A total of 562 patients met the inclusion criteria for the current study. 63 (11.2%) suffered from severe ACAS. Compared to the non-severe ACAS group, patients with severe ACAS experienced a longer operation time (5.0 ± 1.6 vs. 4.2 ± 1.0, p < 0.0001), a higher EuroSCORE (11.0 ± 6.2 vs. 8.3 ± 3.7, p < 0.0001), a lower left ventricular ejection fraction (LVEF) (45.6 ± 19.5 vs. 53.7 ± 14.2, p < 0.0001), and had a higher prevalence of peripheral arterial disease (50.8% vs. 35.3%, p = 0.032) and heart failure (38.0% vs. 23.6%, p = 0.041). In addition, severe ACAS was found to be more common in current smokers (41.3% vs. 24.2%, p = 0.016).

Short-term postoperative events are summarized in Table 4. The SOFA maximum in the severe ACAS group was significantly higher than that in the non-severe ACAS group (9.76 ± 3.03 vs. 7.75 ± 2.96, p < 0.0001, (Figure 2), and a higher proportion of patients in the severe ACAS group exhibited severe multi-organ dysfunction (44.4% vs. 14.0%, p < 0.0001). In addition, severe ACAS was related to an increased rate of 30-day postoperative MACCEs (15.9% vs. 6.6%, p = 0.027), including a 30-day postoperative stroke (9.5% vs. 3.0%, p = 0.033). Severe ACAS was associated with an elevated risk of delirium (6.3% vs. 0.8%, p = 0.010), and AKI (12.7% vs. 1.6%, p < 0.0001). For the other short-term events, there were no significant differences between the two groups.

The results of the multivariate analysis (Table 5) demonstrated that severe ACAS may be independently associated with severe multi-organ dysfunction (OR, 7.37, 95% CI 4.80–14.30, p < 0.0001) after OPCAB. In addition, the higher body mass index (BMI) (OR, 1.35, 95%CI 1.25–1.46, p < 0.0001), higher EuroSCORE (OR, 1.07, 95% CI 1.02–1.12, p-0.010), peripheral arterial disease (OR, 2.10, 95% CI 1.27–3.48, p = 0.004), previous MI (OR, 2.26, 95% CI 1.39–3.69, p = 0.001), perioperative IABP use (OR, 3.42, 95% CI 1.74–6.69, p < 0.0001), emergency (OR 7.60, 95% CI 3.94–14.36, p < 0.0001), ventricular aneurysm (OR, 3.92, 95% CI 1.49–7.70, p = 0.004), and longer operating time (OR, 1.32, 95% CI 1.06–1.64, p = 0.013) were independent risk factors for severe multi-organ dysfunction. On the contrary, higher preoperative LVEF may be independently related to a decreased incidence of severe multi-organ dysfunction.

Based on the results of multivariate analysis (Table 6), the current research also demonstrated severe ACAS may be independently associated with 30-day postoperative stroke (OR, 2.83, 95% CI 1.03–7.75, p = 0,043). The male sex (OR 2.68, 95% CI 1.08–6.62, p = 0.033), emergency (OR, 10.67, 95% CI 3.62–31.40, p < 0.0001), and longer operating time (OR, 1.86, 95% CI 1.30–2.65, p = 0.001) were independent risk factors for 30-day postoperative stroke.

To the best of our knowledge, this is the first single-center, retrospective observational study that demonstrate the correlation between severe ACAS and the incidence of multi-organ dysfunction after OPCAB. The key results of this study are that SOFA maximum in the severe ACAS group was significantly higher than that in the non-severe ACAS group, and the severe ACAS was independently associated with severe multi-organ dysfunction after OPCAB, which may be associated further with an increased rate of 30-day postoperative mortality and complications. In addition, we demonstrated that severe ACAS may be independently associated with 30-day stroke after OPCAB.

Although severe ACAS is associated with an increased risk of stroke and the European Society of Cardiology/American Heart Association guidelines classify individuals with severe ACAS as high-risk for MACCEs prevention, its potential impact on the 30-day adverse events after OPCAB remains incomprehensible. For the 30-day postoperative cerebral events, Santarpino et al. found that ACAS ≥ 90% was independently associated with 30-day stroke after OPCAB (4). However, Preop screening of CAS is routine in CABG and OPCAB, thus ACAS will be seen (4). On the contrary, Mahmoudi et al. found that severe ACAS is not an independent predictor for the 30-day postoperative stroke in patients undergoing OPCAB, and pre-operative screening for ACAS prior to OPCAB should be personalized and based on clinical discretion (19). A meta-analysis focusing on ACAS individuals revealed that patients with bilateral ACAS ≥ 50% had a stroke risk of 6.5% following cardiac surgery (20). No significant differences in the incidence of 30-day stroke after OPCAB between patients with and without severe ACAS had also been reported in other studies (21–23). In addition, at present there is a paucity of clinical studies examining the association between severe ACAS and 30-day postoperative mortality, as well as other organ-related events. In summary, firstly we thought the inconsistent criteria utilized for evaluating severe ACAS may contribute to the discrepant findings reported in the previous literature. There is a lack of literature regarding the definition of severe ACAS using the criteria recommended by current guidelines. Secondly, the limited sample size precludes directed the exploration of the independent correlation between severe ACAS and 30-day postoperative mortality in patients undergoing OPCAB. Based on the limited data available, it is imperative to employ a novel primary endpoint that makes it possible to investigate the association between severe ACAS and 30-day mortality, as well as complications after OPCAB.

As a robust predictor of 30-day outcomes following cardiac surgery, severe multi-organ dysfunction demonstrates superior accuracy, specificity, and independence from treatment when forecasting patient outcomes (14, 24). Four scoring systems were used to define multi-organ dysfunction: the Glasgow Coma Scale, poison severity score, Multiple Organ Dysfunction Score (MODS), and SOFA score. The SOFA score was adopted based on the following advantages: (1) A maximum SOFA score ≥11, namely severe multi-organ dysfunction, is the gold standard for evaluating 30-day mortality after OPCAB with a sensitivity of 95% (13); (2) the SOFA score is more feasible with cardiovascular and cerebrovascular function evaluation (24). The current research regarded the severe multi-organ dysfunction instead of the 30-day postoperative mortality as the first endpoint.

The potential adverse effects of severe ACAS on the 30-day postoperative mortality and organ-related complications may be attributed to the following factors. First, in severe ACAS patients undergoing OPCAB, the occurrence of 30-day cerebral events may be ascribed to the impairment in cerebral hemodynamics. Preexisting hemodynamic impairments serve as a key predictive factor for the occurrence of stroke/TIA (25). Severe ACAS, especially asymptomatic carotid artery occlusion, can lead to not only a reduction in the perfusion pressure on the ipsilateral side but a recruitment of secondary collaterals, both of which may be associated with hemodynamic impairment (3, 26). And the presence of hemodynamic impairment in both hemispheres has been reported in asymptomatic individuals with carotid artery occlusion. Secondly, the rupture of the severe ACAS that was associated with atherosclerotic plaque can result in distal embolism and subsequent 30-day postoperative mortality and stroke/TIA (3). Thirdly, atherosclerosis of severe ACAS is another significant cause of 30-day adverse outcomes after OPCAB (27). Kanemitsu et al. confirmed that the prevalence of complications was significantly higher in individuals with severe atherosclerosis who underwent OPCAB, compared to those who without severe atherosclerosis (28).

Whether severe ACAS patients will lead to a clinically meaningful benefit from a OPCAB combined carotid endarterectomy remains to be investigated further. Mahmoudi et al. identified that severe ACAS may lead to the development of 30-day postoperative adverse outcomes, but its role is unlikely to be a critical one in severe ACAS patients undergoing OPCAB. Therefore, they opposed the customary employment of OPCAB with carotid endarterectomy (19). In the Coronary Artery Bypass Graft Surgery in Patients with Asymptomatic Carotid Stenosis Study (CABACS), the authors compared with OPCAB alone, severe ACAS patients undergoing OPCAB with carotid endarterectomy had a similar five-year risk of mortality and stroke (29). They recommended OPCAB alone for severe ACAS individuals (29). Our findings supported personalized surgical management based on refined clinical evaluation for severe ACAS patients undergoing OPCAB. Since our results confirmed that severe ACAS was independently associated with severe multi-organ dysfunction after OPCAB, a prompt intervention for severe ACAS may improve the prognosis of patients undergoing OPCAB theoretically (RCTs verification required). However, it has been reported that the combination of such an intervention with OPCAB is associated with a higher incidence of adverse postoperative outcomes (1, 30). Therefore, the potential benefits and risks of OPCAB with carotid endarterectomy should be assessed and personalized. In addition, the role of multi-organ parameters, especially the cardio-cerebral factors, should be emphasized during the process of severe ACAS management. For the etiology of 30-day mortality or stroke, the North American Symptomatic Carotid Endarterectomy Trial (NASCET) (27) demonstrated that strokes of cardioembolic origins among the severe ACAS patients was probably underestimated and could not be prevented by carotid endarterectomy. And as discussed above, severe cardio-cerebral atherosclerosis is another significant cause of 30-day adverse outcomes after OPCAB.

It is worth mentioning that the current study demonstrated a longer operation time was associated with severe multi-organ dysfunction and an increased rate of 30-day MACCEs. Our thinking on this issue is that patients with ACAS have increased risk factors before surgery, such as more severe atherosclerosis and ischemic damage to brain blood flow. In addition, we also observed that the degree and number of coronary artery stenosis may be more complex in patients with ACAS. Therefore, the anesthesia time and surgical plan may be adjusted, and the final time may be longer. Previous study confirmed that a longer operation time is an independent predictor of longer ICU stay, regardless of factors such as the number of blood products transfused, CPB/myocardial ischemic times, and ejection fraction, which are indirect markers to assess the complexity level of OPCAB procedures (31). However, prospective studies are still needed to directly demonstrate whether the association between surgical duration and adverse outcomes is affected by the complexity of cardiovascular disease and OPCAB procedures.

Our study has some limitations. First, the results lack long-term follow-up. Therefore the findings are limited to the 30-day timeframe and cannot be extrapolated beyond it. In addition, it is a small, single-center, retrospective observational study. High quality, large-scale, and multicenter randomized controlled trials are required to further confirm the optimal management of severe ACAS patients undergoing OPCAB. In addition, the explanation of adverse outcomes in the presence of ACAS is multifactorial. For instance, a valuable study demonstrated the risk of 30-day MACCEs was significantly greater in patients with diabetes, without clinical cardiovascular disease, who have both a longer diabetes duration and significant ACAS, compared with those who with a shorter duration and/or nonsignificant ACAS (32). And the confounding factor, namely diabetes, has been eliminated through multivariate analysis in the current study. However, since this is a retrospective observational study, the possibility of some unmeasured confounding variables still cannot be ruled out.

Severe ACAS was independently associated with severe multi-organ dysfunction, measured by SOFA maximum ≥11 after OPCAB, which may be associated further with an increased rate of 30-day postoperative mortality and complications. Our data contributes to the growing evidence that highlights the importance of personalized assessment for potential advantages and disadvantages in prognosis of severe ACAS patients undergoing OPCAB with carotid endarterectomy. Nevertheless, the role of multi-organ parameters, especially cardio-cerebral factors, should be emphasized during the process of severe ACAS management.