Influence of false lumen status on systemic inflammatory response triggered by acute aortic dissection

doi:10.21203/rs.3.rs-4698569/v1

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Influence of false lumen status on systemic inflammatory response triggered by acute aortic dissection

https://doi.org/10.21203/rs.3.rs-4698569/v1

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We aimed to investigate the influence of false lumen (FL) status on systemic inflammatory response triggered by acute aortic dissection (AAD) using cytokine profiling. The study included 44 AAD patients. Patients were divided between those with a thrombosed FL (Group T, n=21) and those with a non-thrombosed FL (Group P, n=23). On-admission serum concentrations of 29 cytokines were compared between unmatched and propensity-score matched (n=10 pairs) FL groups and a control group (non-ruptured thoracic aortic aneurysm, Group C, n=20). Unmatched analysis showed twelve cytokines differed between groups and fell into three categories: Category A (increased expression in both FL groups: IL-6, IL-10, IL-15, G-CSF); Category B (increased expression only in Group P: IL-1Ra, IL-1β, IL-8, IL-12p70, GM-CSF); and Category C (others: IP-10, VEGF-A, eotaxin). The increases in Category A and Category B cytokines in Group T were attenuated, but not significantly, compared to their increases in Group P. Propensity-score matching analysis revealed a similar expression pattern with respect to all four Category A cytokines, four Category B cytokines (IL-1β, IL-1Ra, IL-12p70, and GM-CSF), and two Category C cytokines (IP-10 and VEGF-A). A robust inflammatory response occurs in patients with AAD, but the response is attenuated when the FL is thrombosed.

Health sciences/Cardiology

Health sciences/Signs and symptoms

Acute aortic dissection

Inflammatory response

Cytokine

False lumen

Acute aortic dissection (AAD) remains a life-threatening cardiovascular disorder for which mortality and morbidity rates are high. The aortic damage characteristic of AAD provokes a systemic inflammatory reaction. An elevated peak C-reactive protein (CRP) concentration is reported to predict oxygenation impairment1 and late adverse events (death or an aortic event) in patients with type B AAD2. Recent studies of type A AAD have shown an elevated leukocyte count3 and an increased neutrophil/lymphocyte ratio4 to be associated with in-hospital mortality. Studies of biomarkers have shown that various cytokines are increased in the circulating blood of patients with AAD4-12. Elevation of interleukin (IL)-6, representative of cytokines involved in the inflammatory response associated with AAD, has been reported to predict in-hospital mortality4,5 and preoperative hypoxia6 in patients with type A AAD. Clinical factors, such as obesity7 and endovascular treatment13, are reported to affect IL-6 expression. However, the influence of dissection morphology, especially false lumen (FL) status, on systemic IL-6 expression remains to be elucidated.

Our group has reported that on-admission leukocyte counts differ in relation to the extent of dissection and FL status in patients with type A AAD14. We have also shown a thrombosed FL to be a predictor of a decreased on-admission D-dimer concentration (≤ 8.3 g/mL) in patients with type A AAD15. Herein, we describe an observational study in which we investigated, by measuring multiple cytokines/chemokines, the influence of FL status on the systemic inflammatory response associated with AAD to identify morphologic factors that affect expression of inflammatory biomarkers.

Patients and study protocol

We conducted a retrospective multi-center observational study of patients with AAD who were admitted to Nihon University Hospital, Tokyo, Japan, or Saitama Medical Center, Jichi Medical University, Saitama, Japan. A flow diagram of the two-part study is given in Fig. 1. The Part 1 study included 44 patients drawn from among 130 patients who were admitted for treatment of AAD at Nihon University Hospital or Saitama Medical Center, Jichi Medical University between April 2020 and March 2021. Fifty-six of the 130 patients were excluded because they had been admitted 48 h or more after symptom onset; they were in shock (systolic blood pressure < 80 mmHg); they were suffering organ malperfusion, hematologic disease, or autoimmune disease; or they were under dialysis for chronic kidney disease. The 44 patients with AAD were included because blood samples had been collected from them on admission, whereas blood samples had not been collected from the remaining 30 patients (either because of lack of time to obtain the necessary informed consent from patients with type A AAD or unavailability of a research team member to obtain the samples). For control, the Part 1 study also included 20 patients who underwent elective surgery for a non-dissecting thoracic aortic aneurysm at Saitama Medical Center, Jichi Medical University between January 2021 and March 2021. Blood samples had also been obtained from these 20 patients, and none had a known hematologic disorder or autoimmune disease or were on hemodialysis for chronic kidney disease. The total study patients were divided into three groups: those with a thrombosed FL (Group T, n = 21), those with a non-thrombosed FL (Group P, n = 23), and those with non-dissecting thoracic aortic aneurysm, i.e., the control patients (Group C, n = 20). Aortic segments involved in the dissection process were classified by zone¹⁶. Concentrations of 29 cytokines/chemokines, including IL-6, were compared between the three groups. Categorization was performed for cytokines/chemokines that were differentially expressed between the three groups. Furthermore, we matched patients with AAD on the basis of propensity scores to create two propensity score-matched groups (propensity score-matched (PSM) Group T and PSM Group P) that were comparable in terms of clinical characteristics and disease morphology, and we compared laboratory values and cytokine/chemokine concentrations between the two resulting groups and the control group. In the Part 2 study, we investigated the influence of FL thickness on cytokine/chemokine expression in patients with a thrombosed FL. First, correlation between FL thickness and cytokine/chemokine concentrations was assessed for cytokines/chemokines differentially expressed in Group T in comparison to expression in Group C. The 21 patients in the Group T were divided into two subgroups based on FL thickness, whether a thin thrombosed FL (FL thickness ≤ 11 mm [Group T-thin FL, n = 10]) or a thick thrombosed FL (FL thickness > 11 mm) [Group T-thick FL, n = 11]). We did so because the 2014 European Society of Cardiology Guidelines list aortic wall thickness > 11 mm as a predictor of intramural hematoma complications¹⁷. Then, we compared IL-6 and G-CSF concentrations between the thin and thick FL groups.

Patients were assigned to Group T or Group P on the basis of FL patency, defined as reported previously¹⁵. Briefly, a thrombosed FL with a small intimal tear (ulcer-like projection) was classified as thrombosed. An FL that was enhanced during delayed-phase computed tomography (CT) (90–120 s after the start of contrast medium injection) was classified as a non-thrombosed FL. For patients who did not undergo delayed-phase CT, FL patency was judged on the basis of early-phase data. A completely patent FL and a partially patent FL were both classified as a non-thrombosed FL.

Measurement of cytokines/chemokines

Peripheral arterial blood samples had been collected into ethylenediaminetetraacetic acid-containing tubes. The samples were left undisturbed at room temperature for 20 min, allowing the blood to clot. The ethylenediaminetetraacetic acid-treated blood was then centrifuged at 1,500 x g for 15 min. Serum was aspirated and stored in aliquots at − 80˚C until analysis to prevent thawing of the frozen parent samples.

Serum concentrations of inflammatory proteins were measured with the use of Milliplex MAP Human Cytokine/Chemokine Magnetic Bead Panel (catalogue number: HCYTMAG-60K-PX29; Merck Millipore, Billerica, MA). Samples were run on a Luminex 200 (Merck Millipore) according to the manufacturer’s instructions and analyzed by means of STarStation software (Version 3.0, Applied Cytometry Systems, Sheffield, UK). The following 29 inflammatory proteins were measured: endothelial growth factor (EGF), G-CSF, granulocyte macrophage-colony stimulating factor (GM-CSF), interferon-α-2b (IFNα2), IFN-γ, IL-1α, IL-1β, IL-1 receptor antagonist (IL-1Ra), IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL-17A, interferon gamma-induced protein 10 (IP-10), chemokine (C-C motif) ligand 2 (CCL2)/monocyte chemotactic protein 1 (MCP-1), CCL3/macrophage inflammatory protein (MIP)-1α, CCL4/MIP-1β, tumor necrosis factor (TNF)-α, TNF-β, vascular endothelial growth factor-A (VEGF-A), and CCL11/eotaxin.

Standards for determination of a linear curve plus two control samples representing high and low concentrations for each cytokine/chemokine were included in each assay. Values determined to be beyond the lower limit of detection were assigned a value half that of the lowest standard value. Values determined to be beyond the upper limit of detection were assigned a value twice that of the highest standard value. Values that were extrapolated from the standard curve beyond the standard range were assigned the determined value.

Statistical analysis

Continuous variables are shown as median [25th, 75th percentile] values, and categorical variables are shown as the number (percentage) of patients. Differences in patients’ clinical characteristics and disease morphology between the three main study groups were analyzed by Kruskal-Wallis test, Mann Whitney U test, chi-square test, or Fisher’s exact test, as appropriate. Propensity scores were calculated as fitted values from logistic regression, with FL status (thrombosed or non-thrombosed) taken as the dependent variable and age, sex, Marfan syndrome, hypertension, diabetes, maximum aortic diameter, Stanford classification, and aortic segment involved in dissection process taken as the independent (matching) variables. The propensity score matching resulted in two groups of 10 patients each matched 1:1. Differences in laboratory values and serum cytokine/chemokine concentrations between three groups were analyzed by Kruskal-Wallis test plus Dunn’s multiple comparison test. Differences in laboratory values and serum cytokine/chemokine concentrations between two groups were analyzed by Mann Whitney U test. Correlation between FL thickness and IL-6, IL-10, IL-15, G-CSF, and VEGF-A concentrations in Group T was assessed by Spearman’s rank correlation coefficient. All statistical analyses were performed with IBM SPSS Statistics 26.0 for Windows (IBM Corp., Armonk, NY, USA), and P < 0.05 was considered significant.

Ethics approval

The study followed the Declaration of Helsinki guidelines and was approved by the institutional review boards of Nihon University Hospital (273-1) and Jichi Medical University (G18-19) on December 1, 2019, and May 1, 2018, respectively.

Patient consent

Patients provided written informed consent for blood sample collection and use of their anonymized clinical information, which was obtained from hospital records.

Clinical characteristics, disease morphology, and laboratory values, per FL group

Patients’ clinical characteristics and disease morphology are shown per group in Table 1. Median age (76 years in Group T, 61 years in Group P, 75 years in Group C) and maximum aortic diameter (37 mm, 47 mm, 57 mm, respectively) differed significantly between groups (all, P < 0.001). The prevalence of male sex, comorbidities, and type A or type B aortic dissection did not differ between groups. Included in Table 1 are dissected aortic segments, shown by zone, also per group. Dissection into Zone 7 (superior mesenteric artery area), Zone 8 (pararenal abdominal aorta), and Zone 9 (infrarenal abdominal aorta) was more prevalent in Group P than in Group T. The longitudinal extent of the aortic dissection tended to be greater in Group P than in Group T (Supplementary Fig. S1). On-admission laboratory values are shown in Fig. 2. The leukocyte count (x10E3/µL) was significantly increased in both FL groups (Group T: 9.5 [7.7, 11.7]; Group P: 14.0 [10.4, 18.0]) in comparison to that in Group C: 5.8 [5.0. 7.1]; both, P < 0.001). The D-dimer concentration (µg/mL) was significantly increased in Group P (28.8 [8.6, 108], P < 0.001) but not in Group T (2.9 [1.5, 5.3], P = 0.87) (vs. Group C: 2.5 [1.4, 4.9]). The liver transaminase level was increased only in Group P. The hemoglobin level, hematocrit, platelet count, and CRP concentration did not differ between groups.

Table 1

Clinical characteristics and disease morphology, per study group
	Group T (n = 21)	Group P (n = 23)	Group C (n = 20)	P value
Interval between symptom onset and blood sample collection (h)	8 [4, 21]	12 [6, 28]	NA	0.24
Age (years)	76 [64, 83]	61 [56, 71]	75 [73, 77]	< 0.001*
Male sex	12 (57%)	14 (61%)	14 (70%)	0.68
Marfan syndrome	0 (0%)	0 (0%)	0 (0%)	1.0
Bicuspid aortic valve	1 (4.8%)	1 (4.3%)	0 (0%)	0.62
Obesity (BMI > 30)	1 (4.8%)	1 (4.3%)	0 (0%)	0.62
History of smoking	13 (62%)	9 (39%)	11 (55%)	0.29
Hypertension	16 (76%)	14 (61%)	17 (85%)	0.19
Diabetes	3 (14%)	1 (4%)	4 (20%)	0.29
Dyslipidemia	6 (29%)	5 (22%)	8 (40%)	0.42
COPD	3 (14%)	0 (0%)	1 (5%)	0.14
Hemodialysis	0 (0%)	0 (0%)	0 (0%)	1.0
Maximum aortic diameter (mm)	37 [33, 41]	47 [38, 50]	57 [54, 60]	< 0.001*
Shock (sBP < 80 mmHg)	0 (0%)	0 (0%)	0 (0%)	1.0
Organ malperfusion	0 (0%)	0 (0%)	0 (0%)	1.0
Type A AD	7 (33%)	14 (61%)	NA	0.068
Type B AD	14 (67%)	9 (39%)	NA	0.068
Dissected aortic segment
Zone 0	7 (33%)	14 (61%)	NA	0.068
Zone 1	7 (33%)	14 (61%)	NA	0.068
Zone 2	7 (33%)	14 (61%)	NA	0.068
Zone 3	17 (81%)	18 (78%)	NA	1.0
Zone 4	19 (91%)	22 (96%)	NA	0.59
Zone 5	19 (91%)	21 (91%)	NA	1.0
Zone 6	13 (62%)	19 (83%)	NA	0.18
Zone 7	10 (48%)	18 (78%)	NA	0.035
Zone 8	8 (38%)	16 (70%)	NA	0.036
Zone 9	5 (24%)	14 (61%)	NA	0.013
Zone 10	3 (14%)	8 (35%)	NA	0.12
Median [25th, 75th percentile] values or number (%) of patients are shown. Group T thrombosed false lumen group, Group P non-thrombosed false lumen group, Group C non-ruptured aortic aneurysm (control) group, BMI body mass index, COPD chronic obstructive pulmonary disease, sBP systolic blood pressure, AD aortic dissection, NA not applicable. *by Kruskal-Wallis test.

Cytokine concentrations, per FL group (Part 1 study)

Concentrations of 12 cytokines/chemokines differed significantly between groups (Table 2), whereas concentrations of 17 cytokines/chemokines, EGF, IFNα2, IFN-γ, IL-1α, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-12p40, IL-13, IL-17A, CCL 2/MCP-1, CCL3/MIP-1α, CCL4/MIP-1β, TNF-α, and TNF-β, did not differ significantly between groups (Supplementary Table S1). The 12 cytokines/chemokines differentially expressed in Groups T and Group P (in comparison to expression in Group C) fell into three categories (Fig. 3). Category A included four cytokines/chemokines, IL-6, IL-10, IL-15, and G-CSF, that were significantly increased in both FL groups. Notably, the IL-6 concentration (pg/mL) was markedly increased in Group T (17 [5, 36]) and Group P (30 [14, 54]) in comparison to that in Group C (0 [0, 0]) (each, P < 0.001). Category B included five cytokines/chemokines, IL-1β, IL-1Ra, IL-8, IL-12p70, and GM-CSF, that were significantly increased only in Group P. Category C included three other cytokines/chemokines, IP-10 (significantly decreased only in Group P), VEGF-A (significantly increased only in Group T), and CCL11/eotaxin (no significant difference between Group T or Group P and Group C after adjustment for multiple comparisons). Increases in the Category A and Category B cytokines/chemokines tended to be less pronounced in Group T than in Group P, but the differences in concentrations between these two groups were not significant. Further, we analyzed concentrations of the 12 differentially expressed cytokines/chemokines between Group P patients with a partially patent FL (n = 12) and those with a completely patent FL (n = 11). As shown in Supplementary Table S2, the G-CSF concentration was increased in patients with a partially patent FL, compared to the concentration in those with a completely patent FL. However, concentrations of the remaining 11 cytokines/chemokines did not differ significantly between these two groups of patients.

Table 2

The 12 cytokines/chemokines for which the concentration differed significantly between groups, per study group
Cytokine/chemokine	Group T (n = 21)	Group P (n = 23)	Group C (n = 20)	P value*
IL-6	17 [5, 36]	30 [14, 54]	0 [0, 0]	< 0.001
IL-10	0 [0, 16]	8 [0, 106]	0 [0, 0]	< 0.001
IL-15	2 [0, 4]	3 [1, 5]	0 [0, 1.5]	< 0.001
G-CSF	13 [0, 26]	21 [6, 50]	0 [0, 3]	< 0.001
IP-10	265 [164, 384]	195 [140, 273]	337 [275, 566]	0.001
GM-CSF	0 [0, 0]	0 [0, 5]	0 [0, 0]	0.003
VEGF-A	163 [0, 271]	97 [0, 252]	41 [0, 83]	0.010
IL-1β	0 [0, 0]	0 [0, 2]	0 [0, 0]	0.013
IL-1Ra	0 [0, 0]	0 [0, 63]	0 [0, 0]	0.017
IL-12p70	0 [0, 0]	0 [0, 7]	0 [0, 0]	0.022
IL-8/CXCL	9 [5, 18)	11 [6, 19]	6 [3, 8)	0.033
CCL11/eotaxin	78 [49, 133]	27 [9, 85]	73 [42, 173]	0.047
Cytokines/chemokines are listed along with their median [25th, 75th percentile] concentrations (pg/mL). Group T thrombosed false lumen group, Group P non-thrombosed false lumen group, Group C non-ruptured aortic aneurysm (control) group. *by Kruskal-Wallis test.

We compared cytokine/chemokine concentrations between the propensity score-matched patients and Group C patients. Clinical and disease morphology after propensity score matching are shown in Supplementary Table S3. After matching, no covariate differed between the groups. On-admission laboratory values in each propensity score-matched group were similar to those in the unmatched patient group and those in the control group (data not shown). Concentrations of 14 cytokines/chemokines differed significantly between the three groups (Table 3). After matching, expression of four cytokines/chemokines, CCL3/MIP-1α, IFN-γ, IL-17a, and IL-2, differed significantly between the three groups, whereas expression of IL-8 and CCL11/eotaxin did not. Cytokine/chemokine concentrations are shown per propensity score-matched group in Supplementary Fig. S2. Propensity score-matching analysis revealed similar expression patterns with respect to all four Category A cytokines, four Category B cytokines (IL-1β, IL-1Ra, IL-12p70, and GM-CSF), and two Category C cytokines (IP-10 and VEGF-A).

Table 3

The 14 cytokines/chemokines for which the concentration differed significantly between propensity-score matched groups, per study group
Cytokine/chemokine	PSM Group T (n = 10)	PSM Group P (n = 10)	Group C (n = 20)	P value*
IL-6	25 [7.5, 46]	40 [6, 56]	0 [0, 0]	< 0.001
IL-15	2 [1.5, 5]	3 [1.5, 6.3]	0 [0, 1.5]	< 0.001
GM-CSF	0 [0, 1]	1.5 [0, 11.5]	0 [0, 0]	< 0.001
G-CSF	19 [0, 29]	22 [5.3, 72]	0 [0, 3]	0.001
VEGF-A	143 [0, 212]	218 [96, 362]	41 [0, 83]	0.001
IL-10	4 [0, 38]	3 [0, 43]	0 [0, 0]	0.002
IL-1β	0 [0, 0.75]	0.5 [0, 2.3]	0 [0, 0]	0.005
IP-10	197 [141, 277]	234 [158, 325]	337 [275, 566]	0.005
IL-12p70	0 [0, 1]	4 [0, 100]	0 [0, 0]	0.008
CCL3/MIP-1α	0 [0, 0]	0 [0, 7.3]	0 [0, 0]	0.009
IFN-γ	0 [0, 1]	2.5 [0, 23]	0 [0, 0]	0.009
IL-1Ra	0 [0, 4.5]	1.5 [0, 228]	0 [0, 0]	0.019
IL-17a	0 [0, 0.25]	11.5 [0, 36]	0 [0, 0]	0.019
IL-2	0 [0, 0]	0 [0, 6.8]	0 [0, 0]	0.037
Cytokines/chemokines are listed along with their median [25th, 75th percentile] concentrations (pg/mL). PSM Group T propensity score-matched thrombosed false lumen group, PSM Group P propensity score-matched non-thrombosed false lumen group, Group C non-ruptured aortic aneurysm (control) group. PSM propensity score matched *by Kruskal-Wallis test.

Influence of FL thickness on cytokine concentrations in patients with a thrombosed FL (Part 2 study)

Five cytokines, IL-6, IL-10, IL-15, G-CSF, and VEGF-A, were found to be significantly increased in Group T compared to concentrations in Group C. To further elucidate the influence of dissection morphology on cytokine expression, we investigated correlation between FL thickness and concentrations of the five cytokines that were increased in Group T. Positive correlation was observed between FL thickness and the IL-6 and G-CSF concentrations (Supplementary Fig. S3).

To validate the positive correlation between FL thickness and cytokine/chemokine concentrations, we divided the Group T patients into two subgroups, Group T-thin FL (FL thickness ≤ 11 mm, n = 10) and Group T-thick FL (FL thickness > 11 mm, n = 11), as noted above (Methods). We then compared IL-6 and G-CSF concentrations, the WBC count, and the D-dimer concentration between these two subgroups. Baseline characteristics and clinical status of the patients are shown per subgroup in Supplementary Table S4. Clinical characteristics, including age, sex, and comorbidities, did not differ significantly between the two subgroups. Similarly, no morphologic characteristic, except FL thickness, including type A or type B aortic dissection, maximum aortic diameter, and distal extent of the aortic dissection, differed significantly between the two subgroups. Consistent with the positive correlation between IL-6 and G-CSF concentrations and FL thickness, IL-6 and G-CSF concentrations were significantly decreased in Group T-thin FL compared to concentrations in Group T-thick FL. The WBC count and D-dimer concentration did not differ between the two subgroups (Fig. 4).

A systemic inflammatory response can occur in association with various cardiovascular emergencies, including cardiogenic shock and acute myocardial infarction, and such a response increases the risk of both short- and long-term mortality¹⁸. Cardiogenic shock or organ malperfusion per se contributes to the systemic inflammatory response associated with AAD. In addition, aortic repair provokes multiple adverse biologic reactions related to the use of cardiopulmonary bypass and surgical trauma. Therefore, adjustment of con founding factors is important in investigating the effect of morphologic factors on the systemic inflammatory response triggered by aortic dissection. In this study of AAD, after excluding patients with complications and those with hematologic or autoimmune disease, we compared on-admission cytokine/chemokine concentrations between full unmatched and propensity score-matched patients with a thrombosed FL, patients with a non-thrombosed FL, and, for control, patients with a non-ruptured thoracic aortic aneurysm. The major findings of our study were as follows: (1) a robust inflammatory response occurred regardless of FL status, but the number of differentially expressed cytokines was decreased in patients with a thrombosed FL; (2) IL-6, IL-10, IL-15, and G-CSF concentrations were significantly increased in both FL groups, but the increase was attenuated in patients with a thrombosed FL; and (3) among patients with a thrombosed FL, IL-6 and G-CSF concentrations correlated with FL thickness. To the best of our knowledge, our study is the first reported cytokine profiling study designed to investigate the influence of FL status on expression of multiple cytokine/chemokines in patients with AAD.

The initial AAD event is occurrence of an intimal tear, which is followed by influx of blood into the aortic wall, resulting in FL formation. Medial degeneration is considered a key background histologic factor in cases of aortic dissection^19,20. Influx of blood into the aortic wall commonly progresses to the outer third of the media alongside the vasa vasorum²¹. Separation of the medial layer triggers recruitment of inflammatory cells. Histopathologic study has shown initial neutrophil accumulation in the adventitia of the dissected aorta, followed by infiltration of monocytes and lymphocytes^22,23. Regarding progression of local inflammation to a systemic inflammatory response, using a murine experiment model, Anzai et al. showed that AAD triggers CXCL-1 and G-CSF expression in locally activated myofibroblasts and resident macrophages in the adventitia, leading to elevation of circulating CXCL1/G-CSF and a reduction of CXCL12 in bone marrow. These chemokine changes promote neutrophil mobilization from the bone marrow to the peripheral circulation, resulting in further neutrophil infiltration into the aortic wall²³. The adventitial inflammation serves to repair the damaged aortic tissue, but excessive inflammation weakens the aortic wall, and aortic expansion and catastrophic aortic rupture ensue²³. Our study showed four cytokines, IL-6, IL-10, IL-15, and G-CSF, to be increased in both FL groups, but these elevations were somewhat attenuated in patients with a thrombosed FL. In addition, six cytokines, including GM-CSF and IL-8, were increased only in patients in the non-thrombosed FL group. G-CSF and IL-8 function as neutrophil chemoattractants^24,25. We hypothesize that FL thrombosis suppresses production of neutrophil chemoattractant in the dissected aorta and thus its release into the circulating blood. In this scenario, transport through the microvessel network in the adventitia and/or direct efflux from the dissected aorta into the luminal blood is impaired in the thrombosed FL. Another possible mechanism is decreased production of neutrophil chemoattractant in the thrombosed FL. A future histopathologic study is needed to elucidate the mechanisms of neutrophil-mediated adventitial inflammation following AAD.

Previous studies on biomarkers have shown various pro- and anti-inflammatory cytokines, including IL-6^4,8,9, IL-8^4,8, TNF-a^4,8, IL-10^8–10, GM-CSF¹² and IL-17¹¹, to be increased in the circulating blood of patients with AAD. Consistent with these reports, IL-6, IL-8, IL-10, or GM-CSF was elevated in one or two of our FL groups. IL-6 is an important pro-inflammatory cytokine, and growing evidence suggests that overexpression of IL-6 plays a pivotal role in the pathophysiology of aortic dissection^23,26,27. Aoki et al. reported that IL-6 activates the intracellular Jak/signal transducer and activator of transcription 3 (STAT3) signal pathway to alter the gene expression profile and the cellular response, promoting a local inflammatory response in the dissected aorta²⁶. The role of IL-6 in aortic pathology includes macrophage maturation, increased transcription of MCP-1 and MMP-9, and promoting differentiation of native T cells into Th17 cells²⁷. Anzai et al. reported that IL-6-producing neutrophils accumulate in the adventitia of patients with AAD and that IL-6 deficiency attenuated aortic expansion and rupture after AAD in a murine experiment model²³. Our study showed the IL-6 concentration to be positively correlated with FL thickness in patients with a thrombosed FL. FL thickness has been reported to predict adverse events associated with AAD involving a thrombosed FL (intramural hematoma)²⁸. An attenuated IL-6-induced systemic inflammatory response in patients with a thin thrombosed FL may contribute to favorable outcomes in this group.

Systemic inflammatory response may occur even in patients with a thrombosed FL if they suffer shock or organ malperfusion. Furthermore, other morphologic factors, such as aortic diameter and longitudinal extent of aortic dissection may influence systemic inflammatory response in AAD. Regarding aortic diameter, the serum concentration of angiopoietin-like protein 8, a hormone involved in the regulation of lipid metabolism and inflammation, has been was positively associated with aortic diameter in patients with thoracic aortic dissection²⁹. We noted that the longitudinal extent of dissection tended to be greater in our Group P than in our Group T. This phenomenon was reported in both type A³⁰ and type B³¹ AAD. Although our propensity score-matching analysis showed a similar pattern of cytokine/chemokine expression after adjustment for the extent of dissection, our patient volume is small. Limited dissection extension might have been related to attenuating systemic inflammatory response in patients with a thrombosed FL.

The major complication caused by systemic inflammatory response following AAD is acute lung injury. Pan et al. reported a 53.8% (70/130) incidence of preoperative acute lung injury (arterial partial pressure of oxygen (PaO2)/fraction of inspiratory oxygen (FiO2) ratio < 300 mmHg) among patients with type A AAD and showed age, obesity, and IL-6 to be independent factors for preoperative acute lung injury⁹. Kurabayashi et al. reported correlation between impairment of oxygenation in patients with type B AAD and FL volume/descending aortic volume ratio³². Suppression of the systemic inflammatory response may become a therapeutic target for acute lung injury following AAD.

Limitations

Our investigation had several limitations. First, the sample size was relatively small. A large-scale study is needed to confirm our findings. Second, median age of our Group T patients was significantly greater than that of our Group P patients. Elderly patients tend to be in a chronic inflammatory state due to age-related disease, including atherosclerosis³³, and age-related inflammation may lead to dysregulation of the innate immune response, characterized by impaired cell migration and effector functions³⁴. The inflammatory response shown in our Group T might have been influenced by the basic immune status of the elderly patients. Third, we did not investigate patients’ neutrophil/lymphocyte ratio.

Our cytokine profiling study showed that a robust inflammatory response to AAD occurs regardless of FL status but that the response is somewhat attenuated in patients with a thrombosed FL. In AAD patients with a thrombosed FL, FL thickness is associated with expression of IL-6 and G-CSF in peripheral blood.

Data availability

The data supporting this study are available from the corresponding author upon reasonable request.

Acknowledgement

We would like to thank Dr. Akio Matsuda for technical assistance in the measurement of cytokines.

Author contributions

N.K.: Conceptualization, formal analysis, investigation, data collection, writing, review and editing. Y.M.: Formal analysis, investigation; data collection, writing. D.H.: Supervision. M.M.: Methodology, validation. N.E.: Data collection. M.S.: Supervision. A.Y: Supervision. K.M: Investigation, supervision. M.T.: Funding acquisition, supervision. All authors reviewed the manuscript.

Funding

This work was supported by JSPS KAKENHI Grant Number #21K08849 (grantee: M.T.) (Ministry of Education, Culture, Sports, Science and Technology, Japan).

Competing interests

The authors declare no competing intersts.

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Influence of false lumen status on systemic inflammatory response triggered by acute aortic dissection

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Abstract

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Introduction

Methods

Patients and study protocol

Measurement of cytokines/chemokines

Statistical analysis

Ethics approval

Patient consent

Results

Clinical characteristics, disease morphology, and laboratory values, per FL group

Cytokine concentrations, per FL group (Part 1 study)

Discussion

Limitations

Conclusion

Declarations

References

Additional Declarations

Supplementary Files

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