Aortic Agatston score correlates with the progression of acute type A aortic dissection.

Aortic calcification in the tunica media is correlated with aortic stiffness, elastin degradation, and wall shear stress. The study aim was to determine if aortic calcifications influence disease progression in patients with acute type A aortic dissection (ATAAD). We retrospectively reviewed a total of 103 consecutive patients who had undergone surgery for ATAAD at our institution between January 2009 and December 2019. Of these, 85 patients who had preoperatively undergone plain computed tomography angiography (CTA) for evaluation of their aortic calcification were included. Moreover, we assessed the progression of aortic dissection after surgery via postoperative CTA. Using a classification and regression tree to identify aortic Agatston score thresholds predictive of disease progression, the patients were classified into high-score (Agatston score ≥ 3344; n  =   36) and low-score (<3344; n  =   49) groups. Correlations between aortic Agatston scores and CTA variables were assessed. Higher aortic Agatston scores were significantly correlated with the smaller distal extent of aortic dissection (p < 0.001), larger true lumen areas of the ascending (p  =  0.009) and descending aorta (p =   0.002), and smaller false lumen areas of the descending aorta (p =  0.028). Patients in the high-score group were more likely to have DeBakey type II dissection (p =  0.001) and false lumen thrombosis (p  =  0.027) than those in the low-score group, thereby confirming the correlations. Aortic dissection in the high-score group was significantly less distally extended (p < 0.001). A higher aortic Agatston score correlates with the larger true lumen area of the ascending and descending aorta and the less distal progression of aortic dissection in patients with ATAAD. Interestingly, the findings before and after surgery were consistent. Hence, aortic Agatston scores are associated with aortic dissection progression and may help predict postoperative residual dissected aorta remodeling.

Introduction

Aging, dyslipidemia, tobacco use, inflammatory disease, chronic kidney disease, and diabetes mellitus are considered to be factors that predispose individuals to aortic calcification, which is increasingly recognized as a strong predictor of cardiovascular events and all-cause mortality [1-3]. Interestingly, aortic calcification reportedly can be detected in the tunica media of the human aorta before being observed in neo-intima plaques [4, 5]. Moreover, pathological research has indicated that the average amount of calcification at all ages is higher in the tunica media than in the intima [6, 7].

ATAAD is a life-threatening cardiovascular event that requires immediate surgical repair [8]. Aortic dissection results from the separation of the aortic wall layers, and a tear in the intimal layer allows blood to enter the tunica media, which causes progressive dissection [9]. Aortic calcifications extending from the aortic intima to the media may prevent progression of aortic dissection by restricting the separation [10]. Although several studies have investigated the association between aortic calcifications and abdominal aortic aneurysms (AAAs) [11], few have examined the association of aortic calcifications with ATAAD [12-14]. Aortic calcifications have been shown to increase the peak wall shear stress and decrease the biomechanical stability of AAAs [15]. Furthermore, aortic stiffening, increased pulse pressure, reduced coronary blood flow, and left ventricular hypertrophy have been found to be strongly associated with aortic calcifications in the intima and media [16-18]. It is plausible that aortic calcifications could alter the biomechanical properties of the aorta in patients with acute type A aortic dissection (ATAAD), thereby influencing aortic dissection progression.

The severity of coronary artery calcification is often represented by an Agatston score, which is an independent risk marker for cardiac events, cardiac mortality, and all-cause mortality [19, 20]. Even though aortic Agatston scores have been used in a large number of studies for assessment of aortic calcification severity [21-24], no study to date has focused on aortic Agatston scores in patients with ATAAD. Hence, we conducted this study to explore the association of aortic Agatston scores with disease progression in patients with ATAAD.

Materials and methods

Patients

After obtaining approval and a waiver of informed consent from our Institutional Review Board, we retrospectively reviewed a total of 103 consecutive patients who had undergone emergency surgery for ATAAD at Yokosuka General Hospital Uwamachi between 2009 and 2019. Eighteen patients without preoperative aortic calcification measurements by plain computed tomography angiography (CTA) were excluded. The remaining 85 patients were included in the study. We used a classification and regression tree (CART), a machine-learning algorithm for clinical decision-making that can be used to determine the breakpoint and identify aortic Agatston score thresholds predictive of disease progression (distal extent of aortic dissection) in patients with ATAAD (S1 Fig). CART is a nonparametric decision tree learning technique that produces either classification or regression trees based on whether the dependent variable is categorical or numeric, respectively [25, 26]. The patients were divided into two groups according to the Agatston score cutoff value identified by CART (cutoff value = 3344): the high-score group had 36 patients with Agatston score ≥ 3344, whereas the low-score group had 49 patients with Agatston score < 3344. Then, we examined the association between aortic calcifications and the extent of aortic dissection in these patient groups. Furthermore, to investigate the early progression of aortic dissection after surgery, we also examined the association between aortic calcifications and postoperative CTA variable of the descending aorta in the patients, excluding those who had DeBakey type II dissection (n = 20) and those who died before performing the postoperative CTA (n = 4). The patient selection flowchart is illustrated in Fig 1.

Fig 1

Patient selection flowchart.

Data collection

CTA and echocardiography were performed to establish a definitive diagnosis. Upon confirmation of the ATAAD diagnosis, the patients were transferred to the operating room as soon as possible. Intraoperative findings confirmed ATAAD as well. Postoperative CTA was performed within 7 days after surgery to assess early aortic dissection progression after the initial surgery and changes in CTA variables from pre- to post-surgery. Furthermore, postoperative plain computed tomography (CT) scan was conducted 6 months after surgery to assess midterm changes in descending aortic dimension and diameter after surgery between the two groups. Data on the following variables were collected from the patients’ medical records and compared between the two groups: preoperative CTA variables, including aortic diameters, area of the ascending aorta at the level of the right pulmonary artery, area of the descending aorta at the level of the aortic valve, true and false lumen areas, the location of major entry, distal extent of aortic dissection, volume and surface area of total aortic calcifications, and aortic Agatston score; postoperative CTA variables, including the totally thrombosed false lumen of both the descending and abdominal aortas, aortic diameters, total aortic area, and true and false lumen areas of the descending aorta at the level of the aortic valve. The location of the major entry was identified on the preoperative CTA, and it was confirmed during surgery in case the entry site was located in the proximal aorta (aortic root, ascending aorta) or the aortic arch.

Measurement of aortic calcifications and areas on CTA

Aortic calcifications were measured by using Synapse Vincent software (version 5.3; Fujifilm, Tokyo, Japan). Calcified lesions located from the sinuses of Valsalva to the aortic bifurcation were identified with a density of > 130 Hounsfeld units (HU) on preoperative plain CT. Subsequently, a calcium score was calculated for each region by multiplying the area by a cofactor (i.e., cofactor 1, 130–199 HU; cofactor 2, 200–299 HU; cofactor 3, 300–399 HU; and cofactor 4, > 400 HU). Finally, a total aortic Agatston score was calculated by adding the scores for all individual lesions. CT images were reconstructed at a 5-mm slice thickness on a Phillips Brilliance CT64 (Philips, Amsterdam, Netherlands) or TSX301B-1A (Canon, Tokyo, Japan).

As false and true lumen areas, the ratio of false lumen area to true lumen area, and false lumen thrombosis are associated with disease prognosis, we also measured these variables to assess their association with aortic calcification. Total aortic area and diameters as well as true and false lumen areas were measured for the ascending aorta at the level of the right pulmonary artery and for the descending aorta at the aortic valve level. These parameters, however, were not evaluated for the descending aorta in patients with DeBakey type II dissection. Representative images for both groups are shown in Fig 2. The area ratio of the true lumen to total lumen was calculated as follows:

Fig 2

Representative images of aortic area measurements.

(A), (B), and (C) depict representative computed tomography images from patients in the high-score group, whereas (D), (E), and (F) are those from patients in the control group. (C), (F) Total and true aortic lumen areas were evaluated at the (1) ascending and (2) descending aorta. (A), (D) The delineated area on the ascending aorta was measured at the level of the right pulmonary artery. (B), (E) The delineated area on the descending aorta was assessed at the level of the aortic valve. Total and true aortic lumen areas are marked by broken-line and dotted-line circles, respectively. AV = aortic valve; Asc = ascending aorta; Des = descending aorta; PA = pulmonary artery; TL = true lumen.

The false lumen area was calculated as the true lumen area subtracted from the total aortic lumen area.

Assessment of disease progression in aortic dissection on CTA

The Society for Vascular Surgery/Society of Thoracic Surgeons (SVS/STS) Aortic Dissection Classification System was used to assess the progression of aortic dissection [27]. According to the SVS/STS system, the distal extent score defined the zone to where the aortic dissection was distally extended to as shown in Fig 3. The distal extent score ranged from 0 (aortic dissection within ascending aorta) to 12 (aortic dissection extended to femoral artery), wherein lower scores reflected less progression of the dissection.

Fig 3

Scheme of distal extent score according to the Society for Vascular Surgery/Society of Thoracic Surgeons Aortic Dissection Classification System.

A. In the example illustrated, the dissection process extends distally to zone 12, which indicates the distal extent score of “12”.

Surgical procedure

Our surgical procedure consisted of a median sternotomy with a standard cardiopulmonary bypass. The subclavian artery, left ventricular apex, or femoral artery was used for arterial cannulation. An antegrade or retrograde infusion of cold blood cardioplegic solution was administered for myocardial protection. Surgery was performed under hypothermic circulatory arrest (bladder temperature, 20°C–26°C), and open distal anastomosis was performed under circulatory arrest with or without antegrade selective cerebral perfusion. Basically, a tear-oriented surgical strategy was adopted [28]. An ascending aortic replacement was performed when the entry site was located in the ascending aorta or when an entry tear could not be identified in the ascending aorta or aortic arch (DeBakey IIIb retrograde dissection). On the other hand, total or partial arch replacement was performed for patients with an entry site in the aortic arch. Although aortic valves were preserved whenever possible, we performed aortic root replacement for cases with an intimal tear extending to the sinuses of Valsalva or those with aortic root dilation associated with annuloaortic ectasia.

Statistical analysis

Continuous data were expressed as the median (interquartile range) and compared between the two groups by performing the Mann–Whitney U test. Categorical data were expressed as frequencies (%) and analyzed by performing the chi-square test or Fisher’s exact test. To examine the relationship between aortic Agatston scores and CTA variables, correlation coefficients were calculated by using the nonparametric Spearman correlation analysis. All statistical analyses were performed by using EZR software (Saitama Medical Center, Jichi Medical University, Saitama, Japan). Values of p < 0.05 were considered to be indicative of statistical significance.

Results

Patients’ characteristics

The preoperative clinical characteristics of the patients are presented in Table 1. The patients in the high-score group were significantly older than those in the low-score group (77.5 vs. 63 years, respectively; p < 0 .001). Furthermore, the body mass index was significantly lower in the high-score group than in the low-score group (p   = 0 .002). There were no significant differences in sex, hypertension, diabetes mellitus, chronic kidney disease, hyperlipidemia, ischemic heart disease, peripheral artery disease, smoking history, preoperative shock status (systolic blood pressure < 80 mmHg), and neurological deficit between the two groups. Interestingly, cardiac tamponade was more frequently observed in the high-score group than in the low-score group (p  = 0 .005). No significant difference was observed in each malperfusion between the studied groups.

Table 1

Preoperative characteristics.

Characteristics	Total (n = 85)	Low-score group (n = 49)	High-score group (n = 36)	p-value
Age	68 (60–77)	63 (53–69)	77.5 (71–83)	<0.001
Female	44 (51.8%)	20 (40.8%)	24 (66.7%)	0.028
BMI	23.8 (21–27.6)	25.3 (21.3–29.8)	22.8 (19.5–24.5)	0.002
Hypertension	73 (85.9%)	40 (81.6%)	33 (91.7%)	0.224
Diabetes mellitus	6 (7.1%)	5 (10.2%)	1 (2.8%)	0.236
Chronic kidney disease	46 (54.1%)	23 (46.9%)	23 (63.9%)	0.131
Hyperlipidemia	20 (23.5%)	11 (22.4%)	9 (25%)	0.801
Ischemic heart disease	3 (3.5%)	1 (2%)	2 (5.6%)	0.571
Peripheral artery disease	0 (0%)	0 (0%)	(0%)	>0.99
Smoking history	20 (23.5%)	15 (30.6%)	5 (13.9%)	0.119
Preoperative shock	12 (14.1%)	4 (8.2%)	8 (22.2%)	0.112
Cardiac tamponade	46 (54.1%)	20 (40.8%)	26 (72.2%)	0.005
Cardiopulmonary resuscitation	2 (2.4%)	2 (4.1%)	0 (0%)	0.506
Neurologic deficit	5 (5.9%)	3 (6.1%)	2 (5.6%)	>0.99
Malperfusion
Paraplegia	2 (2.4%)	2 (4.1%)	0 (0%)	0.506
Limb	11 (12.9%)	7 (14.3%)	4 (11.1%)	0.753
Renal	9 (10.6%)	6 (12.2%)	3 (8.3%)	0.727
Brain	11 (12.9%)	8 (16.3%)	3 (8.3%)	0.342
Coronary	3 (3.5%)	1 (2%)	2 (5.6)	0.571
Mesenteric	11 (12.9%)	9 (18.4%)	2 (5.6%)	0.108

BMI, body mass index.

Correlations between Agatston scores and preoperative CTA variables

Spearman correlation coefficients were used to evaluate the relationships between Agatston scores and preoperative CTA variables (Table 2). The Agatston scores were highly correlated with the average CT value (p  <  0.001), maximum CT value (p  <  0.001), aortic calcification volume (p  <  0.001), and aortic calcification surface area (p  <  0.001). Despite having no correlations with the diameters and total areas of the ascending and descending aortas, the Agatston scores were significantly correlated with the true lumen areas of the ascending and descending aorta (p  =  0.009 and p  =  0.002, respectively) and with the ratios of the true lumen area to total lumen area for the ascending and descending aortas (p  =  0.009 and p  < 0.001, respectively). Although the Agatston scores did not correlate with the false lumen area of the ascending aorta, they displayed a significant correlation with the false lumen area of the descending aorta (p  =   0.028). The results suggested that higher Agatston scores were significantly correlated with larger true lumen areas of the ascending and descending aortas and with smaller false lumen areas of the descending aorta. Interestingly, the correlation of Agatston scores with the true and false lumen areas of the descending aorta appeared to be stronger than the correlation with the true and false lumen areas of the ascending aorta.

Table 2

Correlation between Agatston score and CTA variables.

Correlations	rho	p-value
Distal extent score	−0.494	<0.001
Asc diameter (mm)	0.184	0.094
Asc area (mm2)	0.203	0.062
True lumen area of Asc (mm2)	0.28	0.009
False lumen area of Asc (mm2)	−0.103	0.357
True lumen/total lumen area ratio of Asc	0.28	0.009
Des diameter (mm)	0.057	0.647
Des area (mm2)	0.081	0.522
True lumen area of Des (mm2)	0.456	0.002
False lumen area of Des (mm2)	−0.273	0.028
True lumen/total lumen area ratio of Des	0.487	<0.001
Average of CT value	0.795	<0.001
Max of CT value	0.879	<0.001
Calcification volume (mm3)	0.996	<0.001
Calcification surface area (mm2)	0.998	<0.001

CTA, computed tomography angiography; Asc, ascending aorta; Des, descending aorta.

As shown in Table 3, DeBakey type II dissection and false lumen thrombosis were more commonly observed in the high-score group than in the low-score group (p = 0.036, p = 0.002, respectively). Further, the distal extent score was significantly lower in the high-score group than in the low-score group (5 vs. 10, p < 0.001). No significant difference was found in the major entry location. The true lumen areas of the ascending and descending aortas were significantly larger in the high-score group than in the low-score group (731.9 vs. 480.4 mm2, p   =  0.025; 376.2 vs. 250.9 mm2, p  <  0.001), whereas the diameters and total areas of the ascending and descending aortas were not significantly different between the groups. We also found that the true lumen area/total lumen area ratios of the ascending and descending aortas were significantly higher in the high-score group than in the low-score group (0.369 vs. 0.293, p   =  0.039; 0.469 vs. 0.323, p  <  0.001). Furthermore, the false lumen area of the descending aorta was significantly smaller in the high-score group than in the low-score group (421.9 vs. 519.5 mm2, p  =  0.02). Additionally, we noticed that the average CT value, maximum CT value, aortic calcification volume, and aortic calcification surface area were significantly greater in the high-score group than in the low-score group (p <  0.001 for all variables).

Table 3

Preoperative CTA variables.

Preoperative CTA variables	Total (n = 85)	Low-score group (n = 49)	High-score group (n = 36)	p-value
DeBakey Ⅰ or Ⅲb retrograde	65 (76.5%)	44 (89.8%)	21 (58.3%)	0.001
DeBakey Ⅱ	20 (23.5%)	5 (10.2%)	15 (41.7%)	0.001
Distal extent score	8 (4–10)	10 (7–11)	5 (0–8)	<0.001
Major entry location
Aortic root	5 (5.9%)	2 (4.1%)	3 (8.3%)	0.646
Ascending aorta	43 (50.6%)	25 (51%)	18 (50%)	>0.99
Aortic arch	24 (28.2%)	16 (32.7%)	8 (22.2%)	0.337
Descending aorta	2 (2.4%)	1 (2%)	1 (2.8%)	>0.99
Unidentified	11 (12.9%)	5 (10.2%)	6 (16.7%)	0.516
False lumen thrombosis	39 (45.9%)	17 (34.7%)	22 (61.1%)	0.027
Asc diameter (mm)	46.5 (43.6–50.1)	46.5 (43.3–48.8)	47.2 (44.2–51.3)	0.268
Asc area (mm2)	1752 (1554–2026)	1745 (1544–1996)	1794 (1609–2160)	0.185
True lumen area of Asc (mm2)	581 (333–993)	497 (320–782)	743 (376–1150)	0.033
False lumen area of Asc (mm2)	1110 (795–1404)	1119 (833–1442)	1083 (761–1295)	0.388
True lumen/total lumen area ratio of Asc	0.34 (0.21–0.52)	0.28 (0.2–0.47)	0.38 (0.23–0.6)	0.058
Des diameter (mm)	30.9 (29.7–34.1)	31 (29.5–33.5)	30.7 (29.9–34.3)	0.874
Des area (mm2)	800 (688–906)	805 (681–890)	763 (698–919)	0.833
True lumen area of Des (mm2)	295 (229–393)	256 (207–351)	385 (335–430)	0.002
False lumen area of Des (mm2)	483 (406–593)	518 (441–612)	413 (337–533)	0.017
True lumen/total lumen area ratio of Des	0.36 (0.29–0.48)	0.32 (0.28–0.39)	0.47 (0.38–0.58)	0.001
Average of CT value	273 (238–314)	245 (212–269)	314 (298–365)	<0.001
Max of CT value	1026 (678–1507)	730 (439–986)	1600 (1264–1746)	<0.001
Calcification volume (mm3)	3627 (519–9892)	629 (328–2722)	12080 (8034–20373)	<0.001
Calcification surface area (mm2)	629 (104–1978)	122 (57–475)	2416 (1607–4075)	<0.001
Agatston score	2171 (352–7519)	381 (162–1574)	8718 (5374–14939)	<0.001

CTA, computed tomography angiography; Asc, ascending aorta; Des, descending aorta.

Associations between Agatston scores and postoperative CTA variables in patients with DeBakey I or IIIb retrograde

To investigate the association between aortic calcification and early remodeling of aortic dissection after surgery among the 61 patients with DeBakey Ⅰ or IIIb retrograde, postoperative CTA variables were compared between 21 patients in the high-score group and 40 patients in the low-score group (Table 4). No significant difference was found in the surgical procedures between the two groups. The distal extent score after surgery was significantly lower in the high-score group than in the low-score group (p < 0.001). The false lumens of both the descending and abdominal aortas were more frequently totally thrombosed in the high-score group after surgery than in the low-score group (75% [21 of 28] vs. 32.4% [12 of 37], respectively; p = 0.001). Although the aortic diameter and total aortic area of the descending aorta were not significantly different between the groups, the true lumen area and true lumen/total lumen area ratio of the descending aorta were significantly larger in the high-score group than in the low-score group (486 vs. 301 mm2, p = 0.001; 0.6 vs. 0.41, p = 0.003, respectively). Further, the false lumen area of the descending aorta was significantly smaller in the high-score group than in the low-score group (p = 0.042). Compared with preoperative CTA variables, the postoperative true lumen dimension of the descending aorta was small in the high- and low-score groups (p = 0.038, 0.058, respectively). However, the distal extent score after surgery did not significantly change (S1 Table). Moreover, there was no remarkable difference in the changes in the distal extent score and true and false lumen area of the descending aorta from pre- to post-surgery between the two groups (S2 Table). Hence, high aortic Agatston scores could be correlated with a slower progression of residual dissected descending aorta before and after surgery.

Table 4

Surgical procedures and postoperative CTA variables in the patients with DeBakey I or IIIb retrograde.

Postoperative CTA variables	Total (n = 61)	Low-score group (n = 40)	High-score group (n = 21)	p-value
Ascending aorta replacement	49 (80.3%)	31 (77.5%)	18 (85.7%)	0.518
Aortic arch replacement	10 (16.4%)	8 (20%)	2 (9.5%)	0.47
Aortic root replacement	2 (3.3%)	1 (2.5%)	1 (4.8%)	>0.99
Concomitant AVR	5 (8.2%)	3 (7.5%)	(9.5%)	>0.99
Concomitant CABG	1 (1.6%)	0 (0%)	1 (4.8%)	0.344
False lumen thrombosis	38 (62.3%)	19 (47.5%)	17 (81%)	0.015
Distal extent score	9 (8–11)	10 (9–11)	8 (6–10)	0.025
Des diameter (mm)	32.3 (30.8–35.3)	32.3 (31.1–34.4)	33.2 (30.6–36.3)	0.606
Des area (mm2)	841 (748–960)	819 (760–895)	859 (715–1077)	0.495
True lumen area of Des (mm2)	379 (261–515)	315 (240–482)	486 (377–663)	0.002
False lumen area of Des (mm2)	451 (327–572)	496 (394–582)	327 (276–551)	0.024
True lumen/total lumen area ratio of Des	0.47 (0.31–0.6)	0.4 (0.29–0.53)	0.6 (0.47–0.67)	0.003

CTA, computed tomography angiography; AVR, aortic valve replacement; CABG, coronary artery bypass grafting; Des, descending aorta.

Moreover, we assessed and compared the midterm changes in descending aortic diameter and area via plain CT scan 6 months after surgery and CT variables within 7 days after surgery. Interestingly, dilatation of the descending aortic diameter and area 6 months after surgery were smaller in the high-score group than in the low-score group (Des diameter change: 0.98 [0.87–1.04] vs. 1.01 [0.94–1.1], p = 0.058; Des area change: 1.03 [0.88–1.13] vs. 1.11 [0.97–1.29], p = 0.031, in fold change/CT variables within 7days after surgery) (S3 Table).

Discussion

This study demonstrated the following: 1) aortic Agatston scores significantly correlated with the progression of aortic dissection and the true lumen areas and true lumen area/total lumen area ratios of the ascending and descending aortas; 2) DeBakey type II dissection and false lumen thrombosis were significantly more likely and aortic dissection was less distally extended in the high-score group than in the low-score group; and 3) consistent with the preoperative findings, in the postoperative CTA variables among the patients with DeBakey Ⅰ or IIIb retrograde, the false lumens of the descending and abdominal aortas were more frequently totally thrombosed and the true lumen area of the descending aorta was significantly larger in the high-score group, although no significant difference in the surgical procedure was noted. In the current study, the aforementioned points 1) and 2) could be the most important findings supporting our hypothesis.

Blumenthal et al. studied the relationship between age and the amounts of calcium in the intima and media of 540 human aortic specimens and found that calcifications were more common in the tunica media than in the intima at all ages [29]. Moreover, pathological examinations have indicated that aortic dissection initially develops in the tunica media [9]. Therefore, aortic calcifications present between the intima and the tunica media may prevent separation of these aortic wall layers and consequently reduce progression of the aortic dissection. Based on an in vitro study, vascular smooth muscle cell in the tunica media regulates vascular microcalcification via several miRNAs and modulates vascular remodeling [30, 31]. Vascular calcification is strongly associated with elastin degradation and smooth muscle cell phenotypic change [32, 33]. This indicates that aortic calcifications change the biomechanical properties of the tunica media in the aorta and influence the true and false lumen dimension and the distal extent of ATAAD in the high-score group.

In preoperative CTA, aortic dissection was significantly less distally extended in the high-score group than in the low-score group. Accordingly, DeBakey type II and false lumen thrombosis were more frequently observed in the high-score group than in the low-score group. DeBakey type II dissections were correlated with atherosclerotic disease, and the prevalence of distally extended aortic dissection was lower in patients with non-communicating false lumens than in those with patent false lumens, which are consistent with the results of previous studies [34, 35]. Furthermore, there is a greater decrease in false lumen pressure in aortic dissection with a thrombosed false lumen compared with a patent false lumen [36]. A false lumen thrombosis in the high-score group might cause a decrease in the false lumen pressure and slow the disease progression. In fact, we found that the true lumen/total lumen area ratios of the ascending and descending aorta were likely to be larger in the high-score group than those in the low-score group on preoperative CTA. These findings suggest that the ratio of the true lumen pressure to the false lumen pressure in the high-score group could be higher than that in the low-score group.

Intriguingly, in the early postoperative CTA, the true lumen area of the descending aorta was significantly larger and false lumen thrombosis was significantly more frequently observed in the high-score group. Moreover, changes in the distal extent score and true and false lumen area of the descending aorta from pre- to post-surgery did not significantly differ between the groups. Hence, a lower disease progression in the high-score group before surgery could be consistent with that after surgery. Interestingly, dilatation of the residual dissected descending aorta was smaller in the high-score group than in the low-score group 6 months after surgery. Several imaging findings can help predict the course of residual dissected aorta remodeling after surgery for ATAAD. Progressive dilatation of the descending aorta, persistent intimal tear at the residual aorta, and refilling from the false lumen of a dissected aortic arch were considered the predictors of failing residual aortic remodeling after surgical repair for ATAAD [37, 38]. The current study showed that the aortic Agatston score could be correlated with ATAAD progression and could help predict postoperative residual dissected descending aorta remodeling. Although further investigation is needed to elucidate the influence of the aortic Agatston score on clinical outcomes in patients who undergo surgical repair for ATAAD, our primary aim was to reveal the association between the aortic Agatston score and disease progression of ATAAD in terms of CTA variables.

The most obvious limitations of this study were its retrospective nature, small number of participants, and single-center design, which are potential sources of bias. This study was further limited by the lack of pathological proof and that we did not specifically determine whether calcifications were located in the intima or in the media of the aortic wall. However, it should be noted that we did not aim to unravel the pathology of these calcifications. Further studies with a larger number of patients and greater emphasis on hemodynamic and biomechanical parameters should be performed to evaluate these associations. These data provide important new insights into the association between aortic calcification and the progression of aortic dissection and potentially contribute to the development of a risk assessment system in the patients with high Agatston scores.

Conclusions

In conclusion, we found that high aortic Agatston scores were significantly correlated with larger true lumen areas of the ascending and descending aorta and with smaller false lumen areas of the descending aorta in patients with ATAAD. Furthermore, compared with the patients with the low Agatston scores, the patients with the high Agatston scores were more likely to have DeBakey type II dissection and false lumen thrombosis, and their aortic dissection was less distally extended. In the early postoperative CTA, the true lumen area of the descending aorta was significantly larger, and false lumen thrombosis was more frequently observed in patients with high Agatston scores, which were consistent with preoperative findings. The aortic Agatston scores could be correlated with ATAAD progression and could help predict postoperative residual dissected descending aorta remodeling.

Regression tree for aortic Agatston score thresholds predictive of distal extent score in CART analysis.

(TIFF)

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CTA variables of descending aorta before and after surgery in the patients with DeBakey Ⅰ or Ⅲb retrograde.

(DOCX)

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Early Postoperative changes of CTA variables in the patients with DeBakey Ⅰ or Ⅲb retrograde (before—after surgery).

(DOCX)

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Mid-term Postoperative changes of plain CTA variables in the patients with DeBakey Ⅰ or Ⅲb retrograde in 6 months after surgery.

(DOCX)

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15 Oct 2021

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Reviewer #2: Yes

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Reviewer #1: In this study, the authors aimed to explore the association of aortic Agatston scores with disease progression in patients with ATAAD. This was a retrospective analysis of 85 patients who had preoperatively undergone CTA for evaluation of aortic calcification. The patients were classified into high score (Agatston score ≥ 3344; n = 49) and low-score (<3344; n = 36) groups. Correlations between aortic Agatston scores and CTA variables were assessed. Higher aortic Agatston scores were significantly correlated with the smaller distal extent of aortic dissection (p <0.001), larger true lumen areas of the ascending (p = 0.009) and descending aorta (p = 0.002), and smaller false lumen areas of the descending aorta (p = 0.028). Patients in the high-score group were more likely to have DeBakey type II dissection (p = 0.001) and false lumen thrombosis (p = 0.027) than those in the low-score group, thereby confirming the correlations. Aortic dissection in the high score group was significantly less distally extended (p < 0.001). The authors concluded that higher aortic Agatston score correlates with the larger true lumen area of the ascending and descending aorta and the less distal progression of aortic dissection in patients with ATAAD.

This manuscript is engaging and thought-provoking. I present the following suggestions / comments in the hopes of improving the manuscript. At this current stage, I recommend major revision for publication in PlosOne.

Major Comments

1. Introduction: Line 69 represents a transition point, and therefore, I recommend a new paragraph that guides the reader more concisely to purpose of this investigation. In line 67, instead of “we hypothesize”, I recommend “It is plausible aortic calcification could alter the biomechanical…”

2. The follow up study time frame of 7 days is too abbreviated to evaluate early aortic progression especially since it is not clear if the extent of dissection changed from pre- and post-op CTA (Norton et al., 2020, J Thorac Cardiovasc Surg, PMID: 32517536). This lack of clarification is a major limitation of the current manuscript version. It seems more appropriate for this study to evaluate the association of aortic calcification and extent of aortic dissection and other properties of the aorta.

3. Methods: Line 88-89 should be revised to examine the association of aortic calcification with the extent of aortic dissection.

4. Results: The extent of dissection from pre- to post-op needs to be evaluated; otherwise, the reader does not know if the outcome changed.

5. Discussion: This manuscript has a small sample size with the possibility of having a straightforward objective and conclusion. The sample size is a limitation, but this is overcome if the authors remain focused on the central findings, which from my view, is the potential clinical utility of Agatston score to evaluate extent of dissection and other aortic properties.

I recommend rewriting the discussion, starting with deleting the introductory paragraph of Discussion as it repeats to the Introduction and starting with “This study demonstrates…points 1-3” The subsequent paragraph should follow points 1-3 with supportive evidence. Of points 1-3, which is the most clinically important finding? Start the discussion addressing this point and then build in the other discussion points. The conclusion paragraph reiterates the results, but there is conclusion statement that tells the reader the translational importance of this work. Reworking the discussion will strengthen this manuscript.

6. Abstract: Please rewrite after revising the analysis.

Reviewer #2: The authors provide an interesting and potential important manuscript describing "Aortic Agatston score correlates with the progression of acute type A aortic dissection", The main issues concerning this paper are those concerning the potential associations between Aortic Agatston score and type A aortic dissection.

There are some weak points that need to be addressed by the authors

Major

1. Why Agatston Score 3344 is selected as the thresholds between the high and low scores of ATAAD.

2. Some recent literature on arterial dissection and calcification needs to be cited

**********

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Submitted filename: PONE-D-21-14950_reviewer.docx

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19 Nov 2021

November 27, 2021

Dr. Emily Chenette

Editor-in-Chief

PLOS ONE

Manuscript ID: PONE-D-21-14950

Aortic Agatston score correlates with the progression of acute type A aortic dissection

Dear Editor:

Please find enclosed the responses to the reviewers’ comments. Thank you for providing us the opportunity to revise the manuscript. The revisions, both marked and unmarked, are included. Our team will be honored if the manuscript is published in PLOS ONE.

Reviewer #1: In this study, the authors aimed to explore the association of aortic Agatston scores with disease progression in patients with ATAAD. This was a retrospective analysis of 85 patients who had preoperatively undergone CTA for evaluation of aortic calcification. The patients were classified into high score (Agatston score ≥ 3344; n = 49) and low-score (<3344; n = 36) groups. Correlations between aortic Agatston scores and CTA variables were assessed. Higher aortic Agatston scores were significantly correlated with the smaller distal extent of aortic dissection (p <0.001), larger true lumen areas of the ascending (p = 0.009) and descending aorta (p = 0.002), and smaller false lumen areas of the descending aorta (p = 0.028). Patients in the high-score group were more likely to have DeBakey type II dissection (p = 0.001) and false lumen thrombosis (p = 0.027) than those in the low-score group, thereby confirming the correlations. Aortic dissection in the high score group was significantly less distally extended (p < 0.001). The authors concluded that higher aortic Agatston score correlates with the larger true lumen area of the ascending and descending aorta and the less distal progression of aortic dissection in patients with ATAAD.

This manuscript is engaging and thought-provoking. I present the following suggestions / comments in the hopes of improving the manuscript. At this current stage, I recommend major revision for publication in PlosOne.

Major Comments

1. Introduction: Line 69 represents a transition point, and therefore, I recommend a new paragraph that guides the reader more concisely to purpose of this investigation. In line 67, instead of “we hypothesize”, I recommend “It is plausible aortic calcification could alter the biomechanical…”

→Thank you very much for the suggestion. We have revised the statement to “It is plausible that aortic calcifications could alter the biomechanical properties of the aorta in patients with acute type A aortic dissection (ATAAD)” (page 3, lines 69-71).

2. The follow up study time frame of 7 days is too abbreviated to evaluate early aortic progression especially since it is not clear if the extent of dissection changed from pre- and post-op CTA (Norton et al., 2020, J Thorac Cardiovasc Surg, PMID: 32517536). This lack of clarification is a major limitation of the current manuscript version. It seems more appropriate for this study to evaluate the association of aortic calcification and extent of aortic dissection and other properties of the aorta.

→Thank you for the insightful comment.

In CTA within 7 days after surgery, the true lumen area of the descending aorta was significantly larger in the high-score group than in the low-score group. Further, the false lumen area of the descending aorta was significantly smaller in the high-score group than in the low-score group.

However, as you suggested, we must validate the change from pre-surgery to early post-surgery. We assessed changes in CTA variables from pre- to post-surgery in each group (S1 Table A) and differences in changes between groups (S1 Table B). Compared with preoperative CTA variables, the postoperative true lumen dimension of the descending aorta was small in the high- and low-score groups (p = 0.038, 0.058, respectively). However, the distal extent score after surgery did not significantly change (S1 Table A). Moreover, there was no remarkable difference in the changes in the distal extent score and the true and false lumen area of the descending aorta from pre-surgery to early post-surgery between the two groups (S1 Table B). Therefore, the pre- and postoperative results were consistent.

With a smaller distal extent score, the prevalence of false lumen thrombosis was higher, and larger true lumen area in the descending aorta in the high-score group could be correlated with midterm residual dissected descending aorta remodeling after surgery1, 2. Moreover, we evaluated the midterm changes in descending aortic diameter and area after surgery between the groups. We collected data about descending aortic diameter and area via plain CT scan 6 months after surgery and assessed changes 6 months after surgery between groups.

Interestingly, dilatation of the descending aortic diameter and area 6 months after surgery was smaller in the high-score group than in the low-score group (Des diameter change in fold change/CT variables 6 months after surgery – high-score group: 0.98 [0.87–1.04] vs. low-score group: 1.01 [0.94–1.1], p=0.058; Des area change 7 days after surgery – 1.03 [0.88–1.13] vs. 1.11 [0.97–1.29], p=0.031) (S2 Table). Although other clinical factors should be adjusted to compare midterm descending aorta remodeling, these findings suggested that the aortic Agatston score could be an important factor for predicting descending aortic dilatation after surgery.

The following sentences were added in the Methods and Results sections.

“Postoperative CTA was performed within 7 days after surgery to assess early aortic dissection progression after the initial surgery and changes in CTA variables from pre- to post-surgery. Furthermore, postoperative plain computed tomography (CT) scan was conducted 6 months after surgery to assess midterm changes in descending aortic dimension and diameter after surgery between the two groups.” (page 5. lines 104–108).

“Compared with preoperative CTA variables, the postoperative true lumen dimension of the descending aorta was small in the high- and low-score groups (p = 0.038, 0.058, respectively). However, the distal extent score after surgery did not significantly change (S1 Table A). Moreover, there was no remarkable difference in the changes in the distal extent score and true and false lumen area of the descending aorta from pre- to post-surgery between the two groups (S1 Table B). Hence, high aortic Agatston scores could be correlated with a slower progression of residual dissected descending aorta before and after surgery.

Moreover, we assessed and compared the midterm changes in descending aortic diameter and area via plain CT scan 6 months after surgery and CT variables within 7 days after surgery. Interestingly, dilatation of the descending aortic diameter and area 6 months after surgery were smaller in the high-score group than in the low-score group (Des diameter change: 0.98 [0.87–1.04] vs. 1.01 [0.94–1.1], p = 0.058; Des area change: 1.03 [0.88–1.13] vs. 1.11 [0.97–1.29], p = 0.031, in fold change/CT variables within 7days after surgery) (S2 Table).” (page 14, lines 243–255).

3. Methods: Line 88-89 should be revised to examine the association of aortic calcification with the extent of aortic dissection.

→Thank you for the suggestion.

This statement was revised to “Then, we examined the association between aortic calcifications and the extent of aortic dissection in these patient groups.” (page 4, lines 92–93).

4. Results: The extent of dissection from pre- to post-op needs to be evaluated; otherwise, the reader does not know if the outcome changed.

→Thank you very much.

The distal extent score before and after surgery did not significantly differ between the two groups, as shown in S1 Table A. The following sentences were added in the Results section:

“Compared with preoperative CTA variables, the postoperative true lumen dimension of the descending aorta was small in the high- and low-score groups (p = 0.038, 0.058, respectively). However, the distal extent score after surgery did not significantly change (S1 Table A)” (page 14, lines 243–246).

5. Discussion: This manuscript has a small sample size with the possibility of having a straightforward objective and conclusion. The sample size is a limitation, but this is overcome if the authors remain focused on the central findings, which from my view, is the potential clinical utility of Agatston score to evaluate extent of dissection and other aortic properties.

I recommend rewriting the discussion, starting with deleting the introductory paragraph of Discussion as it repeats to the Introduction and starting with “This study demonstrates…points 1-3” The subsequent paragraph should follow points 1-3 with supportive evidence. Of points 1-3, which is the most clinically important finding? Start the discussion addressing this point and then build in the other discussion points. The conclusion paragraph reiterates the results, but there is conclusion statement that tells the reader the translational importance of this work. Reworking the discussion will strengthen this manuscript.

Thank you for the advice.

We deleted the introductory paragraph and started the Discussion with the findings. To validate which is the most important finding in the study, the following sentences were added in the Discussion section:

“In the current study, the aforementioned points 1) and 2) could be the most important findings supporting our hypothesis.” (page 16, lines 270–271).

We added the following data from new references to explain that aortic calcification could be an important factor for changes in the biomechanical property of the tunica media in vitro and could influence ATAAD progression.

“Based on an in vitro study, vascular smooth muscle cell in the tunica media regulates vascular microcalcification via several miRNAs and modulates vascular remodeling [30, 31]. Vascular calcification is strongly associated with elastin degradation and smooth muscle cell phenotypic change [32, 33]. This indicates that aortic calcifications change the biomechanical properties of the tunica media in the aorta and influence the true and false lumen dimension and the distal extent of ATAAD in the high-score group.” (page 16, lines 277–283).

30. Badi I, Mancinelli L, Polizzotto A, Ferri D, Zeni F, Burba I, Milano G, Brambilla F, Saccu C, Bianchi ME, Pompilio G, Capogrossi MC and Raucci A. miR-34a Promotes Vascular Smooth Muscle Cell Calcification by Downregulating SIRT1 (Sirtuin 1) and Axl (AXL Receptor Tyrosine Kinase). Arterioscler Thromb Vasc Biol. 2018;38:2079-2090.

31. Shi N, Mei X and Chen SY. Smooth Muscle Cells in Vascular Remodeling. Arterioscler Thromb Vasc Biol. 2019;39:e247-e252.

32. Pai A, Leaf EM, El-Abbadi M and Giachelli CM. Elastin degradation and vascular smooth muscle cell phenotype change precede cell loss and arterial medial calcification in a uremic mouse model of chronic kidney disease. Am J Pathol. 2011;178:764-73.

33. Bhat OM, Yuan X, Cain C, Salloum FN and Li PL. Medial calcification in the arterial wall of smooth muscle cell-specific Smpd1 transgenic mice: A ceramide-mediated vasculopathy. J Cell Mol Med. 2020;24:539-553.

The following data based on new references were added to provide evidence that DeBakey type II dissections was correlated with atherosclerotic disease, which is consistent with our findings.

“DeBakey type II dissections were correlated with atherosclerotic disease, and the prevalence of distally extended aortic dissection was lower in patients with non-communicating false lumens than in those with patent false lumens, which are consistent with the results of previous studies [34, 35].” (page 16, lines 285–288).

34. Akutsu K, Yoshino H, Tobaru T, Hagiya K, Watanabe Y, Tanaka K, Koyama N, Yamamoto T, Nagao K and Takayama M. Acute type B aortic dissection with communicating vs. non-communicating false lumen. Circ J. 2015;79:567-73.

35. Philip JL, De Oliveira NC, Akhter SA, Rademacher BL, Goodavish CB, DiMusto PD and Tang PC. Cluster analysis of acute ascending aortic dissection provides novel insight into mechanisms of distal progression. J Thorac Dis. 2017;9:2966-2973.

The following data from new references were added to explain postoperative findings and confirm whether the aortic Agatston score can predict postoperative residual dissected descending aorta remodeling.

“Moreover, changes in the distal extent score and true and false lumen area of the descending aorta from pre- to post-surgery did not significantly differ between the groups. Hence, a lower disease progression in the high-score group before surgery could be consistent with that after surgery. Interestingly, dilatation of the residual dissected descending aorta was smaller in the high-score group than in the low-score group 6 months after surgery. Several imaging findings can help predict the course of residual dissected aorta remodeling after surgery for ATAAD. Progressive dilatation of the descending aorta, persistent intimal tear at the residual aorta, and refilling from the false lumen of a dissected aortic arch were considered the predictors of failing residual aortic remodeling after surgical repair for ATAAD [37, 38]. The current study showed that the aortic Agatston score could be correlated with ATAAD progression and could help predict postoperative residual dissected descending aorta remodeling.” (page 17, lines 298–308).

37. Leontyev S, Haag F, Davierwala PM, Lehmkuhl L, Borger MA, Etz CD, Misfeld M, Gutberlet M and Mohr FW. Postoperative Changes in the Distal Residual Aorta after Surgery for Acute Type A Aortic Dissection: Impact of False Lumen Patency and Size of Descending Aorta. Thorac Cardiovasc Surg. 2017;65:90-98.

38. Saremi F, Hassani C, Lin LM, Lee C, Wilcox AG, Fleischman F and Cunningham MJ. Image Predictors of Treatment Outcome after Thoracic Aortic Dissection Repair. Radiographics. 2018;38:1949-1972.

The following sentences were added in the Conclusion section.

“In the early postoperative CTA, the true lumen area of the descending aorta was significantly larger, and false lumen thrombosis was more frequently observed in patients with high Agatston scores, which were consistent with preoperative findings. The aortic Agatston scores could be correlated with ATAAD progression and could help predict postoperative residual dissected descending aorta remodeling.” (page 18, lines 327–332).

6. Abstract: Please rewrite after revising the analysis.

→Thank you very much. The abstract was modified by adding new analysis results.

Reviewer #2: The authors provide an interesting and potential important manuscript describing "Aortic Agatston score correlates with the progression of acute type A aortic dissection", The main issues concerning this paper are those concerning the potential associations between Aortic Agatston score and type A aortic dissection.

There are some weak points that need to be addressed by the authors

Major

1. Why Agatston Score 3344 is selected as the thresholds between the high and low scores of ATAAD.

→Thank you very much for this question.

We used the classification and regression tree (CART), a machine-learning algorithm for clinical decision-making that can be used to determine the breakpoint and identify aortic Agatston score thresholds predictive of disease progression (distal extent of aortic dissection) in patients with ATAAD. CART is a nonparametric decision tree learning technique that produces either classification or regression trees based on whether the dependent variable is categorical or numeric, respectively [3].

The current study found that the distal extent score of ATAAD was strongly correlated with aortic Agatston score (rho = −0.446, 95% CI: −0.602 to −0.257, p value < 0.001), as shown in Table 2. According to Reference [4], the statistician established the regression tree to identify aortic Agatston score thresholds predictive of distal extent score with R software (Saitama Medical Center, Jichi Medical University, Saitama, Japan) (S1 Fig). The threshold of aortic Agatston score was 3344. In fact, we confirmed that the distal extent score of patients with an aortic Agatston score of ≥ 3344 was significantly lower than that of patients with an aortic Agatston score of < 3344 (5 [0-8] vs. 10 [7-11], p < 0.001), as shown in Table 3.

We added sentences with references and a supplemental figure in the Methods section.

“CART is a nonparametric decision tree learning technique that produces either classification or regression trees based on whether the dependent variable is categorical or numeric, respectively [25, 26].” (page 4. lines 87–89).

25. L. Breiman, J.H. Friedman, R.A. Olshen, and C.J Stone, "Classification and Regression Trees," Wadsworth, Belmont, Ca, 1983.

26. Terry M. Therneau, Elizabeth J. Atkinson, Mayo Foundation, "An Introduction to Recursive Partitioning Using the RPART Routines," https://rdrr.io/cran/rpart/f/ inst/doc/longintro.pdf, April 11, 2019.

S1 Fig. Regression tree for aortic Agatston score thresholds predictive of distal extent score in CART analysis

2. Some recent literature on arterial dissection and calcification needs to be cited

→Thank you very much.

Only few reports have investigated the association between aortic calcifications and aortic dissection [12-14].

12. Akiyoshi K, Kimura N, Aizawa K, Hori D, Okamura H, Morita H, Adachi K, Yuri K, Kawahito K and Yamaguchi A. Surgical outcomes of acute type A aortic dissection in dialysis patients. Gen Thorac Cardiovasc Surg. 2019;67:501-509.

13. Yang CJ, Tsai SH, Wang JC, Chang WC, Lin CY, Tang ZC and Hsu HH. Association between acute aortic dissection and the distribution of aortic calcification. PLoS One. 2019;14:e0219461.

14. de Jong PA, Hellings WE, Takx RA, Isgum I, van Herwaarden JA and Mali WP. Computed tomography of aortic wall calcifications in aortic dissection patients. PLoS One. 2014;9:e102036.

We added new references explaining that aortic calcification could be an important factor for managing the biomechanical property of tunica media in vitro study and could influence ATAAD progression [30-33].

30. Badi I, Mancinelli L, Polizzotto A, Ferri D, Zeni F, Burba I, Milano G, Brambilla F, Saccu C, Bianchi ME, Pompilio G, Capogrossi MC and Raucci A. miR-34a Promotes Vascular Smooth Muscle Cell Calcification by Downregulating SIRT1 (Sirtuin 1) and Axl (AXL Receptor Tyrosine Kinase). Arterioscler Thromb Vasc Biol. 2018;38:2079-2090.

31. Shi N, Mei X and Chen SY. Smooth Muscle Cells in Vascular Remodeling. Arterioscler Thromb Vasc Biol. 2019;39:e247-e252.

32. Pai A, Leaf EM, El-Abbadi M and Giachelli CM. Elastin degradation and vascular smooth muscle cell phenotype change precede cell loss and arterial medial calcification in a uremic mouse model of chronic kidney disease. Am J Pathol. 2011;178:764-73.

33. Bhat OM, Yuan X, Cain C, Salloum FN and Li PL. Medial calcification in the arterial wall of smooth muscle cell-specific Smpd1 transgenic mice: A ceramide-mediated vasculopathy. J Cell Mol Med. 2020;24:539-553.

The following references were added to provide evidence showing that DeBakey type III dissections were correlated with atherosclerotic disease [35] and to explain the predictor of postoperative residual dissected descending aorta remodeling [37, 38].

35. Philip JL, De Oliveira NC, Akhter SA, Rademacher BL, Goodavish CB, DiMusto PD and Tang PC. Cluster analysis of acute ascending aortic dissection provides novel insight into mechanisms of distal progression. J Thorac Dis. 2017;9:2966-2973.

37. Leontyev S, Haag F, Davierwala PM, Lehmkuhl L, Borger MA, Etz CD, Misfeld M, Gutberlet M and Mohr FW. Postoperative Changes in the Distal Residual Aorta after Surgery for Acute Type A Aortic Dissection: Impact of False Lumen Patency and Size of Descending Aorta. Thorac Cardiovasc Surg. 2017;65:90-98.

38. Saremi F, Hassani C, Lin LM, Lee C, Wilcox AG, Fleischman F and Cunningham MJ. Image Predictors of Treatment Outcome after Thoracic Aortic Dissection Repair. Radiographics. 2018;38:1949-1972.

References

1. Leontyev S, Haag F, Davierwala PM, Lehmkuhl L, Borger MA, Etz CD, Misfeld M, Gutberlet M and Mohr FW. Postoperative Changes in the Distal Residual Aorta after Surgery for Acute Type A Aortic Dissection: Impact of False Lumen Patency and Size of Descending Aorta. Thorac Cardiovasc Surg. 2017;65:90-98.

2. Saremi F, Hassani C, Lin LM, Lee C, Wilcox AG, Fleischman F and Cunningham MJ. Image Predictors of Treatment Outcome after Thoracic Aortic Dissection Repair. Radiographics. 2018;38:1949-1972.

3. L. Breiman, J.H. Friedman, R.A. Olshen, and C.J Stone, "Classification and Regression Trees," Wadsworth, Belmont, Ca, 1983.

4. Terry M. Therneau, Elizabeth J. Atkinson, Mayo Foundation, "An Introduction to Recursive Partitioning Using the RPART Routines," https://rdrr.io/cran/rpart/f/ inst/doc/longintro.pdf, April 11, 2019.

Submitted filename: response_for_reviewer.docx

Click here for additional data file.

31 Jan 2022

Aortic Agatston score correlates with the progression of acute type A aortic dissection

PONE-D-21-14950R1

Dear Dr Dashima

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Xianwu Cheng, M.D., Ph.D., FAHA

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Although the original reviewer has declined to review the revised manuscript, all of original concerns have been addressed by the authors.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

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Reviewer #2: Yes

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Reviewer #2: Yes

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Reviewer #2: (No Response)

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Reviewer #2: No

3 Feb 2022

PONE-D-21-14950R1

Aortic Agatston score correlates with the progression of acute type A aortic dissection

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