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Long-term follow-up and clinical implications in Chinese patients with aortic intramural hematomas
IJCA-26626; No of Pages 5 International Journal of Cardiology xxx (2018) xxx–xxx
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Long-term follow-up and clinical implications in Chinese patients with aortic intramural hematomas☆ Yan-Jie Liu 1, Quan-Yu Zhang 1, Zhan-Kui Du, Lin Yang, Lei Zhang, Rui-Xia He, Ya Wang, Ya-Ling Han ⁎, Xiao-Zeng Wang ⁎ Department of Cardiology, Institute of Cardiovascular Research, General Hospital of Shenyang Military Region, Shenyang, 110016, China
a r t i c l e
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Article history: Received 24 March 2018 Received in revised form 6 May 2018 Accepted 18 June 2018 Available online xxxx Keywords: Aortic intramural hematoma Chinese patients Clinical outcomes
a b s t r a c t Background: Intramural hematomas (IMHs) are reported to dynamically evolve into different clinical outcomes ranging from regression to aortic rupture, but no practice guidelines are available in China. Objective: To determine the evolution of IMHs after long-term follow-up and to identify the predictive factors of IMH outcomes in the Chinese population. Methods: A total of 123 IMH patients with clinical and imaging follow-up data were retrospectively studied. The primary endpoints were aortic disease-related death, aortic dissection, penetrating aortic ulcer (PAU), thickening of the aortic hematoma and aortic complications requiring surgical or endovascular treatment. Results: All 123 IMH patients were monitored clinically. The follow-up duration ranged from 1.4 to 107 months (median, 20 months). Thirty-nine patients had type A IMH, and 84 had type B. The multivariate analysis showed that a baseline MAD ≥ 44.75 mm (2.9% vs 61.4%, P b 0.001) and acute PAUs (2.9% vs 34.1%, P = 0.008) were independent predictors of aorta-related events. Conclusions: Medication and short-term imaging are recommended for Chinese IMH patients with a hematoma thickness b 10.45 mm and a baseline MAD b 44.75 mm. Rigorous medical observation should also be performed during the acute phase of IMH. © 2018 Published by Elsevier B.V.
1. Introduction In aortic disease, both intramural hematoma (IMH) and aortic dissection (AD) belong to the spectrum of acute aortic syndrome (AAS) [1]. IMH accounts for 5–30% of AAS cases and leads to AD, aneurysm formation and reabsorption [2]. The etiology of IMH is not clear but may be
Abbreviations: IMH, aortic intramural hematoma; AD, aortic dissection; AAS, acute aortic syndrome; ESC, European Society of Cardiology; TEVAR, thoracic endovascular aortic repair; MDCT, multidetector computed tomography; PAU, penetrating aortic ulcer; MAD, maximal aorta diameter; ROC, receiver operating characteristic; CHD, chronic heart disease; AUC, areas under the curve; ACCF, American College of Cardiology Foundation; JCS, Japanese Circulation Society. ☆ This work was supported by the National Key Project of Research and Development Plan during the Thirteenth Five-year Plan Period [2016YFC1301300], China, and the Construction Program of the National Clinical Priority Specialty. ⁎ Corresponding authors. E-mail addresses: [email protected] (Y.-L. Han), [email protected] (X.-Z. Wang). 1 Yan-Jie Liu and Quan-Yu Zhang contribute equally to this article.
related to spontaneous vasa vasorum bleeding in the aortic wall media without intimal disruption [3]. Previous studies [4] have reported that pre-existing atherosclerosis and hypertension may be risk factors for IMHs, whereas a younger age, an aortic diameter b 4–4.5 cm and a hematoma diameter b 1 cm may be protective factors [5]. Although AD and IMH have entirely different pathological bases, similar therapeutic strategies are adopted for them in routine clinical work [5]. Furthermore, the long-term evolution of IMHs toward progression or regression under different conditions is unclear [6]. American and European guidelines recognize IMHs as a type of AAS with a surgery indication, but guidelines from Asia consider IMH a pathological process that is different from AAS and suggest medical treatment. For type A IMH treatment, the Asian guidelines advise medical treatment (IIaC), but the European and American guidelines recommend surgery (IC, IIaC). For type B IMH, the Asian and American guidelines suggest medical treatment, but the ESC recommends thoracic endovascular aortic repair (TEVAR) as an alternative (IIaC). However, data from Chinese patients with IMH are lacking. Thus, further longterm and larger scale IMH studies involving the Chinese population are warranted.
https://doi.org/10.1016/j.ijcard.2018.06.077 0167-5273/© 2018 Published by Elsevier B.V.
Please cite this article as: Y.-J. Liu, et al., Long-term follow-up and clinical implications in Chinese patients with aortic intramural hematomas, Int J Cardiol (2018), https://doi.org/10.1016/j.ijcard.2018.06.077
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The aims of the present study were to determine the different characteristics of IMH after long-term follow-up and to establish predictive factors for the evolution of IMH in Chinese patients. 2. Methods 2.1. Study patients From February 2003 to May 2017, 1770 consecutive patients were diagnosed with AAS at the General Hospital of Shenyang Military Region, including 270 IMH patients, of which 123 patients were retrospectively examined. 39 patients presented with type A aortic IMH, and 84 presented with type B aortic IMH (Supplementary material–Fig. S1). The study was approved by the ethics committee of the General Hospital of Shenyang Military Region. 2.2. Management and follow-up protocol Multidetector computed tomography (MDCT) was performed in all cases [7]. The lesions were characterized using the following clinical and radiologic criteria: [1] the aortic Table 1 Clinical characteristics, aortic segments with IMH, and baseline morphological findings, and laboratory examination (n = 123). Characteristic Demographic and clinical Age, y Men, n (%) BMI Systemic hypertension, n (%) Smoking, n (%) Hyperlipidemia, n (%) Diabetes, n (%) Imaging Descending thoracic aorta, n (%) Abdominal aorta, n (%) Aortic arch, n (%) Ascending aorta, n (%) Abdominal aortic aneurysm, n (%) Maximum ascending aorta diameter, mm Maximum ascending aorta hematoma thickness*, mm Maximum descending aorta diameter, mm Maximum descending aorta hematoma thickness, mm Circular shape, n (%) Echolucent areas, n (%) Atherosclerotic ulcerated plaque, n (%) Atherosclerosis plaque, n (%) Pleural effusion, n (%) Pericardial effusion, n (%) Medical Antiplatelet agents, n (%) Anticoagulants, n (%) Beta-blockers, n (%) Calcium antagonists, n (%) ACE inhibitors, n (%) ARB inhibitors, n (%) Nitrates, n (%) Statins, n (%) Systolic BP, mm Hg Diastolic BP, mm Hg Heart rate, BPM Lab examinations CKMB, ng/ml TNT exception, n (%) ALT, U/L AST*, U/L WBC, 109/L PLT, 109/L HG, g/L BUN, mmol/L CR, umol/L C-reactive protein*, mg/dL D-dimer, ng/ml
No. (%) 59.91 ± 11.20 84(68.3) 24.62 ± 3.26 102(82.9) 57(46.3) 13(10.6) 11(8.9) 80(65.0) 2(1.6) 8(6.5) 9(7.3) 3(2.4) 43.19 ± 5.09 2.83(0.00–6.00) 29.73 ± 5.58 10.17 ± 3.79 64(52.0) 59(48.0) 42(34.1) 35(28.5) 38(30.9) 6(4.9) 5(4.1) 0 15(12.2) 48(39.0) 16(13.1) 15(12.2) 2(1.6) 3(2.4) 149.39 ± 25.54 85.28 ± 16.45 79.82 ± 10.95 13.18 ± 8.15 10(8.1) 37.87 ± 12.92 34.58(17.43–27) 9.98 ± 3.95 211.15 ± 62.05 133.17 ± 18.03 6.13 ± 3.99 78.32 ± 42.38 30.47(3.90–30.00) 4.44(050–5.20)
BMI, Body Mass Index; ACE, Angiotensin-converting Enzyme; ARB, Angiotensin Receptor Blocker; BP, Blood Pressure; CKMB, Creatine Phosphokinase-myocardial Band; TNT, Troponin-T; BNP, Brain Natriuretic Peptide; ALT, Alanine Aminotransferase; AST, Aspartate aminotransferase; WBC, White Blood Cell; PLT, Platelets Count; HG, Hemoglobin; CR, Creatinine. * Median(Quartile Q1–Q3).
hematoma lesion type was classified based on the initial diagnosis (type A or type B) using the earliest available imaging data; the initial diagnosis was not changed even if the lesion type changed (e.g., from type B to type A); [2] IMH was characterized by crescentic or circular shadowing and expansion within the aortic wall, which contained an aortic wall hematoma with bleeding within the media but without initial intimal flap formation; and [3] rupture was determined by the presence of extra-aortic blood confirmed by radiology, surgical examination, or post-mortem examination, clinical behavior (persistent pain despite medical treatment), or intra-operative findings of an impending rupture (peri-aortic hematoma without frank rupture or extreme wall thinning) [8]. Progression of the observed pathologies was classified as follows: [1] a decrease in the size or disappearance of the hematoma was recorded as “resolution”; [2] “worsening” referred to deterioration in the aortic condition, including significant increases in the thickness of the lesion, the progression of IMHs to penetrating aortic ulcer(PAU), the progression to classic dissection, or rupture; and [3] patients whose lesions did not improve or worsen significantly were noted as “stable”. After discharge, all cases were followed up promptly at 1, 3, 6, and 12 months. Surgical or endovascular treatment during follow-up was considered if any of the following criteria were observed: aortic rupture; rapid growth of the PAU or the aortic diameter (N5 mm/ year); or a MAD N 55 mm [8]. We operated on all patients in the rupture state and all ascending lesions when clinically possible. For descending IMHs, we provided standard initial anti-impulse therapy but maintained a low threshold for catheterization intervention in cases of radiographic worsening on follow-up. 2.3. Endpoints The primary endpoint during the follow up was a composite endpoint that consisted of aortic disease-related death, AD, PAUs, thickening of the aortic hematoma, and aortic complications requiring surgical or endovascular treatment. The acute phase of IMH was b15 days, the sub-acute phase was 15 to 90 days, and the chronic phase was N90 days from the onset of aortic disease-related pain [9]. 2.4. Imaging techniques CT was performed in all acute phase patients [10]. The location, maximum thickening, and circular or crescentic forms were assessed by CT as reported previously. CT was performed using a 64-detector Siemens Sensation and intravenous boluses with 80 to 150 mL of nonionic contrast medium. 2.5. Statistical analysis Continuous variables are reported as the mean ± SD (proportions depend on the variable distribution) or the median (quartile 1 to quartile 3). Categorical variables were expressed as frequencies and percentages and were compared using the χ2 or Fisher's exact-test. For the baseline characteristics, continuous variables were expressed as the mean ± SD and were compared using a t-test. Survival curves were generated via the Kaplan–Meier method with significant differences assessed for time-to-event data using log-rank tests. Cox regression models were constructed to identify factors associated with the primary endpoint. To evaluate whether the maximum aortic hematoma thickness could be an effective predictor of the primary endpoint, a receiver operating characteristic (ROC) curve analysis was performed [11]. The optimal cutoff level was calculated by determining the shortest distance between the ROC curve and the upper left corner of the graph. Patients above the optimal cutoff level were considered to exhibit a high maximum aortic hematoma thickness. A P value b 0.05 was considered significant. The analyses were performed using SPSS version 22.0 (SPSS, Chicago, Illinois).
3. Results 3.1. Study patients All 123 cases were diagnosed b24 h from the imaging examination and included acute, sub-acute and chronic type A and type B aortic IMH cases. Thirty-nine cases presented with type A IMH, and 84 presented with type B IMH. Among the 39 type A patients, 6 died after the diagnosis, and 33 survived. Among the 84 type B patients, 3 died and 81 survived. Among the 33 surviving type A patients, 4 accepted surgical treatment, 7 underwent TEVAR and 22 received medical treatment. Among the 81 surviving type B patients, 10 accepted TEVAR and 71 received medical treatment (Supplementary material–Fig. S1). 3.2. Baseline characteristics and adverse events for the entire cohort The baseline characteristics of the entire cohort (123 cases) are shown in Table 1. The average age was 59.91 ± 11.20 years. Eightyfour patients were male. The incidence of systemic hypertension was 82.9%. Nearly half of the patients were smokers (46.3%). A total of 10.6% and 8.9% of the patients had hyperlipidemia and diabetes,
Please cite this article as: Y.-J. Liu, et al., Long-term follow-up and clinical implications in Chinese patients with aortic intramural hematomas, Int J Cardiol (2018), https://doi.org/10.1016/j.ijcard.2018.06.077
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Table 2 Relationship between IMH baseline morphological findings and final morphological outcomes. Morphologic finding
Regression/no change (n = 68)
Aortic dissection (n = 11)
PAU (n = 35)
Type A Type B Maximum ascending aorta diameter, mm Maximum ascending aorta hematoma thickness, mm Maximum descending aorta diameter, mm Maximum descending aorta hematoma thickness, mm Circular shape, n (%) Echolucent areas, n (%) Atherosclerosis plaque, n (%)
16(2.4) 52(76.5) 42.29 ± 5.60 1.54 ± 3.88 30.68 ± 5.48 8.33 ± 4.01 38(55.9) 30(44.1) 23(33.8)
5(4.4) 6(5.3) 40.32 ± 9.87 6.69 ± 12.31 26.48 ± 5.87 11.43 ± 3.68 4(3.5) 7(6.1) 3(2.6)
12(10.5) 23(20.2*) 42.72 ± 8.93 2.32 ± 4.49 29.63 ± 7.45 10.49 ± 3.43 17(14.9) 18(15.8) 4(3.5)
PAU, Penetrating Aortic Ulcer. * Pb0.05 compared with PAU in type A.
respectively. The baseline imaging data are also provided in Table 1. Eighty descending thoracic aortas were observed (65%). The maximum ascending and descending aortic diameters were 43.19 ± 5.09 mm and 29.73 ± 5.58 mm, respectively. The maximum ascending and descending aortic hematoma thicknesses were 2.81 ± 4.70 mm and 10.17 ± 3.79 mm, respectively. We found 42 atherosclerotic ulcerated plaques and 35 atherosclerotic plaques. We found 38 cases with pleural effusion and 6 cases with pericardial effusion. The medication and laboratory examination data are also provided in Table 1. Nine patients suddenly died 10 days after diagnosis. Two patients died from non-cardiovascular causes; one patient was type A, and the other was type B. Three patients suffered from CHD, and 1 patient suffered from cerebral infarction (Supplementary material–Table S1). 3.3. Associations between the morphological findings and clinical outcomes Table 2 shows the associations between the morphological findings and evolution. Patients who regressed had a relatively smaller maximum descending aortic hematoma thickness than those who underwent AD (8.33 ± 4.01 vs 11.43 ± 3.68, P b 0.05) and those with PAUs (8.33 ± 4.01 vs 10.49 ± 3.43, P b 0.05). More type B and fewer type A patients were included in the regression group (2.4% vs 76.5%, P b 0.05). In contrast, the type B patients presented with more PAUs (20.2% vs 10.5%, P b 0.05). No data were available regarding the maximum ascending aortic hematoma thickness in the regression patients because the ascending aortic hematoma recovered in the 2 type A patients. No differences were observed in the morphological findings, including the circular shape, echolucent areas, and atherosclerotic plaques. 3.4. Predictive value of the hematoma thickness for prognosis in Chinese patients The ROC curve analysis demonstrated that the hematoma thickness and aortic diameter could distinguish between patients with or without multiple endpoints, including death, AD, PAU and thickening of the aortic hematoma (Fig. 1). The optimal cutoff values for the hematoma thickness and aortic diameter in Chinese patients were 10.45 mm and 44.75 mm, with areas under the curve (AUCs) of 0.727 and 0.807, respectively. The log rank survival curve analysis showed that patients with an aortic diameter b 44.75 mm had a significantly lower aortarelated risk than those with an aortic diameter N 44.75 mm (50% (34/ 68) vs 98.2% (54/55), P = 0.0048). (Supplementary material–Fig. S2). 3.5. Baseline characteristics of patients with/without PAUs in the acute/ chronic phases A total of 123 patients were diagnosed after imaging, of whom 116 patients were in the acute phase and 7 were in the chronic phase; thirty-one of these PAUs (26.7%) developed during the acute phase. Considering all acute phase and chronic phase patients, the number of patients with dyslipidemia was higher in the PAU group (21.6% vs
5.6%, P = 0.021). During the acute phase, the numbers of patients with dyslipidemia and who smoked were higher in the PAU group (22.2% vs 6.3%, P = 0.027, and 61.1% vs 41.3%, P = 0.047) (Supplementary material–Table S2). 3.6. Follow-up in patients with/without PAUs in the acute/chronic phases The follow-up duration ranged from 1 to 107 months (mean: 20 ± 20 months; median: 20 months; quartile 1 to quartile 3: 25 to 57 months), A total of 108 patients were in the acute phase, and 6 patients were in the chronic phase. No differences in the aorta-related mortality and/or invasive treatment rate were observed between the two groups. Imaging follow-up was completed in 114 patients. The imaging review was performed 7–10 days after the diagnosis for all 114 patients. At 7–10 days after diagnosis, 54 patients had no change, 14 patients regressed, and 46 patients showed aggravated symptoms (for details, see Supplementary material–Fig. S3). In addition, the survival curve of the primary endpoint for all patients was used to determine the cumulative hazard over time. Forty-two adverse aorta-related events occurred within 30 days, with only 7 primary endpoints occurring between 30 and 180 days. Forty-two cumulative adverse events occurred within 30 days (hazard ratio = 1.95), whereas only 7 cumulative events occurred from 30 to 180 days (hazard ratio for 180 days = 3.2; for details see Supplementary material–Fig. S4). 3.7. Multivariate predictor analysis The multivariate analysis showed that a baseline MAD ≥ 44.75 mm (2.9% vs 61.4%, P b 0.001) and an acute PAU (2.9% vs 34.1%, P = 0.008) were independent predictors of aorta-related events. No significant trend was observed for age, gender, hypertension, dyslipidemia, diabetes mellitus or an initial hematoma thickness ≥ 10.45 mm (Supplementary material–Table S3). 3.8. Morphological evolution of aortic IMHs Typical morphological MDCT imaging data obtained during the acute phase of aortic IMH evolution to a PAU and dissection were shown in Fig. 2C–D and Fig. 2A–B respectively. Typical imaging data showing aortic IMH recovery and enlargement were shown in Fig. 2E– F and Fig. 2G–H respectively. 4. Discussion To our knowledge, the present report describes the first large-scale and long-term follow-up study of the Chinese population and shows that the incidence, evolution, follow-up, and multivariate predictors of IMHs in Chinese patients with both type A and type B IMHs with or without PAUs may lead to different prognoses. The principal findings were as follows. First, during follow-up, a PAU was associated with a higher cumulative hazard of aorta-related events, especially for acute phase IMHs; most adverse aorta-related events occurred within the
Please cite this article as: Y.-J. Liu, et al., Long-term follow-up and clinical implications in Chinese patients with aortic intramural hematomas, Int J Cardiol (2018), https://doi.org/10.1016/j.ijcard.2018.06.077
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Fig. 1. Receiver operating characteristic (ROC) curve analysis for prediction of IMH based on the maximal aortic hematoma and maximal aortic diameters.
first month after the IMH diagnosis, which may greatly contribute to guiding clinical practice. Second, in the ROC curve analysis, we obtained the first Chinese cutoff values for hematoma thickness (10.45 mm) and aortic diameter (44.75 mm) for the prediction of aorta-related events. Third, we share the first evidence in the Chinese population that the morphological evolution of aortic IMHs was aggravated and regressed. Together, the findings and evidence from the present study may greatly contribute to improvements in Chinese practice guidelines for IMH [12]. The present study provides the first evidence in the Chinese population that the cutoff value for hematoma thickness to predict aortarelated events is 10.45 mm, which is in accordance with the Asia Task Force practice guidelines for aortic diseases (JCS-AD 2011 guidelines). In the 2011 JCS-AD guidelines, medical treatment is recommended for a type A IMH (IIaC) in patients with a hematoma thickness b 11 mm and an aortic diameter b 50 mm. However, the European (ESC-AD
2014 guidelines) and American (ACCF-AD 2011 guidelines) guidelines recommend surgery (IC and IIaC). For type B IMH cases, the American and Asian guidelines suggest medical treatment, but the ESC guidelines recommend the alternative TEVAR (IIaC) [10]. The results from our study support the recommendation of the Asian guidelines for type A IMH treatment. The differences between the Eastern and Western guidelines suggest that race, habits and customs may affect treatment strategies. Thus, data and evidence for IMH therapy must be obtained for the Chinese population. In 1920, Krukenberg E described IMH for the first time as “dissection without intimal tear” [13]. However, the etiology and exact mechanism of IMH remain unclear. One potential cause of IMH is rupture of the vasa vasorum in the aorta. IMH should not contain any intimal disruptions at onset [14]; thus, we excluded all cases of demonstrable intimal disruption in the present study. After enrollment, PAUs occurred in 30.1% of the patients during evolution (37/123). The mechanism of PAU formation may warrant additional study [15]. Potential mechanisms of PAU formation are as follows. First, “microtears” [16] and intima injury may be caused by deformations of the aortic intima around the IMH. Previous studies reported that N50% of IMH cases had “microtears” or micro-communications in the aortic intima [17]. Kitai [18] reported that nearly 36% of IMH patients had tiny intimal disruptions. Second, an ulcer-like projection of the aorta secondary to IMH may account for PAUs [19]. Our unpublished data show that a PAU is closely correlated with coronary arteriosclerosis, which may indicate serious systemic vascular atherosclerosis in the whole body. In the present study, CT was repeated 7–10 days after the PAU diagnosis to provide a medical evaluation and timely treatment. Interestingly, based on our results and the above analysis, the present study supports the hypothesis that intensive lipid-lowering treatment after diagnosis, which may make a vascular intimal lipid plaque more stable in the acute phase of IMH [20–21], might be a feasible solution for preventing PAUs. The present study showed that 42 adverse aorta-related events occurred within 30 days after diagnosis, with only 7 primary endpoints
Fig. 2. IMH evolution to AD over a 12-day period. A, C, E, and G, in the acute phase, MDCT shows a high signal intensity suggestive of IMH. B, Twelve days later, MDCT reveals a typical dissection; D, at 8 days of follow-up, MDCT shows an atherosclerotic ulcerated plaque (arrow) with IMH in the upper part of the descending aorta; F, at 2 months of follow-up, a CT scan shows that the intima has almost completely disappeared; H, 15 days later, the intima became enlarged.
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occurring between 30 and 180 days. Coincidentally, Kitai et al. [18] reported that 36% of patients developed focal intimal disruption within the first 30 days after the IMH diagnosis. In Kitai's study, none of the patients developed a new focal intimal disruption after 30 days. In the study of Sergio Moral et al., 74% of focal intimal disruption was diagnosed after discharge, with 56% of patients diagnosed at 1–3 months, and only 18% diagnosed at 3–6 months. Based on the findings from the present study, we hypothesized that increased pressure due to the IMH in the aortic wall triggered a focal intimal injury during the acute phase, which may account for the high hazard ratio in the first 30 days after diagnosis.
4.1. Limitations The present study was a retrospective observational study with inherent shortcomings. First, due to the non-randomized design and low incidence of IMH in the normal population, our study should be considered as hypothesis-generating. Second, the number of patients enrolled was small due to low morbidity and high mortality rate of IMH, which might have limited the power to distinguish a difference between the acute and chronic phases of IMH. Third, we were unable to confirm the exact time of IMH onset and evolution using imaging techniques. Therefore, a large-scale randomized control trial is required.
5. Conclusions The present study suggests that most adverse aorta-related events occur within 30 days in Chinese IMH patients. The cutoff values for predicting aorta-related events are a hematoma thickness of 10.45 mm and a baseline MAD of 44.75 mm. An acute PAU and a MAD ≥ 44.75 mm in IMH patients predict a poor prognosis.
5.1. Clinical perspectives Data from Chinese patients with aortic intramural hematomas are lacking. Thus, further long-term and larger scale aortic intramural hematomas studies involving the Chinese population are warranted. The present study provides the first evidence in the Chinese population that the cutoff value for hematoma thickness to predict aorta-related events is 10.45 mm. A large-scale randomized control trial is required.
Funding sources This work was supported by the National Key Project of Research and Development Plan during the Thirteenth Five-year Plan Period of China (No. 2016YFC1301300), and the Construction Program of the National Clinical Priority Specialty of China.
Disclosures The authors declare that there is no conflict of interest.
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Long-term follow-up and clinical implications in Chinese patients with aortic intramural hematomas☆ Yan-Jie Liu 1, Quan-Yu Zhang 1, Zhan-Kui Du, Lin Yang, Lei Zhang, Rui-Xia He, Ya Wang, Ya-Ling Han ⁎, Xiao-Zeng Wang ⁎ Department of Cardiology, Institute of Cardiovascular Research, General Hospital of Shenyang Military Region, Shenyang, 110016, China
a r t i c l e
i n f o
Article history: Received 24 March 2018 Received in revised form 6 May 2018 Accepted 18 June 2018 Available online xxxx Keywords: Aortic intramural hematoma Chinese patients Clinical outcomes
a b s t r a c t Background: Intramural hematomas (IMHs) are reported to dynamically evolve into different clinical outcomes ranging from regression to aortic rupture, but no practice guidelines are available in China. Objective: To determine the evolution of IMHs after long-term follow-up and to identify the predictive factors of IMH outcomes in the Chinese population. Methods: A total of 123 IMH patients with clinical and imaging follow-up data were retrospectively studied. The primary endpoints were aortic disease-related death, aortic dissection, penetrating aortic ulcer (PAU), thickening of the aortic hematoma and aortic complications requiring surgical or endovascular treatment. Results: All 123 IMH patients were monitored clinically. The follow-up duration ranged from 1.4 to 107 months (median, 20 months). Thirty-nine patients had type A IMH, and 84 had type B. The multivariate analysis showed that a baseline MAD ≥ 44.75 mm (2.9% vs 61.4%, P b 0.001) and acute PAUs (2.9% vs 34.1%, P = 0.008) were independent predictors of aorta-related events. Conclusions: Medication and short-term imaging are recommended for Chinese IMH patients with a hematoma thickness b 10.45 mm and a baseline MAD b 44.75 mm. Rigorous medical observation should also be performed during the acute phase of IMH. © 2018 Published by Elsevier B.V.
1. Introduction In aortic disease, both intramural hematoma (IMH) and aortic dissection (AD) belong to the spectrum of acute aortic syndrome (AAS) [1]. IMH accounts for 5–30% of AAS cases and leads to AD, aneurysm formation and reabsorption [2]. The etiology of IMH is not clear but may be
Abbreviations: IMH, aortic intramural hematoma; AD, aortic dissection; AAS, acute aortic syndrome; ESC, European Society of Cardiology; TEVAR, thoracic endovascular aortic repair; MDCT, multidetector computed tomography; PAU, penetrating aortic ulcer; MAD, maximal aorta diameter; ROC, receiver operating characteristic; CHD, chronic heart disease; AUC, areas under the curve; ACCF, American College of Cardiology Foundation; JCS, Japanese Circulation Society. ☆ This work was supported by the National Key Project of Research and Development Plan during the Thirteenth Five-year Plan Period [2016YFC1301300], China, and the Construction Program of the National Clinical Priority Specialty. ⁎ Corresponding authors. E-mail addresses: [email protected] (Y.-L. Han), [email protected] (X.-Z. Wang). 1 Yan-Jie Liu and Quan-Yu Zhang contribute equally to this article.
related to spontaneous vasa vasorum bleeding in the aortic wall media without intimal disruption [3]. Previous studies [4] have reported that pre-existing atherosclerosis and hypertension may be risk factors for IMHs, whereas a younger age, an aortic diameter b 4–4.5 cm and a hematoma diameter b 1 cm may be protective factors [5]. Although AD and IMH have entirely different pathological bases, similar therapeutic strategies are adopted for them in routine clinical work [5]. Furthermore, the long-term evolution of IMHs toward progression or regression under different conditions is unclear [6]. American and European guidelines recognize IMHs as a type of AAS with a surgery indication, but guidelines from Asia consider IMH a pathological process that is different from AAS and suggest medical treatment. For type A IMH treatment, the Asian guidelines advise medical treatment (IIaC), but the European and American guidelines recommend surgery (IC, IIaC). For type B IMH, the Asian and American guidelines suggest medical treatment, but the ESC recommends thoracic endovascular aortic repair (TEVAR) as an alternative (IIaC). However, data from Chinese patients with IMH are lacking. Thus, further longterm and larger scale IMH studies involving the Chinese population are warranted.
https://doi.org/10.1016/j.ijcard.2018.06.077 0167-5273/© 2018 Published by Elsevier B.V.
Please cite this article as: Y.-J. Liu, et al., Long-term follow-up and clinical implications in Chinese patients with aortic intramural hematomas, Int J Cardiol (2018), https://doi.org/10.1016/j.ijcard.2018.06.077
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The aims of the present study were to determine the different characteristics of IMH after long-term follow-up and to establish predictive factors for the evolution of IMH in Chinese patients. 2. Methods 2.1. Study patients From February 2003 to May 2017, 1770 consecutive patients were diagnosed with AAS at the General Hospital of Shenyang Military Region, including 270 IMH patients, of which 123 patients were retrospectively examined. 39 patients presented with type A aortic IMH, and 84 presented with type B aortic IMH (Supplementary material–Fig. S1). The study was approved by the ethics committee of the General Hospital of Shenyang Military Region. 2.2. Management and follow-up protocol Multidetector computed tomography (MDCT) was performed in all cases [7]. The lesions were characterized using the following clinical and radiologic criteria: [1] the aortic Table 1 Clinical characteristics, aortic segments with IMH, and baseline morphological findings, and laboratory examination (n = 123). Characteristic Demographic and clinical Age, y Men, n (%) BMI Systemic hypertension, n (%) Smoking, n (%) Hyperlipidemia, n (%) Diabetes, n (%) Imaging Descending thoracic aorta, n (%) Abdominal aorta, n (%) Aortic arch, n (%) Ascending aorta, n (%) Abdominal aortic aneurysm, n (%) Maximum ascending aorta diameter, mm Maximum ascending aorta hematoma thickness*, mm Maximum descending aorta diameter, mm Maximum descending aorta hematoma thickness, mm Circular shape, n (%) Echolucent areas, n (%) Atherosclerotic ulcerated plaque, n (%) Atherosclerosis plaque, n (%) Pleural effusion, n (%) Pericardial effusion, n (%) Medical Antiplatelet agents, n (%) Anticoagulants, n (%) Beta-blockers, n (%) Calcium antagonists, n (%) ACE inhibitors, n (%) ARB inhibitors, n (%) Nitrates, n (%) Statins, n (%) Systolic BP, mm Hg Diastolic BP, mm Hg Heart rate, BPM Lab examinations CKMB, ng/ml TNT exception, n (%) ALT, U/L AST*, U/L WBC, 109/L PLT, 109/L HG, g/L BUN, mmol/L CR, umol/L C-reactive protein*, mg/dL D-dimer, ng/ml
No. (%) 59.91 ± 11.20 84(68.3) 24.62 ± 3.26 102(82.9) 57(46.3) 13(10.6) 11(8.9) 80(65.0) 2(1.6) 8(6.5) 9(7.3) 3(2.4) 43.19 ± 5.09 2.83(0.00–6.00) 29.73 ± 5.58 10.17 ± 3.79 64(52.0) 59(48.0) 42(34.1) 35(28.5) 38(30.9) 6(4.9) 5(4.1) 0 15(12.2) 48(39.0) 16(13.1) 15(12.2) 2(1.6) 3(2.4) 149.39 ± 25.54 85.28 ± 16.45 79.82 ± 10.95 13.18 ± 8.15 10(8.1) 37.87 ± 12.92 34.58(17.43–27) 9.98 ± 3.95 211.15 ± 62.05 133.17 ± 18.03 6.13 ± 3.99 78.32 ± 42.38 30.47(3.90–30.00) 4.44(050–5.20)
BMI, Body Mass Index; ACE, Angiotensin-converting Enzyme; ARB, Angiotensin Receptor Blocker; BP, Blood Pressure; CKMB, Creatine Phosphokinase-myocardial Band; TNT, Troponin-T; BNP, Brain Natriuretic Peptide; ALT, Alanine Aminotransferase; AST, Aspartate aminotransferase; WBC, White Blood Cell; PLT, Platelets Count; HG, Hemoglobin; CR, Creatinine. * Median(Quartile Q1–Q3).
hematoma lesion type was classified based on the initial diagnosis (type A or type B) using the earliest available imaging data; the initial diagnosis was not changed even if the lesion type changed (e.g., from type B to type A); [2] IMH was characterized by crescentic or circular shadowing and expansion within the aortic wall, which contained an aortic wall hematoma with bleeding within the media but without initial intimal flap formation; and [3] rupture was determined by the presence of extra-aortic blood confirmed by radiology, surgical examination, or post-mortem examination, clinical behavior (persistent pain despite medical treatment), or intra-operative findings of an impending rupture (peri-aortic hematoma without frank rupture or extreme wall thinning) [8]. Progression of the observed pathologies was classified as follows: [1] a decrease in the size or disappearance of the hematoma was recorded as “resolution”; [2] “worsening” referred to deterioration in the aortic condition, including significant increases in the thickness of the lesion, the progression of IMHs to penetrating aortic ulcer(PAU), the progression to classic dissection, or rupture; and [3] patients whose lesions did not improve or worsen significantly were noted as “stable”. After discharge, all cases were followed up promptly at 1, 3, 6, and 12 months. Surgical or endovascular treatment during follow-up was considered if any of the following criteria were observed: aortic rupture; rapid growth of the PAU or the aortic diameter (N5 mm/ year); or a MAD N 55 mm [8]. We operated on all patients in the rupture state and all ascending lesions when clinically possible. For descending IMHs, we provided standard initial anti-impulse therapy but maintained a low threshold for catheterization intervention in cases of radiographic worsening on follow-up. 2.3. Endpoints The primary endpoint during the follow up was a composite endpoint that consisted of aortic disease-related death, AD, PAUs, thickening of the aortic hematoma, and aortic complications requiring surgical or endovascular treatment. The acute phase of IMH was b15 days, the sub-acute phase was 15 to 90 days, and the chronic phase was N90 days from the onset of aortic disease-related pain [9]. 2.4. Imaging techniques CT was performed in all acute phase patients [10]. The location, maximum thickening, and circular or crescentic forms were assessed by CT as reported previously. CT was performed using a 64-detector Siemens Sensation and intravenous boluses with 80 to 150 mL of nonionic contrast medium. 2.5. Statistical analysis Continuous variables are reported as the mean ± SD (proportions depend on the variable distribution) or the median (quartile 1 to quartile 3). Categorical variables were expressed as frequencies and percentages and were compared using the χ2 or Fisher's exact-test. For the baseline characteristics, continuous variables were expressed as the mean ± SD and were compared using a t-test. Survival curves were generated via the Kaplan–Meier method with significant differences assessed for time-to-event data using log-rank tests. Cox regression models were constructed to identify factors associated with the primary endpoint. To evaluate whether the maximum aortic hematoma thickness could be an effective predictor of the primary endpoint, a receiver operating characteristic (ROC) curve analysis was performed [11]. The optimal cutoff level was calculated by determining the shortest distance between the ROC curve and the upper left corner of the graph. Patients above the optimal cutoff level were considered to exhibit a high maximum aortic hematoma thickness. A P value b 0.05 was considered significant. The analyses were performed using SPSS version 22.0 (SPSS, Chicago, Illinois).
3. Results 3.1. Study patients All 123 cases were diagnosed b24 h from the imaging examination and included acute, sub-acute and chronic type A and type B aortic IMH cases. Thirty-nine cases presented with type A IMH, and 84 presented with type B IMH. Among the 39 type A patients, 6 died after the diagnosis, and 33 survived. Among the 84 type B patients, 3 died and 81 survived. Among the 33 surviving type A patients, 4 accepted surgical treatment, 7 underwent TEVAR and 22 received medical treatment. Among the 81 surviving type B patients, 10 accepted TEVAR and 71 received medical treatment (Supplementary material–Fig. S1). 3.2. Baseline characteristics and adverse events for the entire cohort The baseline characteristics of the entire cohort (123 cases) are shown in Table 1. The average age was 59.91 ± 11.20 years. Eightyfour patients were male. The incidence of systemic hypertension was 82.9%. Nearly half of the patients were smokers (46.3%). A total of 10.6% and 8.9% of the patients had hyperlipidemia and diabetes,
Please cite this article as: Y.-J. Liu, et al., Long-term follow-up and clinical implications in Chinese patients with aortic intramural hematomas, Int J Cardiol (2018), https://doi.org/10.1016/j.ijcard.2018.06.077
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Table 2 Relationship between IMH baseline morphological findings and final morphological outcomes. Morphologic finding
Regression/no change (n = 68)
Aortic dissection (n = 11)
PAU (n = 35)
Type A Type B Maximum ascending aorta diameter, mm Maximum ascending aorta hematoma thickness, mm Maximum descending aorta diameter, mm Maximum descending aorta hematoma thickness, mm Circular shape, n (%) Echolucent areas, n (%) Atherosclerosis plaque, n (%)
16(2.4) 52(76.5) 42.29 ± 5.60 1.54 ± 3.88 30.68 ± 5.48 8.33 ± 4.01 38(55.9) 30(44.1) 23(33.8)
5(4.4) 6(5.3) 40.32 ± 9.87 6.69 ± 12.31 26.48 ± 5.87 11.43 ± 3.68 4(3.5) 7(6.1) 3(2.6)
12(10.5) 23(20.2*) 42.72 ± 8.93 2.32 ± 4.49 29.63 ± 7.45 10.49 ± 3.43 17(14.9) 18(15.8) 4(3.5)
PAU, Penetrating Aortic Ulcer. * Pb0.05 compared with PAU in type A.
respectively. The baseline imaging data are also provided in Table 1. Eighty descending thoracic aortas were observed (65%). The maximum ascending and descending aortic diameters were 43.19 ± 5.09 mm and 29.73 ± 5.58 mm, respectively. The maximum ascending and descending aortic hematoma thicknesses were 2.81 ± 4.70 mm and 10.17 ± 3.79 mm, respectively. We found 42 atherosclerotic ulcerated plaques and 35 atherosclerotic plaques. We found 38 cases with pleural effusion and 6 cases with pericardial effusion. The medication and laboratory examination data are also provided in Table 1. Nine patients suddenly died 10 days after diagnosis. Two patients died from non-cardiovascular causes; one patient was type A, and the other was type B. Three patients suffered from CHD, and 1 patient suffered from cerebral infarction (Supplementary material–Table S1). 3.3. Associations between the morphological findings and clinical outcomes Table 2 shows the associations between the morphological findings and evolution. Patients who regressed had a relatively smaller maximum descending aortic hematoma thickness than those who underwent AD (8.33 ± 4.01 vs 11.43 ± 3.68, P b 0.05) and those with PAUs (8.33 ± 4.01 vs 10.49 ± 3.43, P b 0.05). More type B and fewer type A patients were included in the regression group (2.4% vs 76.5%, P b 0.05). In contrast, the type B patients presented with more PAUs (20.2% vs 10.5%, P b 0.05). No data were available regarding the maximum ascending aortic hematoma thickness in the regression patients because the ascending aortic hematoma recovered in the 2 type A patients. No differences were observed in the morphological findings, including the circular shape, echolucent areas, and atherosclerotic plaques. 3.4. Predictive value of the hematoma thickness for prognosis in Chinese patients The ROC curve analysis demonstrated that the hematoma thickness and aortic diameter could distinguish between patients with or without multiple endpoints, including death, AD, PAU and thickening of the aortic hematoma (Fig. 1). The optimal cutoff values for the hematoma thickness and aortic diameter in Chinese patients were 10.45 mm and 44.75 mm, with areas under the curve (AUCs) of 0.727 and 0.807, respectively. The log rank survival curve analysis showed that patients with an aortic diameter b 44.75 mm had a significantly lower aortarelated risk than those with an aortic diameter N 44.75 mm (50% (34/ 68) vs 98.2% (54/55), P = 0.0048). (Supplementary material–Fig. S2). 3.5. Baseline characteristics of patients with/without PAUs in the acute/ chronic phases A total of 123 patients were diagnosed after imaging, of whom 116 patients were in the acute phase and 7 were in the chronic phase; thirty-one of these PAUs (26.7%) developed during the acute phase. Considering all acute phase and chronic phase patients, the number of patients with dyslipidemia was higher in the PAU group (21.6% vs
5.6%, P = 0.021). During the acute phase, the numbers of patients with dyslipidemia and who smoked were higher in the PAU group (22.2% vs 6.3%, P = 0.027, and 61.1% vs 41.3%, P = 0.047) (Supplementary material–Table S2). 3.6. Follow-up in patients with/without PAUs in the acute/chronic phases The follow-up duration ranged from 1 to 107 months (mean: 20 ± 20 months; median: 20 months; quartile 1 to quartile 3: 25 to 57 months), A total of 108 patients were in the acute phase, and 6 patients were in the chronic phase. No differences in the aorta-related mortality and/or invasive treatment rate were observed between the two groups. Imaging follow-up was completed in 114 patients. The imaging review was performed 7–10 days after the diagnosis for all 114 patients. At 7–10 days after diagnosis, 54 patients had no change, 14 patients regressed, and 46 patients showed aggravated symptoms (for details, see Supplementary material–Fig. S3). In addition, the survival curve of the primary endpoint for all patients was used to determine the cumulative hazard over time. Forty-two adverse aorta-related events occurred within 30 days, with only 7 primary endpoints occurring between 30 and 180 days. Forty-two cumulative adverse events occurred within 30 days (hazard ratio = 1.95), whereas only 7 cumulative events occurred from 30 to 180 days (hazard ratio for 180 days = 3.2; for details see Supplementary material–Fig. S4). 3.7. Multivariate predictor analysis The multivariate analysis showed that a baseline MAD ≥ 44.75 mm (2.9% vs 61.4%, P b 0.001) and an acute PAU (2.9% vs 34.1%, P = 0.008) were independent predictors of aorta-related events. No significant trend was observed for age, gender, hypertension, dyslipidemia, diabetes mellitus or an initial hematoma thickness ≥ 10.45 mm (Supplementary material–Table S3). 3.8. Morphological evolution of aortic IMHs Typical morphological MDCT imaging data obtained during the acute phase of aortic IMH evolution to a PAU and dissection were shown in Fig. 2C–D and Fig. 2A–B respectively. Typical imaging data showing aortic IMH recovery and enlargement were shown in Fig. 2E– F and Fig. 2G–H respectively. 4. Discussion To our knowledge, the present report describes the first large-scale and long-term follow-up study of the Chinese population and shows that the incidence, evolution, follow-up, and multivariate predictors of IMHs in Chinese patients with both type A and type B IMHs with or without PAUs may lead to different prognoses. The principal findings were as follows. First, during follow-up, a PAU was associated with a higher cumulative hazard of aorta-related events, especially for acute phase IMHs; most adverse aorta-related events occurred within the
Please cite this article as: Y.-J. Liu, et al., Long-term follow-up and clinical implications in Chinese patients with aortic intramural hematomas, Int J Cardiol (2018), https://doi.org/10.1016/j.ijcard.2018.06.077
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Fig. 1. Receiver operating characteristic (ROC) curve analysis for prediction of IMH based on the maximal aortic hematoma and maximal aortic diameters.
first month after the IMH diagnosis, which may greatly contribute to guiding clinical practice. Second, in the ROC curve analysis, we obtained the first Chinese cutoff values for hematoma thickness (10.45 mm) and aortic diameter (44.75 mm) for the prediction of aorta-related events. Third, we share the first evidence in the Chinese population that the morphological evolution of aortic IMHs was aggravated and regressed. Together, the findings and evidence from the present study may greatly contribute to improvements in Chinese practice guidelines for IMH [12]. The present study provides the first evidence in the Chinese population that the cutoff value for hematoma thickness to predict aortarelated events is 10.45 mm, which is in accordance with the Asia Task Force practice guidelines for aortic diseases (JCS-AD 2011 guidelines). In the 2011 JCS-AD guidelines, medical treatment is recommended for a type A IMH (IIaC) in patients with a hematoma thickness b 11 mm and an aortic diameter b 50 mm. However, the European (ESC-AD
2014 guidelines) and American (ACCF-AD 2011 guidelines) guidelines recommend surgery (IC and IIaC). For type B IMH cases, the American and Asian guidelines suggest medical treatment, but the ESC guidelines recommend the alternative TEVAR (IIaC) [10]. The results from our study support the recommendation of the Asian guidelines for type A IMH treatment. The differences between the Eastern and Western guidelines suggest that race, habits and customs may affect treatment strategies. Thus, data and evidence for IMH therapy must be obtained for the Chinese population. In 1920, Krukenberg E described IMH for the first time as “dissection without intimal tear” [13]. However, the etiology and exact mechanism of IMH remain unclear. One potential cause of IMH is rupture of the vasa vasorum in the aorta. IMH should not contain any intimal disruptions at onset [14]; thus, we excluded all cases of demonstrable intimal disruption in the present study. After enrollment, PAUs occurred in 30.1% of the patients during evolution (37/123). The mechanism of PAU formation may warrant additional study [15]. Potential mechanisms of PAU formation are as follows. First, “microtears” [16] and intima injury may be caused by deformations of the aortic intima around the IMH. Previous studies reported that N50% of IMH cases had “microtears” or micro-communications in the aortic intima [17]. Kitai [18] reported that nearly 36% of IMH patients had tiny intimal disruptions. Second, an ulcer-like projection of the aorta secondary to IMH may account for PAUs [19]. Our unpublished data show that a PAU is closely correlated with coronary arteriosclerosis, which may indicate serious systemic vascular atherosclerosis in the whole body. In the present study, CT was repeated 7–10 days after the PAU diagnosis to provide a medical evaluation and timely treatment. Interestingly, based on our results and the above analysis, the present study supports the hypothesis that intensive lipid-lowering treatment after diagnosis, which may make a vascular intimal lipid plaque more stable in the acute phase of IMH [20–21], might be a feasible solution for preventing PAUs. The present study showed that 42 adverse aorta-related events occurred within 30 days after diagnosis, with only 7 primary endpoints
Fig. 2. IMH evolution to AD over a 12-day period. A, C, E, and G, in the acute phase, MDCT shows a high signal intensity suggestive of IMH. B, Twelve days later, MDCT reveals a typical dissection; D, at 8 days of follow-up, MDCT shows an atherosclerotic ulcerated plaque (arrow) with IMH in the upper part of the descending aorta; F, at 2 months of follow-up, a CT scan shows that the intima has almost completely disappeared; H, 15 days later, the intima became enlarged.
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occurring between 30 and 180 days. Coincidentally, Kitai et al. [18] reported that 36% of patients developed focal intimal disruption within the first 30 days after the IMH diagnosis. In Kitai's study, none of the patients developed a new focal intimal disruption after 30 days. In the study of Sergio Moral et al., 74% of focal intimal disruption was diagnosed after discharge, with 56% of patients diagnosed at 1–3 months, and only 18% diagnosed at 3–6 months. Based on the findings from the present study, we hypothesized that increased pressure due to the IMH in the aortic wall triggered a focal intimal injury during the acute phase, which may account for the high hazard ratio in the first 30 days after diagnosis.
4.1. Limitations The present study was a retrospective observational study with inherent shortcomings. First, due to the non-randomized design and low incidence of IMH in the normal population, our study should be considered as hypothesis-generating. Second, the number of patients enrolled was small due to low morbidity and high mortality rate of IMH, which might have limited the power to distinguish a difference between the acute and chronic phases of IMH. Third, we were unable to confirm the exact time of IMH onset and evolution using imaging techniques. Therefore, a large-scale randomized control trial is required.
5. Conclusions The present study suggests that most adverse aorta-related events occur within 30 days in Chinese IMH patients. The cutoff values for predicting aorta-related events are a hematoma thickness of 10.45 mm and a baseline MAD of 44.75 mm. An acute PAU and a MAD ≥ 44.75 mm in IMH patients predict a poor prognosis.
5.1. Clinical perspectives Data from Chinese patients with aortic intramural hematomas are lacking. Thus, further long-term and larger scale aortic intramural hematomas studies involving the Chinese population are warranted. The present study provides the first evidence in the Chinese population that the cutoff value for hematoma thickness to predict aorta-related events is 10.45 mm. A large-scale randomized control trial is required.
Funding sources This work was supported by the National Key Project of Research and Development Plan during the Thirteenth Five-year Plan Period of China (No. 2016YFC1301300), and the Construction Program of the National Clinical Priority Specialty of China.
Disclosures The authors declare that there is no conflict of interest.
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Please cite this article as: Y.-J. Liu, et al., Long-term follow-up and clinical implications in Chinese patients with aortic intramural hematomas, Int J Cardiol (2018), https://doi.org/10.1016/j.ijcard.2018.06.077