Admission Values of D-dimer and C-reactive Protein (CRP) Predict the Long-term Outcomes in Acute Aortic Dissection

Transcription

1 ORIGINAL ARTICLE Admission Values of D-dimer and C-reactive Protein (CRP) Predict the Long-term Outcomes in Acute Aortic Dissection Kentaro Mori 1, Hidetaka Tamune 1, Hiroyuki Tanaka 2 and Mitsuhiro Nakamura 3 Abstract Objective Admission D-dimer and C-reactive protein (CRP) values have been reported to predict the shortterm outcomes in acute aortic dissection (AAD). However, the association between D-dimer values and the long-term outcomes has not been investigated. Methods The primary endpoints included events determined to be all-cause death, recurrence of aortic dissection, aortic rupture, and surgical intervention for the aortic aneurysm following the first hospital discharge. We performed a receiver operating characteristic analysis and determined the optimal cut-off levels of admission D-dimer, admission CRP and peak CRP values in terms of the sensitivity and specificity for predicting the presence of events. Using the optimal cut-off values, we performed a multiple Cox analysis and investigated the hazard ratio of admission D-dimer, admission CRP and peak CRP. Patients We retrospectively identified 173 AAD patients hospitalized between January 2005 and December Results A multiple Cox regression analysis revealed that the hazard ratios were 3.4 for admission D-dimer [95% Confidence Interval (CI) 1.5 to 7.3, p=0.004] and 2.7 for admission CRP (95% CI 1.2 to 5.5, p= 0.014). Conclusion Admission D-dimer and CRP values may predict the long-term outcomes in AAD. Moreover, admission D-dimer values may be a valuable marker to predict not only the short-term outcomes, but also the long-term outcomes in AAD. Key words: acute aortic dissection, admission D-dimer, admission CRP, long-term outcomes (Intern Med 55: , 2016) () Introduction In general, acute aortic dissection (AAD) is a lifethreating condition characterized by an acute onset, rapid development, and high mortality in the acute phase. Even after a survival past the acute phase, the probability of severe adverse events such as death or the reoccurrence of aortic dissection remains high, with a 10-year mortality rate of 30-88% (1-5). Therefore, classifying high-risk patients with a poor long-term prognosis is clinically important. With respect to the short-term outcomes in AAD, admission D-dimer and admission CRP values were found to predict in-hospital death (6). On the other hand, the peak CRP level reportedly predicted the long-term outcomes in type B AAD (7). However, the association between admission D- dimer and admission CRP values and long-term outcomes in AAD has rarely been investigated. The present retrospective cohort study was an effort to answer this question. Patients and follow-up Materials and Methods This study was a retrospective cohort study conducted at Tokyo Metropolitan Tama Medical Center, Japan, a 789-bed tertiary care teaching hospital providing emergency care to approximately 4 million people in the Tama area of Tokyo. Department of Emergency Rescue, Tokyo Metropolitan Tama Medical Center, Japan, Department of Cardiovascular Medicine, Tokyo Metropolitan Tama Medical Center, Japan and Department of Mental Health, Graduate School of Medicine, The University of Tokyo, Japan Received for publication August 18, 2015; Accepted for publication October 20, 2015 Correspondence to Dr. Kentaro Mori, kenmori713@yahoo.co.jp 1837

2 The emergency department (ED) at this institution takes in an average of 38,000 patients, including 7,200 ambulances, annually. Data from hospital admission records were collected by participating members and compiled in a chart from which AAD patients hospitalized between January 2005 and December 2013 were retrospectively identified. The inclusion criteria were AAD presenting within 14 days of symptom onset and confirmed with non-contrast computed tomography (CT) or contrast-enhanced CT imaging. The exclusion criteria were death during the first admission, failure to obtain the admission D-dimer values, or failure to make an outpatient visit after discharge. The first day of discharge was set as the beginning of the follow-up period. The study s primary endpoint was the presence of an event determined to be all-cause death, the recurrence of aortic dissection, aortic rupture, or surgical treatment of the aortic aneurysm following the first hospital discharge. In keeping with previous studies (8-11), not only death due to aortic events, but also other causes of death were included. Patients were followed until the occurrence of an event. Patients with no reported events were followed until their last outpatient visit. This study was performed in accordance with the Helsinki Declaration and was approved by the institutional review board of Tokyo Metropolitan Tama Medical Center with a waiver of informed consent to review the patient records (approval number 28). Definition of the clinical criteria Assays were conducted with Nanopia R D-dimer and Nanopia R CRP, which utilize a monoclonal antibody (Sekisui Medical, Tokyo, Japan; normal limit <1 mcg/ml and <0.3 mg/dl, respectively). Several studies (12, 13) have reported that D-dimer levels were elevated within 6 hours and reached their peak within 24 hours after the onset of aortic dissection. Therefore, we adopted the value of D-dimer at the time of admission. On the other hand, CRP levels gradually elevated, reaching their peak within 4-6 days post-onset. Consequently, we adopted the CRP value at admission and the CRP peak value within 6 days after onset during the first period of admission. Hypertensive patients were identified by a history of hypertension in their clinical record or from their use of antihypertensive agents before the initial admission. Patients suffering from diabetes mellitus were similarly identified by their clinical record or by their treatment with oral hypoglycemic agents or insulin prior to the initial admission. A history of dyslipidemia was identified according to the clinical records or the use of lipid lowering agents before the initial admission. A partial enhancement of the false lumen was defined as the non-thrombosed type, and the absence of an enhancement of the false lumen as the thrombosed type. Non-contrast CT images were interpreted by boardcertified radiologists blinded to the clinical data. Whenever there was any difficulty in identifying the false lumen type, the cases in question were removed from consideration. The maximum aortic diameter of the dissected aorta in all of the patients was determined by measuring one cross-sectional CT image. Other clinical criteria were defined according to the clinical record. We regarded any data not included in the records to be outside the scope of the present study. Statistical analysis Continuous normally distributed variables were expressed as the mean (± standard deviation) and not-normally distributed variables as the medians (interquartile range). These variables were compared with Student s t-test. Categorical variables were compared with the chi-square test when appropriate; otherwise, Fisher s exact test was used. A receiver operating characteristic (ROC) analysis was performed to determine the optimal cut-off values for admission D-dimer, admission CRP, and peak CRP values in predicting the presence of events with high sensitivity and specificity. After the subjects were divided into two groups using the cut-off values, the cumulative incidences for admission D-dimer, admission CRP, and peak CRP values were estimated by the Kaplan-Meier method, and differences were assessed using the log-rank test and Wilcoxon test to reveal how event-free rates of the high and low groups changed in the long-term. Finally, a multiple Cox regression analysis was performed to investigate whether admission D-dimer, admission CRP, or peak CRP values were related to the presence of adverse events even after adjusting for other factors. These factors were adjusted for age and sex in addition to relative variables, which were selected by the stepwise method. p values <0.05 were considered to be statistically significant. All data analyses were performed using a commercially available statistical software package (JMP1 10, SAS Institute, Cary, USA). Results Between January, 2005 and December, 2013, 219 patients were diagnosed with AAD using a non-contrast CT image or contrast-enhanced CT image before admission to Tokyo Metropolitan Tama Medical Center (Fig. 1). The D-dimer value was not measured at the time of admission in 2 patients; 27 patients died during the first admission, and 17 failed to make an outpatient visit, leaving 173 patients for inclusion in this analysis. Among these patients, 31 patients experienced events including 14 all-cause deaths, 3 recurrences of aortic dissection, 1 aortic rupture, and 13 surgeries for an aortic aneurysm, while 142 patients experienced no events during the follow-up period. The mean follow-up period was 1,087.9 days (event group: 1,081.4 days; non-event group: 1,087.9 days). First, the baseline characteristics including the admission D-dimer, admission CRP, and peak CRP values of the event group were compared with those of the non-event group (Table 1). As a result, the percentage of patients with a history of aortic aneurysm (13.0 vs. 2.1%, p=0.021), admission D-dimer (32.4±45.0 vs. 13.6±22.2 mcg/ml, p<0.001), admission CRP (3.6±5.3 vs. 1.49±3.2 mg/dl, p=0.004), peak 1838

3 219 AAD patients enrolled 46 Excluded 2 = No admission D-dimer 27 = In-hospital death 17 = No outpatient visit 173 Patients included Event group 31 patients Non-event group 142 patients Figure 1. Patient selection. AAD: acute aortic dissection CRP (14.2±7.1 vs. 11.2±7.0 mg/dl, p=0.035), and maximum aortic diameter (44.1±9.5 vs. 40.2±9.1 mm, p=0.033) were significantly higher in the event group. Next, a ROC analysis was performed to determine the optimal cut-off values for admission D-dimer, admission CRP, and peak CRP values for predicting the presence of events with high sensitivity and specificity (Table 2). According to the results, the following values were chosen as cut-off values: 31.1 mcg/ml for D-dimer (sensitivity: 32.2%, specificity: 89.4%, odds ratio: 4.0, 95% CI 1.6 to 10.2, p=0.004), 1.6 mg/dl for admission CRP (sensitivity: 41.9%, specificity: 81.7%, odds ratio: 3.2, 95% CI 1.4 to 7.4, p=0.008), 12.2 mg/dl for peak CRP (sensitivity: 66.6%, specificity: 57.9%, odds ratio: 2.8, 95% CI 1.2 to 6.5, p=0.015). The area under the curve was for admission D-dimer, for admission CRP, and for peak CRP. According to these cut-off values, the subjects were divided into high and low groups. The details of the events in each group are shown in Table 3. The significant differences in related factors between the high and low groups for admission D-dimer were systolic blood pressure (BP) at admission (131±35.3 vs ±39.5 mmhg, p=0.024), peak CRP (17.5±9.0 vs. 10.8±6.3 mg/dl, p<0.001), platelet count (13.8±4.6 vs. 18.9± /mcl, p<0.001), the percentage of patients prescribed calcium channel blockers at discharge (44.0 vs. 67.8%, p=0.041) and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACE-I/ARB) at discharge (28.0 vs. 54.1%, p=0.018), and the maximum aortic diameter (44.4±9.7 vs. 40.0±9.5 mm, p=0.038). In addition, 17 patients who were excluded because they had failed to make an outpatient visit were assessed with the result that no significant difference was observed between the groups (systolic BP at admission: p=0.317, peak CRP: p= 0.221, platelet count: p=0.466, calcium channel blocker: p= 0.559, ACE-I/ARB at discharge: p=1.000, maximum aortic diameter: p=0.126) except for diastolic BP at discharge (89.0±1.4 vs. 66.0±11.7 mmhg, p=0.019). We next evaluated the cumulative incidences for admission D-dimer, admission CRP, and peak CRP by the Kaplan-Meier method. With respect to admission D-dimer and admission CRP values, the event-free rate for the high group gradually decreased and showed a significantly poorer prognosis compared with that of the low group (admission D-dimer: p=0.004; admission CRP: p=0.008; Fig. 2). On the other hand, no significant difference between the event-free rate for the high and low groups was detected, although the event-free rate for the high group showed a tendency to decrease gradually for peak CRP (p=0.098; Fig. 2). Next, the stepwise method was utilized to select variables relevant to the presence of an event, with the result that a history of aortic aneurysm (p=0.021), surgery at initial hospitalization (p=0.170), admission D-dimer (p=0.019) and admission CRP (p=0.027) were selected. Because the Kaplan- Meier curve showed that peak CRP was not a significant determinant of the long-term clinical outcomes, it was excluded from the variables in a multiple Cox regression analysis, which was performed to determine whether admission D-dimer and admission CRP remained relevant to the presence of events, even after adjusting for the relevant variables besides age and sex. The results showed that the heart rate (HR) was 3.4 for admission D-dimer (95% CI 1.5 to 7.3, p=0.004) and 2.7 for admission CRP (95% CI 1.2 to 5.5, p=0.014) (Table 4). When focusing only on type B AAD, the following were chosen as the cut-off values: 31.1 mcg/ml for D-dimer (sensitivity: 28.6%, specificity: 91.3%, odds ratio: 4.2, 95% CI 1.3 to 13.8, p=0.023), 1.6 mg/dl for admission CRP (sensitivity: 52.3%, specificity: 82.6%, odds ratio: 5.2, 95% 1839

4 Table 1. Baseline Characteristics of the Event Group and Non-event Group. Event group Non-Event group p value Male sex, n (%) 21/31 (67.7) 84/142 (59.2) Age, n (years) 67.1±13.7, ±13.5, Time from onset to admission, n (days) 0.8±1.6, ±1.8, History of smoking, n (%) 12/24 (50.0) 61/111 (55.5) History of hypertension, n (%) 19/31 (61.3) 91/141 (64.5) History of diabetes mellitus, n (%) 1/31 (3.2) 13/141 (9.2) History of dyslipidemia, n (%) 6/31 (19.4) 31/141 (22.0) History of asthma, n (%) 0/31 (0) 8/141 (5.7) History of atrial fibrillation, n (%) 2/31 (6.5) 4/141 (2.8) History of Marfan s syndrome, n (%) 1/31 (3.2) 2/141 (1.4) History of MI or angina, n (%) 0/31 (0) 4/141 (2.8) History of aortic aneurysm, n (%) 4/31 (13.0) 3/141 (2.1) History of aortic dissection, n (%) 2/31 (6.5) 1/142 (0.7) Surgery at initial hospitalization, n (%) 6/31 (19.4) 45/141 (31.9) Systolic BP at admission, n (mmhg) 146.6±37.9, ±39.9, Diastolic BP at admission, n (mmhg) 87.9±21.0, ±24.3, Heart rate at admission, n (per min) 73.4±13.4, ±20.1, Systolic BP at discharge, n (mmhg) 117.2±16.0, ±16.8, Diastolic BP at discharge, n (mmhg) 67.2±9.5, ±10.8, Heart rate at discharge, n (per min) 67.8±12.6, ±14.8, Admission D-dimer, n (mcg/ml) 11.1 ( ), ( ), 142 <0.001 Admission CRP, n (mg/dl) 0.4 ( ), ( ), Peak CRP, n (mg/dl) 13 ( ), ( ), Platelet count, n (* 10 3 /mcl) 16.4±6.9, ±6.1, egfr at admission, n (ml/min/1.73m 2 ) 66.3 ( ), ( ), White blood cell counts at admission, 88 (71-127), ( ), n ( 10 3 /mm 3 ) egfr at discharge, n (ml/min/1.73m 2 ) 60.8 ( ), ( ), Statins at discharge, n (%) 7/31 (22.6) 27/142 (19.0) Calcium channel blocker at discharge, 17/31 (54.8) 91/142 (64.1) n (%) ACE-I/ARB at discharge, n (%) 14/31 (45.2) 74/142 (52.1) blocker at discharge, n (%) 23/31 (74.2) 93/142 (65.5) blocker at discharge, n (%) 5/31 (16.1) 26/142 (18.3) Diuretics, n (%) 8/31 (25.8) 43/142 (30.3) Non-thrombosed type, n (%) 18/30 (60.0) 68/137 (50.0) Maximum aorta diameter, n (mm) 44.1±9.5, ±9.1, Type A AD, n (%) 10/31 (32.3) 49/142 (34.5) Continuous normally distributed variables were expressed as mean (±standard deviation) and not-normally distributed variables as medians (interquartile range). n: number, MI: Myocardial infarction, BP: Blood pressure, CRP: C-reactive protein, egfr: estimated glomerular filtration rate, ACE-I: Angiotensin-converting enzyme inhibitor, ARB: angiotensin II receptor blocker, AD: Aortic dissection Table 2. Cut-off Values for Admission D-dimer, Admission CRP, and Peak CRP. Cut-off values of Sensitivity (%) Specificity (%) Odds ratio 95% CI p value admission D-dimer (mcg/ml) to to to 65.2 <0.001 Cut-off values of admission CRP (mg/dl) to to to Cut-off values of peak CRP (mg/dl) to to to CRP: C-reactive protein, CI: confidence interval CI 1.9 to 14.4, p=0.002), and 12.4 mg/dl for peak CRP (sensitivity: 55.4%, specificity: 71.4%, odds ratio: 3.1, 95% CI 1.1 to 8.7, p=0.023). The area under the curve was for admission D-dimer, for admission CRP, and for peak CRP. We evaluated the cumulative incidences for admission D-dimer, admission CRP, and peak CRP by the 1840

5 Table 3. Details of Events in Each Group for Admission D-dimer and Admission CRP. Admission D-dimer (cut-off values: 31.1mcg/mL ) Low High Death 9 Death 5 Sudden death 4 Sudden death 3 Recurrence of aortic dissection 2 Small intestine necrosis 1 Liver cirrhosis 1 Pneumonia 1 Cancer 2 Recurrence of aortic dissection 2 Recurrence of aortic dissection 1 Rupture of abdominal aortic aneurysm 1 Aortic rupture 0 Surgery 9 Surgery 4 Replacement of descending thoracic aorta 3 Replacement of descending thoracic aorta 3 Replacement of ascending aorta 1 Replacement of total arch 1 Replacement of abdominal aortic aneurysm 4 Replacement of thoraco abdominal aorta 1 Admission CRP (cut-off values: 1.6 mg/dl) Low High Death 9 Death 5 Sudden death 6 Sudden death 1 Recurrence of aortic dissection 1 Recurrence of aortic dissection 1 Liver cirrhosis 1 Cancer 2 Small intestine necrosis 1 Pneumonia 1 Recurrence of aortic dissection 1 Recurrence of aortic dissection 2 Rupture of abdominal aorticaneurysm 1 Aortic rupture 0 Surgery 7 Surgery 6 Replacement of descending thoracic aorta 3 Replacement of descending thoracic aorta 3 Replacement of ascending aorta 1 Replacement of abdominal aortic aneurysm 2 Replacement of abdominal aortic aneurysm 2 Replacement of thoraco abdominal aorta 1 Replacement of total arch 1 CRP: C-reactive protein Figure 2. Kaplan-Meier analyses for admission D-dimer (cut-off: 31.1mcg/mL), admission CRP (cut-off: 1.6mg/dL), and peak CRP (cut-off: 12.2mg/dL) values. Kaplan-Meier curves for the absence of events in admission D-dimer and admission CRP show that the prognosis of the high group was significantly inferior to the prognosis of the low group (admission D-dimer: p=0.004, Log-rank test; admission CRP: p=0.008, Log-rank test). The Kaplan-Meier curve for the absence of events in peak CRP showed that the difference in the prognosis between the groups was not significant (p=0.098, Log-rank test). CRP: C-reactive protein, No: number Table 4. Multiple Cox Regression Analysis. Variables Hazard ratio 95% CI p value Male sex to Age >=71 years to History of aortic aneurysm to 44.3 <0.001 Surgery at initial hospitalization to Admission D-dimer >=31.1 mcg/ml to Admission CRP >=1.6 mg/dl to The high and low age groups were divided by 71 years old. CI: confidence interval, CRP: C-reactive protein Kaplan-Meier method. With respect to the admission D- dimer and admission CRP values, the event-free rate for the high group showed a significantly poorer prognosis compared with that of the low group (admission D-dimer: p= 0.047; admission CRP: p=0.001). No significant difference between the event-free rate for the high and low groups was 1841

6 detected for peak CRP (p=0.091). A Cox regression analysis could not be performed because there were only 22 events for type B AAD patients. Discussion High values for admission D-dimer and admission CRP were found to be potentially related to poor long-term outcomes in AAD. No significant difference between the eventfree rate for the high and low groups for peak CRP was found, although that of the high group showed a tendency to decrease gradually compared with that of the low group. The correlation between a high admission D-dimer value and the long-term outcomes in AAD could be explained by the fact that the absolute level of D-dimer may correlate with the extent of aortic dissection (14-16). An extensively dissected wall is weakened and gradually enlarged over time or otherwise ruptures, or patients experience re-dissection suddenly several months later due to reasons such as transient blood pressure elevation. From a pathophysiological point-of-view, D-dimer is produced as a degradation product of cross-linked fibrin (17, 18). We hypothesize that the more extensive the aortic dissection, the greater the amounts of tissue thromboplastin and plasminogen produced, leading to high activation of both coagulation and fibrinolysis. This, in turn, leads to a greater production of D-dimer from plasminogen and stabilized fibrin. The present study did not establish whether absolute levels of D-dimer correlated with the extent of aortic dissection due to the difficulty of determining the extent of aortic dissection by CT imaging alone. However, a previous study (14-16) reported that the type of AAD correlated with the D-dimer values and demonstrated that the D-dimer values tended to be higher with more extensive aortic dissection. The results of the study support the finding that the value of D-dimer accurately reflects the size of the dissection. A potential explanation of the association between the admission CRP value to the long-term outcomes in AAD is that elevated admission CRP values might affect the remodeling of the dissected aortic wall. CRP was reportedly normal at admission in most AAD patients (19, 20). Therefore, it is likely that the elevation of admission CRP was not caused by AAD but by other forms of chronic inflammation which existed before the onset of AAD. CRP may progress to arteriosclerosis, amplify the immune response, and affect coagulation (21-25). The elevation of admission CRP itself might affect remodeling of the dissected aortic wall. However, these ideas are nothing but speculation. Further prospective studies are needed to clarify these uncertainties. AAD is a life-threating disease with a high probability of adverse events such as death and the reoccurrence of aortic dissection in the chronic phase. We believe that classifying high risk patients who have poor long-term outcomes is clinically important. With respect to the short-term outcomes in AAD, admission D-dimer and admission CRP values were found to have a predictive value for hospital death (6). Regarding the long-term outcomes, several studies (9, 18, 26-28) reported that female sex, history of aortic aneurysm, false lumen closure state, and the aortic diameter were prognostic factors. However, evaluating aortic closure is difficult when the anatomy of the aortic dissection is complex or the patient can only be evaluated using noncontrast CT images due to kidney function failure. In addition, evaluating the maximum aortic diameter at the surgical site is often difficult with one cross-sectional CT image. In such situations, it appears that these parameters alone are not sufficient to evaluate the long-term prognosis. Sakakura et al. (7) reported in 2010 that peak CRP predicts the longterm outcomes in type B AAD. In addition, we found that admission D-dimer and admission CRP values might also be useful markers to predict the long-term outcomes in AAD. Given our results, we suspect that admission D-dimer and admission CRP might serve well as markers for predicting the long-term outcomes in AAD. Moreover, the long-term outcomes might be predicted more precisely if other useful markers, such as the results of CT imaging, are incorporated. In most cases, D-dimer and CRP evaluations are ordered at admission for the diagnosis of AAD, allowing the physician to refer to them later to predict the long-term outcomes. Limitation There are several limitations associated with the present study. The study population was limited, with only 219 patients enrolled. In addition, this single-center retrospective study design poses a risk for patient selection bias. D-dimer rises in pregnancy, or in the presence of cancer, pneumonia, and so on. Therefore, the values obtained in some of the cases may reflect not just AAD, but other concurrent processes as well. Due to the small number of events, a multiple Cox regression analysis could not be used to analyze admission D-dimer and admission CRP values using either factors selected by the stepwise method or important clinical factors besides age and sex. Finally, the data collected in this study were derived from the patients medical records in our hospital, which imposes another limitation on our study in terms of the amount of information available. Conclusion Our retrospective study showed that admission D-dimer and admission CRP might serve as predictors for adverse long-term events in AAD patients. Further prospective studies are necessary to validate these findings. In addition, the correlation between the admission D-dimer value and the extent of the dissected area should be confirmed by further studies. A careful clinical follow-up may be desirable in those patients who have high admission D-dimer and high admission CRP values. The authors state that they have no Conflict of Interest (COI). 1842

7 Acknowledgement We thank Mr. Yoshihiko Takayanagi for his unfailing diligence in gathering the references, and the entire staff of the Department of Emergency Rescue, the Department of Cardiovascular Medicine, and the Department of Cardiovascular Surgery at Tokyo Metropolitan Tama Medical Center, Tokyo, Japan for their input and continuing care of the patients. References 1. Doroghazi RM, Slater EE, DeSanctis RW, et al. Long-term survival of patients with treated aortic dissection. J Am Coll Cardiol 3: , Umana JP, Lai DT, Mitchell RS, et al. Is medical therapy still the optimal treatment strategy for patients with acute type B aortic dissections? J Thorac Cardiovasc Surg 124: , Bernard Y, Zimmermann H, Chocron S, et al. False lumen patency as a predictor of late outcome in aortic dissection. Am J Cardiol 87: , Chiappini B, Schepens M, Tan E, et al. Early and late outcomes of acute type A aortic dissection: analysis of risk factors in 487 consecutive patients. Eur Heart J 26: , Glower DD, Speier RH, White WD, Smith LR, Rankin JS, Wolfe WG. Management and long-term outcome of aortic dissection. Ann Surg 214: 31-41, Wen D, Du X, Dong JZ, Zhou XL, Ma CS. Value of D-dimer and C reactive protein in predicting inhospital death in acute aortic dissection. Heart 99: , Sakakura K, Kubo N, Ako J, et al. Peak C-reactive protein level predicts long-term outcomes in type B acute aortic dissection. Hypertension 55: , Tsai TT, Fattori R, Trimarchi S, et al. Long-term survival in patients presenting with type B acute aortic dissection: insights from the International Registry of Acute Aortic Dissection. Circulation 114: , Tsai TT, Evangelista A, Nienaber CA, et al. Partial thrombosis of the false lumen in patients with acute type B aortic dissection. N Engl J Med 357: , Estrera AL, Miller CC 3rd, Safi HJ, et al. Outcomes of medical management of acute type B aortic dissection. Circulation 114: I384-I389, Tsai TT, Isselbacher EM, Trimarchi S, et al. Acute type B aortic dissection: does aortic arch involvement affect management and outcomes? Insights from the International Registry of Acute Aortic Dissection (IRAD). Circulation 116: I150-I156, Akutsu K, Sato N, Yamamoto T, et al. A rapid bedside D-dimer assay (cardiac D-dimer) for screening of clinically suspected acute aortic dissection. Circ J 69: , Suzuki T, Distante A, Zizza A, et al. Diagnosis of acute aortic dissection by D-dimer: the International Registry of Acute Aortic Dissection Substudy on Biomarkers (IRAD-Bio) experience. Circulation 119: , Weber T, Hogler S, Auer J, et al. D-dimer in acute aortic dissection. Chest 123: , Ohlmann P, Faure A, Morel O, et al. Diagnostic and prognostic value of circulating D-Dimers in patients with acute aortic dissection. Crit Care Med 34: , Iyano K, Kawada T, Aiba M, Takaba T. Correlation of hemostatic molecular markers and morphology of the residual false lumen in chronic aortic dissection. Ann Thorac Cardiovasc Surg 10: , ten Cate JW, Timmers H, Becker AE. Coagulopathy in ruptured or dissecting aortic aneurysms. Am J Med 59: , Hata M, Sezai A, Niino T, et al. Prognosis for patients with type B acute aortic dissection: risk analysis of early death and requirement for elective surgery. Circ J 71: , Komukai K, Shibata T, Mochizuki S. C-reactive protein is related to impaired oxygenation in patients with acute aortic dissection. IntHeartJ46: , Makita S, Ohira A, Tachieda R, et al. Behavior of C-reactive protein levels in medically treated aortic dissection and intramural hematoma. Am J Cardiol 86: , Verma S, Wang CH, Li SH, et al. A self-fulfilling prophecy: C- reactive protein attenuates nitric oxide production and inhibits angiogenesis. Circulation 106: , Venugopal SK, Devaraj S, Jialal I. C-reactive protein decreases prostacyclin release from human aortic endothelial cells. Circulation 108: , Nakagomi A, Freedman SB, Geczy CL. Interferon-gamma and lipopolysaccharide potentiate monocyte tissue factor induction by C-reactive protein: relationship with age, sex, and hormone replacement treatment. Circulation 101: , Yeh ET, Anderson HV, Pasceri V, Willerson JT. C-reactive protein: linking inflammation to cardiovascular complications. Circulation 104: , Di Napoli M, Papa F, Bocola V. Prognostic influence of increased C-reactive protein and fibrinogen levels in ischemic stroke. Stroke 32: , Akutsu K, Nejima J, Kiuchi K, et al. Effects of the patent false lumen on the long-term outcome type B acute aortic dissection. Eur J Cardiothorac Surg 26: , Takahashi J, Wakamatsu Y, Okude J, et al. Maximum aortic diameter as a simple predictor of acute type B aortic dissection. Ann Thorac Cardiovasc Surg 14: , Onitsuka S, Akashi H, Tayama K, et al. Long-term outcome and prognostic predictors of medically treated acute type B aortic dissections. Ann Thorac Surg 78: , The Japanese Society of Internal Medicine