- Email: [email protected]
Biomarkers in descending thoracic aortic dissection
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M I N A R S I N
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A S C U L A R
SU
R G E R Y
27 (2014) 196–199
Available online at www.sciencedirect.com
www.elsevier.com/locate/semvascsurg
Biomarkers in descending thoracic aortic dissection Sherene Shalhub, MD, MPHa,n, Anahita Dua, MD, MS, MBAb, and Jared Brooks, BAa a
Division of Vascular Surgery, Department of Surgery, University of Washington, 1959 NE Pacific Street, Box 356410, Seattle, WA 98195-6410 b Department of Surgery, Medical College of Wisconsin, Milwaukee, WI
article info
abstract The clinical application of serum biomarkers (D-dimer, C-reactive protein) to predict the natural history of descending thoracic aortic dissection remains elusive. In this review, our current understanding of biomarkers in descending thoracic aortic dissection detection, predicting complications, and aiding in patient management is discussed. & 2015 Elsevier Inc. All rights reserved.
1.
Introduction
Aortic dissection (AD) starts as an initial intimal tear, followed by the rapid growth of an intramural hematoma that dissects the media within the aortic wall leading to blood flow through a double-barrel aorta with a true and false lumen [1]. Diagnosis of AD and prognosis prediction remain a challenge. The most sensitive clinical test for AD diagnosis is sudden onset of severe ripping pain in the chest, back, or upper abdomen [2]. This can be absent in 5% to 20% of patients [1,2]. In terms of prognosis, the estimated 3-year mortality of descending thoracic aortic (DTA) AD, also known as Stanford Type B AD or DeBakey III AD, is 20%. The ability to predict the natural history of DTA AD in any given patient for future risk stratification remains elusive [3]. The role of biomarkers has been investigated both in diagnosis and identifying progression of DTA AD. The biomarkers studied were selected based on the understanding of the natural history of DTA AD. It is hypothesized that the acute dissection process activates the extrinsic pathway of the coagulation cascade due to release of tissue factor from the injured aortic wall along the length of the false lumen [4]. False lumen thrombosis is hypothesized to activate the intrinsic pathway of the coagulation cascade and subsequently n
Corresponding author. E-mail address: [email protected] (S. Shalhub).
http://dx.doi.org/10.1053/j.semvascsurg.2015.01.001 0895-7967/$ - see front matter & 2015 Elsevier Inc. All rights reserved.
the fibrinolytic system is activated. The cross-linked fibrin is degraded and then D-dimer is formed [5]. Additionally, an inflammatory response has been described to be associated with AD [6]. DTA AD can lead to complications in the short term, such as aortic rupture; refractory pain; and spinal, visceral, renal, and extremity malperfusion. In the subacute and chronic phase of aortic dissection, aortic remodeling begins. Aortic remodeling is characterized by ongoing fibrinolysis, and active proteolysis of the extracellular matrix [4,5,7]. Over the long term, the aorta can undergo gradual dilation and aneurysmal degeneration. This review was undertaken to discern the current understanding of biomarkers in DTA AD detection and complications prediction.
2. Biomarkers in the detection of descending Thoracic Aortic Dissection The utilization of biomarkers in AD diagnosis has been investigated as a screening test to direct further imaging in a manner similar to venous thromboembolic disease. Several biomarkers have been investigated for that purpose; the most widely studied biomarker to date has been serum D-dimer.
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D-dimer, the degradation product of cross-linked fibrin, is an indirect marker of the coagulation system activation. Serum D-dimer levels have been reported to be elevated in cases of thromboembolic disease, liver disease, pregnancyrelated complications, malignancy, or generalized inflammation [8]. The testing is inexpensive, widely available, and can be completed expeditiously [9]. In AD, serum D-dimer has been shown to be elevated as much as 20 times that of a normal subject. This is similar to the levels detected in pulmonary embolism cases [4,5,10,11]. In general, serum Ddimer levels in acute AD are higher than in cases with acute myocardial infarction and in those with chronic AD [4]. Two large meta-analysis studies evaluated the utility of D-dimer as a test to detect AD in patients with chest pain and thus direct further aortic imaging. The positive test threshold was set at the threshold for pulmonary embolism detection. These meta-analyses showed that serum D-dimer had a sensitivity of 94% to 95% and a specificity ranging between 40% and 100% for AD detection [10,12]. Serum D-dimer levels show a trend for gradual decrease within the first few days of AD, thus it has been proposed as a biomarker to differentiate acute AD from chronic AD [4]. Given the high sensitivity and low specificity of the test, it is useful as a screening test in patients with low clinical probability of acute AD [10]. Serum D-dimer levels appear to be correlated to the anatomic extent of AD with higher levels detected in Stanford Type A AD and in those with larger aortic diameters [9]. In studies where the extent of the dissection was classified according to the DeBakey classification, the highest levels of serum D-dimers in the acute phase were detected in DeBakey I AD, followed by DeBakey III AD then DeBakey II AD [5,13]. This led to the hypothesis that the extent of coagulation and fibrinolysis pathways activation is proportionately related to the surface of contact between the bloodstream and the exposed thrombogenic elements in the false lumen. The finding was not replicated in a smaller study (n ¼ 18) comparing D-dimer levels between Stanford Type A and B AD [11]. Additionally, this finding has not been replicated in Stanford Type B specifically. In a study of 30 patients with Stanford Type B AD, no significant correlation was found between admission serum D-dimer levels and extent of dissection as classified according to the DeBakey classification IIIa versus IIIb [14]. D-dimer levels have been shown to be significantly lower in cases of false lumen thrombosis and intramural hematoma. The latter entities lack a patent false lumen and have a smaller anatomic extension compared to a classic AD [13,14]. Given these results, the use of serum D-dimer testing as a singular test modality in cases with high index of clinical suspicion for AD cannot be recommended [15]. Several other biomarkers have been studied as diagnostic for AD. These include plasma smooth muscle myosin heavy chains, soluble elastin fragments, and calponin, a smooth muscle troponin-like protein. These biomarkers are thought to be released from the injured aortic media during AD and have been shown in small studies to detect AD with high sensitivity and specificity, although at this time they remain impractical in the clinical emergency setting [16–18]. Plasma N-terminal pro-B-type natriuretic peptide (BNP) levels were also evaluated. In a prospective study, in 18
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patients with acute AD (13 Stanford Type A AD, 5 Stanford Type B AD), plasma BNP levels were found to be elevated in acute AD compared to normal controls [11]. A potential hypothesis to explain this finding is the associated history of long-standing hypertension in patients with AD, as plasma BNP levels have been shown to be elevated in patients with essential hypertension and diastolic dysfunction. This is supported by the finding in the same study that plasma BNP levels were also increased in patients with chronic thoracic aneurysms [11].
3. Biomarkers in predicting descending Thoracic Aortic dissection prognosis The utilization of biomarkers has been investigated as prognostic indicator in the short and long term. Candidate biomarkers include serum D-dimer, C-reactive protein (CRP), metalloproteinases, and genetic markers. D-dimer levels have been demonstrated to be predictive of hospital short-term mortality [4,9]. In a prospective study of 114 patients with acute AD (64 Stanford Type A AD, 50 Stanford Type B AD), elevated admission plasma D-dimer levels were associated with high risk of short-term mortality [9]. D-dimer levels have also been evaluated as a marker for early in-hospital complications. In a retrospective study of 16 patients with acute AD (6 Stanford Type A AD, 10 Stanford Type B AD), complicated AD cases, as defined by contained aortic rupture and tamponade, had higher serum D-dimer levels compared to uncomplicated cases [4]. In a prospective study of 30 patients with Stanford Type B AD focused on serial D-dimer measurements, re-elevation of D-dimer during hospitalization was associated with complications defined as re-dissection in (n ¼ 3) and venous thromboembolic events (n ¼ 4) during hospitalization [14]. The acute-phase reactant CRP is a biomarker of systemic inflammation that is produced mainly by the liver. Elevation of plasma CRP levels and leukocytosis have been described in acute AD with plasma CRP levels increased by more than five times compared to normal subjects [11]. Plasma CRP levels in AD have been demonstrated to be time dependent, with a rapid rise in the first 4 to 6 hours, reaching a peak between 36 hours and 6 days post AD, and then followed by a decline in the chronic phase [19,20]. The use of CRP testing in evaluating the severity of AD was first described in 1991 in a cohort of 42 cases of DTA AD [21]. The marker was followed during hospital admission for medical management of the DTA AD and the patients were discharged once the levels had normalized. A second peak was noted in 26% of the patients and the majority of these patients had either progression of the AD or recurrent pain [21]. In a prospective study of 114 patients with AD (64 Stanford Type A AD, 50 Stanford Type B AD), elevated admission plasma CRP levels (>6.3 mg/dL) have been associated with high risk of short-term mortality in the acute phase. In a retrospective study of 255 consecutive patients with symptomatic thoracic, abdominal aortic aneurysms, and AD (including 27 patients with DTA AD), the highest serum CRP quartile level was an independent predictor of mortality, with a 2.6 increase in mortality after adjusting for age, sex, aortic rupture, shock, mechanical
198
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ventilation, coronary artery disease, hemoglobin level, diabetes, and treatment [22]. In a retrospective study of 16 patients with AD (6 Stanford Type A AD, 10 Stanford Type B AD), there was a trend toward a higher serum CRP levels in patients who died during the in-hospital period, although the timing of serum CRP levels in relation to onset of AD was unclear [4]. This finding has not been consistently demonstrated. In a retrospective study of 220 patients with Stanford Type B AD, admission serum CRP levels were not a significant predictor of poor outcomes [23]. Subsequent studies evaluated peak CRP levels rather than admission levels. Peak CRP, which is reached on day 3 to 6 post AD, is thought to be a better prognostic marker than an initial CRP and is thought to be reflective of the severity of the AD. In a retrospective study of 200 patients with Stanford Type B AD and a median follow-up of 4.2 years, elevated peak CRP during the initial hospitalization was found to be associated with long-term adverse events, defined as all-cause mortality, and aortic events, including surgery of the thoracic aorta, recurrence of AD, and aortic rupture [24]. Serial CRP levels were also evaluated as predictors of subsequent aneurysmal degeneration during initial hospitalization. In a prospective study of 32 patients with Stanford Type B AD, serial CRP measurements were followed and did not appear to correlate with an increase in aortic diameter as detected by computed tomography scanning during hospitalization [20]. Pentraxin 3, a vascular inflammation-related biomarker similar to CRP but not affected by liver damage, was also investigated. Serial levels of plasma Pentraxin 3 were explored in 41 patients with Stanford Type B AD and shown to peak at 4.3 days post AD. The peak levels did not correlate with all-cause death during the mean follow-up period of 2 years. Of interest, plasma Pentraxin 3 levels were associated with the amount of transient pleural fluid accumulation. Although at this time, the role of this biomarker in AD is not fully understood, it has been shown to be elevated in patients with acute lung injury, acute respiratory distress syndrome, and septic shock [25]. Matrix metalloproteinases (MMPs) are a group of extracellular matrix proteases released by interstitial cells and play an important role in degrading the extracellular matrix, including elastin, fibronectin, and collagen in the aortic wall. Elevated levels of MMP-9 have been associated with decreased aortic wall elasticity, aortic remodeling, and injury [26]. In a series of 4 patients with Stanford Type B AD, plasma MMP-9 levels were elevated early in the acute phase of aortic dissection and increased during follow-up for up to 2 months when compared to controls [27]. This finding was again demonstrated in a study comparing plasma MMP-9 concentrations between patients with acute (n ¼ 64) and chronic (n ¼ 42) AD [19]. The significance of this is unclear, as it is hypothesized that this may contribute to degradation of the aortic wall or could be that MMP-9 is significant in tissue remodeling [26]. Genetic testing in the management of DTA dissection is an emerging field. Gene mutations leading to aortic aneurysms and dissections have been described mainly in ascending aortic aneurysms and dissections and are termed thoracic aortic aneurysms and dissection genes. These mutations can lead to syndromic disease, ie, associated with disease
R G E R Y
27 (2014) 196–199
manifestations affecting other organ systems, and nonsyndromic disease. Examples of syndromic mutations associated with AD include mutations leading to Marfan syndrome (FBN1), Loeys-Dietz syndrome (TGFBR1 and TGFBR2), vascular Ehlers-Danlos syndrome (COL3A1), aneurysm-osteoarthritis syndrome (SMAD3), and TGFB2 mutations. The nonsyndromic mutations include TGFBR1, TGFBR2, ACTA2, MYH11, MYLK, and PRKG1. Genetic testing is presently time-consuming and is not suitable for the detection of AD in acute phase, but it can play a role in predicting future prognosis of AD and thus directing management options [28].
4. Descending Thoracic Aortic dissection biomarkers research limitations and future Many of the DTA dissection biomarkers studies are limited by small study sizes, variability in marker assays, variable marker levels among individual patients, and the retrospective nature in the majority of studies. Additionally, assays of serum biomarkers are often time-consuming, with the exception of serum D-dimer assays, which has been readily incorporated into clinical practice [8]. This stresses the importance that a single biomarker by itself will remain inadequate, as different disease processes and genetic variation affect each individual biomarker level at a given time during a disease process. It is the sum of the ongoing changes in the metabolome of an individual as dictated by the combined effect of the genomic and environmental background that holds the most promise in utilizing biomarkers for aortic dissection. The future of these studies lies in multicenter prospective studies utilizing serial measurement protocols that may be able to overcome the challenges experienced by previous studies.
re fe r en ces
[1] Hagan PG, Nienaber CA, Isselbacher EM, et al. The International Registry of Acute Aortic Dissection (IRAD): new insights into an old disease. JAMA 2000;283:897–903. [2] Sullivan PR, Wolfson AB, Leckey RD, et al. Diagnosis of acute thoracic aortic dissection in the emergency department. Am J Emerg Med 2000;18:46–50. [3] 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 2006;114:2226–31. [4] Eggebrecht H, Naber CK, Bruch C, et al. Value of plasma fibrin D-dimers for detection of acute aortic dissection. J Am Coll Cardiol 2004;44:804–9. [5] Weber T, Hogler S, Auer J, et al. D-dimer in acute aortic dissection. Chest 2003;123:1375–8. [6] Luo F, Zhou XL, Li JJ, et al. Inflammatory response is associated with aortic dissection. Ageing Res Rev 2009;8:31–5. [7] Schneiderman J, Bordin GM, Adar R, et al. Patterns of expression of fibrinolytic genes and matrix metalloproteinase9 in dissecting aortic aneurysms. Am J Pathol 1998;152: 703–10. [8] Fedullo PF, Tapson VF. Clinical practice. The evaluation of suspected pulmonary embolism. N Engl J Med 2003;349: 1247–56.
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[9] Wen D, Du X, Dong JZ, et al. Value of D-dimer and C reactive protein in predicting inhospital death in acute aortic dissection. Heart 2013;99:1192–7. [10] Marill KA. Serum D-dimer is a sensitive test for the detection of acute aortic dissection: a pooled meta-analysis. J Emerg Med 2008;34:367–76. [11] Sbarouni E, Georgiadou P, Marathias A, et al. D-dimer and BNP levels in acute aortic dissection. Int J Cardiol 2007;122:170–2. [12] Shimony A, Filion KB, Mottillo S, et al. Meta-analysis of usefulness of d-dimer to diagnose acute aortic dissection. Am J Cardiol 2011;107:1227–34. [13] Ohlmann P, Faure A, Morel O, et al. Lower circulating StaLiatest D-Di levels in patients with aortic intramural hematoma compared with classical aortic dissection. Crit Care Med 2009;37:899–901. [14] Jo Y, Anzai T, Ueno K, et al. Re-elevation of D-dimer as a predictor of re-dissection and venous thromboembolism after Stanford type B acute aortic dissection. Heart Vessels 2010;25:509–14. [15] Ohlmann P, Morel O, Radulescu B, et al. D-Dimer in ruling out acute aortic dissection: sensitivity is not 100%. Eur Heart J 2008;29:828–9. [16] Suzuki T, Katoh H, Tsuchio Y, et al. Diagnostic implications of elevated levels of smooth-muscle myosin heavy-chain protein in acute aortic dissection. The smooth muscle myosin heavy chain study. Ann Intern Med 2000;133:537–41. [17] Shinohara T, Suzuki K, Okada M, et al. Soluble elastin fragments in serum are elevated in acute aortic dissection. Arterioscler Thromb Vasc Biol 2003;23:1839–44. [18] Suzuki T, Distante A, Zizza A, et al. Preliminary experience with the smooth muscle troponin-like protein, calponin, as a novel biomarker for diagnosing acute aortic dissection. Eur Heart J 2008;29:1439–45.
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[19] Wen D, Zhou XL, Li JJ, et al. Plasma concentrations of interleukin-6, C-reactive protein, tumor necrosis factoralpha and matrix metalloproteinase-9 in aortic dissection. Clin Chim Acta 2012;413:198–202. [20] 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 2000;86:242–4. [21] Hara K, Yamaguchi T, Wanibuchi Y, et al. The role of medical treatment of distal type aortic dissection. Int J Cardiol 1991;32:231–40. [22] Schillinger M, Domanovits H, Bayegan K, et al. C-reactive protein and mortality in patients with acute aortic disease. Intensive Care Med 2002;28:740–5. [23] Sakakura K, Kubo N, Ako J, et al. Determinants of in-hospital death and rupture in patients with a Stanford B aortic dissection. Circ J 2007;71:1521–4. [24] Sakakura K, Kubo N, Ako J, et al. Peak C-reactive protein level predicts long-term outcomes in type B acute aortic dissection. Hypertension 2010;55:422–9. [25] Arao K, Fujiwara T, Taniguchi Y, et al. Implications of pentraxin 3 levels in patients with acute aortic dissection. Heart Vessels 2014 Jan 29. [26] Akiyama M, Ohtani H, Sato E, et al. Up-regulation of matrix metalloproteinase-2 and membrane-type 1-matrix metalloproteinase were coupled with that of type I procollagen in granulation tissue response after the onset of aortic dissection. Virchows Arch 2006;448:811–21. [27] Sangiorgi G, Trimarchi S, Mauriello A, et al. Plasma levels of metalloproteinases-9 and -2 in the acute and subacute phases of type A and type B aortic dissection. J Cardiovasc Med (Hagerstown) 2006;7:307–15. [28] Milewicz DM, Regalado ES. Use of genetics for personalized management of heritable thoracic aortic disease: how do we get there? J Thorac Cardiovasc Surg 2014 Aug 5.
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Available online at www.sciencedirect.com
www.elsevier.com/locate/semvascsurg
Biomarkers in descending thoracic aortic dissection Sherene Shalhub, MD, MPHa,n, Anahita Dua, MD, MS, MBAb, and Jared Brooks, BAa a
Division of Vascular Surgery, Department of Surgery, University of Washington, 1959 NE Pacific Street, Box 356410, Seattle, WA 98195-6410 b Department of Surgery, Medical College of Wisconsin, Milwaukee, WI
article info
abstract The clinical application of serum biomarkers (D-dimer, C-reactive protein) to predict the natural history of descending thoracic aortic dissection remains elusive. In this review, our current understanding of biomarkers in descending thoracic aortic dissection detection, predicting complications, and aiding in patient management is discussed. & 2015 Elsevier Inc. All rights reserved.
1.
Introduction
Aortic dissection (AD) starts as an initial intimal tear, followed by the rapid growth of an intramural hematoma that dissects the media within the aortic wall leading to blood flow through a double-barrel aorta with a true and false lumen [1]. Diagnosis of AD and prognosis prediction remain a challenge. The most sensitive clinical test for AD diagnosis is sudden onset of severe ripping pain in the chest, back, or upper abdomen [2]. This can be absent in 5% to 20% of patients [1,2]. In terms of prognosis, the estimated 3-year mortality of descending thoracic aortic (DTA) AD, also known as Stanford Type B AD or DeBakey III AD, is 20%. The ability to predict the natural history of DTA AD in any given patient for future risk stratification remains elusive [3]. The role of biomarkers has been investigated both in diagnosis and identifying progression of DTA AD. The biomarkers studied were selected based on the understanding of the natural history of DTA AD. It is hypothesized that the acute dissection process activates the extrinsic pathway of the coagulation cascade due to release of tissue factor from the injured aortic wall along the length of the false lumen [4]. False lumen thrombosis is hypothesized to activate the intrinsic pathway of the coagulation cascade and subsequently n
Corresponding author. E-mail address: [email protected] (S. Shalhub).
http://dx.doi.org/10.1053/j.semvascsurg.2015.01.001 0895-7967/$ - see front matter & 2015 Elsevier Inc. All rights reserved.
the fibrinolytic system is activated. The cross-linked fibrin is degraded and then D-dimer is formed [5]. Additionally, an inflammatory response has been described to be associated with AD [6]. DTA AD can lead to complications in the short term, such as aortic rupture; refractory pain; and spinal, visceral, renal, and extremity malperfusion. In the subacute and chronic phase of aortic dissection, aortic remodeling begins. Aortic remodeling is characterized by ongoing fibrinolysis, and active proteolysis of the extracellular matrix [4,5,7]. Over the long term, the aorta can undergo gradual dilation and aneurysmal degeneration. This review was undertaken to discern the current understanding of biomarkers in DTA AD detection and complications prediction.
2. Biomarkers in the detection of descending Thoracic Aortic Dissection The utilization of biomarkers in AD diagnosis has been investigated as a screening test to direct further imaging in a manner similar to venous thromboembolic disease. Several biomarkers have been investigated for that purpose; the most widely studied biomarker to date has been serum D-dimer.
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D-dimer, the degradation product of cross-linked fibrin, is an indirect marker of the coagulation system activation. Serum D-dimer levels have been reported to be elevated in cases of thromboembolic disease, liver disease, pregnancyrelated complications, malignancy, or generalized inflammation [8]. The testing is inexpensive, widely available, and can be completed expeditiously [9]. In AD, serum D-dimer has been shown to be elevated as much as 20 times that of a normal subject. This is similar to the levels detected in pulmonary embolism cases [4,5,10,11]. In general, serum Ddimer levels in acute AD are higher than in cases with acute myocardial infarction and in those with chronic AD [4]. Two large meta-analysis studies evaluated the utility of D-dimer as a test to detect AD in patients with chest pain and thus direct further aortic imaging. The positive test threshold was set at the threshold for pulmonary embolism detection. These meta-analyses showed that serum D-dimer had a sensitivity of 94% to 95% and a specificity ranging between 40% and 100% for AD detection [10,12]. Serum D-dimer levels show a trend for gradual decrease within the first few days of AD, thus it has been proposed as a biomarker to differentiate acute AD from chronic AD [4]. Given the high sensitivity and low specificity of the test, it is useful as a screening test in patients with low clinical probability of acute AD [10]. Serum D-dimer levels appear to be correlated to the anatomic extent of AD with higher levels detected in Stanford Type A AD and in those with larger aortic diameters [9]. In studies where the extent of the dissection was classified according to the DeBakey classification, the highest levels of serum D-dimers in the acute phase were detected in DeBakey I AD, followed by DeBakey III AD then DeBakey II AD [5,13]. This led to the hypothesis that the extent of coagulation and fibrinolysis pathways activation is proportionately related to the surface of contact between the bloodstream and the exposed thrombogenic elements in the false lumen. The finding was not replicated in a smaller study (n ¼ 18) comparing D-dimer levels between Stanford Type A and B AD [11]. Additionally, this finding has not been replicated in Stanford Type B specifically. In a study of 30 patients with Stanford Type B AD, no significant correlation was found between admission serum D-dimer levels and extent of dissection as classified according to the DeBakey classification IIIa versus IIIb [14]. D-dimer levels have been shown to be significantly lower in cases of false lumen thrombosis and intramural hematoma. The latter entities lack a patent false lumen and have a smaller anatomic extension compared to a classic AD [13,14]. Given these results, the use of serum D-dimer testing as a singular test modality in cases with high index of clinical suspicion for AD cannot be recommended [15]. Several other biomarkers have been studied as diagnostic for AD. These include plasma smooth muscle myosin heavy chains, soluble elastin fragments, and calponin, a smooth muscle troponin-like protein. These biomarkers are thought to be released from the injured aortic media during AD and have been shown in small studies to detect AD with high sensitivity and specificity, although at this time they remain impractical in the clinical emergency setting [16–18]. Plasma N-terminal pro-B-type natriuretic peptide (BNP) levels were also evaluated. In a prospective study, in 18
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197
patients with acute AD (13 Stanford Type A AD, 5 Stanford Type B AD), plasma BNP levels were found to be elevated in acute AD compared to normal controls [11]. A potential hypothesis to explain this finding is the associated history of long-standing hypertension in patients with AD, as plasma BNP levels have been shown to be elevated in patients with essential hypertension and diastolic dysfunction. This is supported by the finding in the same study that plasma BNP levels were also increased in patients with chronic thoracic aneurysms [11].
3. Biomarkers in predicting descending Thoracic Aortic dissection prognosis The utilization of biomarkers has been investigated as prognostic indicator in the short and long term. Candidate biomarkers include serum D-dimer, C-reactive protein (CRP), metalloproteinases, and genetic markers. D-dimer levels have been demonstrated to be predictive of hospital short-term mortality [4,9]. In a prospective study of 114 patients with acute AD (64 Stanford Type A AD, 50 Stanford Type B AD), elevated admission plasma D-dimer levels were associated with high risk of short-term mortality [9]. D-dimer levels have also been evaluated as a marker for early in-hospital complications. In a retrospective study of 16 patients with acute AD (6 Stanford Type A AD, 10 Stanford Type B AD), complicated AD cases, as defined by contained aortic rupture and tamponade, had higher serum D-dimer levels compared to uncomplicated cases [4]. In a prospective study of 30 patients with Stanford Type B AD focused on serial D-dimer measurements, re-elevation of D-dimer during hospitalization was associated with complications defined as re-dissection in (n ¼ 3) and venous thromboembolic events (n ¼ 4) during hospitalization [14]. The acute-phase reactant CRP is a biomarker of systemic inflammation that is produced mainly by the liver. Elevation of plasma CRP levels and leukocytosis have been described in acute AD with plasma CRP levels increased by more than five times compared to normal subjects [11]. Plasma CRP levels in AD have been demonstrated to be time dependent, with a rapid rise in the first 4 to 6 hours, reaching a peak between 36 hours and 6 days post AD, and then followed by a decline in the chronic phase [19,20]. The use of CRP testing in evaluating the severity of AD was first described in 1991 in a cohort of 42 cases of DTA AD [21]. The marker was followed during hospital admission for medical management of the DTA AD and the patients were discharged once the levels had normalized. A second peak was noted in 26% of the patients and the majority of these patients had either progression of the AD or recurrent pain [21]. In a prospective study of 114 patients with AD (64 Stanford Type A AD, 50 Stanford Type B AD), elevated admission plasma CRP levels (>6.3 mg/dL) have been associated with high risk of short-term mortality in the acute phase. In a retrospective study of 255 consecutive patients with symptomatic thoracic, abdominal aortic aneurysms, and AD (including 27 patients with DTA AD), the highest serum CRP quartile level was an independent predictor of mortality, with a 2.6 increase in mortality after adjusting for age, sex, aortic rupture, shock, mechanical
198
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ventilation, coronary artery disease, hemoglobin level, diabetes, and treatment [22]. In a retrospective study of 16 patients with AD (6 Stanford Type A AD, 10 Stanford Type B AD), there was a trend toward a higher serum CRP levels in patients who died during the in-hospital period, although the timing of serum CRP levels in relation to onset of AD was unclear [4]. This finding has not been consistently demonstrated. In a retrospective study of 220 patients with Stanford Type B AD, admission serum CRP levels were not a significant predictor of poor outcomes [23]. Subsequent studies evaluated peak CRP levels rather than admission levels. Peak CRP, which is reached on day 3 to 6 post AD, is thought to be a better prognostic marker than an initial CRP and is thought to be reflective of the severity of the AD. In a retrospective study of 200 patients with Stanford Type B AD and a median follow-up of 4.2 years, elevated peak CRP during the initial hospitalization was found to be associated with long-term adverse events, defined as all-cause mortality, and aortic events, including surgery of the thoracic aorta, recurrence of AD, and aortic rupture [24]. Serial CRP levels were also evaluated as predictors of subsequent aneurysmal degeneration during initial hospitalization. In a prospective study of 32 patients with Stanford Type B AD, serial CRP measurements were followed and did not appear to correlate with an increase in aortic diameter as detected by computed tomography scanning during hospitalization [20]. Pentraxin 3, a vascular inflammation-related biomarker similar to CRP but not affected by liver damage, was also investigated. Serial levels of plasma Pentraxin 3 were explored in 41 patients with Stanford Type B AD and shown to peak at 4.3 days post AD. The peak levels did not correlate with all-cause death during the mean follow-up period of 2 years. Of interest, plasma Pentraxin 3 levels were associated with the amount of transient pleural fluid accumulation. Although at this time, the role of this biomarker in AD is not fully understood, it has been shown to be elevated in patients with acute lung injury, acute respiratory distress syndrome, and septic shock [25]. Matrix metalloproteinases (MMPs) are a group of extracellular matrix proteases released by interstitial cells and play an important role in degrading the extracellular matrix, including elastin, fibronectin, and collagen in the aortic wall. Elevated levels of MMP-9 have been associated with decreased aortic wall elasticity, aortic remodeling, and injury [26]. In a series of 4 patients with Stanford Type B AD, plasma MMP-9 levels were elevated early in the acute phase of aortic dissection and increased during follow-up for up to 2 months when compared to controls [27]. This finding was again demonstrated in a study comparing plasma MMP-9 concentrations between patients with acute (n ¼ 64) and chronic (n ¼ 42) AD [19]. The significance of this is unclear, as it is hypothesized that this may contribute to degradation of the aortic wall or could be that MMP-9 is significant in tissue remodeling [26]. Genetic testing in the management of DTA dissection is an emerging field. Gene mutations leading to aortic aneurysms and dissections have been described mainly in ascending aortic aneurysms and dissections and are termed thoracic aortic aneurysms and dissection genes. These mutations can lead to syndromic disease, ie, associated with disease
R G E R Y
27 (2014) 196–199
manifestations affecting other organ systems, and nonsyndromic disease. Examples of syndromic mutations associated with AD include mutations leading to Marfan syndrome (FBN1), Loeys-Dietz syndrome (TGFBR1 and TGFBR2), vascular Ehlers-Danlos syndrome (COL3A1), aneurysm-osteoarthritis syndrome (SMAD3), and TGFB2 mutations. The nonsyndromic mutations include TGFBR1, TGFBR2, ACTA2, MYH11, MYLK, and PRKG1. Genetic testing is presently time-consuming and is not suitable for the detection of AD in acute phase, but it can play a role in predicting future prognosis of AD and thus directing management options [28].
4. Descending Thoracic Aortic dissection biomarkers research limitations and future Many of the DTA dissection biomarkers studies are limited by small study sizes, variability in marker assays, variable marker levels among individual patients, and the retrospective nature in the majority of studies. Additionally, assays of serum biomarkers are often time-consuming, with the exception of serum D-dimer assays, which has been readily incorporated into clinical practice [8]. This stresses the importance that a single biomarker by itself will remain inadequate, as different disease processes and genetic variation affect each individual biomarker level at a given time during a disease process. It is the sum of the ongoing changes in the metabolome of an individual as dictated by the combined effect of the genomic and environmental background that holds the most promise in utilizing biomarkers for aortic dissection. The future of these studies lies in multicenter prospective studies utilizing serial measurement protocols that may be able to overcome the challenges experienced by previous studies.
re fe r en ces
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