Biomarkers in TAA—The Holy Grail

doi:10.1016/j.pcad.2013.05.004

Progress in Cardiovascular Diseases

Volume 56, Issue 1, July–August 2013, Pages 109-115

https://doi.org/10.1016/j.pcad.2013.05.004 Get rights and content

Abstract

Thoracic aortic aneurysm (TAA) is a silent disease, often discovered at a time point that dramatic complications, as rupture and dissection, occur. For the detection of asymptomatic TAA and prevention of such complications, it is essential to have an adequate screening tool. Until now, routine laboratory blood tests have played only a minor role in the screening, diagnosis, tracking and prediction of the natural history of TAAs. However, the knowledge about biomarkers is rapidly expanding in the cardiovascular field, and there are several potential biomarkers that might be implemented into TAA clinical practice in the near future. The most important and promising markers for TAA will be discussed in this overview.

Section snippets

d-Dimer

d-Dimer is a fibrin degradation product and is elevated in almost all patients presenting with venous thromboembolism. It has become widely used because of its high negative predictive value to exclude thromboembolism and pulmonary embolism.[3], [4], [5] Elevated levels can be found in various forms of malignancies, infections, renal diseases, recent trauma, after recent surgery, acute aortic dissection or disseminated intravascular coagulation.[3], [4], [6] Increased levels of d-dimer have

Matrix metalloproteinases

Matrix metalloproteinases (MMP) and their tissue inhibitors (TIMPs) can degrade the extracellular matrix (ECM) proteins, such as collagen, fibronectin, elastin, and proteoglycans. MMPs are a group of zinc enzymes, which have been found to play a significant role in the pathogenesis of aortic aneurysms, weakening the ECM and thus the aortic wall.⁹ In TAA patients, increased levels of different members of the MMP family, such as MMP-1, MMP-2, MMP-3 and MMP-9, have been demonstrated.¹⁰

Serum markers of collagen and elastin metabolism

In patients with TAA, structural modifications involve the main components of the aortic wall: collagen and elastin.[17], [18] In TAA the structure of elastin is modified, and increased levels of elastolytic enzymes, like elastase, have been demonstrated.¹⁹ Higher elastolysis, expressed by specific markers, such as serum elastin peptides, plasma elastin alpha1 antitrypsin complex, and serum propeptide of type III procollagen, seems to be associated with increased wall distensibility in patients

Cytokines and gene expression signature in peripheral blood

Initial experiences with increased circulating levels of inflammatory cytokines, such as interleukin 1 and 6, and tumor necrosis factor-α, were described in patients with AAA.[21], [22], [23], [24] In patients affected by TAA, gene expression patterns in peripheral blood seem to be a useful tool for assessing the status of the aneurysm. It has been shown that a 41-gene signature in peripheral blood cells is able to distinguish TAA patients from control patients, with almost 80% classification

Acute-phase reactants

In patients presenting with symptomatic or ruptured AAA, C-reactive protein (CRP) and white blood cell counts are increased.[34], [35] However, increased levels of serum CRP were present also in asymptomatic AAA.³⁶ In addition, level of CRP was correlated with aneurysmal size.³⁶ In patients with TAA, CRP has been demonstrated to be increased compared to patients with coronary artery disease and healthy controls.³⁷

Lipoprotein(a)

Serum lipoprotein(a) consists of a molecule in which apolipoprotein(a) is linked to apolipoprotein B100, with a structure similar to plasminogen, which has been shown in atherosclerotic and coronary and aortic diseases.[38], [39] Increased serum levels of lipoprotein(a) have been found in patients with AAA, but currently a causal relationship is unclear.⁴⁰ Lipoprotein(a) has been shown also in patients with TAAs caused by dissection, but serum levels were comparable with healthy individuals.⁴⁰

Activators and inhibitors of plasminogen, fibrinogen, and hemostatic markers

Plasmin has been suggested to be a common activator of the proteolytic systems involved in aneurysmal degradation and has been reported to be associated with the expansion of AAA.⁴¹ It has been shown that the degradation of the aortic matrix in AAA may be partly caused by activation of plasminogen by tissue-type plasminogen activator.³⁹ Fibrinolysis has been demonstrated to be increased, due to a reduced fibrinolytic inhibition, in patients with acutely symptomatic non-ruptured AAAs compared

Endothelin

Endothelin is a vasoconstrictive peptide produced by endothelial cells. There are three types of endothelin: endhothelin 1 (ET-1), ET-2, and ET-3. In TAA, the endothelin pathway, including endothelin-converting enzyme 2, is up-regulated. The release of endothelin-converting enzyme is stimulated by several factors, such as angiotensin II, vasopressin, adrenaline, hypoxia, and vascular injury.⁴³ ET-1 and ET-2 levels were found to be significantly increased in patients with large AAAs compared to

Homocysteine

Plasma homocysteine is independently and significantly correlated with the degree of atherosclerosis in the thoracic aorta.⁴⁵ Although homocysteine is a known factor for coronary and cerebral events, and it has been already reported as a marker for atherosclerosis, its role is still to be defined in early diagnosis of aortic lesions.[45], [46], [47]

Transforming growth factor β

Transforming growth factor β (TGF-β) is a protein that controls, in particular, proliferation and cellular differentiation. In the pathophysiology of aneurysm formation in non-syndromic and syndromic diseases, such as Marfan syndrome, an increased activity of TGF-β has been demonstrated, which leads to an increase in matrix degeneration and promotes weakening of the aortic wall and development of TAA.⁴⁸ In Marfan mice models, levels of TGF-β correlated with the level of aortic growth.⁴⁹ A human

Novel biomarkers

Recently there have been added new biomarkers to the list of potential biomarkers for TAAs.

Preliminary results measuring the mean telomere length of blood leukocytes have shown that shorter telomeres were detected in patients with sporadic TAA compared to controls. As a result, this might be a marker for sporadic TAA.⁵¹

Fibulin is the prototypic member of a multigene family of extracellular matrix proteins, consisting of fibulin-1 to -7. Mutations in the fibulin-4 gene are the cause of the cutis

Conclusions

There is a robust effort to develop new knowledge about biomarkers for TAA, focusing in particular on biomarkers identifying tissue inflammation, matrix degeneration, and fibrinolysis. The aim of such research is to obtain, through a simple blood test, useful biomarkers for detecting TAA in asymptomatic patients. Ideally, these biomarkers should also predict adverse events of TAA, such as growth, rupture or dissection, in order to select patients that might benefit from medical or surgical

Statement of Conflict of Interest

All authors declare that there are no conflicts of interest.

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The most common reason for ascending aorta resection is an aneurysm or dissection. Aortic dissection is a life-threatening condition in which an aneurysm is a crucial risk factor. The essential criteria for aneurysm resection include the diameter, genetic predisposition, and aortic valve disease. This study aimed to compare the histological findings in aneurysms and dissections and correlate them with clinical parameters to determine whether histopathological findings correspond with the current clinical approach. A total of 160 ascending aorta surgical specimens, separate or with an aortic valve, were collected and divided into four groups: aneurysm-tricuspid (n = 40; median 67 y), aneurysm-malformed (n = 68; median 50 y), dissection-tricuspid (n = 48; median 65.5 y), and dissection-malformed (n = 4; median 52.5 y). Male preponderance was observed in all groups; the youngest patients were in the aneurysm-malformed group. None of the specimens showed normal aortic histology. The most common finding in the aortic samples was medial degeneration, which was the most severe and most common in dissection. The mildest findings were found in the aneurysm-malformed group. Atherosclerosis was predominant and most severe in the aneurysm-tricuspid group, while only mild in both dissection groups, suggesting its protective effect against this complication. Chronic aortitis was the least common pathology, found only in the aneurysm-tricuspid group. The aortic valve was resected and examined simultaneously with the ascending aorta in 76 cases, most commonly in the aneurysm-malformed group (n = 53). Myxoid degeneration was the major finding in the tricuspid aortic valves, with calcifications in the malformed. Comparing the histopathological results with the clinical aspects, aneurysms with a malformed aortic valve seem to be managed appropriately, with the findings not reaching the severity as in patients with a tricuspid valve. In contrast, in patients with a tricuspid valve, there were more dissections than aneurysms, with a significant subset of aneurysms showing histological findings almost identical to those of dissections. Supported by histological findings, patients with a diseased ascending aorta and tricuspid aortic valve represent an underdiagnosed risk group that would benefit from earlier diagnosis and intervention to prevent dissection. There is a need to find a marker for dissection risk other than the aortic diameter.
Commentary: Preventing the virulent lethality of ascending aortic aneurysm
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Citation Excerpt :
However, patients with silent asymptomatic TAA who do not undergo such imaging studies run the risk of not being identified in time, before such lethal complications as aortic rupture or dissection occur. There is some promise in development of biomarkers that could be useful in detecting patients with thoracic aortic disease6-9; however, most biomarkers are primarily effective at detecting aortic disease after aortic dissection or rupture have occurred. All of this underscores the importance of identifying clinical markers to aid in detection of individuals at risk of harboring a thoracic aneurysm or developing one in the future.
Thoracic aortic aneurysms (TAA) pose a serious detection challenge owing to their clinically silent nature. Only a small fraction of TAAs cause symptoms in patients. However, the mortality burden of this disease in the population is significant, given the high lethality of such complications as aortic rupture and dissection. Widespread screening for TAA has not been shown to be cost-effective. Therefore, currently most patients with a TAA are identified incidentally during an imaging study conducted for other reasons. Once a TAA diagnosis is established, prophylactic surgical treatment can safely be performed for aneurysms of the ascending aorta, aortic arch, and descending or thoracoabdominal aorta, thus preventing aneurysm-related death. To facilitate early detection of TAA, recent studies have identified several “associates” of TAA that may be useful in making a timely diagnosis. These “associates” include intracranial aneurysm, aortic arch anomalies, abdominal aortic aneurysm, simple renal cysts, bicuspid aortic valve, temporal arteritis, a positive family history of aneurysm disease, and a positive thumb-palm sign, among others. Although for many of these “associates” the underlying mechanism that would explain the association remains to be elucidated, the clinical correlation is strong enough to suggest screening patients with these findings for TAA. This article introduces the “Guilt by Association” paradigm for detection of silent thoracic aortic disease based on detection of clinical markers associated with this condition.
Genetic contribution in sporadic thoracic aortic aneurysm? Emerging evidence of genetic variants related to TLR-4-mediated signaling pathway as risk determinants
2015, Vascular Pharmacology
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Accordingly, we observed significant increased amounts of CD3 + CD4 + CD8 + CD68 + CD20 + cells in tissue aorta samples from patients with Stanford type A aortic dissection [32]. Increased plasma levels of inflammatory markers, such as C-reactive protein (CRP) and inflammatory cytokines have been observed in aortic dissection and sporadic TAA patients [48]. In accordance with these data, we assessed higher plasma levels of Interleukin-(IL-) 6, Tumor necrosis factor-α (TNF-α), Interferon (INF)-γ, CRP, MMP-2 and-9 plasma levels in Stanford type A aortic dissection and sporadic TAA patients than controls (12.66 ± 2.1 vs. 3.1 ± 0.99, P < 0.001; 16.78 ± 1.2 vs. 7.1 ± 2.2, P < 0.0001; 12.13 ± 1.7 vs. 2.1 ± 0.5 P < 0.0001; 14.66 ± 3.2 vs. 4.6 ± 1.67, P < 0.0001; 56.8 ± 3.8 vs. 12.54 ± 1.6, P < 0.0001; and 59.7 ± 3.7 vs. 11.7 ± 2.6, P < 0.0001, respectively) [32].
Sporadic thoracic aortic aneurysms (TAA) and dissections are one of the major causes of morbidity and mortality worldwide, especially in those older than 65 years. The presentation of TAA is varied and often silent. Thus, sporadic TAA detection is often fortuitous, with identification occurring during a routine physical examination or during an unrelated medical evaluation. Once suspected, confirmation by imaging clinical approaches is needed to allow the choose of the unique treatments for TAA, namely the surgery procedures, including elective surgery or endovascular repair before the onset of catastrophic and fatal complications, such as dissection or rupture. At present, there are no biomarkers available to identify TAAs before visible symptoms. However, recent progresses in understanding of molecular and cellular mechanisms involved in the patho-physiology of sporadic TAA are suggesting different molecular pathways and their genetic variants as potential biomarkers, which might be applied into TAA clinical practice in the near future. Here, we report literature evidence on some disease pathways and their genetic variants on TAA susceptibility and compliances, and their translation as promising TAA preventive and prognostic biomarkers and targets for new personalized therapeutic treatments.
Understanding and treating aortopathy in bicuspid aortic valve
2015, Trends in Cardiovascular Medicine
Citation Excerpt :
MMP isoform 9 expression in aneurysmal BAV aortic tissue has been shown [14,40]. Yet several other investigations did not find meaningful differences in the plasma expression, mRNA, or allelic makeup of MMP in affected individuals [41–44]. In atherosclerotic aortas, the risk of aortic dissection and rupture increases exponentially with aortic dimension [45], with a 4.3-fold increased risk of rupture or dissection in an aneurysm 60–69 mm in diameter compared to an aneurysm 40–49 mm in diameter (Fig. 5) [46].
Bicuspid aortic valve is a simple yet common condition with surprising clinical complexity. Patients are typically found to have enlargement of the ascending aorta, either root or midascending, independent of valve function. This enlargement is perceived to be a risk of aortic dissection, and therefore, prophylactic surgery is often recommended when the aorta reaches 50–55 mm in diameter. Despite the prevalence and potential health impact, there is to date no published data on the role of medical therapy. The emerging trend, however, is to address this question through clinical research. Early trials are underway designed to address the question of potential medical therapy. This article reviews current knowledge of the condition, its potential etiology, and ongoing work to assess the role of medical therapy.
Predictors of aortic growth in uncomplicated type B aortic dissection
2014, Journal of Vascular Surgery
Citation Excerpt :
Although FDP has not been introduced as a routine screening tool, blood tests for such biomarkers, in association with other predictors, might be useful for detecting those ABAD patients at higher risk for aortic growth at an early stage. Future research should investigate if the different biomarkers for thoracic aortic aneurysm may also be predictive for aortic growth in uncomplicated ABAD patients.35 Most of the studies that were analyzed focused on morphologic predictors at the initial aortic imaging stage.
Patients with uncomplicated acute type B aortic dissection (ABAD) generally can be treated with conservative medical management. However, these patients may develop aortic enlargement during follow-up, with the risk for rupture, which necessitates intervention. Several predictors have been studied in recent years to identify ABAD patients at high risk for aortic enlargement who may benefit from early surgical or endovascular intervention. This study systematically reviewed and summarized the current available literature on prognostic variables related to aortic enlargement during follow-up in uncomplicated ABAD patients.
Studies were included if they reported predictors of aortic growth in uncomplicated ABAD patients. Studies about type A aortic dissection, aortic aneurysm, intramural hematoma, or ABAD that required acute intervention were excluded.
A total of 18 full-text articles were selected. The following predictors of aortic growth in ABAD patients were identified: age <60 years, white race, Marfan syndrome, high fibrinogen-fibrin degradation product level (≥20 μg/mL) at admission, aortic diameter ≥40 mm on initial imaging, proximal descending thoracic aorta false lumen (FL) diameter ≥22 mm, elliptic formation of the true lumen, patent FL, partially thrombosed FL, saccular formation of the FL, presence of one entry tear, large entry tear (≥10 mm) located in the proximal part of the dissection, FL located at the inner aortic curvature, fusiform dilated proximal descending aorta, and areas with ulcer-like projections. Tight heart rate control (<60 beats/min), use of calcium-channel blockers, thrombosed FL, two or more entry tears, FL located at the outer aortic curvature, and circular configuration of the true lumen were associated with negative or limited aortic growth.
Several predictors might be used to identify those ABAD patients at high risk for aortic growth. Although conservative management remains indicated in uncomplicated ABAD, these patients might benefit from closer follow-up or early endovascular intervention.

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: Statement of Conflict of interest: see page 113.

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Biomarkers in TAA—The Holy Grail

Abstract

Section snippets

d-Dimer

Matrix metalloproteinases

Serum markers of collagen and elastin metabolism

Cytokines and gene expression signature in peripheral blood

Acute-phase reactants

Lipoprotein(a)

Activators and inhibitors of plasminogen, fibrinogen, and hemostatic markers

Endothelin

Homocysteine

Transforming growth factor β

Novel biomarkers

Conclusions

Statement of Conflict of Interest

J Vasc Interv Radiol

Clin Lab Med

Eur J Vasc Endovasc Surg

Ann Thorac Surg

J Thorac Cardiovasc Surg

J Thorac Cardiovasc Surg

J Vasc Surg

J Thorac Cardiovasc Surg

J Vasc Surg

Eur J Vasc Endovasc Surg

J Surg Res

Am J Pathol

J Vasc Surg

J Vasc Surg

J Thorac Cardiovasc Surg

Ann Thorac Surg

Atherosclerosis

Eur J Vasc Endovasc Surg

J Vasc Surg

J Vasc Surg

J Vasc Surg

Eur J Vasc Endovasc Surg

Am Heart J

J Thorac Cardiovasc Surg

Rev Esp Cardiol

Am J Hum Genet

Am J Cardiol

Int J Cardiol

J Thorac Cardiovasc Surg

Hum Pathol

Int J Cardiol

Diagnosis and management issues in thoracic aortic aneurysm

Am Heart J

Fibrin and cancer

Thromb Haemost