Acute aortic syndromes (AAS) encompass a group of conditions affecting the thoracic aorta including aortic dissection (AD), intramural haematoma (IMH), penetrating atherosclerotic ulcer (PAU), which can all lead to rupture (Isselbacher et al., 2022). These present as acute emergencies so affected patients require hospitalisation and urgent treatment. Type A AD has a mortality rate of 1-2% per hour after symptom onset (for the first 48 hours) while Type B has a mortality rate of 10% after 30 days (Tsai et al., 2005). Ruptured aortic aneurysms are a severe acute complication with high mortality figures of approximately 150,000-200,000 deaths worldwide per year (Bossone & Eagle, 2021).

The incidence of AAS has remained relatively static for the last 20 years at approximately 7.67 per 100,000, despite the overall decrease in cardiovascular disease during this time (Dermartino et al., 2018). These statistics demonstrate the need for further research in this area of cardiovascular surgery to alter this stagnation. Current literature suggests, to varying extents, the interlinking of AAS with multiple different factors as potential precipitators for the disease. However, it is not clear whether these factors are predictors of the onset of AAS or whether they correlate with AAS. As such, this paper categorises these factors into two groups. Correlators are studied with the aim of further understanding the pathophysiology of AAS and exploring any association between the correlators and the pathophysiology. Predictors are examined to further understand the pathophysiology of AAS with the intention of identifying ways in which diagnosis, prevention and treatment can be improved.

Although the components of AAS are distinct conditions with unique structural impairments, the underlying pathophysiology and associated risk factors are similar. Each component is demonstrated in Table 1.

A combination of prolonged elevated luminal pressures causing abnormal shear stress, and release of inflammatory mediators, result in injury to the aortic wall, which is a hallmark pathological feature of AAS, summarised in Figure 1. Guo et al (GUO et al., 2006) discussed the key process of the upregulation of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), which contribute to recruiting monocytes (GUO et al., 2006). The resultant activation of macrophages stimulates them to release matrix metalloproteinases (MMPs), which destroy the aortic wall components such as collagen and elastin (Rimmer et al., 2020). Macrophages also release inflammatory mediators such as interleukins and tumour necrosis factor (TNF)-alpha, which causes a loss of vascular smooth muscle cells (VSMCs) in AAS (GUO et al., 2006; Rimmer et al., 2020). The role of transforming growth factor (TGF)-beta in the development of AAS is becoming evident in relation to loss-of-function mutations causing impaired signalling as investigated by Takeda et. al (Takeda et al., 2018) in their study of mechanisms underlying AAS (Isselbacher et al., 2022).

A diagnosis of AAS should be considered in all patients presenting with sudden onset tearing chest pain, regardless of radiation to the back. As in acute coronary syndrome, women with AAS are more likely to present atypically, with non-specific symptoms or discomfort as opposed to pain, leading to underdiagnosis and undertreatment (Bossone et al., 2018). The anatomical and pathophysiological changes characteristic of AAS can be visualised clearly using a computed tomography angiography (CTA) scan or magnetic resonance imaging (MRI) (Dudzinski & Isselbacher, 2015). However, CTA is preferred due to higher sensitivity and accessibility (Dudzinski & Isselbacher, 2015). Transthoracic echocardiography (TTE) is effective in visualising the aortic root and the proximal to middle segment of the ascending aorta (Dudzinski & Isselbacher, 2015).

AAS has life-threatening complications and urgent management is always indicated. Intensive medical therapy including beta-blockers is useful in gaining haemodynamic stability by lowering heart rate and blood pressure (Bonaca & O’Gara, 2014). For the majority, surgical management is the mainstay. Urgent open surgery is indicated for Stanford Type-A AD, and it may be considered for Type-A IMH after observation (Bossone et al., 2018; Dudzinski & Isselbacher, 2015). Complicated Stanford Type-B AD and Type B IMH are both treated with thoracic endovascular aortic repair (TEVAR) (Bossone et al., 2018; Dudzinski & Isselbacher, 2015). PAU can be managed with TEVAR or watchful waiting (Bossone et al., 2018; Dudzinski & Isselbacher, 2015). Rapidly expanding or ruptured aortic aneurysms are treated with surgery or TEVAR, depending on their location (Bossone et al., 2018; Dudzinski & Isselbacher, 2015). Complicated presentations include haemodynamically unstable patients, those with signs of rupture or impending rupture, evidence of malperfusion syndrome or uncontrolled hypertension (Moulakakis et al., 2014).

Compromised aortic blood flow can cause significant end-organ damage. Malperfusion syndrome arises due to a combination of dynamic and static arterial obstruction (Crawford et al., 2016). Cerebral malperfusion particularly, caused by limited blood flow in the carotids, is most associated with Type-A AD (Munir et al., 2021). The peripheral malperfusion caused by AAS leads to clinical manifestations such as renal failure and cerebrovascular accidents. Local complications of AAS include aortic regurgitation and cardiac tamponade (Isselbacher et al., 2022).

The implementation of guidelines from the European Society of Cardiology (ESC) and the American Heart Association (AHA) has allowed for standardisation in the care of thoracic aortic pathologies. The discrepancies within the guidance for AAS start with the definition: ESC differs from AHA with the inclusion of contained rupture of aortic aneurysm in their definition (Erbel et al., 2014; Isselbacher et al., 2022).

Both guidelines stress the importance of a risk-scoring system and reference the same system developed by AHA. The diagnostic use of D-dimer is discussed in the two guidelines, with differing outcomes- where ESC sees the need for testing for differential diagnoses and negates AAS for low-risk patients with a negative result, AHA was unable to recommend serum D-dimer for all patients as the biomarker is not considered diagnostic. The differences found within the guidelines could be due to the 8-year difference in publication. Regarding imaging, the use of a TTE as initial imaging is recommended by the ECS, while the AHA recommends the use of CT first and TTE as an alternative. Both, however, recognise the high sensitivity and specificity of TTE and CT, along with MRI.

Both guidelines include a short genetic section based on the presentation of thoracic aortic aneurysm and dissection (TAAD) (Erbel et al., 2014; Isselbacher et al., 2022). Although both mention the inclusion of syndromic mutations (e.g. vascular Ehlers-Danlos, Marfan), AHA further addresses altering the management of female patients with Marfan contemplating pregnancy. Considering nonsyndromic familial TAAD, both guidelines discuss recommendations such as investigations of first-degree relatives. However, ESC is quick to refer to geneticists if familial TAAD is suspected, whereas AHA breaks down their diagnosis through individual steps; imaging of first-degree relatives and referral once a mutant gene is detected as well as sequencing.

The ESC guideline only has a brief genetic section and a lacks of consideration for women with TAAD. Further to this, the guideline is the older of the two and is nine years old in itself. These factors collectively reduce the guideline’s value to clinicians and increase the need for a more up-to-date version (Erbel et al., 2014; Isselbacher et al., 2022).

Age

Aortic disease is known to positively correlate with age (Gawinecka et al., 2017). This was demonstrated in a 20-year study conducted by the International Registry of Acute Aortic Dissections (IRAD) showing the mean ages for acute Type-A and B AD were 61.5 and 63.6 years.

Moreover, age seemingly influences management as rates of surgical intervention decrease after the sixth decade. A possible explanation is that mortality following surgical intervention increases with age (Trimarchi, Eagle, et al., 2010).

The effect of age on acute Type-A AD patients was seen by Wang et al. (J.-X. Wang et al., 2022). Older patients were more likely to have co-morbidities preoperatively and experience higher complication rates and mortality postoperatively. Of the 154, 105 (68.2%) were over 50 (p-value=0.016). A 17-month follow-up period showed a similar pattern, finding that 25/38 (68.3%) discharged patients that died were over 50 (J.-X. Wang et al., 2022). Their large sample size (n=1092) increases validity, but retrospective analysis reduces reliability. Another key study is by Devereux et al (Devereux et al., 2012) which concluded that aortic diameter generally increases with age, out of a significantly large population of 1207 patients.

Experimental studies also provide some insight into the effects of advancing age. The study by Groenink et al. (Groenink, 1999) investigated the influence of ageing and aortic stiffness on the structure of the thoracic aorta. They found increasing age was associated with lower pressures required to cause structural changes and greater degrees of irreversible dilation, which may precipitate the effect of AAS (Groenink, 1999). Although effective as the exclusion criteria were aortic disease considering the sole effect of ageing, the sample size was too small (Groenink, 1999).

Chronobiology: all about timing?

Cardiovascular pathologies such as myocardial infarction, ventricular arrhythmia, and pulmonary embolism (PE) have been linked to seasonal and circadian occurrence.

Manfredini et. al. (Manfredini et al., 2004) produced a comprehensive review regarding the relationship between aortic dissection and abdominal aortic aneurysms (AAA) and their temporal patterns. Studies were found that identified a circadian variation. Exclusively concerning AAA ruptures, multiple studies stated that the risk was significantly increased in the early morning with many describing a peak time starting from 8 am; there was variation regarding when the peak ended but the latest time given was 11 am. Specifically regarding aortic dissections, this same early morning risk was identified but this was based on a single report, thus making the conclusion unreliable. Very little research has been done to examine the presence of a weekly variation, and of those that have been performed, the results were conflicting. In contrast, a seasonal variation has been identified. For both aortic dissections and AAA ruptures, there was a significant increase in risk during the winter months, particularly during the month of January (Manfredini et al., 2004).

The seasonal variability of AAD was further explored in a large international systematic review published in 2015 (Vitale et al., 2015). It yielded similar results, demonstrating a peak incidence of aortic rupture or dissection occurring in December. A potential explanation for these seasonal trends is colder temperatures and decreased daylight, which have been associated with increased blood pressure, platelet activation, and haematocrit which all increase stress within the aortic wall (Stewart et al., 2017).

Therefore, some chronobiological patterns affect AAS incidence. This is applicable through better-allocating resources for winter, along with potentially altering the time of medication administration to decrease aortic wall stress.

Polycystic Kidney Disease

Polycystic kidney disease (PCKD) is the most common single-gene inherited condition associated with significantly raised mortality, particularly relating to cardiovascular complications including AD.

Silverio et. al. (Silverio et al., 2015) conducted a literature review to examine the relationship between PCKD and AD. Mean age of AD was reduced in the PCKD population (p < 0.001) compared to controls, 49(± 12) and 62(± 14) respectively (Silverio et al., 2015). This suggests patients with PCKD are at increased risk of earlier complications, like AD, than those without. However, the retrospective nature introduces information and selection bias. Furthermore, the study fails to include diabetes status in the list of participant characteristics.

Torra et. al (Torra et al., 1996) explored the association between PCKD and AAA with sonographic investigations of the aorta of PCKD patients. They found no significant correlation between aortic diameter and PCKD, and no link between AAA prevalence and PCKD. They concluded that whilst PCKD could be a predisposition for AAA, it is not a cause. Despite the large sample size (n=288), selection methods, and the single-centre, retrospective nature have implications on the results’ validity.

Studies are beginning to shed light on how PCKD differs from the classic presentation of aortic dissection. Additional investigations into PCKD pathogenesis and its potential role in AAS development are needed.

Immunology

On the microscopic level, factors such as immunological processes and MMPs have been implicated in the pathogenesis of AAS.

The type and role of infiltrates were investigated in 16 patients and compared to 5 controls. They found significant increases in the levels of CD3+ and CD68+ in patients with aneurysms or dissections, compared to controls (He et al., 2006). The study had restrictions, including a small sample size and the exclusive use of end-stage disease tissue samples. Finally, since patients were put on cardiopulmonary bypass, with the aid of hypothermic circulatory arrest, they concluded that the possibility these processes contributed to raised markers cannot be excluded (He et al., 2006).

A more recent study with a larger sample (n=28) by del Porto et al. investigated the immune cells present in the aortic wall in type-A dissections. Macrophages and cytokines (i.e. MCP-1, IL-6, IL-8, and TNF-a) were detected in all cases (Del Porto et al., 2010). This suggests a role for macrophages in AAS, which is complemented by another study by del Porto et al. (n=21), suggesting the release of MMP12 and VEGF (Del Porto et al., 2014). T-lymphocyte count was higher in independent atherosclerotic sites, suggesting their smaller role in AAS pathogenesis (Del Porto et al., 2014).

Anzai et al. triggered acute-AD in mice and investigated subsequent gene expression of IL-6. They found increased expression, predominantly in the adventitia, in mice with dissections (Anzai et al., 2015). They also analysed IL-6 levels in humans with uncomplicated acute Type-B dissections and found consistently raised levels (Anzai, 2018; Anzai et al., 2015). Therefore, an implied correlation exists between IL-6 and AAS, however, the direction of this correlation is unclear.

Recent studies have widened our understanding of the immunological mechanisms involved in AAS. Nappi et al. summarised the potential contribution of Human Cytomegalovirus (HCMV) infection to AAS pathogenesis, mediated by miRNAs that alter immune responses and vascular integrity (Nappi et al, 2023). The use of these biomarkers may allow early detection of AD in the future. A study by Yang et al. explored the role of neutrophil extracellular traps (NETs) in AAS. They found that NETs were abundant in AAD patients and contributed to vascular inflammation and damage. The study highlighted that NET levels correlate with disease severity, highlighting a potential diagnostic target (Yang et al., 2021). Note however that the study is only a single centre with a small sample size which hinders its predictions within the wider population.

Furthermore, a study by Suh et al investigated the role of T-cells in AAA and found that regulatory T-cells (Tregs) were significantly decreased in patients with AAA and significantly decreased aneurysm progression in mice with Treg cells (Suh et al., 2020). This suggests that an imbalance in Treg-mediated immune regulation may contribute to the pathogenesis of AAA. However, the study's use of acute animal models limits its ability to establish causality.

Regarding immunology in IMH or PAU, the literature is limited. Several case-based studies suggested IgG4 in the role of, or mimicking an IMH, thereby serving as a potential correlator (L. Li et al., 2016). These are gaps for further research to identify potential correlations.

D-Dimer

Multiple studies have shown that D-dimer was raised during acute AD and therefore recommend its diagnostic use (Watanabe et al., 2016).

A systematic review by Watanabe et. al. (Watanabe et al., 2016) included 22 articles with 1140 AAD and 3860 non-AAD subjects, to investigate the accuracy of D-dimer for AAS. Results showed an area under the curve (AUC) of 0.946 (95% CI:0.903-0.994) and a diagnostic OR of 28.5. An AUC of 0.950 (95% CI:0.847-1.000) was observed in 12 studies using a cut-off value of 500 ng/ml, which is the same as for PE (Watanabe et al., 2016). The positive and negative likelihood ratios for the 12 studies using 500 ng/mL as their cut-off value were 2.4 and 0.079 respectively, indicating that d-dimer below 500 ng/mL is useful in ruling out AAS.

This is further supported by Sodeck et. al. (Sodeck et al., 2007) who concluded that D-dimer can be used to rule out AAS and that a D-dimer <0.1 g/mL will exclude acute AD in 100% of cases.

This indicates that D-dimer can be used to rule out AAS and elevated values increases the risk of AAS. Therefore, clinicians should consider AAS in patients with elevated D-dimer values in the acute setting.

Diabetes Mellitus… a paradoxical relation?

Despite diabetes mellitus (DM) being a well-known cardiovascular risk factor, various studies have indicated an inverse relationship between DM and AAS (Golledge et al., 2008).

A study by De Rango et al. (De Rango et al., 2012) carried out secondary data analysis from the CAESAR trial. They concluded that progression of small AAA was 60% lower in diabetics compared to non-diabetics. Despite small sample sizes and secondary analysis, various primary studies and trials have had similar findings, concluding that diabetes is associated with reduced aneurysmal growth rates (Nordness et al., 2021).

A variety of studies have looked further into the potential pathophysiological mechanisms contributing to this relationship. Golledge et al. (Golledge et al., 2008) investigated atherosclerotic samples from 20 diabetic patients. They found glycated ECM played a role in reducing the production of MMPs, and levels of IL6, MMP-2 and MMP-9. Note, that these patients were not randomly sampled but selected having readily available data, which affects the results’ reliability. However, a similar trend was seen in an experimental animal study analysing the effect of hyperglycaemia on aortic aneurysm progression by Miyami et al. (Miyama et al., 2010). Aneurysmal enlargement was lowest in hyperglycaemic mice. In the cohort on insulin therapy, was associated with aneurysmal enlargement. Further analysis showed reduced levels of MMP-9 and macrophage infiltration. Various literature reviews have shown several different factors that may contribute to the protective nature of DM, including reductions in wall stress, inflammation and neoangiogenesis (Arun et al., 2021). Figure 2 provides a visual summary of the correlators of AAS.