https://orcid.org/0000-0003-4113-7030
A thoracic aortic aneurysm (TAA) is a localized dilatation of the ascending and thoracic aorta that can lead to dissection and rupture of the vessel wall.1 The most worrisome aspect of this clinical condition is related to its silent clinical progression with one in two cases completely asymptomatic and indeed diagnosed incidentally during imaging studies performed for other clinical condition.1 In addition, its first clinical manifestation may occur as an acute dissection which carries a very high risk for extra- and intra-hospital mortality.1
Emerging clinical evidence has shown a significant prevalence of TAA among patients with atrial fibrillation (AF). In a retrospective analysis in nationwide population database, Hsu et al.2 reported a bidirectional association between AA and AF, showing in patients with AF compared to those without AF, an increased incidence of AA evident at 13 years follow-up [hazard ratio (HR) (adjusted HR 1.243, 95% confidence interval (CI) 1.101–1.398; P < 0.001)]. Similarly, patients with AA had a higher risk for presenting with AF at follow-up compared to patients without a diagnosis of TAA (adjusted HR 1.187, 95% CI 1.079–1.301, P < 0.001). This association remained significant after adjustment for other risks factors.2 In sub-analysis carried out considering only TAA, a higher incidence was detected in patients with AF compared to those without (0.14 vs. 0.09%, P < 0.001).
Ramchad et al.3 in a cross-sectional study carried out in patients with AF undergoing gated chest computer tomography performed as part of the assessment for pulmonary vein isolation, reported a TAA prevalence of 20%, with 1% of the TAA detected having a size approaching the current surgery indication. There was a direct correlation between the CHARGE-AF risk score predicting the risk of AF basing on several risk factors such as age, weight, blood pressure, smoking, diabetes, prior MI, and heart failure, and the dimension of the thoracic aorta.3 Accordingly, a pathophysiological component of TAA is atherosclerosis, of which peripheral or coronary artery diseases are other common clinical manifestations. These are associated with incident AF and AF-related complications, and AF is a common complication after aortic procedures such as transcatheter aortic valve replacement.4
While the associations may simply reflect shared risk factors, these findings rise the issue regarding the clinical monitoring of patients with AF for the risk of developing TAA. Comparing the prevalence of silent TAA with a size susceptible of surgery correction among patients with AF and the general population, respectively 1% and 0.1%,3 an indication for TAA screening in patients with AF may be debated.
From a pathological perspective, the findings regarding AF and TAA could be just a non-casual association related to the increasing prevalence of both diseases with ageing and consequently the sharing of other risk factors such as hypertension and hyperlipidaemia. Indeed, the prevalence of TAA is around 4% in patients over 65 years and accounts for 6000 deaths a year in the UK.5 Similarly, the prevalence of AF increases exponentially with age and around 6.9% in subjects over 65 years old, though the burden of mortality linked to AF remains more elusive.6
To further explore the link between these AF and TAA and identify a possible causal association, we should examine the four lines of causality identified by Hill.7 In 1965, Sir Austin Bradford Hill7 proposed a set of criteria to ascertain a causal inference between two diseases; (i) strength of the association; (ii) consistency of association; (iii) the detection of a biological gradient; and (iv) biological plausibility. While additional studies will be needed to confirm the strength and consistency of association as well as the existence of a biological gradient, the association between the two diseases shares some biological plausibility based on multiple pathological pathways.
1. TGF-β1, AT1, and MMP activation: shared pathways in TAA and AF pathophysiology
Experimental and clinical studies on syndromic TAA have outlined a key role played by transforming growth factor (TGF-β1) in the formation of TAA.8 In the e aorta, TGF-β1is present in the extracellular matrix and upon binding by ligand can activate through cell receptors of smooth muscle vascular cells different molecular pathways leading to remodelling of vessel wall layers.8
In the vascular smooth muscle cells, the two principal pathways of TGF-β1 signalling are the classical Smad protein complex which leads to collagen and elastin synthesis and deposition and increased production of tissue inhibitors of metalloproteinase.9 While these classical pathways preserve the integrity and homeostasis of the extracellular matrix of the vessel wall, it can be hypothesized that in pathological conditions, the pro-fibrotic activation mediated by the Smad complex may lead to the secretion of defective collagen subtype which may weaken the stability of the vessel. The other pathway of intra-cellular signal transmission is the extracellular signal-regulated kinase ERK 1/2 which acts directly in the smooth muscle vessel cells switching from a contractile function to a predominant secretive activity of t-PA, metalloproteinase MMP-2, and MMP-9 that enhances the proteolysis of extracellular matrix ECM.9 The activation of AT-1 receptor by Angiotensin II up-regulates the TGF-β1 cascade and through p38 mitogen-activated protein kinase (MAPK) and enhances the production of microRNA29 which directly modulate MMP synthesis and vascular smooth muscle cell apoptosis.9
TGF-β1 is believed to play a central role also in AF, promoting, the differentiation and activation of fibroblasts into secreting myofibroblasts which lead to fibrotic atrial remodelling.10 The TGFβ receptor acts synergically with AT1 receptors to activate MAPK. The pathway of TGF-β1 transduction signal is the TGF-β1 kinase 1 (TAK1) which is part of the MAPK family.10 Eventually the activation of the MAPK results in the modulation of transcription factors directly involved with inflammatory cytokine secretion, procollagen production, and cellular apoptosis (Graphical abstract).
While the activation cascade of AT1 is mainly via G proteins pathway, in the atrial myofibroblast the TGF-β1 signalling process also occurs through the phosphorylation of Smad complex which translocates in the nucleus and through binding to regulatory regions of genes enhance collagen secretion.10 The activated Smad in the nucleus binds also to the TGF-β inhibitory elements promoters, which regulates the transcription of MMPs and tissue inhibitors of MMPs.10 An additional pathway of activation of the TGF-β is the c-Jun N terminal kinase (JNK) which in the nucleus enhances transcription of nuclear factor kappa B and activating protein-1 with consequent inflammatory response.10
2. Clinical implications
A better understanding of the commonalities in pathological pathways underlying different diseases has several implications. First, the optimal medical management can be chosen in relation to its effect also in concurrent comorbidities, e.g., ACE inhibitor in patients with AF and TAA. Second, insights into these molecular mechanisms encourage the perception of multimorbidity as a spectrum of the same molecular dysfunction in different organ systems but not simply as different diseases. It can be hypothesized that the shared molecular alteration is based on the effect of environmental factors and less so on susceptible genetic polymorphisms. In any case, such molecular perspectives improve the holistic assessment of the patient, identifying the burden of risk linked to risk factors not in relation to the development of a one disease but on the effect of the individual’s health. Finally, supporting evidence on the biological plausibility and strength of association can be relevant in disease states such as TAA which are characterized by silent clinical manifestations but have a high mortality risk. Establishing non-casual associations between diseases may identifying subgroup of patients at higher risk in which screening programmes can have a relevant impact in terms of lives saved.
Conflict of interest: none declared.
References
Authors
Biography: Dr Riccardo Proietti, graduated at the Catholic University of Rome in 1997. He then specialized in cardiology at the University of Perugia and achieved a PhD degree in Cardiovascular Science at the University of Padua. He accomplished a fellowship in clinical electrophysiology at McGill University Canada. He worked as Consultant Cardiologist at Luigi Sacco Hospital of Milan with a focus in cardiac pacing and electrophysiology for more than 10 years. He is certified in cardiac pacing by the European Heart Rhythm society and in Clinical Electrophysiology by the Heart Rhythm Society. He was appointed as senior lecturer at Liverpool Centre for Cardiovascular Science at the University of Liverpool in July 2020.
Biography: Professor Lip, MD, is Price-Evans Chair of Cardiovascular Medicine, at the University of Liverpool, UK—and Director of the Liverpool Centre for Cardiovascular Science at the University of Liverpool and Liverpool Heart & Chest Hospital. He is also Distinguished Professor at Aalborg University, Denmark; Adjunct Professor at Yonsei University and Seoul National University, Seoul, Korea. He also holds Visiting or Honorary Professorships in various other Universities in UK, Serbia (Belgrade), China (Beijing, Nanjing, Guangzhou), Thailand (Chiangmai), and Taiwan (Taipei). Professor Lip has had a major interest into the epidemiology of atrial fibrillation (AF), as well as the pathophysiology of thromboembolism in this arrhythmia. Furthermore, he has been researching stroke and bleeding risk factors, and improvements in clinical risk stratification. The CHA2DS2-VASc and HAS-BLED scores—for assessing stroke and bleeding risk, respectively—were first proposed and independently validated following his research, and are now incorporated into international guidelines. The ABC (Atrial fibrillation Better Care) pathway proposed by him is the core recommendation in the 2020 European AF guidelines, and has been shown to reduce adverse outcomes in AF patients. In 2014, Professor Lip was ranked by Expertscape as the world's leading expert in the understanding and treatment of AF, a position still maintained in 2021 (https://bit.ly/3eP3qR4). Professor Lip was on the writing committee for various international guidelines, including the American College of Chest Physicians (ACCP) Antithrombotic Therapy Guidelines for Atrial Fibrillation, as well as various guidelines and/or position statements from the European Society of Cardiology (ESC) or EHRA. Professor Lip has acted as senior/section editor for major international textbooks and at senior editorial level for major international journals, including Thrombosis & Haemostasis (Editor-in-Chief, Clinical Studies); Europace (Associate Editor); and Circulation (Guest Editor).
Biography: Riaz Akhtar graduated from UMIST in 2003 with a First Class M.Eng. (Hons) degree in Biomedical Materials Science with Industrial Experience. In 2007, he completed a Ph.D. degree at The University of Manchester on the micromechanical behaviour of bone. Following this, he undertook a postdoctoral position investigating the micromechanical properties of soft tissue. In 2008, Riaz was awarded a British Heart Foundation Advanced Training fellowship investigating vascular stiffening and diabetes. He joined the University of Liverpool in October 2011 as a lecturer in Biomedical Engineering and was later promoted to Senior Lecturer. Riaz’s key research interests are in the structure–property–function of aortic tissues and is a founding member of the Liverpool Aortic Biomechanics and Biochemistry Research Group (www.labb-group.com) and is a member of the Liverpool Centre for Cardiovascular Sciences.
Biography: Professor Field started higher education at the University of Leeds in 1986 with a BSc Hon in Biochemistry and Pharmacology. He then completed a DPhil in Biochemistry at the University of Oxford in 1993. Following this training in research methods, he moved to the University of Nottingham to complete medical training (1993-1998), being awarded a BMed Sci (First class) and BMBS. Post graduate surgical training took place within the Trent Surgical Rotation when he completed his MRCS. Cardiac Surgery training took place in Nottingham, Sheffield and Liverpool and finished in 2009. He was appointed a consultant at LHCH in 2009.
