Natural history of mm root/ascending aortic aneurysms in the current era of dedicated thoracic aortic clinics

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1 European Journal of Cardio-Thoracic Surgery 50 (2016) doi: /ejcts/ezw123 Advance Access publication 24 Apri l 2016 ORIGINAL ARTICLE Cite this article as: Gagné-Loranger M, Dumont É, Voisine P, Mohammadi S, Dagenais F. Natural history of mm root/ascending aortic aneurysms in the current era of dedicated thoracic aortic clinics. Eur J Cardiothorac Surg 2016;50: Natural history of mm root/ascending aortic aneurysms in the current era of dedicated thoracic aortic clinics Maude Gagné-Loranger, Éric Dumont, Pierre Voisine, Siamak Mohammadi and François Dagenais* Department of Cardiovascular Surgery, Quebec Heart and Lung Institute, Laval University, Sainte-Foy, Canada * Corresponding author. Department of Cardiovascular, Surgery, Institut Universitaire de Cardiologie et Pneumologie de Québec, 2725 chemin Sainte-Foy, G1V 4G5 Sainte-Foy, Canada. Tel: ; francois.dagenais@chg.ulaval.ca (F. Dagenais). Received 25 September 2015; received in revised form 3 January 2016; accepted 25 January 2016 Abstract OBJECTIVE: The natural history of root/ascending aortic aneurysms is based on studies from the 1980s to 1990s. Imaging and follow-up guidelines are based on these studies. Dedicated thoracic aortic clinics (TAC) ensure strict patient/imaging follow-up and tight blood pressure (BP) control. The aim of this study was to evaluate the natural history of medically treated root/ascending aortic aneurysms in the current era of dedicated TAC. METHOD: Two hundred and fifty-one patients with mm root/ascending aneurysms (all other aortic segments of <40 mm) were identified through a prospective collected databank. Patients were followed in a dedicated TAC. Serial (12 18 months interval) thoraco-abdominal computed tomographies (CTs), tight BP control (24 h arterial blood pressure monitoring) and isometric and exercise BP monitoring were performed. RESULTS: The mean age was 65.4 ± 10.9 years; 29.5% of patients were female. Fifty-nine percent of patients had high BP. Aneurysm aetiology was atherosclerotic in 48.2% of patients, annulo-ectasia in 25.1% of patients, bicuspid valve-related in 21.5% of patients and another aetiology in 5.2% of patients. The initial aneurysm diameter was 46 ± 2.6 mm; 74.1% being between 46 and 50 mm. The mean follow-up (FU) was 4.3 ± 2.5 years, with a mean of 2.8 ± 1.1 CTs/pt. During FU, the increase in aortic size/year was 0.42 ± 0.82 mm/year for the root/ ascending aorta (40 45 mm: 0.55 ± 0.77 mm/year vs mm: 0.38 ± 0.84 mm/year; P = 0.14), 0.66 ± 1.11 mm/year for the arch, 0.45 ± 1.06 mm/year for the mid-descending aorta, 0.43 ± 1.0 mm/year for the aortic hiatus, 0.39 ± 0.87 mm/year for the suprarenal aorta and 0.41 ± 1.03 mm/year for the infrarenal aorta. Thirty patients (12%) were operated during FU. Surgical indication was disease progression on the aortic valve in 8 patients, root/ascending aorta progression of >50 mm in 14 patients and a root/ascending aorta replacement during FU without progression in 8 patients. One patient was operated emergently for an intramural haematoma after 3 years of followup. No patient required operation distal to the aortic arch. Operative mortality was 0/30 (0%). Thirty percent of patients required a concomitant hemiarch replacement. Four patients died during FU, with all deaths resulting from non-aortic causes. Freedom from acute aortic-related event and survival at 5 years were respectively 99.4 and 97.6%. CONCLUSION: The present study suggests that the growth rate of mm root/ascending aneurysms followed in a dedicated TAC aorta is lower than that shown in previously reported series. Freedom from aortic-related events and survival are high, thus necessitating longterm follow-up. These results challenge the current guidelines in terms of interval between imaging examinations and the extent and type of aortic imaging. Keywords: Thoracic aneurysm Natural history Imaging surveillance INTRODUCTION The thoracic aorta expands slowly with age at a rate of 0.7 mm in women and 0.9 mm in men per decade of life [1]. A thoracic aortic aneurysm (TAA) is diagnosed when the thoracic aorta reaches a diameter of 40 mm. Approximately, 60% of TAA occurs in the Presented at the Postgraduate Course of the 29th Annual Meeting of the European Association for Cardio-Thoracic Surgery, Amsterdam, Netherlands, 4 October ascending aorta [2]. Current guidelines recommend a surgical intervention for root/ascending aortic aneurysms at an aortic diameter of >50 mm with familial predisposition or in the presence of connective tissue disorder, >55 mm in patients without risk factors or >50 mm in patients with risk factors (small stature, bicuspid aortic valve, concomitant aortic valve disease, patient preference) [3]. Medical therapy in patients with non-operative TAA (NO-TAA) aims to control blood pressure (BP) dp/dt and other atherosclerotic risk factors, smoking cessation and avoidance of strenuous isometric exercises [4]. The Author Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

2 M. Gagné-Loranger et al. / European Journal of Cardio-Thoracic Surgery 563 The growth rate of TAA is variable and reported between 1.0 and 4.2 mm/year [5]. Specific growth rates of NO-TAA are lacking. Since the natural history of NO-TAA is ill-defined, specific recommendations in terms of the type and frequency of imaging follow-up remain unclear [3]. The purpose of the present study is to establish the growth rate of NO-TAA of the root/ascending aorta and to suggest an imaging surveillance protocol. divided by the timeframe (years) between the first and the last CT. Aortic replacement procedures performed during the study were identified and reasons leading to the surgery defined. In operated patients, aortic growth rate was cumulated until the date of surgery which was considered as the end of follow-up. Deaths were registered and aortic involvement was assessed. In the case of an unknown death cause, the death was adjudicated to an aortic cause. METHODS At the Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), a dedicated thoracic aortic clinic was instituted in Concomitantly, a prospective databank was implanted and approved by the IUCPQ research and scientific committees. Patient inclusion criteria and follow-up All patients who have been followed at the IUCPQ since 2001 with a root/ascending aortic diameter of mm were identified. Patients required at least two chest computed tomographies (CTs) at follow-up. Patients with a TAA of >40 mm on another aortic segment as well as with familial or genetic TAA aetiologies were excluded. Patients were followed yearly at the IUCPQ thoracic aortic clinic. Follow-up was complete in all patients. Yearly 24-h BP monitoring was prescribed and the target BP was <140/90 mmhg. In young (<60 years old) active patients, a kinesiology evaluation was performed to assess BP elevation on VO 2 max study and during isometric exercises using standardized protocols. Furthermore, smoking cessation counselling was encouraged and serum lipid profile optimized. Once the diagnosis of root/ascending TAA was established, CT follow-up was done 1 year later and months thereafter. Chest CTs were performed either at the IUCPQ or at a referral centre. All images were sent to the clinic and measures were prospectively performed by the two surgeons in charge of the clinic (François Dagenais and Éric Dumont). CT measurements were standardized as follows: aortic measurements were performed on axial images with diameters assessed at the aortic sinuses, ascending aorta (usually at the carina level), mid-arch ( just distal to the innominate artery), at the aortic isthmus (distal to the left sub-clavian artery), mid-descending aorta (at the level of carina), the aortic hiatus ( just above the diaphragmatic aortic hiatus), the suprarenal aorta (level of the coeliac trunk) and the infrarenal aorta. Measurements were obtained on contrast-enhanced CT images using the outer-to-outer diameter. In cases where the measurements were inconclusive on the axial cuts, measures in the sagittal or coronal plans were analysed and noted within the measurement file to ensure comparable measures for future CT controls. The largest diameter of the root/ascending aorta was registered as maximal root/ascending aortic diameter and used for comparison throughout the study period. End-points and data analysis Maximum aortic diameters of the root/ascending aorta were compared throughout the study period. Yearly aortic growth was defined as maximal root/ascending aortic diameter at the last CT maximal root/ascending aortic diameter at the first CT Statistical analysis All continuous descriptive variables are reported as mean ± standard deviation. Student s t-test or Wilcoxon rank-sum test was performed to compare groups. Nominal variables are reported as frequencies. Fisher s exact test was used to test if the samples came from the same distribution. Product-limit analyses (Kaplan Meier) were performed to examine the time-dependent cumulative probabilities of the outcomes. The results were considered significant with P-values of <0.05. Analyses were conducted using the statistical packages SAS, version 9.4 (SAS Institute, Inc., Cary, NC, USA). RESULTS Patient characteristics and aneurysm growth Two hundred and fifty-one patients met the inclusion criteria. The mean follow-up duration was 4.3 ± 2.5 years (range: years) with a mean of 2.8 ± 1.1 CTs/pt (range: 2 8). Patients characteristics are listed in Table 1. Patients were relatively young (mean age 65.4 ± 10.9 years), with a maximal root/ascending aortic diameter between 46 and 50 mm in 74.1% at diagnosis. During the study period, root/ascending aortic growth was 0.42 ± 0.82 mm/year. Figure 1 depicts a steady and comparable growth rate at each Table 1: Patient characteristics n (%) Age 65.4 ± 10.9 (66) Sex female 74 (29.5%) Body mass index 28.1 ± 4.9 (27.5) Hypertension 148 (59.0%) Smoking history 31 (12.4%) Diabetes 21 (8.4%) Chronic renal failure 9 (3.6%) COPD 20 (8.0%) Hyperlipidaemia 113 (45.0%) Peripheral vascular disease 20 (8.0%) CAD 40 (15.9%) Maximal root/ascending size mm 65 (25.9%) mm 186 (74.1%) Aortic aneurysm aetiology Atherosclerosis 121 (48.2%) Bicuspid aortic valve 54 (21.5%) Annulo-ectasia 63 (25.1%) Other 13 (5.2%) COPD: chronic obstructive pulmonary disease; CAD: coronary artery disease. AORTIC SURGERY

3 564 M. Gagné-Loranger et al. / European Journal of Cardio-Thoracic Surgery Figure 1: Increase in root/ascending aortic size at each follow-up year. Figure 2: Freedom from emergent and elective surgery. follow-up year. The growth rate of the root/ascending aorta was similar according to the aneurysm aetiology: atherosclerosis: 0.37 ± 0.59 mm/year, bicuspid aortic valve: 0.43 ± 0.71 mm/year and annulo-ectasia: 0.39 ± 0.82 mm/year; P = ns. Only 12 patients showed an annual aortic growth rate of >2 mm during follow-up; the annual mean aortic growth rate was 3.3 ± 1.6 mm/year in these 12 patients. By univariate analysis, only the presence of renal failure (GFR measured <50 cc/min) was significantly associated with an aortic growth of >2 mm. Annual growth rate was comparable for patients with an initial root/ascending diameter of mm (0.55 ± 0.77 mm) vs mm (0.38 ± 0.84 mm) P = Annual growth rates for other thoracic aortic segments were as follows: arch: 0.66 ± 1.11 mm; aortic isthmus: 0.45 ± 1.02 mm; mid-descending: 0.45 ± 1.06 mm; aortic hiatus: 0.43 ± 1.0 mm; and abdominal segments: suprarenal aorta: 0.39 ± 0.87 mm and infrarenal aorta: 0.41 ± 1.03 mm. The mean aortic growth rates of the thoracic segments were compared with that of abdominal segments. No significant difference in growth was observed: thoracic segments: 0.48 ± 0.10 mm/year vs abdominal segments: 0.40 ± 0.01 mm/year; P =0.32. Operative rates and outcome Thirty patients (12%) were operated during follow-up. Among these, the root/ascending aorta was replaced in 8 patients in whom the primary operative indication was disease progression of the aortic valve (aortic diameter: initial CT: 47.5 ± 1.1 mm, at surgery: 48.4 ± 0.7 mm; P = 0.11). Eight patients were selected to have a root/ascending aortic replacement during follow-up without significant aortic growth (initial CT: 46.0 ± 3.1 mm preop CT: 46.9 ± 2.9 mm; P = 0.06). In 14 patients, the decision to operate was based on progression of the aortic diameter of >50 mm at a mean follow-up of 2.9 ± 2.3 years (initial root\ascending aortic diameter: 47.9 ± 1.9 mm (median: 48); diameter at operation: 51.3 ± 1.5 mm (median: 51). Distal aortic progression to the ascending aortic did not show a significant difference between patients undergoing an operation and non-operated patients. All operations were conducted on an elective basis except in 1 patient who presented with an acute aortic syndrome owing to an intramural haematoma of the ascending aorta at 3 years of followup. No perioperative mortality occurred in these 30 patients. A concomitant hemiarch replacement under circulatory arrest was Figure 3: Survival. required in 10 patients (30%). During the follow-up period, no patient within the cohort necessitated an aortic replacement procedure distal to the aortic arch. Five-year freedom from an acute aortic-related event was 99.4% (Fig. 2). Overall 5-year survival was 97.6% (Fig. 3). Four late deaths occurred; none died of aortic cause: 2 patients died of neoplasia, one of a motor vehicle accident and another due to a myocardial infarction. DISCUSSION The natural history of TAAs is based on reports of the 1980s and 1990s. These pioneer studies correlated the risk of aneurysmal complication to aortic size with a significant risk of rupture/dissection over 6 cm for the ascending aorta and 7 cm for the descending aorta [6]. Current guidelines for operative treatment are based on these findings. However, these studies include a heterogeneous population incorporating different sizes, types (fusiform vs saccular) and locations of aneurysm. It is well known that aneurysms of the descending aorta and large size aneurysms grow faster, thus rendering specific measurements for the root/ascending aorta difficult to assess [7, 8]. The current study however, focuses on a frequently encountered clinical situation: an incidental finding of an

4 M. Gagné-Loranger et al. / European Journal of Cardio-Thoracic Surgery 565 isolated non-operative aneurysm of the root/ascending aorta. The study population is homogenous and treated uniformly according to the current guidelines within a specialized aortic clinic. Our results show a very slow growth rate (0.42 ± 0.82 mm/year) in a large cohort of patients with a non-operative root/ascending aortic aneurysm; the growth rate is times higher than in patients without an aneurysm [1]. Coady et al. reported an annual growth rate of 1.2 mm/year in a mixed TAA population [9], whereas Hirose et al. demonstrated a 4.2 mm/year growth in a similar heterogeneous TAA population [10]. Shores et al. reported a 1.2 mm/year ascending aortic growth rate in patients treated with β-blockers and 4.2 mm/year without β-blocker treatment underlying the importance of medical therapy on aneurysm stabilization [11]. More recently, small observational studies have suggested that statins may limit TAA expansion [12]. Optimal BP and dp/dt management as well as support in lifestyle changes may have contributed to explain the lower growth rate encountered in our study compared with the historical data of the 1980s and 1990s. Our report further outlines the low rate of dissection or rupture in a non-operative population with a root/ascending aneurysm between 40 and 50 mm. The Yale group observed a 4.4 times greater risk of aortic dissection/rupture for aneurysms of mm compared with aneurysms of mm [7]. However, a yearly incidence of 2% was still reported with aneurysms of mm. Our study shows a 99.4% freedom from aortic dissection/ rupture at 5 years in patients with mm aneurysms of the root/ascending aorta. Clinical implications and recommendations The 2014 European guidelines for aortic diseases suggest an annual imaging for TAA of <45 mm and every 6 months for TAA between 45 and 55 mm (recommendation: Class I, Level C) [3]. The low aortic growth rate observed in the current study does not support such a short interval between imaging. With the widespread availability of imaging modalities and the ageing population, new cases of mm of root/ascending aortic aneurysms are increasing. Annual or biannual imaging remains non costeffective in light of the slow growth pattern of these aneurysms. Furthermore, as assessed, the survival of this patient cohort is excellent, thus mandating long-term imaging follow-up with the inherent risk of radiation-induced neoplasia owing to the cumulative radiation with serial CTs. The risk is typically higher in women of <60 years old submitted to cumulative high radiation doses [13]. In light of the present results, we recommend the following protocol for patients with isolated mm aneurysms of the root/ascending aorta. Following the diagnosis, the entire aorta should be imaged by either CT or magnetic resonance imaging (MRI) to identify synchronous aneurysms. In the event of the aneurysm is localized to the root/ascending aorta, we believe a repeat imaging should be obtained after a year. If the diameter remains stable, repeat imaging should be obtained every months. In patients showing aortic growth of >2 mm, imaging should be repeated annually. We suggest imaging the entire aorta at least every 3 4 years to identify new aneurysms on other aortic segments. In patients showing concomitant aortic valve disease, transthoracic echocardiography may be used an alternatively with CT to assess aortic diameter. Furthermore, for the evaluation of the entire aorta, MRI should be considered instead of CT in young patients to minimize the risks of cumulative radiation. The proposed imaging recommendations target specifically patients with aneurysms of atherosclerotic, annulo-ectasia or bicuspid aortic valve aetiology. In patients with familial aneurysms or connective tissue disorders, imaging follow-up should be conducted annually until further data are available. Limitations The proposed recommendations are based on a large homogeneous population managed in a dedicated clinic. We believe these recommendations to be reliable and accurate at mid-term although long-term validation is required. Aortic measurements were mainly performed using axial images. However, aortic measurements using the maximal diameter perpendicular to the centreline of 3D CT reconstructions are now considered more reliable and accurate. On a daily basis, such 3D reconstructions are often unavailable while axial, sagittal and coronal sections are more readily accessible. Using such axial images, inter- and intraobserver variability for CT aortic measurements has been reported up to 5 and 3 mm, respectively. We believe that having only two physicians performing measurements at pre-defined aortic levels minimizes the risk of error owing to the inter/intraobserver variability. On the other hand, the inherent variability between measures further supports the slow growth of root/ascending non-operative aortic aneurysms documented in our study. CONCLUSION Isolated root/ascending aortic aneurysms of non-genetic aetiology between 40 and 50 mm show slow growth with optimal medical therapy. Rupture/dissection is rare and mid-term survival is excellent. Interval between imaging follow-ups may be extended to months in the presence of a stable disease. We further stress the benefits of establishing dedicated aortic clinics to optimize the management of patients with aortic diseases. Further contemporary studies are required to support these findings. Conflict of interest: none declared. REFERENCES [1] Vriz O, Driussi C, Bettio M, Ferrara F, D Andrea A, Bossone E. Aortic root dimensions and stiffness in healthy subjects. Am J Cardiol 2013;112: [2] Isselbacher EM. Thoracic and abdominal aortic aneurysms. Circulation 2005;111: [3] Erbel R, Aboyans V, Boileau C, Bossone E, Bartolomeo RD, Eggebrecht H et al ESC Guidelines on the diagnosis and treatment of aortic diseases: document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. The Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC). Eur Heart J 2014;35: [4] Hiratzka LF, Bakris GL, Beckman JA, Bersin RM, Carr VF, Casey DE et al ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the diagnosis and management of patients with thoracic aortic disease. 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5 566 M. Gagné-Loranger et al. / European Journal of Cardio-Thoracic Surgery [5] Coady MA, Rizzo JA, Hammond GL, Kopf GS, Elefteriades JA. Surgical intervention criteria for thoracic aortic aneurysms: a study of growth rates and complications. Ann Thorac Surg 1999;67: [6] Kuzmik GA, Sang AX, Elefteriades JA. Natural history of thoracic aortic aneurysms. J Vasc Surg 2012;56: [7] Davies RR, Goldstein LJ, Coady MA, Tittle SL, Rizzo JA, Kopf GS et al. Yearly rupture or dissection rates for thoracic aortic aneurysms: simple prediction based on size. Ann Thorac Surg 2002;73: [8] Elefteriades JA. Natural history of thoracic aortic aneurysms: indications for surgery, and surgical versus nonsurgical risks. Ann Thorac Surg 2002; 74:S [9] Coady MA, Rizzo JA, Hammond GL, Mandapati D, Darr U, Kopf GS et al. What is the appropriate size criterion for resection of thoracic aortic aneurysms? J Thorac Cardiovasc Surg 1997;113: [10] Hirose Y, Hamada S, Takamiya M, Imakita S, Naito H, Nishimura T. Aortic aneurysms: growth rates measured with CT. Radiology 1992;185: [11] Shores J, Berger KR, Murphy EA, Pyeritz RE. Progression of aortic dilatation and the benefit of long-term beta-adrenergic blockade in Marfan s syndrome. N Engl J Med 1994;330: [12] Jovin IS, Duggal M, Ebisu K, Paek H, Oprea AD, Tranquilli M et al. Comparison of the effect on long-term outcomes in patients with thoracic aortic aneurysms of taking versus not taking a statin drug. Am J Cardiol 2012;109: [13] Einstein AJ, Henzlova MJ, Rajagopalan S. Estimating risk of cancer associated with radiation exposure from 64-slice computed tomography coronary angiography. JAMA 2007;298: APPENDIX. CONFERENCE DISCUSSION Scan to your mobile or go to to search for the presentation on the EACTS library Dr F. Kari (Freiburg, Germany): Your reported growth rate is small and aortic dissection seems to occur rarely in this patient cohort. However, for me, this also shows the need of new risk markers of aortic dissection. We do not yet understand aortic valve and root biomechanics well enough to really identify patients at risk for dissection, when they have smaller size aneurysms or little diameter dynamics. I have just two questions. First, there were around 20% of bicuspid aortic valves in your cohort, and we know that the bicuspid complex involves many different distinct phenotypes, and it would be extremely interesting to know the type of bicuspid aortic valve, root geometry or valve function impacted on growth rates. Did you look into any of these variables? The second question is, the same accounts for aneurysm subtypes or according, for example, to the Stanford Fazel clusters or aneurysm phenotypes. For example, did root plus ascending versus isolated ascending aneurysm or non-eccentric versus eccentric make a difference with respect to growth rates? Dr Dagenais: I strongly agree with you that we have to find new markers and that this just is the tip of the iceberg in terms of what we should start to know about aneurysms and their natural history. This is a clinical problem we deal with every day and I think this was the main driving force to do this kind of study. In terms of type of etiology, there was no difference between atherosclerotic versus bicuspid disease in terms of growth rate. However, we did not specifically look into the bicuspid per se. At first glance I would not see that there would be a difference. I think this question is very relevant, especially since when we had to do the operation there was a third of patients that required to have a hemiarch procedure. I think the take-home message, is that we overkill these patients with yearly examinations and if the aortic diameter is stable it is very secure to have more, deferred intervals such as 2 years between examinations. Dr G. Bolotin (Haifa, Israel): What is your recommendation for the patient regarding aerobic activity, running, biking, and do you start beta-blockers on a normal blood pressure patient? Dr Dagenais: That is a very good question, and that is a problem, because as cardiac surgeons we don t own a lot of diseases, but I think in terms of disease of thoracic aorta we can own this disease, and to be able to own this disease we have to better assess these patients in terms of recommendations such as level of activity. One issue you deal with every day, is for example, a patient who arrives with a diagnosis of a 44 mm aneurysm and says that he has a bomb and has been said to stop all activity. Why do we try to have a more objective approach in these patients. When these patients are very active, we refer them to kinesiology experts in our institution, and have a series of isometric exercises performed with blood pressure readings. When we do these tests we see sometimes, patients that have normal 24-hour atrial blood pressure monitoring who have a very high increase in blood pressure when they exercise. Also the patient learns to know the blood pressure that correlates to a specific level of activity. So we try to individualize the treatment of the level of activity with this kind of evaluation. We are starting to have data on this type of evaluation, and I think this will be very useful. Does this impact the fact we didn t have a lot of acute aortic events? Maybe, but I think we have to learn more about the level of activity in these young patients we treat medically and avoid impacting negatively their quality of life.