The evolution of surgical and medical treatment of aortic root aneurysm

Abstract

Since first report of aortic root replacement in 1968, the surgical risk and long term outcome of patients with aortic root aneurysm have been continuously improving. In the last 30 years, the surgical approach is also evolving towards more valve conservation with prophylactical intervention at an earlier clinical stage. Translational research has also led to emerging surgical innovation and new drug therapy. Their efficacies are currently under vigorous clinical trials and evaluations.

Keywords

aortic root aneurysm / aortic root replacement / valve sparing root replacement / personalised external aortic root support

Introduction

There is little known about the natural history of the thoracic aorta, including age-dependent changes, the effect of smoking and other potential influences on the development of significant pathology (penetrating ulcer, dissection and aneurysm). Previous studies have identified an increasing rate of presentations for both dissection and aneurysm [ 1, 2]. One small study has investigated age-dependent changes in the diameter of the aortic root, up to the age of 60 years only, in the Marfan syndrome (MFS) [ 3].

Dissection and aneurysmal dilatation of the ascending aorta are characteristic manifestations of Marfan syndrome. Dissection is the commonest cause of premature death, with as many as 70% of patients with Marfan syndrome dying in their 2nd, 3rd or 4th decades. Currently, prevention of dissection relies on prophylactic replacement of the ascending aorta and aortic root. The classical study of the natural history of Marfan syndrome comes from Murdoch and colleagues from the Johns Hopkins Hospital, Baltimore, USA published in 1972 [ 4]. At that time the authors estimated that for a 20-year-old patient there was a 50% chance of death by the age of 46. Faced with these data it was evident that death at a young age was the most likely outcome for people with Marfan syndrome. International guidelines now recommend that patients with the Marfan syndrome phenotype or with a family history of Marfan syndrome should be screened by echocardiography and measurement of the aortic root. Current cardiovascular treatment includes careful follow-up, prophylactic surgical intervention to replace the aneurysmal root, and medical therapy to slow or arrest the development of clinical manifestations of MFS.

This brief review is aimed to provide an update of recent progress in the surgical treatment of aortic root aneurysm and the ongoing clinical trials of pharmacological intervention in Marfan aortic aneurysm.

Early surgical experience

The advances in aortic surgery published by Cooley and coworkers in 1966 [ 5] and the case report of total root replacement for Marfan syndrome in 1968 [ 6] offered an opportunity to change the outcome for these people. As the operative risk reduced, the case for elective replacement became compelling. Early recommendations suggested a threshold aneurysm diameter of 60 mm, above which operation was considered justified on the grounds that the risk of rupture appeared to rise abruptly beyond that size [ 7]. It should be emphasized that this measurement relates to the diameter at the widest point in the sinuses of Valsalva and more precisely, in recent work, to the diameter at the closure of the aortic leaflets [ 8]. Observational data from an echocardiography database showed a strong statistical relationship between size and dissection [ 9] without an obvious threshold.

During the 1990s as echo measurement became routinely available and surgery became safer, operation for Marfan-related aortic root aneurysms was offered at progressively lower aortic size. In successive international guidelines the threshold for advising prophylactic aortic root surgery has fallen from 55 mm to the current 45 mm and to 50 mm for the non-Marfan syndrome patients [ 10]. It should be remembered that as root replacement has become widespread, and something of a routine procedure, the true natural history in the absence of surgery and in the era of modern monitoring, is no longer attainable.

Composite root replacement with a mechanical valve (total root replacement)

In the early days an inclusion technique was used: the coronary orifices were sutured en face into the graft and the native aorta wrapped around the tube graft. Precise anastamosis of the coronary arteries with an aortic button obviated the need for an inclusion technique and the operation became standardised and highly reproducible (Fig.1). A recent systematic review and meta-analysis provides the most comprehensive summary of outcomes for total root replacement (TRR) [ 11]. The review includes seven publications spanning 1971 to 2006 reporting a total of 972 patients whose average age was 35 years at the time of operation. The authors were unable to extract data on the aortic dimension prior to the operation. Furthermore, the rate of change, the degree of aortic regurgitation and family history of dissection were not retrievable from the data provided, all considerations in recommending such surgery.

In collected worldwide series of 455 elective operations the 30-day mortality was 1.5% [ 12] and in the Johns Hopkins experience there were no deaths in 235 consecutive root replacement operations for Marfan syndrome [ 13]. In the meta-analysis calculated estimates of the thromboembolic hazards associated with a mechanical valve were 0.7% per year, endocarditis 0.3% per year, re-intervention 0.3% per year and composite valve-related events 1.3% per year [ 11]. For a 20-year-old patient this translates into a 65% probability of a valve-related event in addition to a day in day out concern with treading a path between thrombosis and bleeding.

While excellent reproducible results are obtained with the modern “Button-Bentall” operation, these young patients are committed to a life-long risk of valve-related thromboembolism and an accompanying fear of bleeding from the anticoagulation required to minimise that risk. Neither the authors of the meta-analysis nor of the decision analysis [ 14] were able to estimate the impairment of health related quality of life attributable to these factors but ideally they are needed for the purposes of any future analysis and particularly for a thorough incremental cost-effectiveness evaluation.

Valve sparing root replacement (VSRR)

Yacoub [ 15] and David [ 16] pioneered methods of preserving the aortic valve while excising the aortic root in patients with Marfan syndrome and other connective tissue diseases. These operations have been through several iterations, each seeking to correct the failings of an earlier version (Fig.2). The systematic review [ 11] includes data on a total of 413 patients of average age 33 who underwent aortic valve-sparing surgery in six reports spanning 1993 to 2006. The patients are a little younger than others in the analysis and the clinical series start 20 years later. Both of these might bias the results in favor of VSRR and any direct comparison must be made cautiously.

The re-intervention rate, probably largely for valve failure, was 1.3% per year which, within the limits of the meta-analysis, was independent of follow-up duration. This means that by 20 years more than a quarter of patients who have had valve-sparing surgery might need further aortic valve surgery and at best only half of them are likely to complete their life span without another aortic root operation. The thromboembolic rate was 0.3% per year and the endocarditis rate was 0.2% per year. These were lower but not significantly so compared with TRR and notably were not zero. The composite valve-related event rate for VSRR was 1.9% per year, significantly greater than TRR. For a 20-year-old patient hoping for a full life span this translates into a 95% probability of a valve related event [ 11].

Selective aortic sinus replacement

Except for Marfan syndrome, the pathological cause of aortic root aneurysm and dissection include aortic stenosis and regurgitation, senile aortic dilatation and hypertension, etc. Selective aortic sinus replacement has been performed in hypertensive patient with atheromatous ascending aneurysms since 1996 in Oxford [ 17]. The pattern of root dilatation is determined by pressure and flow characteristics in this case. The sino-tubular junction usually dilates first followed by the non-coronary sinus and right coronary sinus. Left coronary sinus retains normal geometry until a very advanced stage. Remodelling of the sino-tubular junction with selective aortic sinus replacement restores valve competence, with no leak in 69% patients and Grade 1 aortic regurgitation in 24% patients after maximal 72 months follow-up.

This operation may decrease operative time and complexity, which is important during an acute type A aortic dissection or advanced age. The sinuses contributing to the aortic aneurysm formation or the dissection were excised and replaced with Dacron graft [ 18]. Graft size was kept equivalent to or slightly larger than the aortic annulus diameter, the graft tailored for repair and distal anastomosis performed. Comparing with total root replacement or root remodelling using valve sparing surgery, selective aortic sinus replacement has been reported to have an increase in sinus and sino-tubular junction diameters, but this does not cause significant difference in aortic regurgitation during a medium term follow-up [ 19].

Personalised external aortic root support

The placement of a personalised external aortic support (PEARS), computer designed and manufactured to match the aortic root morphology of the individual patient, was introduced in 2004 as a conservative approach for Marfan patients. The device manufacture and operative method were the result of research and development between 2000 and 2004 when the first operation was performed. The computer aided design (CAD), manufacturing method and surgical technique have all remained consistent without the iterative development which has characterized the evolution of both TRR and VSRR. After proof of principle [ 8] and prospective evaluation in the first 20 patients [ 20], the technique has undergone Health Technology Appraisal by the British National Institute for Health and Care Excellence (NICE).

From cross-sectional digital images, the patient’s own aorta is modeled by computer aided design and a replica is made in thermoplastic by rapid prototyping. On this, a personalised support of a macroporous polymer mesh is manufactured. The mesh is positioned around the aorta, closely applied from the aorto-ventricular junction proximally to the brachiocephalic artery distally. The operation is performed with a beating heart and usually without cardiopulmonary bypass (Fig.3). Between 2004 and 2011, 30 patients with median age 28 years (IQR 20-44) had this operation and have been prospectively followed up for 1.4 to 8.8 years by February 2013. During a total of 133 patient-years there were no deaths or cerebrovascular, aortic or valve-related events [ 21].

The aortic valve, the root architecture, and the blood/endothelial interface are conserved. The perioperative burden is less and there has been freedom from aortic and valvular events. A prospective comparative study is planned.

Pharmacological treatment for aortic root dilatation

Until recently, pharmacological treatment for aortic root dilatation was confined to the use of β-adrenergic blocking drugs. The invoked mechanisms of action have included reduction in aortic wall shear stress, in ejection impulse and in heart rate. β blocker therapy has been reported to reduce the rate of aortic root dilatation and increase the life span [ 22, 23]. However, it does not improve the underlying pathology process that results in weakness and dilatation of the aortic wall.

Marfan syndrome is a dominantly inherited disorder caused by mutations in the fibrillin-1 gene, which have been demonstrated in 92% of classically affected MFS type 1 cases [ 24]. Recent studies in basic science have improved our understanding of the pathogenesis of MFS. It is postulated that abnormal fibrillin-1 in MFS causes insufficient sequestration and consequent excessive activation of transforming growth factor-β (TGF-β), a cytokine involved in cell migration, proliferation and programmed cell death. TGF-β appears to contribute to the pathogenesis of many phenotypic features of MFS [ 25].

Based on the ability of the angiotensin receptor blocker (ARB), such as losartan, to inhibit TGF-β signaling, Dietz and colleagues [ 26] developed a mouse model with fibrillin-1 mutation of MFS to examine the effect of losartan on aortic growth. In the losartan-treated mice, aortic growth and aortic wall thickness by echocardiographic measurement were comparable with those of wild-type controls. And losartan prevented elastic fiber fragmentation, and blunted TGF-β signaling in the aortic media as well. Furthermore, when compared with propanolol-treated mice, losartan was also considerably more effective. Propranolol-treated MFS mice showed a slower rate of aortic growth and no effect on aortic wall thickness compared to the placebo group. Therefore it is particularly attractive to lower blood pressure with β blocker therapy along with decrease of TGF-β signaling using ARB.

These results from animal study were so fascinating that the clinicians at the Johns Hopkins undertook a small prospective trial in 18 children with MFS and found similar effects of ARB on reducing the aortic root dilatation. Preliminary data indicated the average change in aortic root diameter was 3.5 mm/year, 0.5mm /year and 1.67 mm/year, in pre-treatment, following losartan treatment and following β blocker treatment, respectively [ 27]. Groenink and colleagues [ 28] have reported on the first prospective randomized controlled trial (COMPARE) and have shown a beneficial effect in operated and unoperated adults with MFS after 3 years follow-up. The authors evaluated the aortic root dilatation rate using both MRI and TTE measurement in 145 patients, and found the rate of root expansion to be significantly lower in the losartan group compared with that of controls, with a number needed to treat of 5.3 patients. The reduction of mean aortic root dilatation rate in the losartan group was irrespective of age, sex, blood pressure, aortic root size, presence of a FBN1 mutation and concomitant β blocker usage. However, there are no significant differences in clinical endpoint (aortic dissection, elective aortic surgery, cardiovascular death) between the losartan group and control group. Larger scale clinical trial is required to ascertain the efficacy of losartan in MFS patients.

Currently, several prospective, randomized trials are ongoing, including the one with placebo-controlled, double-blind, multicenter study—Aortic Irbesartan Marfan Study (AIMS) in UK [ 29]. In this study, we investigate whether the ARB Irbesartan can reduce aortic sinus dilatation in MFS compared to placebo. The study was designed to recruit 500 unoperated MFS patients from over 20 UK centers. The patients are aged from 6 years to 40 years, and will receive standard treatment including β blocker therapy if tolerated. The primary outcome measure is the absolute change in aortic root diameter per year using echocardiography, which is analyzed by Oxford Echo Core Laboratory that is also blinded to the treatment. A similar study in USA recruits 608 pediatric and adult MFS patients (age 6 months to 25 years). It is designed to evaluate ARB losartan effects on aortic dilatation using echocardiographic measurement after 3 years follow-up [ 30, 31]. However, it focuses on comparing losartan versus β blocker (atenolol).

Summary

In the past 50 years, the therapeutic intervention of aortic aneurysm has undergone significant evolution. While the surgical treatment remains the corner stone in today’s practice, its limitation regarding long-term complication and patient’s quality of life has been the driving force for a continuing innovation of new approaches toward this major cardiac pathology. Personalised external aortic support and ARB treatment may hold new promise for Marfan patients, which also serves as the great examples of translational clinical research.

Compliance with ethics guidelines

Dr. Li Yuan was funded by the Charitable Research Fund of Oxford University Hospitals NHS Trust during her Visiting Fellowship at Oxford University. Xu Yu Jin, Li Yuan, Mario Petrou, and John R. Pepper all declare that they have no conflict of interest. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

References

[1] Olsson C, Thelin S, Ståhle E, Ekbom A, Granath F. Thoracic aortic aneurysm and dissection: increasing prevalence and improved outcomes reported in a nationwide population-based study of more than 14,000 cases from 1987 to 2002. Circulation2006; 114(24): 2611–2618

[2] Howard DP, Banerjee A, Fairhead JF, Perkins J, Silver LE, Rothwell PM; Oxford Vascular Study. Population-based study of incidence and outcome of acute aortic dissection and premorbid risk factor control: 10-year results from the Oxford Vascular Study. Circulation2013; 127(20): 2031–2037

[3] Jeremy RW, Huang H, Hwa J, McCarron H, Hughes CF, Richards JG. Relation between age, arterial distensibility, and aortic dilatation in the Marfan syndrome. Am J Cardiol1994; 74(4): 369–373

[4] Murdoch JL, Walker BA, Halpern BL, Kuzma JW, McKusick VA. Life expectancy and causes of death in the Marfan syndrome. N Engl J Med1972; 286(15): 804–808

[5] Cooley DA, Bloodwell RD, Beall AC Jr, Hallman GL, De Bakey ME. Surgical management of aneurysms of the ascending aorta. Including those associated with aortic valvular incompetence. Surg Clin North Am1966; 46(4): 1033–1044

[6] Bentall H, De Bono A. A technique for complete replacement of the ascending aorta. Thorax1968; 23(4): 338–339

[7] Isselbacher EM. Thoracic and abdominal aortic aneurysms. Circulation2005; 111(6): 816–828

[8] Pepper J, Golesworthy T, Utley M, Chan J, Ganeshalingam S, Lamperth M, Mohiaddin R, Treasure T. Manufacturing and placing a bespoke support for the Marfan aortic root: description of the method and technical results and status at one year for the first ten patients. Interact Cardiovasc Thorac Surg2010; 10(3): 360–365

[9] Murgatroyd F, Child A, Poloniecki J, Treasure T, Pumphrey C. Does routine echocardiographic measurement of the aortic root diameter predict the risk of aortic dissection in the Marfan syndrome. European Heart Journal1991; 12(abstract supplement): 410

[10] Vahanian A, Baumgartner H, Bax J, Butchart E, Dion R, Filippatos G, Flachskampf F, Hall R, Iung B, Kasprzak J, Nataf P, Tornos P, Torracca L, Wenink A;Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology; ESC Committee for Practice Guidelines. Guidelines on the management of valvular heart disease: The Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology. Eur Heart J2007; 28(2): 230–268

[11] Benedetto U, Melina G, Takkenberg JJ, Roscitano A, Angeloni E, Sinatra R. Surgical management of aortic root disease in Marfan syndrome: a systematic review and meta-analysis. Heart2011; 97(12): 955–958

[12] Gott VL, Greene PS, Alejo DE, Cameron DE, Naftel DC, Miller DC, Gillinov AM, Laschinger JC, Pyeritz RE. Replacement of the aortic root in patients with Marfan’s syndrome. N Engl J Med1999; 340(17): 1307–1313

[13] Gott VL, Cameron DE, Alejo DE, Greene PS, Shake JG, Caparrelli DJ, Dietz HC. Aortic root replacement in 271 Marfan patients: a 24-year experience. Ann Thorac Surg2002; 73(2): 438–443

[14] Kim SY, Martin N, Hsia EC, Pyeritz RE, Albert DA. Management of aortic disease in Marfan syndrome: a decision analysis. Arch Intern Med2005; 165(7): 749–755

[15] Yacoub MH, Gehle P, Chandrasekaran V, Birks EJ, Child A, Radley-Smith R. Late results of a valve-preserving operation in patients with aneurysms of the ascending aorta and root. J Thorac Cardiovasc Surg1998; 115(5): 1080–1090

[16] David TE, Armstrong S, Ivanov J, Feindel CM, Omran A, Webb G. Results of aortic valve-sparing operations. J Thorac Cardiovasc Surg2001; 122(1): 39–46

[17] Westaby S, Saito S, Anastasiadis K, Moorjani N, Jin XY. Aortic root remodeling in atheromatous aneurysms: the role of selected sinus repair. Eur J Cardiothorac Surg2002; 21(3): 459–464

[18] Komiya T, Tamura N, Sakaguchi G, Kobayashi T. Modified partial aortic root remodeling in acute type A aortic dissection. Interact Cardiovasc Thorac Surg2009; 8(3): 306–309

[19] Charitos EI, Stierle U, Sievers HH, Misfeld M. Valve-sparing aortic root remodeling with partial preservation of the intact native aortic sinuses. Eur J Cardiothorac Surg2009; 36(3): 589–591

[20] Treasure T, Crowe S, Chan KM, Ranasinghe A, Attia R, Lees B, Utley M, Golesworthy T, Pepper J. A method for early evaluation of a recently introduced technology by deriving a comparative group from existing clinical data: a case study in external support of the Marfan aortic root. BMJ Open2012; 2(2): e000725

[21] Treasure T, Takkenberg JJ, Golesworthy T, Rega F, Petrou M, Rosendahl U, Mohiaddin R, Rubens M, Thornton W, Lees B, Pepper J. Personalised external aortic root support (PEARS) in Marfan syndrome: analysis of 1-9 year outcomes by intention-to-treat in a cohort of the first 30 consecutive patients to receive a novel tissue and valve-conserving procedure, compared with the published results of aortic root replacement. Heart2014; 100(12): 969–975

[22] 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 Med1994; 330(19): 1335–1341

[23] Silverman DI, Burton KJ, Gray J, Bosner MS, Kouchoukos NT, Roman MJ, Boxer M, Devereux RB, Tsipouras P. Life expectancy in the Marfan syndrome. Am J Cardiol1995; 75(2): 157–160

[24] Collod-Béroud G, Le Bourdelles S, Ades L, Ala-Kokko L, Booms P, Boxer M, Child A, Comeglio P, De Paepe A, Hyland JC, Holman K, Kaitila I, Loeys B, Matyas G, Nuytinck L, Peltonen L, Rantamaki T, Robinson P, Steinmann B, Junien C, Béroud C, Boileau C. Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database. Hum Mutat2003; 22(3): 199–208

[25] Neptune ER, Frischmeyer PA, Arking DE, Myers L, Bunton TE, Gayraud B, Ramirez F, Sakai LY, Dietz HC. Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat Genet2003; 33(3): 407–411

[26] Habashi JP, Judge DP, Holm TM, Cohn RD, Loeys BL, Cooper TK, Myers L, Klein EC, Liu G, Calvi C, Podowski M, Neptune ER, Halushka MK, Bedja D, Gabrielson K, Rifkin DB, Carta L, Ramirez F, Huso DL, Dietz HC. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science2006; 312(5770): 117–121

[27] Brooke BS, Habashi JP, Judge DP, Patel N, Loeys B, Dietz HC 3rd. Angiotensin II blockade and aortic-root dilation in Marfan’s syndrome. N Engl J Med2008; 358(26): 2787–2795

[28] Groenink M, den Hartog AW, Franken R, Radonic T, de Waard V, Timmermans J, Scholte AJ, van den Berg MP, Spijkerboer AM, Marquering HA, Zwinderman AH, Mulder BJ. Losartan reduces aortic dilatation rate in adults with Marfan syndrome: a randomized controlled trial. Eur Heart J2013; 34(45): 3491–3500

[29] Mullen MJ, Flather MD, Jin XY, Newman WG, Erdem G, Gaze D, Valencia O, Banya W, Foley CE, Child A. A prospective, randomized, placebo-controlled, double-blind, multicenter study of the effects of irbesartan on aortic dilatation in Marfan syndrome (AIMS trial): study protocol. Trials2013; 14(1): 408

[30] Lacro RV, Dietz HC, Wruck LM, Bradley TJ, Colan SD, Devereux RB, Klein GL, Li JS, Minich LL, Paridon SM, Pearson GD, Printz BF, Pyeritz RE, Radojewski E, Roman MJ, Saul JP, Stylianou MP, Mahony L; Pediatric Heart Network Investigators<?Pub Caret?>. Rationale and design of a randomized clinical trial of beta-blocker therapy (atenolol) versus angiotensin II receptor blocker therapy (losartan) in individuals with Marfan syndrome. Am Heart J2007; 154(4): 624–631

[31] Lacro RV, Guey LT, Dietz HC, Pearson GD, Yetman AT, Gelb BD, Loeys BL, Benson DW, Bradley TJ, De Backer J, Forbus GA, Klein GL, Lai WW, Levine JC, Lewin MB, Markham LW, Paridon SM, Pierpont ME, Radojewski E, Selamet Tierney ES, Sharkey AM, Wechsler SB, Mahony L; Pediatric Heart Network Investigators.Characteristics of children and young adults with Marfan syndrome and aortic root dilation in a randomized trial comparing atenolol and losartan therapy. Am Heart J2013; 165(5): 828–835, e3

RIGHTS & PERMISSIONS

Higher Education Press and Springer-Verlag Berlin Heidelberg