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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3734_Библиотеки_им_академика_М_И_Перельмана
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External Aortic Support andOther
https://t.me/med1917
Alternative Strategies intheManagement
ofAortic Pathology ofPatients
withConnective Tissue Disorders
JohnPepper
Introduction
Due to an increasing awareness of thoracic aortopathy and an exponential growth in
genetic diagnostic services, patients with Marfan syndrome and other connective
tissue disorders are presenting earlier in their natural history seeking advice on how
to prevent aortic dissection, aortic aneurysm, rupture and death. As the disease is
usually inherited, the patients are generally well informed and want to understand
the risks and benets of all options available.
There is a long history of the use of drugs to delay aortic root dilatation. The
effectiveness of beta-blockers has not been tested in large clinical trials and the
justication for their use is expert opinion based on small studies and the reassurance that at least they will not cause harm. The initial enthusiasm for angiotensin
receptor blockers (ARBs), specically Losartan, has met with scepticism following
four large international randomised controlled trials [1]. Except for the rst trial
report from the Netherlands, the subsequent three trials all showed no effect on the
rate of aortic dilatation, although Losartan appears to be a reasonable alternative to
a beta-blocker for those patients unable to tolerate the drug. Using a more potent
ARB, Irbesartan, the latest results from the AIMS trial, reported at the ESC 2018,
showed a modest treatment effect on the rate of dilatation of the Sinus of Valsalva,
which was from placebo 0.74mm/year to Irbesartan 0.52mm/year.
A manuscript submitted for a chapter in Aortic Dissection and Acute Aortic Syndromes edited
by Frank Sellke, Thoralf Sundt, Joseph Coselli, Joseph Bavaria and Neel Sodha to be published by
Springer.
J. Pepper (*)
Department of Surgery, Royal Brompton Hospital, London, UK
e-mail: j.pepper@rbht.nhs.uk
J. S. Coselli et al. (eds.), Aortic Dissection and Acute Aortic Syndromes,
https://doi.org/10.1007/978-3-030-66668-2_33
469© Springer Nature Switzerland AG 2021
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The current strategy for the prevention of ascending aortic dissection depends on
aortic root replacement surgery. The Bentall total root replacement is wellestablished, has a low mortality and excellent long-term results. But the need for
valve replacement imposes a risk of either long-term anticoagulation for a mechanical prosthesis or structural valve degeneration in the case of a tissue valve. The
valve-sparing root replacement (VSRR) has been developed to deal with these
issues and in the hands of very experienced surgeons excellent results have been
obtained [2]. But it is difcult to judge the generalisability of these outcomes. The
report from a multi-centre registry by Coselli and co-workers [3] showed a substantial risk of signicant aortic regurgitation at a rate of 7% at one-year follow-up in
Marfan patients. The meta-analysis of Benedetto [4] who compared Bentall and
VSRR operations showed a re-intervention rate of 1.3% per year after VSRR in
Marfan patients.
Personalised External Aortic Root Support (PEARS) may provide an alternative
to aortic root replacement in selected patients and thus complement the existing
armamentarium. The implantation of a personalised external aortic root support,
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 [5]. The device manufacture and operative method were the result of
research and development between 2000 and 2004 when the rst operation was
performed. The computer aided design (CAD), the rapid prototyping (RP) manufacturing method and the surgical technique have all remained consistent without the
iterative development which has characterised the evolution of both TRR and
VSRR.After proof of principle [6] and prospective evaluation in the rst 20 patients
[7], the technique has undergone Health Technology Appraisal by the British
National Institute for Health and Care Excellence (NICE).
J. Pepper
Methods
The implant required for the PEARS operation is an ExoVasc mesh support made
from the same polymer (polyethylene terephthalate) as standard vascular prostheses. (See Fig.1 and its legend) The fabric of the ExoVasc has an open mesh structure
with 0.7mm pores compared with the familiar low porosity corrugated vascular
grafts. Technical efcacy was reported in the rst 10 patients [6], a comparative
analysis of bypass, operative times and blood product usage in the rst 20 [7], and
clinical results up to 9years in the rst 30 patients [5]. Technical details of the methods of manufacture have remained consistent throughout the series [8]. The primary
indication remains prophylactic treatment of root aneurysms to prevent further
expansion with the intention of averting the risk of dissection and rupture.
Experimental implantation in sheep [9–11], and autopsy examination of one
patient who died with an intact sleeved aorta [12], have shown that the mesh is consistently incorporated to form a neo-aorta with conservation of the endothelium/
blood interface. In one of the sheep studies [11] a histological comparison was made
ac
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b
def
471
Fig. 1 From left to right the gure illustrates the design, manufacture and implantation of the
ExoVasc personalised mesh support. Digital image (a) is used to make a 3D replica (b) of the
patient’s ascending aorta and aortic root. Small holes mark the position of the coronary ostia. On
this a customised sleeve of an open mesh fabric is manufactured (c). Each stage requires expertise
and time measured in hours. The aorta is dissected down to the aorto-ventricular junction (d). Here
the surgeon is demonstrating that the dissection extends below (that is proximal to) the left main
coronary artery. The mesh longitudinal seam is opened and incisions are made to the point where
the main coronary arteries must pass through, making asterisk shaped incisions to conserve the
mesh support. It extends from the aorto-ventricular junction proximally to the brachiocephalic
artery distally (e). The nal image (f) is that of the rst recipient 14years after implantation
between the microporous mesh of PEARS and the standard low-porosity Dacron
graft (Fig.2). In the rst 24 patients, all operated in the lead hospital and with high
quality imaging available, the three commissure-to-cusp diameters were measured
after an average of 50months [7]. Based on 72 (24×3) measurements, there was a
small but signicant reduction of the mean of the diameters from 4.4 to 4.3cm
(P=0.01). The cross-sectional area was also reduced (NS) from 16.3±1.9cm
2
to
15.7±2.7cm2. In none of the patients was there an increase in the severity of aortic
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a b
J. Pepper
Fig. 2 Sheep study: transition zone, reconstruction of images taken at 10× magnication, longitudinal slices. (a) low-porosity graft (LPG) overview, Haematoxylin and Eosin. Buckling of the wall.
(b) LPG detail with Verhoeff’s elastic stain. Buckling of highly atrophic tunica media (arrowhead)
and compression of adventitia underneath ridges with severed structural bres (*). (c) macroporous mesh (MPM) overviews Haematoxylin and Eosin. Gradual transition of architectural changes.
(d) MPM detail with Verhoeff’s elastic stain. Gradual compression with well-preserved architecture
regurgitation or more than mild aortic regurgitation at follow-up. In the 24 patients
studied, nite enlargement was seen in the descending aortic dimensions during a
median period of under 2years, while the aortic root was held at smaller size than
that prior to surgery.
In 2003 an application was made to the Local Research & Ethics Committee and
subsequently approved by the Clinical Practice Committee of our hospital Trust.
Twenty operations were to be performed on patients with Marfan syndrome and the
results reported to the Committee. The inclusion criteria agreed at that time were an
Aortic Root/Sinus of Valsalva and Ascending Aorta with asymptomatic dilation of
between 40 and 50mm in diameter in patients aged 18+ years old. In 2010 after 23
patients had this operation, approval was given to continue the observational study
and to recruit surgeons at other centres. The development group allowed widening
of the criteria, accepting some younger patients. Patients eligible for inclusion in
this report all had surgery for the primary indication: prophylactic treatment of
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life-threatening aortic root aneurysm, usually with a recognised and diagnosed syndrome. Patients considered for the technique have been assessed by clinical members of the study team. Surgeons wishing to join the programme underwent
proctoring from one of the experienced PEARS surgeons, who went to their unit to
assist in surgery, usually on at least two patients.
In 2018 we undertook an audit of all 117 operations who had their PEARS operation before the end of December 2017. We had access to the full manufacturing
records and CAD models which were available from the secure le server at Exstent
Ltd. The surgery case report forms (CRFs) were available from the operating surgeons and kept securely by Exstent. The Exstent records, the Royal Brompton
Hospital database, and correspondence from the operating teams, were used to compile a full data set of demography, aetiology, aortic dimensions, the operation performed, operating time, cardiopulmonary bypass time (if used), and hospital stay
(Table1). Intraoperative adverse events, and any adjunctive surgery were recorded
and any later cardiac, aortic, neurological or infective events were tabulated. The
follow-up interval was from the date of operation to the date on which the patient
was last clinically assessed and/or had cardiac investigations. The Kaplan Meier
method was used to obtain estimates of patient survival and reoperation.
Results
180 PEARS procedures have been successfully carried out at 19units internationally. As of January 1st 2019, 183 patients have received a PEARS implant representing 584 postoperative patient years. 41 patients have been followed for more than
5years and 14 for more than 10years. Of the 183 who had the operation 134 were
Table 1 Table of distributions
Minimum 25% Median 75% Maximum
Age (years)
All patients N=117 15 23 34 46 75
Females N=30 15 27 38 46 65
Males N=87 15 22 32 46 75
Aortic root (mm)
All patients N=117 31 43 47 48 60
Females N=30 31 42 44 47 49
Males N=87 35 45 47 52 60
Operation time minutes N=116
Bypass time minutes N=32
Length of stay days N=116
Follow-up months N=116
a
Cardiopulmonary bypass not used in 85/117 (73%)
b
Not available in one case
c
One death in hospital (no PEARS implanted) excluded
a
60 130 165 236 840
b
22 46 70 90 245
a
5 5 6 7 25
c
2 7 20 89 166
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J. Pepper
carried out for Marfan syndrome, 8 for Loeys-Dietz syndrome, 12 for bicuspid aortic valve, 2 for an enlarged aortic root identied more than 20years following the
arterial switch operation for TGA, 1 Tetralogy of Fallot, 11 Ross operations and 15
for non-syndromic enlargement of the ascending aorta and aortic root. The accrual
of patient numbers and of units joining the programme are shown in Figs.2 and 3.
The operating time in 75% of the procedures was less than 4h. The majority of the
operations (73%) were undertaken without the use of cardiopulmonary bypass. The
length of hospital stay was no longer than 7days in 75% of patients. Further details
with ranges and frequency distributions are provided in Table1.
The breakdown by aetiology of the aortic disease in the 180 operated patients is
shown in the ow chart (Fig.3). Some patients have undergone adjunctive operations
such as mitral valve repair in 12 and coronary artery bypass grafting in 3. The gender
and age distribution of the operated patients is given in Table2 with the aortic diam-
eter at the level where the leaets meet each other. Surgeons changed the operative
plan from PEARS intraoperatively in 4 patients as indicated in the ow chart (Fig.3).
There has been one early postoperative death. The patient suffered damage to his
left main coronary artery at operation. This was repaired and coronary artery grafts
were performed. Myocardial function was severely compromised and he required
ECMO.He died from complications of this on post-operative day 5.
There have been two late deaths. One was unrelated to the PEARS operation at
4.5years after operation [12]. In 2008, a 26-year old man had personalized external
aortic root support (PEARS) with a macro-porous mesh. He was the 16th of 46
patients to have this operation. He had a typical Marfan habitus. His mother died of
this disease as did his brother, with an aortic dissection. The patient himself died
suddenly 4.5years after his PEARS operation. At autopsy, there was no blood in the
pericardium. The coronary orices and proximal arteries were normal. His bicuspid
aortic valve was minimally regurgitant as it was prior to operation and remained
throughout follow-up. Macroscopically the implanted mesh was embedded in the
adventitia and not separable from the aortic wall. Microscopically it was fully incorporated with collagen bres as has been seen in our animal studies. The unsupported
aortic arch showed some focal fragmentation of elastic bres and a mild increase in
mucopolysaccharides consistent with Marfan syndrome (Fig.4). These appearances
were not present in the supported aortic root, which had the histological appearance
of a normal aorta. He was the rst patient to die with an implant. The histological
appearances suggest the possibility that the incorporated support of the aortic root
allowed recovery of the microstructure of the media.
A further patient died 8months after a PEARS procedure due to heart failure
from cardiomyopathy.
Seven patients had signicant perioperative events from which they made a full
recovery as listed in the ow chart. There were no major bleeding events and only
one supercial wound infection. Two patients had intraoperative ischaemic events
resulting in 19 and 25-day hospital stays, but both made a full recovery. The survival
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Patients operated on with Personalised External Aortic Root Suppor t (PEARS)
with prophylactic intent for life-threatening aortic root aneurysms. N=117
Aetiology
94 Marfan
5 Loeys Dietz
9 Non-syndromic
8 BAV
1 Post mechanical AVR(XN 114)
Operations
97 PEARS alone
12 PEARS plus MV repair
3 PEARS plus CABG
1 aborted - no implant (XN32)
4 conversions
- 2 VSRR (XN55) (XN89)
- 1 Florida (XN102)
- 1 TRR (XN113)
Perioperative adverse events
Patients survived without clinical sequelae
1 Re-imaged, PEARS repositioned (XN18)
1 Release of sleeve (XN20)
1 Coronary injury (XN63)
2 Perioperative TIA related to AFib (XN61, 101)
2 Intraoperative ischaemic events (XN114, 117)
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Adverse outcomes
1 Early death (XN32)
1 Death 4.5 years (XN16)
2 Late revision (XN11, 54)
Present status N=117
110 Alive with PEARS
3 Alive with intraoperative conversion
2 Alive with revision at 93 and 105 months
2 Death (unrelated to the device or disease progression)
Fig. 3 This ow chart includes all 117 consecutive patients for whom there was an intention to
treat and who had surgery before the end of December 2017. All perioperative adverse events [10],
conversions [4] and adverse outcomes [4] are described in the Appendix of Clinical Events. There
is 100% follow up and all patients are traceable
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Table 2 Table comparing PEARS with VSRR in AVOOMPS
PEARS VSRR
N=117 N=239
Age (years) 34(23–46) 33±13
Sex, % male 87 (74%) 148 (62%)
Sinus diameter 47 (43–48) 49 (46–52)
Aortic regurgitation
None 84 (72%) None/trivial 106 (46%)
Trivial/mild 28 (24%) Grade 1 86 (37%)
Moderate 5 (4%) Grade 2 27 (12%)
Grade 3 4 (2%)
Grade 4 8 (4%)
Operation time (min) 165 (130–236) 340 (275–441)
Bypass time (32/117) None for 73% 70 (46–90) 194 (148–270)
Hospital stay (days) 6 (5–7) 6 (5–9)
Conversions 4 (3.4%) 6 (2.5%)
30day mortality 1 (0.9) 1 (0.4)
AVOOMPS
and re-operation-free survival for all 117 operated patients are shown in the KaplanMeier analysis (Fig.5) which includes two deaths and two re-operations, one at
9years and one at 6years.
Other Applications ofthePEARS Operation
We have used the mesh material to surround the pulmonary autograft in a Ross
operation. In each instance, the autograft has been implanted in the aortic root as a
free-standing graft with the coronary arteries anastomosed to the autograft root. The
mesh was placed around the root prior to construction of the coronary anastomoses.
We modelled the mesh on the pulmonary root using the same method of CTscan,
CAD and RP.To allow for the effect of systemic pressure on the autograft, formers
were made at 110% before the mesh was heat shrunk against it. In a limited number
of operations, 8, we have found this approach to be satisfactory. We anticipate that
the benet of encasing the autograft root in the mesh will be to prevent late dilatation of the neo-sino-tubular junction and consequent aortic regurgitation. We do not
yet have sufcient length of follow-up to see whether this is a fact.
A limited number of complex cardiac operations in infancy or early childhood
can lead to a late complication of ascending aortic enlargement with a competent
aortic valve. One such procedure was reported in 2016 [13] which involved a
28years old man who was born with transposition of the great vessels and underwent a Mustard operation at the age of 3 years, when a delayed arterial switch
operation was performed. Cardiological surveillance 24 years later revealed an
enlarging aortic root with compression of the left anterior descending artery. A
reduction plasty of the dilated anterior sinus of Valsalva was performed which
cd
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a
b
Fig. 4 (a) Sections from the unsupported aortic arch shows focal fragmentation of elastic bres
and a mild increase in mucopolysaccharides (mag. ×2.5). There is no root in contrast to (c) and the
adventitia is not clearly dened as it is in the ascending aorta. (b) A high-power view of the media
of the unsupported aortic arch (mag. ×10). The appearances are of medial degeneration consistent
with Marfan syndrome. (c) Section of the aortic root of a total thickness of 4.5mm. Collagen bres
(red staining) pass through the interstices between the laments of the root (blue arrows) embedding it in the adventitia. Foreign body-type giant cells and a few scattered chronic inammatory
cells are present (mag. ×2.5). (d) High-power view of the protected aortic root wall (mag. ×10).
The underlying media shows well preserved elastic lamellae with no fragmentation, loss or pooling of mucopolysaccharides
released a stretched left anterior descending coronary artery to allow normal ow
and a PEARS implant was tted around the aortic root and ascending aorta. The
patient and the surgical repair remain intact 3years later.
Discussion
The objective of all three operations performed electively on the aortic root is to
prevent aortic dissection. According to natural history data reported in 1972 for 257
people with Marfan syndrome, median survival was 40–41 years for men and
48–49 years for women [14]. Among 72 patients who were dead at the time of
478
(Reoperation-free) survival (%/100)
Survival and reoperation-free survival
Time (years since operation)
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1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
02
Fig. 5 Kaplan Meier analysis prepared by Professor JJM Takkenberg. Time to event analysis
shows two deaths at 5days and 4.5years and two re-operations at 6 and 9years. The small numbers of patients ‘at risk’ with more than 2years of follow up affects the appearance of the chart.
The single event at 9years has a large impact on the overall analysis of survival because of the few
patients operated on that long ago
N=50 N=38 N=26
468101
N=17 N=11N=4
life- table analysis, the average age at death was 32years. As monitoring has become
easier, operative risks have reduced, and awareness of the risk of dissection is
heightened, root replacement has been advocated at a smaller size. The criterion has
come down from 60 mm through 55 and 50 to the present recommendation of
45mm for Marfan patients in the 2014 ESC Guidelines [15]. Earlier intervention
introduces a new problem for patients and those advising them. It has always been
possible that some patients having elective root replacement were never destined to
have root dissection, and so, as the size criterion was lowered there is likely to be an
increasing number of patients who undergo operation without gaining any years of
life because their survival is determined by other factors. To illustrate the problem,
we can consider carotid endarterectomy for which there are randomised controlled
trials to evaluate the reduction in the risk of stroke. Using the “number needed to
treat” (NNtT) calculation, the number of patients who have an operation in order to
prevent one stroke is 6. These are patients with neurological symptoms and a carotid
stenosis of greater than 70%, for whom the evidence for benet is most compelling,
yet 5 out of 6 patients having the operation gain no benet from it. For clinical recommendations and comparative health economic evaluation, the number needed to
treat to prevent a dissection in Marfan syndrome would be a useful statistic, but is
not presently available. An attempt at decision analysis relied on best guesses from
a handful of clinicians and thus failed for want of objective data [16, 17].
When we began to develop and evaluate PEARS we ensured that the innovation
was evaluated by NICE [18]. We also thoroughly explored the possibility of a randomised controlled trial (RCT). The project development team worked with experienced clinical research scientists, established research agencies and grant giving
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