ArticlePDF AvailableLiterature Review

Pharmacologic Management of Aneurysms

February 2019
Circulation Research 124(4):631-646

DOI:10.1161/CIRCRESAHA.118.312439

Authors:

Leiden University Medical Centre

Current management of aortic aneurysms relies exclusively on prophylactic operative repair of larger aneurysms. Great potential exists for successful medical therapy that halts or reduces aneurysm progression and hence alleviates or postpones the need for surgical repair. Preclinical studies in the context of abdominal aortic aneurysm identified hundreds of candidate strategies for stabilization, and data from preoperative clinical intervention studies show that interventions in the pathways of the activated inflammatory and proteolytic cascades in enlarging abdominal aortic aneurysm are feasible. Similarly, the concept of pharmaceutical aorta stabilization in Marfan syndrome is supported by a wealth of promising studies in the murine models of Marfan syndrome-related aortapathy. Although some clinical studies report successful medical stabilization of growing aortic aneurysms and aortic root stabilization in Marfan syndrome, these claims are not consistently confirmed in larger and controlled studies. Consequently, no medical therapy can be recommended for the stabilization of aortic aneurysms. The discrepancy between preclinical successes and clinical trial failures implies shortcomings in the available models of aneurysm disease and perhaps incomplete understanding of the pathological processes involved in later stages of aortic aneurysm progression. Preclinical models more reflective of human pathophysiology, identification of biomarkers to predict severity of disease progression, and improved design of clinical trials may more rapidly advance the opportunities in this important field.

. Summary of Successful Experimental Targets for Pharmaceutical Abdominal Aortic Aneurysm Stabilization

…

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631

An aneurysm is a localized dilatation of larger blood ves-

sels that is related to regional weakening of the wall

structure.1 Although the large majority of aneurysms presents

within arterial tree, venous aneurysms do occur. Aneurysms

are generally associated with rupture and a life-threatening

hemorrhage, yet some aneurysms (in particular, popliteal2 and

venous aneurysms)3 typically manifest through symptoms of

acute thrombosis and embolism.

There are several classiﬁcation systems for aneurysms.

From the perspective of medical therapy, the most help-

ful attribution is that of primary and secondary aneurysms.

Primary aneurysms relate to a matrix defect in vessel wall

(ie, ﬁbrillin deﬁciency in Marfan syndrome, collagen III de-

ﬁciency in the vascular type Ehlers Danlos syndrome,4 and

unknown defect[s] in aneurysms associated with bicuspid a-

ortic valves).5,6 Secondary aneurysms relate to extensive ma-

trix turnover and pathological vessel wall remodeling5,7 in

response to a primary inﬂammatory insult (ie, infection, im-

mune diseases [Kawasaki syndrome, giant cell arthritis, and

Behçet syndrome],8 and the degenerative abdominal aortic an-

eurysm [AAA]).1

Although aneurysms occur throughout the vascular tree,

there is a remarkable topographical distribution for most an-

eurysms (ie, descending thoracic aorta for giant cell arteritis,

infrarenal aorta in AAA disease, etc).9 Although this may be

caused by local hemodynamic patterns and associated wall

stresses, it likely could reﬂect the different embryological ori-

gins of the vascular tree,9 which result in a persistent regional

diversity in microvascular endothelium,10 mesenchymal cell

characteristics,11–13 and immunologic makeup.14,15 The remark-

able regional diversity in susceptibility is clearly illustrated by

the iliac trajectory: unlike the adjacent common iliac, internal

iliac, and common femoral arteries, the external iliac artery is

remarkably resistant to degenerative aneurysms.

The focus of this compendium will be on the perspectives

for medical therapy in the context of AAA and aneurysms as-

sociated with Marfan syndrome as clinical intervention data

are available for these aneurysms. Systemic immune suppres-

sion in the context of autoimmune diseases, such as Kawasaki

syndrome and giant cell arteritis, and antibiotic strategies for

infection-related aneurysms (Q fever, bacterial) are beyond

the scope of this article.

Abdominal Aortic Aneurysm

An AAA is a localized dilatation caused by segmental weak-

ening of the terminal aorta segment. The prevalence of the

disease depends on the population studied, with reported prev-

alences varying between 1.4% and 12.4%.16 The disease car-

ries a complex genetic predisposition17,18 and predominantly

affects elderly men with a history of smoking.19

AAAs are generally asymptomatic and are usually diag-

nosed by screening or as an incidental ﬁnding. The natural

From the Department of Vascular Surgery, Leiden University Medical Center, the Netherlands (J.H.L.); and Division of Vascular Surgery, School of

Medicine and Public Health, University of Wisconsin, Madison (J.S.M.).

Correspondence to Jan H. Lindeman, MD, PhD, Department of Vascular Surgery, Leiden University Medical Center, K6-r, PO Box 9600, 2300 RC,

Leiden, the Netherlands. Email lindeman@lumc.nl

Aortic Aneurysms Compendium

Abstract: Current management of aortic aneurysms relies exclusively on prophylactic operative repair of larger

aneurysms. Great potential exists for successful medical therapy that halts or reduces aneurysm progression and

hence alleviates or postpones the need for surgical repair. Preclinical studies in the context of abdominal aortic

aneurysm identiﬁed hundreds of candidate strategies for stabilization, and data from preoperative clinical

intervention studies show that interventions in the pathways of the activated inﬂammatory and proteolytic cascades

in enlarging abdominal aortic aneurysm are feasible. Similarly, the concept of pharmaceutical aorta stabilization in

Marfan syndrome is supported by a wealth of promising studies in the murine models of Marfan syndrome–related

aortapathy. Although some clinical studies report successful medical stabilization of growing aortic aneurysms and

aortic root stabilization in Marfan syndrome, these claims are not consistently conﬁrmed in larger and controlled

studies. Consequently, no medical therapy can be recommended for the stabilization of aortic aneurysms. The

discrepancy between preclinical successes and clinical trial failures implies shortcomings in the available models

of aneurysm disease and perhaps incomplete understanding of the pathological processes involved in later stages

of aortic aneurysm progression. Preclinical models more reﬂective of human pathophysiology, identiﬁcation of

biomarkers to predict severity of disease progression, and improved design of clinical trials may more rapidly advance

the opportunities in this important ﬁeld. (Circ Res. 2019;124:631-646. DOI: 10.1161/CIRCRESAHA.118.312439.)

Key Words: aneurysm ◼ aortic aneurysm, abdominal ◼ Marfan syndrome ◼ mice ◼ models, animal ◼

review literature as topic ◼ therapy, drug

Pharmacologic Management of Aneurysms

Jan H. Lindeman, Jon S. Matsumura

Circulation Research is available at https://www.ahajournals.org/journal/res DOI: 10.1161/CIRCRESAHA.118.312439

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632 Circulation Research February 15, 2019

history of the disease is that of slow progression and ultimate

rupture.20 Ruptured AAA is a dramatic catastrophe, and aor-

tic emergencies constitute one of the leading causes of acute

death in elderly men.1,16 Risk of rupture is minimal in small

aneurysms (ie, <50 mm) but progressively increases with en-

larging AAA size; estimated annual rupture risks are <1% for

AAA with a diameter of 50 mm to >30% for an AAA exceed-

ing 80 mm diameter.21

AAA management has been centered for decades on sur-

gical repair of larger aneurysms to mitigate the risks of rup-

ture. Multiple trials have shown no beneﬁt of repair of AAA at

sizes <55 mm diameter, and consequently, current guidelines

advise watchful waiting for aneurysms <55 mm and preven-

tive repair once the AAA grows >55 mm,1,19,21 possibly with

a slightly lower intervention threshold for repair in women.22

The 2 surgical options for repair are open repair (through

a transperitoneal or retroperitoneal approach) or endovas-

cular aneurysm repair (EVAR; through a transarterial ap-

proach).19,21 Decisions for the type of repair are dictated

by AAA-speciﬁc features, such as neck characteristics and

proximity to major important branches, as well as by pa-

tients’ preferences and characteristics, such as frailty and o-

besity.19,21 The majority of patients is currently managed by

EVAR. Open repair comes with signiﬁcant higher periopera-

tive mortality and morbidity; registry-based studies report

30-day mortality rates of ≈4% to 5% for men and 6% to 8%

for women,22,23 and perioperative morbidity of open repair

is considerable.19 However, open repair has an established

long-term durability, although incisional hernia remains a

common cause of late reintervention.19 EVAR has superior

short-term outcomes but comes with higher rates of aortic

reintervention and possibly higher costs.24 Moreover, there is

emerging concern in the published literature about the mid-

and long-term durability of EVAR with possibly excess late

mortality in patients who received EVAR.25,26

Considering the fact that the sole indication for elective

AAA repair is rupture prevention,19 it has been pointed out

that medical stabilization of small diameter aneurysms, keeps

small aneurysms small and thereby prevents or reduces the

need for surgical repair, could be advantageous. This has nat-

ural appeal to patients and from an economic point of view.27

Moreover, medical aneurysm stabilization could be beneﬁ-

cial as add-on strategy in patients considered at high risk for

endoleak.28 It is conceivable that in patients who have aneu-

rysm neck prone to dilation, stabilization of the neck could

reduce the incidence of late type Ia endoleak. All in all, med-

ical AAA stabilization has been brought forward as an unmet

medical need.29

Targets for Medical AAA Therapy

Candidate targets for therapy are dictated by the prevailing

concepts of the processes driving AAA disease progression.

It is generally assumed that AAA progression is driven by a

localized inﬂammatory response and an accompanying pro-

teolytic imbalance.20,30 Consequently, proposed interventions

directly or indirectly aim at targeting aspects of the inﬂamma-

tory response or at rectifying the proteolytic imbalance. The

pertinence of these strategies is supported by a wealth of pre-

clinical studies. The vast majority of these are performed in the

standard rodent models of AAA disease: the elastase model,

the CaCl2 model, or the angiotensin/LDLR−/− (low-density li-

poprotein receptor) model.31,32

The elastase model is based on a transient exposure (gen-

erally brief intraaortic exposure) of an isolated infrarenal aorta

segment with porcine pancreatic elastase.33 The rationale be-

hind the model is the notion that loss of elastin is one of the

most notable features of AAA disease. Yet, although the di-

sease is undoubtedly characterized by extensive loss of elas-

tin, it is important to point out that loss of elastin per se is not

responsible for the critical wall failure in AAA. First of all,

loss of elastin is an early phenomenon in clinical AAA devel-

opment, and the elastolysis is virtually complete before the di-

sease reaches the critical 55-mm diameter threshold.34 Second,

clinical experience shows that chemical or surgical removal of

elastin (endarteriectomy) does not result in aneurysm forma-

tion.35,36 The validity of this clinical observation is supported

by experimental data that show that although elastin critically

contributes to the elastic recoil of the aortic wall, it does not

contribute to the resilience of the wall. In fact, studies by

Dobrin et al37 show that the resilience of the wall essentially re-

lies on vascular collagen. This phenomenon is also reﬂected in

the dynamics of the elastase model in which exposure to pure

elastin does not immediately induce AAA formation38 and in

which the initial response following porcine pancreatic elastin

preparations is a small increase in aortic diameter, presumably

reﬂecting loss of elastic recoil.39 The actual aneurysm forma-

tion is secondary and reﬂects a delayed, secondary response,

elicited by the elastase-induced inﬂammatory response.37

Although the model is referred as the elastase model, ex-

posure to pure pancreatic elastase does not elicit aneurysm

formation.38 As such, contaminants of the porcine pancre-

atic elastase preparation appear crucial for AAA induction.

Further, the model is dependent on the genetic background

of the mouse with a strict requirement for strains with Th1-

dominated inﬂammatory responses,39 underscoring the rele-

vance of the inﬂammatory response in model.

Nonstandard Abbreviations and Acronyms

AAA abdominal aortic aneurysm

ACE angiotensin-converting enzyme

ADAM Aneurysm Detection and Management

ATR1 angiotensin II receptor type 1

EVAR endovascular aneurysm repair

FBN1 ﬁbrillin-1

IL interleukin

LDLR low-density lipoprotein receptor

LDL low-density lipoprotein

LOX lysyl oxidase

MMP matrix metalloproteinase

N-TA^3CT Noninvasive Treatment of Abdominal Aortic Aneurysm Clinical

Trial

NFAT2 nuclear factor of activated T cells-2

PPAR peroxisome proliferator–activated receptor

TGF-β transforming growth factor-β

TNF-α tumor necrosis factor-α

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Lindeman and Matsumura Pharmacologic Management of Aneurysms 633

AAA formation in the elastase models follows a typical

pattern with the initial moderate dilatation resulting from loss

of elastic recoil, followed by a secondary dilatation, the ac-

tual aneurysm formation ≈1 week after the elastase induction

presumably as result of a secondary inﬂammatory response.

The ultimate dilatation reached varies between 150% and

200%.39 A major criticism of the model is the fact that the

model regresses (heals) and is not associated with rupture,31

although early ruptures were observed after preventive IL

(interleukin)-6 neutralization.40 Other reports show that inter-

ference with the healing response either by TGFβ (transform-

ing growth factor-β) neutralization41 or 3-aminopropionitrile

feeding–induced LOX (lysyl oxidase) inhibition42 elicit rup-

ture in the model.

The second most commonly used model of AAA disease

is generally referred to as the CaCl2 model. In this model,

AAA formation is induced by local calcium salt exposure of

an isolated infrarenal aorta segment.31 Although the model

is scrutinized by some as a minimal model,31 there is a wide

variety in Ca++ concentrations used, and there are indications

that CaPO4 rather than the traditional CaCl2 results in supe-

rior AAA formation.43 Like the traditional elastase model, the

model does not proceed to rupture.

Ruptures form an integral aspect of the third most

commonly used model, the angiotensin II/apolipoprotein

E–deﬁcient mouse.31,32 This model is based on the observa-

tion that chronic angiotensin infusion in apolipoprotein E–

deﬁcient mice results in aneurysms in the aortic tree. Although

the model is commonly referred to as an aneurysm model, it

is now clear that the model should be referred to as a model

of aortic dissection.44,45 Hence, conclusions based on the an-

giotensin model may not or only partially translate to human

AAA disease.

Based on experiments in these 3 models, several hun-

dred targets31 have been proposed to limit aneurysm growth.

Although a detailed review of the interventions is beyond the

scope of this article, successfully targeted main clusters for in-

tervention include vascular inﬂammation, tissue remodeling,

blood pressure regulation, and lipid metabolism. An overview

of the reported main clusters and illustrative exemplary stud-

ies are provided in Table 1.

The available literature is dominated by positive stud-

ies; few studies report disease aggravation97,98 or failure of

the studied intervention.99–102 With respect to the latter, most

failing interventions are included as a secondary ﬁnding pre-

sented along with a successful primary ﬁnding, raising the

possibility that the available literature is biased by selective

reporting of positive ﬁndings103 and type I errors (false-posi-

tive conclusions). Strong support for the latter stems from an

elegant evaluation by Trachet et al.104 The authors performed

a meta-analysis of the incidence of dissecting aneurysms and

the mortality rates in the control arm of 194 articles report-

ing on the angiotensin model. The analysis revealed strong

inverse relationships between both the aneurysm incidence

and mortality rate of the control group, and the ﬁnal conclu-

sions of the study (median dissecting AAA incidence: 73%

in studies reporting interventions claimed to reduce AAA

formation, 56% in descriptive studies versus 35% for inter-

ventions claimed to enhance AAA formation).104 Reported

median mortality rates followed the similar inverse trend

(25%, 19%, and 13%, respectively).104

Medical Therapy for Patients With AAA

There are 2 indications for medical therapy in AAA: cardiovas-

cular risk management and pharmaceutical AAA stabilization.

Epidemiological105,106 and cohort studies107–109 character-

ize an AAA as a strong cardiovascular risk factor. In fact,

in patients deemed unﬁt for repair, the risk of dying from

nonaneurysm-related (in particular, cardiovascular) causes

by far exceeds the risk of dying from AAA.110 The profound

impact of an AAA on overall survival is further illustrated by

the relative survival analysis included in a meta-analysis of

patient survival following open or endovascular repair.111 The

observed 0.76 10-year relative survival ratio for patients who

had their AAA repaired clearly illustrates the profound indi-

rect risk of AAA disease.111

Level IIb evidences suggests that cardiovascular risk man-

agement is effective in patients with AAA112,113; hence there

is a case for cardiovascular risk management for all patients

with AAA, irrespective of a possible impact of the risk man-

agement on aneurysm progression. Logically, improvement

in survival because of reduced cardiovascular risk not only

improves the cost-effectiveness of AAA repair but longer sur-

vival will maximize the beneﬁts of an effective pharmaceuti-

cal stabilization program.

Preclinical models show the potential of lipid lower-

ing,78–82 antihypertensive therapy,72–76 and platelet aggregation

inhibitors59 in quenching experimental AAA development.

Yet, there is little evidence for a beneﬁcial effect of these

strategies on clinical AAA progression and stability. The ﬁrst

studies exploring the potential of pharmaceutical therapy for

AAA progression were based on observed beneﬁcial associa-

tions between β-blocker use and aneurysm progression in 2

small (n of 12 and 38) case-control studies.114,115 These stud-

ies were then followed by a further case-control116 and cohort

study117 and later by 2 randomized trials.118,119 All these later

studies were not conﬁrmative, although the interpretation of

the randomized controlled trials is compromised by the poor

tolerability of the β-blocker used (propanol), which resulted in

a 42% dropout rate in the treatment arm.119

The ACE (angiotensin-converting enzyme) inhibitors are

the second class of antihypertensive drugs that received signif-

icant attention in the context of AAA stabilization. Enthusiasm

was spurred by supportive evidence from experimental stud-

ies,74,75 and a population-based case-control study that reported

a beneﬁcial association between ACE inhibitor use and risk of

rupture.120 This study was followed by a series of nonconﬁrma-

tive studies,121–123 one of them suggesting an adverse associa-

tion between ACE inhibitor use and AAA progression.123 These

controversies were ultimately addressed in the AARDVARK

study (Aortic Aneurysmal Regression of Dilation: Value of

Ace-Inhibition on Risk).124 This study concluded that, despite

more effective blood pressure lowering, the ACE inhibitor per-

indopril did not show signiﬁcant impact on aneurysm growth

(compared with both placebo alone and to combined placebo

and amlodipine [a Ca++ antagonist]). A shortcoming of the

AARDVARK study is the lower-than-anticipated aneurysm

growth. As such, the trial may lack the sensitivity to detect

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634 Circulation Research February 15, 2019

minor effect sizes. Although the authors attribute this short-

coming to the high-level medical cardiac risk management in

the population studied,124 it is likely that the lower-than-antic-

ipated growth reﬂects inclusion of a disproportionate group of

patients with relatively small AAAs (≈35 mm).

At this point, the potential of the type 1 angiotensin receptor

antagonist telmisartan is under investigation in the TEDY study

(Effectiveness of Telmisartan in Slowing the Progression of

Abdominal Aortic Aneurysms).125 The rationale for this study is

the fact that AT1 receptor antagonists interfere with the negative

aspects of angiotensin signaling but preserve signaling through

the ATR1 (angiotensin II receptor type 1) receptor, which is

associated with vascular protective activity.126,127 Along these

lines, beneﬁcial associations have been reported between type 1

AT receptor antagonist use and AAA progression.128

The overall conclusion for antihypertensive therapies is

that the available clinical studies refute β-blockers or ACE

inhibitors as pharmaceutical strategies for AAA stabilization.

This indirectly conﬁrms absence of a direct association be-

tween blood pressure and AAA progression.

The potential of statins has been evaluated in 12 studies.

Results of these studies are mixed with 6 studies hinting at a

beneﬁcial association between statin use and AAA progres-

sion129–134 and another 6 studies failing to show an association

between statin use and aneurysm progression.117,122,123,135–137

Conclusions from the studies segregate, with the older and

smaller studies being conﬁrmative and the later and larger

studies being nonconﬁrmative. On this basis, although the car-

diovascular risk beneﬁts of statins are impressive, there is no

role for statins as a pharmaceutical strategy stabilizing AAA.

An effect of antiplatelet therapy on aneurysm progression

has been explored in 6 studies. Beneﬁcial effects have been ob-

served in medium sized cohort study (n=148) of patients under

surveillance of a 40- to 49-mm AAA.138 Unfortunately, the va-

lidity of the study is challenged by the unrealistic high growth

rate in the control group (5.2 mm/y; anticipated growth rate, 2–

3 mm/y139). A potential effect for combined aspirin-statin treat-

ment has been observed in a subanalysis of a study evaluating

the effect of azithromycin on AAA progression.140 A beneﬁt for

nonsteroidal anti-inﬂammatory drugs (NSAIDs) has been re-

ported on the basis of a small (n=19) study; reportedly patients

using NSAID showed reduced AAA progression.141

In contrast, 3 larger studies (the UK small aneurysm trial,123

the ADAM study [Aneurysm Detection and Management],117

and an Australian cohort study136) all fail to conﬁrm a beneﬁ-

cial effect of antiplatelet therapy on AAA progression.

Well-established negative (beneﬁcial) associations exist be-

tween diabetic disease and AAA growth rate.142 Although this

has been attributed to diabetes mellitus–related factors, such as

matrix stabilization by enhanced glycation and modulation of in-

ﬂammation,143 there are indications that this negative (protective)

association relates to off-target effects of metformin—a bigu-

anide antidiabetic that is ﬁrst-line medication for type II diabetes

mellitus. Indeed, metformin use but other classes of antidiabetic

drugs associated with reduced AAA growth rate.144,145 At this

point, 2 trials are planned to test an effect of metformin on AAA

growth (Prof Ron L. Dalman, personal communication).

Above clinical studies, all evaluated potential off-target

(so-called pleiotropic) effects on AAA progression of drugs

that are part of regular cardiovascular risk management. A fur-

ther series of trials evaluate disease-speciﬁc targets that were

deﬁned on basis of the current understanding of AAA disease.

A presumed role for persistent chlamydia infection in the per-

petuation of vascular disease, including AAA, at the millennium

Table 1. Summary of Successful Experimental Targets for Pharmaceutical

Abdominal Aortic Aneurysm Stabilization

Targeted Cluster Strategy

Anti-inﬂammatory NFκB,46 AP-1,47 Rho kinase48 inhibition

IL1,49 TNFα,50 CCL-151

B cell,52 γδT-cell53 depletion

Neutrophil inhibition54

Mast cell inhibition55

Complement inhibition56,57

Oxilipin inhibition58,59

Immune suppression60,61

Protease inhibition MMP inhibition62,63

Cysteine protease inhibition64,65

Serine protease inhibition66,67

Oxidative stress Antioxidant enzymes68,69

Secondary antioxidants70,71

Blood pressure lowering β-Blockers72

Ca antagonists73

ACE inhibitors74,75

ATR1 antagonists76

iNOS inhibition77

Lipid metabolism Statins78,79

HDL80

RXR and PPARα/γ activation81,82

Cell therapy Mesenchymal stem cells83,84

Fibroblasts85

Matrix/morphogens Interference with TGFβ signaling86

Interference with NOTCH87/Wnt88 signaling

Thrombospontin inhibition89

EGFR inhibition90

Metabolism Inhibition of HIF1α91

Activation of AMPK92

Nutriceuticals Polyphenols93

Phytoestrogens94

Sex hormones Castration95

Estrogens96

ACE indicates angiotensin-converting enzyme; AMPK, 5' AMP-activated protein

kinase; AP-1, activator protein-1; ATR1, angiotensin II receptor type 1; CCL-1,

chemokine (C-C motif) ligand; EGFR, epidermal growth factor receptor; HDL, high-

density lipoprotein; HIF1α, hypoxia-inducible factor 1-alpha; IL-1, interleukin-1;

iNOS, inducible NO synthase; MMP, matrix metalloproteinase; NFκB, nuclear

factor-κB; NOTCH, notch homolog, translocation-associated; PPARα/γ,

peroxisome proliferator–activated receptor α/γ; RXR, retinoid X receptor; TGF-β,

transforming growth factor-β; and TNF-α, tumor necrosis factor-α.

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Lindeman and Matsumura Pharmacologic Management of Aneurysms 635

époque resulted in 3 studies, which aimed at anti-chlamydia e-

radication. Two small trials with, respectively, a single 4-week

course of the antibiotic roxithromycin146 or repeated (annual)

4-week courses of roxithromycin147 reported borderline beneﬁts

on aneurysm progression. However, this was not conﬁrmed in a

larger study with azithromycin that did not identify an effect of

16 weeks of macrolide treatment on AAA progression.140

A further series of clinical studies aimed at targeting spe-

ciﬁc aspects of the vascular inﬂammation and proteolytic im-

balance in AAA. In this respect, there is a longstanding interest

in the tetracycline antibiotic doxycycline. Independent of its an-

tibiotic properties, doxycycline has been shown to reduce the

expression of matrix metalloproteinases148 and to quench their

activity.149 Doxycycline effectively interferes with aneurysm

formation in some150,151 but not all99 models of aneurysm for-

mation, and clinical studies showed that doxycycline treatment

reduces aortic wall MMP (matrix metalloproteinase) content

and improves the proteolytic imbalance through its effect on

aneurysm wall protease inhibitor levels.152,153 Three studies154–156

evaluated the effect of doxycycline treatment on aneurysm pro-

gression, and a fourth multicenter randomized trial N-TA^3CT

(Noninvasive Treatment of Abdominal Aortic Aneurysm

Clinical Trial) is ongoing.157 A ﬁrst small study (n=32) evalu-

ated patients after 3 months of doxycycline eradication therapy

with the intent of testing the persistent chlamydia infection hy-

pothesis.154 The report claims an effect of doxycycline therapy

on aneurysm progression in the 6- to 12- and 12- to 18-month

follow-up intervals, but no effect was seen for the initial 0- to

6-month interval and for the overall study period. The second

open phase II study tested the safety and feasibility of 6 months

of doxycycline therapy in patients with AAA.155 The study

showed that chronic doxycycline treatment is feasible and well

tolerated, and it was concluded that aortic wall MMP-9 levels

and AAA progression compared favorably with those of his-

toric controls not receiving treatment. In contrast, data from the

PHAST trial (Pharmaceutical Aneurysm Stabilization Trial)156

testing the effect of 18 months of doxycycline (100 mg/day)

failed to show a beneﬁt of doxycycline therapy on AAA pro-

gression; on the contrary, doxycycline treatment resulted in a

statistically signiﬁcant but clinically insigniﬁcant acceleration

of AAA growth. Although earlier dose-ﬁnding study found dose

equivalence for low-, regular-, and high-dose (50, 100, or 300

mg/day, respectively) doxycycline on all parameters tested,158,159

it has been argued that the dose used in the PHAST study is too

low to elicit an effect. As such, the results of the N-TA^3CT

study that tests the beneﬁt of 200 mg/day157 are eagerly awaited.

A potential beneﬁt of mast cell inhibition through the potent

mast cell stabilizer pemirolast160 was tested in the AORTA trial

(CRD007 for the Treatment of Abdominal Aorta Aneurysm).161

Study results show that 12 months of mast cell inhibition is safe,

but the mast cell inhibition did not inﬂuence AAA progression.161

The ACZ885 (canakinumab) for the Treatment of

Abdominal Aortic Aneurysm study162 tested the effect of IL-

1β neutralization through subcutaneous canakinumab (150

mg) once per month for 12 months. The study enrolled 65 pa-

tients, and 1 year growth data was obtained for 20 participants

in the placebo group and 23 in the canakinumab group. AAA

progression (2.5 mm/y) was similar for both groups, and the

trial was terminated for reasons of futility.162

Apart from these studies on diameter changes, there are

data available for surrogate end points (aneurysm wall inﬂam-

mation). In a small study (6 cases, 10 controls), Motoki et

al163 evaluated the effect of PPAR (peroxisome proliferator–

activated receptor)-γ agonist pioglitzone and observed a re-

duction in aortic wall TNF-α (tumor necrosis factor-α) and

MMP-9 expression. The effects of the PPARα agonist fe-

noﬁbrate on circulating inﬂammatory markers of inﬂamma-

tion have been studied in the FAME trial (Fenoﬁbrate in the

Management of Abdominal Aortic Aneurysm). A randomized

study of 24 weeks of fenoﬁbrate treatment in AAA patients.164

No effect was observed on the circulating markers osteopontin

or kallistatin. Although the authors report an absent effect on

AAA growth,164 it is important to point out that the trial was

not adequately powered to detect such an effect.

A highly speciﬁc suppression of aneurysm wall inﬂam-

mation was observed for the selective vitamin D receptor ago-

nist paricalcitol. It was shown that a 2- to 4-week preoperative

paricalcitol treatment selectively interfered with aspects of

NFAT2 (nuclear factor of activated T cells-2) mediated inﬂam-

mation,165 suggesting that the effects of vitamin D are mainly

mediated by an effect on calcineurin-mediated inﬂammation.

This notion was conﬁrmed in in vitro studies.165 Although

plasma lipids do not associate with incident AAA disease,

there are weak associations between plasma LDL (low-den-

sity lipoprotein) levels and AAA progression.166 In this light,

the observed superior effects of ezetimide/simvastatin over

simvastatin alone on vascular inﬂammation merit attention,167

yet it is unclear how these observations relate to the apparent

absence of statins on AAA progression.117,122,123,135–137

The above overview of preclinical successes and clinical

failures points to a major paradox of numerous preclinical

successes and clinical challenges. Preclinical studies identi-

ﬁed hundreds of successful candidate interventions, yet this

enormous investment has not produced any clinical applica-

tion, and no medical therapy is currently available for the sta-

bilization of growing AAA, although further clinical studies

are underway or planned (Table 2).

More important, the apparent translational gap between

preclinical and clinical studies challenges our concepts of the

processes underlying late-stage AAA disease pathophysiol-

ogy. Undoubtedly, AAA is associated with a sustained and

comprehensive inﬂammatory response, uncontrolled protease

activity, and excess matrix turnover.5,20,153 Short-term preopera-

tive intervention studies in patients undergoing open repair all

proved the potential of indomethacin,168 statins,137,169–176 ACE

inhibitors,121 and doxycycline153,158,159 to effectively quench

vascular inﬂammation and protease activity. Yet, these effects

are not followed by reduction of AAA progression. Along

similar lines, bona ﬁde anti-inﬂammatory strategies, such as

anti–IL-1β therapy162 and mast cell161 stabilization failed to

inﬂuence AAA progression. Interestingly, profound immune

suppression in the context of solid organ transplantation even

results in accelerated AAA progression.177,178 Although these

aforementioned observations do not exclude a role for inﬂam-

mation or protease activity in AAA initiation and progression,

they imply involvement of additional, to date unidentiﬁed crit-

ical factors that are unresponsive to the anti-inﬂammatory/an-

tiproteolytic therapies.

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636 Circulation Research February 15, 2019

One of the possible key factors is failing or defective

compensatory repair. In fact, interference with compensatory

repair mechanisms (stem cell function) may explain the ap-

parent disastrous effects of intense immune suppression,179

chemotherapy,180 and the unexpected negative effect of dox-

ycycline therapy156,181 on aneurysm growth. Moreover, there

are clear indications for defective matrix repair in AAA. The

disease is associated with complete loss of the normal aortic

wall architecture, and the normal aortic matrix is replaced by

a collagenous, ﬁbrotic matrix.153 Although a higher collagen

cross-link content in AAA wall samples may imply more sta-

ble collagen,182 this is actually not the case because of defects

at the level of collagen ﬁbril organization. In the healthy aortic

matrix, the collagen ﬁbrils are laid down in supramolecular, in-

tertwined network structures. As a result, forces are distributed

over the wall. Loss of this network behavior in AAA disease

fundamentally impacts the mechanical stability of the wall182

and may contribute to the aortic wall weakening in the disease.

Fatty degeneration was recently identiﬁed as another poten-

tial contributor to the weakening of the aneurysm wall.183,184 Fatty

degeneration is a known phenomenon in aging and chronically

injured muscle185 and is thought to be a consequence of impaired

repair mechanism in the context of chronic injury.186 Gene-

expression studies on AAA wall specimens suggest that progres-

sive adipocyte accumulation associated with rupture.183,187

Unfortunately, the perpetual inﬂammatory cycle and the im-

paired compensatory repair that hallmark human AAA are not

captured in the rodent models of AAA disease. This shortcoming

may largely reﬂect the spontaneous resolution of inﬂammation

in these models and the superior endogenous healing responses

of small animal models,188,189 as well as their inherent resistance

to develop chronic ﬁbrosis. In an attempt to create more relevant

(viz rupture prone) AAA models, modiﬁed models have been

introduced in which interference with the primary healing re-

sponses resulted in AAA ruptures.41,42 Yet, these models do not

recapitulate the chronically impaired and dysregulated healing

responses that characterize AAA disease. Absence of ﬁbrotic re-

pair in murine models of AAA disease also explains the apparent

beneﬁt of inducing ﬁbrotic repair in stabilizing growing AAA

in murine models.190 Because extensive ﬁbrosis is a hallmark of

human AAA disease, and that process of ﬁbrosis results in dep-

osition of a brittle, poor-quality matrix,153,182 it is questionable

whether a proﬁbrotic strategy will stabilize human AAA.

Considering the wealth of preclinical success and failing clini-

cal attempts to identify molecular strategies for stabilizing AAA

disease, we must acknowledge that our understanding of AAA

disease is far from complete and that the available small animal

models of the disease only partially mimic aspects of the human

disease. There appears a recent trend to include (or demand)

conﬁrmative studies in a second animal model in preclinical

studies. Considering the parallels between the different models,

it is dubious whether this increases the likelihood of the ﬁnd-

ings being more translationally relevant. Future advancement

of the ﬁeld critically relies on an improved mechanistic insight

in the processes that sustain the impaired and ultimately failing

repair mechanisms in advanced clinical AAA disease.

Table 2. Ongoing and Planned Medical Intervention Studies for AAA Stabilization

Study Acronym Intervention Readout

N-TA^3CT,157 NCT01756833 Doxycycline 100 mg BID or placebo 2-y AAA progression (CT scan), repair,

or rupture

TEDY,125 NCT01683084 Telmisartan (AT1 receptor antagonist) 40 mg or placebo 1-y AAA progression (ultrasound and CT

scan), repair, or rupture

VIVAAA, NCT02846883 Mesenchymal stem cells AAA inﬂammation (PET-CT)

Eplerenone in the Management of Abdominal Aortic

Aneurysms, NCT02345590

Eplerenone (selective aldosterone receptor antagonist) or

placebo

Not speciﬁed

TicAAA, NCT02070653 Placebo or none speciﬁed dose ticagrelor (P2Y12 receptor

inhibitor)

1-y AAA progression, surgery, or repair.

FAME,191

ACTRN12612001226897

Fenoﬁbrate (PPARα agonist) 145 mg or placebo 2–4 wk

before elective open repair

Aortic wall macrophage and osteopontin

content

The Effect of Angiotensin II Type 1 Receptor Antagonists

on the Size and Expansion Rate of Abdominal Aortas in

Hypertensive Patients, NCT01670903

Comparison of patients treated with different classes of

antihypertensives (AT1 receptor antagonists, (ARB) ACE

inhibitors, or non-ARB/ACE)

Not speciﬁed

Metformin Therapy in Nondiabetic AAA Patients, NCT03507413 Metformin (1000 mg BID) or placebo 1-y AAA progression (CT)

LIMIT trial, not yet registered Metformin or placebo 2-y AAA progression (CTA)

IMAGEN192 Inositol or placebo 1-y AAA progression (sack volume [CT])

ARREST trial193 1 or 3 106 cells/kg allogenic mesenchymal

cells or placebo

Phase I safety trial. Circulating cytokine

levels and 18-FDG/PET

AAA indicates abdominal aortic aneurysm; ACE, angiotensin-converting enzyme; ARREST, Aortic Aneurysm Repression With Mesenchymal Stem Cells; CT, computed

tomography; CTA, computed tomography angiography; FAME, Fenoﬁbrate in the Management of Abdominal Aortic Aneurysm; FDG, ﬂudeoxyglucose; IMAGEN, Inositol in

the Management of Abdominal Aortic Aneurysm; LIMIT, Limiting AAA With Metformin; N-TA^3CT, Noninvasive Treatment of Abdominal Aortic Aneurysm Clinical Trial;

PET, positron emission tomography; PPARα, peroxisome proliferator–activated receptor-α; TEDY, Study of the Effectiveness of Telmisartan in Slowing the Progression

of Abdominal Aortic Aneurysms; TicAAA, The Efﬁcacy of Ticagrelor on Abdominal Aortic Aneurysm Expansion; and VIVAAA, Safety and Efﬁcacy of Allogeneic MSCs in

Promoting T-Regulatory Cells in Patients With Small Abdominal Aortic Aneurysms.

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Lindeman and Matsumura Pharmacologic Management of Aneurysms 637

Marfan Syndrome

Marfan syndrome is an autosomal-dominant, multisystem con-

nective tissue disorder. The syndrome is caused by mutations

in the Fbn-1 (ﬁbrillin-1) gene region located on chromosome

15 and is estimated to affect ≈2 to 3 of 10 000 individuals.

Over 1000 different Fbn1 mutations have been associated

with the syndrome,194 and the syndrome has extreme heter-

ogeneous genotype-phenotype variability195 (see Table 3 for

the diagnostic criteria196). Ascending, and to a slighter lesser

extent descending, thoracic aortic aneurysms are among the

primary disquieting features of the syndrome.197,198

The Fbn-1 gene codes for ﬁbrillin—a structural connective

tissue macromolecule that has been traditionally been consid-

ered a key chaperone in elastic ﬁber formation. However, in-

volvement of tissues not containing elastin indicates roles far

beyond that as a scaffold of elastin formation. Indeed, defects

in the Fbn-1 gene associate with impaired collagen network

formation,181 and ﬁbrillin is a complex modulator of growth

factor signaling and cell function.199

The aortapathy (thoracic aneurysms, dissections) is among

the leading causes of premature death in patients with Marfan.

Although increased awareness, improved surgical techniques,

and medical therapy have signiﬁcantly improved prospects,

Marfan syndrome still comes with signiﬁcant aorta-related

mortality.200,201 In this respect, strong associations have been

described between the gross genotype (dominant-negative

[abnormal FBN1 protein] or haploinsufﬁcient [reduced FBN1

protein]) and survival, with signiﬁcant better outcomes in pa-

tients with dominant-negative mutations.202,203

Aneurysms in Marfan syndrome are currently managed

by medical therapy (β-blockers and possibly ATR1 antago-

nists [AT2 inhibitors]) and preventive surgical repair once the

aneurysm size exceeds 50 mm.204 Although medical therapy

preventing aortic dilatation has a prominent role in the current

guidelines, it is important to note that the level of evidence is

low.

Recommendations for β-blocker therapy are actually

based on a single, small open study that included 70 patients.205

Conclusions from this study have recently been scrutinized

on basis of its small size and considerable losses during fol-

low-up, and the fact that signiﬁcance was only reached on

creating a composite end point.206 In addition to this single

intervention study, there is supportive data from a series of

observational reports.

The largest observational study is by Silverman et al.207

The authors reported outcomes for 417 patients with deﬁnite

Marfan syndrome who were under surveillance in 4 referral

centers. Groups were created on basis of β-blocker prescrip-

tion. β-blocker usage was unknown for 84 patients, as a re-

sult, 191 patients taking β-blockers and 142 patients who had

never taken β-blockers were evaluated. Despite the impressive

study size, this study comes with signiﬁcant points of concern.

According to the authors, “Median cumulative probability of

survival for patients who had taken β-blockers was 72 years

compared with 70 years for patients who had never taken β-

blockers (P=0.01).” Yet, the reported estimated life expectan-

cies contrast with actual data in the article and with the data

for other populations for the same time interval.200 Moreover,

it is important to point out that the number of patients with

an age >50 years in the study was limited,207 and as a conse-

quence that the study is underpowered to allow detection of a

2-year difference in life expectancy. A further issue with the

study is the fact that authors did not address putative time ef-

fects in their analysis. Although not fully clear from the text,

it appears that the study covers the period between ≈1970

and 1993. It is conceivable that improvements in surgical

techniques coincided with the clinical implementation of β-

blocker usage; making time is a major potential confounder in

this study. As actually pointed out by the authors in the discus-

sion, “it is very likely that increased awareness and improved

diagnostic tools resulted in progressively more mild cases of

the Marfan syndrome being identiﬁed towards the end of the

observation period.”207

A further observational study208 on an effect of β-blockers

on aortapathy reports growth data for 113 juvenile patients

with Marfan from 2 centers. Different dosing schedules were

used by the 2 centers: an intermediate dose in the ﬁrst cen-

ter (1.3 mg/kg; n=80 patients) and a high dose in the second

center (1.9 mg/kg; n=20 patients). Thirteen individuals who

could not or would not take β-adrenergic blockade therapy

constituted the control group.208 On the basis of the slower

rate of aortic root growth in individuals taking β-blockers, the

authors recommended that “β-adrenergic blockade therapy in

patients with Marfan syndrome should begin at the earliest

age possible, and that the dose be adjusted to the largest dose

β-adrenergic blockade therapy that is clinically tolerated.”208

Some concerns of this study include the authors report beneﬁ-

cial effects on the aorta growth rate; yet, this is actually not the

case for the indexed growth rate (mm/m2), for which favorable

effects were only observed for the intermediate-dose group

and not for high-dose group. Reviewing the article208 for a

Table 3. Revised Ghent Criteria for Diagnosing Marfan Syndrome*

In the absence of a family history

1. Z score for the aortic diameter at the sinuses of valva ≥2 or aortic root

dissection and ectopia lentis

2. Z score for the aortic diameter at the sinuses of valva ≥2 or aortic root

dissection and FBN1 mutation

3. Z score for the aortic diameter at the sinuses of valva ≥2 or aortic root

dissection and systemic score ≥7*

4. Ectopia lentis and FBN1 mutation and aortic aneurysm

In the presence of a family history

5. Ectopia lentis and family history of Marfan syndrome (see 1–4)

6. Systemic score ≥7 and family history of Marfan syndrome (see 1–4)*

7. Z score for the aortic diameter at the sinuses of valva ≥2 (>20 y old)

or ≥3 in those <20 y old) and family history of Marfan syndrome*

Systemic score—Wrist and thumb sign: +3 (wrist or thumb sign: +1); pectus

carinatum deformity: +2 (pectus excavatum or chest asymmetry: +1); hindfoot

deformity: +2 (plain pes planus: +1); pneumothorax: +2; dural ectasia: +2;

protrusio acetabuli: +2; reduced upper/lower segment and increased arm/height

and no severe scoliosis: +1; scoliosis or thoracolumbar kyphosis: +1; reduced

elbow extension: +1; facial features (3/5): +1 (dolichocephaly, enophtalmos,

downslanting palpebral ﬁssures, malar hyoplasia, and retrognathia); skin striae:

+1; myopia >3 diopters: +1; mitral valve prolapse (all types): +1. Maximum total:

20 points; score ≥7 indicates systemic involvement. FBN1 indicates ﬁbrillin-1.

*In the absence of discriminating features other genetic syndromes.

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638 Circulation Research February 15, 2019

potential explanation(s) reveals that with similar mean end-of-

follow-up ages in the intermediate-dose and control groups,

mean end-of-follow-up length in the intermediate-dose group

was 174 cm but only 149 cm in the control group.208 An ex-

treme SD in the control group (69 cm [versus 22 cm in the

intermediate-dose group])208 implies severe skewing of the

size distribution to the right in the control group and conse-

quently that the reported mean height overestimates the actual

median height. This implies profound heterogeneity between

control group and the treated groups and consequently that the

conclusions of the study may be prone to bias.

Beneﬁcial effects are further reported by Ladouceur et

al,209 who retrospectively evaluated the effect of β-blockers

in 155 young patients with Marfan in whom the therapy was

initiated before the age of 12 years. The authors concluded

that “β-blockade signiﬁcantly decreased the rate of aortic

dilatation at the level of the sinuses of Valsalva by a mean

of 0.16 mm/y (P<0.05), an effect that increased with treat-

ment duration.”209 Although the authors rightly point out that

the increase in aortic dilatation was less in the treatment arm,

this difference actually reﬂects the larger baseline diameter

in group receiving β-blockers because the actual aortic di-

ameters at the age of 18 years were actually similar in the 2

groups. The claim made by the authors that “a trend toward

lower cardiac mortality, decreased need for preventive aortic

surgery, and less dissection was observed”209 is not justiﬁed by

the data in the article.

Conclusions from Ladouceur et al209 are not conﬁrmed in

a second smaller observational study in young patients with

Marfan.210 This study included 63 children who were moni-

tored for >6 years. Thirty-four patients received β-adrenergic

blockade therapy (atenolol, 0.92 mg/kg), 29 patients not re-

ceiving β-blockers served as control. The authors concluded

that “This study found no difference in the rate of aortic root

dilation in children with Marfan syndrome treated with β-

blockers and those not treated.”210 Like the other reports, this

retrospective analysis is prone to bias. In particular, a higher

percentage of patients with a family history of Marfan syn-

drome in the untreated group (35% versus 69% in the treated

group) may indicate that groups were not balanced with re-

spect to the severity or phenotype.

A further small, open-label study211 nonrandomly assigned

58 adolescent patients with Marfan to β-blocker therapy

(maximum dose, 2 mg/kg) or the ACE inhibitor enalapril. It

was concluded that ACE inhibition resulted in favorable he-

modynamic changes and a smaller increase in aortic root di-

ameter (0.1 [1.0] versus 5.8 [5.2] mm [mean (SD)]).211 Given

the study design, the small sample size, and absence of a con-

trol group, it is difﬁcult to draw conclusions from this study.

A report from Rossi-Foulkes et al212 compares outcomes for

preadolescent patients on different antihypertensive therapy

(β-blockers or Ca antagonists). The authors reported that med-

ication favorably inﬂuenced aortic growth,212 but that it did not

prevent complications. In the absence of a control group, and

profound baseline differences in the medicated and nonmedi-

cated group, this report should be considered inconclusive.

Taken together, this overview of reports on β-adrenergic

blockade in Marfan syndrome shows a paucity of stud-

ies with adequate study designs and appropriate statistical

approaches.213 As a consequence, the currently available ev-

idence does not provide a strong rationale for β-adrenergic

blockade to prevent aortapathy in patients with Marfan syn-

drome.214–216 An adequate evaluation taking into account the

possibility that patient responses to β-adrenergic blockade are

heterogeneous and relate to the underlying genotype217,218 is

missing.

Observed excessive TGFβ signaling in the aortas of murine

models of Marfan syndrome and a preventive effect of inter-

ference with TGFβ signaling through neutralizing antibodies

or the angiotensin II receptor antagonists in the model219 fu-

eled optimism for angiotensin II receptor antagonists (sartans)

as a preventive treatment for aortapathy in Marfan syndrome.

Supportive observations from small (28, 20, and 18 pa-

tients, respectively) open studies in young patients with

Marfan220–222 and a small open-label study on surrogate end

points223 were followed by 1 smaller and 4 larger randomized

trials. A small Belgium trial enrolling 22 patients with Marfan

syndrome failed to observe an add-on effect of losartan when

added to blocker therapy.224

Forteza et al225 performed a larger randomized trial and

randomized 5- to 60-year-old Marfan patients to losartan

(n=70) or atenolol (n=70; both dosed at 100 mg/day in indi-

viduals >50 kg). The trial results show similar aortic root and

ascending aortic diameter progression in the 2 arms for the

3-year follow-up.225 In a French study, incorporating 303 pa-

tients with Marfan aged ≥10 years, Millerton et al226 assigned

patients to losartan or placebo next to their regular treatment

(86% of the participants also used β-blockers). It was con-

cluded that 3-year losartan therapy did not inﬂuence the aorta

parameters tested or the need for surgery.226 Unfortunately, in-

clusion of both young and adult patients creates considerable

heterogeneity both with regard to the geno/phenotype as to

aortic dilation rates potentially interfering with the ability to

detect suppression of growth.

Young patients with Marfan were studied in a semi-blinded

study by the US Marfan network. Six hundred and eight par-

ticipants between 6 months to 25 years of age were allocated

to atenolol (mean dose [SD] achieved, 2.7 [1.1] mg) or losartan

(mean dose [SD], 1.3 [0.2] mg).227 Again, the 3-year follow-up

showed equivalence for β-adrenergic blockade or angiotensin

receptor blockade. The fourth larger randomized trial is a mul-

ticentre, open-label, randomized controlled trial with blinded

assessments performed in the Netherlands.228 The COMPARE

trial (Cozzar in Marfan Patients Reduces Aortic Enlargement)

incorporates 233 adult participants (47% women) who were

randomized to either losartan (n=116) or no additional treat-

ment (n=117). The study showed mixed effects with an effect

of losartan on root dilatation rate but no effect on the more dis-

tal aspects of the aorta. Remarkably, a planned subanalysis per-

formed on the available data of the COMPARE trial228 suggests

that an effect of angiotensin II receptor blockade may depend

on the type of FBN1 mutation because it was concluded that

losartan reduced only aortic root dilatation rate in haploinsuf-

ﬁcient patients and not in dominant-negative patients.229

According to the trial registries, there is currently 1 small

(n=56) ongoing 4-arm trial, The Oxford Marfan Trial version,

which evaluates the effect of irbesartan (150–300 mg), doxy-

cycline (100–200 mg), and a combination of both on markers

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Lindeman and Matsumura Pharmacologic Management of Aneurysms 639

of vascular dysfunction in the Marfan syndrome in patients

>13 years of age.230

With the exception of the potential beneﬁcial effect in

adult haploinsufﬁcient Marfan patients, the clinical trials

uniformly fail to show a beneﬁt of type I angiotensin II re-

ceptor inhibition on the aortapathy in patients with Marfan.

Remarkably, opposite conclusions were drawn in a meta-

analysis of the published prospective trials.231 Evaluation of

the meta-analysis appears to have weaknesses that resulted in

an overestimation of the effect size. Speciﬁcally, the planned

subanalyses performed within the COMPARE trial228 were

included as separate studies, resulting in duplication of the

positive data. Further, the weight distribution attributed to the

studies included in the meta-analysis231 may be incorrect.

These contrasting ﬁndings between promising preclinical

data and the clinical data with respect to the angiotensin II

receptor antagonism may reﬂect profound interspecies differ-

ences, not only with respect to aspects of the immune and in-

ﬂammatory responses but also with respect to healing, as well

as the signiﬁcant heterogeneous character of aorta disease in

Marfan disease.232 Most of the preclinical work is based on

mice with hypomorphic FBN1 mutations (the Fbn1C1039G/+

strain, with 50% of normal and Fbn1mgR/mgR strain with

20% of normal FBN1),233 but alternative models are currently

being developed.234

Given the extreme genotypic and phenotypic varia-

tion in Marfan syndrome, observations from a speciﬁc mu-

rine model may only be relevant to a subset of patients with

Marfan. Translatability of experimental ﬁndings can be fur-

ther interfered by phenotypic aspects such age (disease stage).

Heterogeneity is indicated by the dimorphic effects of TGFβ

neutralization in an experimental model of Marfan syn-

drome.235 Clinical relevance of the genotypic heterogeneity is

as implicated in the subanalysis of the COMPARE trial that

showed an exclusive beneﬁt of losartan in haploinsufﬁcient

patients.229 As such, a reevaluation of the negative trials tak-

ing along the lines of dominant-negative and haploinsufﬁcient

genotypes merits consideration.

Unfortunately, such a meta-analysis may be challenging

because phenotyping was only available for one-third of the

patients in the large Atenolol Versus Losartan Trial performed

by the Pediatric Heart Network.227 Genotype information is

available for 84% of the participants in the Sartan trial (78%

established FBN1 mutation)226 and the trial by Forteza et al225

(82% FBN1 mutation), but information on type FBN1 is miss-

ing in the publications.

Interpretation of currently available randomized trials is

further challenged by the substantial phenotypic heterogene-

ity in the patients studied (young versus adult patients) and by

loss of sensitivity by use of Z scores rather than root size as

clinical end points.236 A meta-analysis based on all individual

patient data has been announced, but conclusions are awaited

at the time of writing this overview.237

A further point of debate is the suggested pivotal role of

TGF-β signaling in Marfan disease.219 The rationale for ATR1

blocker in Marfan syndrome was based on a presumed ex-

cess TGF-β signaling as the underlying cause of aortapathy in

Marfan syndrome. A critical question is whether this assump-

tion is correct as excess TGF-β activation appears a common

phenomenon in aortic aneurysm disease238,239 and may actu-

ally be part of the compensatory healing or anti-inﬂammatory

responses. Such a mechanism is supported by the observation

that TGF-β upregulation in murine models of Marfan syn-

drome is secondary,238,240–242 by the fatal consequences of TGF-

β neutralizing in murine models of aneurysm41,243 and opposite

contextual (disease state) effects of TGFβ on the aorta pathol-

ogy in the Marfan mouse model.235

Taking into account the currently available data, there is in-

sufﬁcient evidence in support for either β-adrenergic blockade

or ATR1 blocker for aortapathy in Marfan syndrome. The ﬁeld

would beneﬁt from the announced meta-analysis (and subanaly-

sis) of the available data from the losartan trials.237 If this is not

deﬁnitive, there is need for an adequately powered, placebo-con-

trolled global trial that would stratify or control multiple known

confounders, including age, genetic heterogeneity of Marfan

syndrome, and diverging effects on blood pressure and pulse.

Currently available data indicate equivalence of β-

adrenergic and ATR1 blockade. In light of the milder side ef-

fects and superior persistence,244 ATR1 antagonists might be

preferable.245

Summary

The inconsistent correlations of preclinical successes and

clinical trial results provide impetus for major advances in re-

search innovation of aortic aneurysm. There are several expla-

nations for this translational gap, including inadequate animal

models, incomplete understanding of the processes involved

in the progression of late stage human disease, poorly de-

signed, underpowered clinical trials, and selective reporting.

Development of humanized models, advancing beyond early

chemically provoked models to those consistently demonstrat-

ing sequential dilation and rupture, addressing dysfunctional

repair mechanisms, clinical studies utilizing digitized phar-

maceutical histories and extensive prior radiographic records

of aneurysm size to explore relationships without the heavy

expense of prospective trials, imaging and genetic biomarkers

predicting stability or rapid progression of aneurysm enlarge-

ment, run-in periods ensuring populations with active aortic

enlargement before randomization of subjects, greater atten-

tion to concomitant medical therapy of cardiovascular risk

factors, and longer follow-up with clinical end points in clin-

ical trials are all areas of opportunity in this important ﬁeld.

Sources of Funding

This study was supported by research grant funding to Leiden

University Medical Center (J.H. Lindeman): Abvie, Cardoz, Eli Lilly,

The Netherlands Organisation for Health Research and Development,

the Dutch Heart Foundation, and the NutsOhra Fund and research

grant funding to the University of Wisconsin (J.S. Matsumura):

Abbott, Gore, Endologix, Cook, Medtronic, and National Institutes

of Health.

Disclosures

None.

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Blood pressure management in cardiovascular emergencies: an evidence-based approach

Article

Jan 2023

Abdominal aortic aneurysms harbor different histomorphology not associated with classic risk factors, the HistAAA study

Preprint

Apr 2024

Albert Busch

Objective: Abdominal aortic aneurysm (AAA) treatment is upon a diameter threshold by open (OAR) or endovascular aortic repair. Attempts for medical growth abrogation have failed. This study aims to elucidate the heterogeneity of AAA based on histomorphology in correlation to individual patient data and aneurysm metrics. Patients and Methods: Aneurysm samples from the left anterior wall from four university center biobanks underwent histologic analysis including angiogenesis, calcification, fibrosis, type and grade of inflammation in adventitia and media. Clinical information included age, comorbidities, etc. as well as type of aneurysm (intact, symptomatic, ruptured, inflammatory). Aneurysm morphology included diameter and semi-automated geometric analysis using Endosize (Therenva) segmentation. Additionally, aneurysm growth was assessed. Results: 364 patient samples (85.4% male, median age 69 years) demonstrated acute (mix/granulocytes) or chronic (monocytes/plasma cells) type inflammation and score, coherent in adventitia and media (p < 0.001), not associated with the type of aneurysm (52x ruptured; 37x symptomatic; p = 0.51) or diameter (57 [52-69] mm; p = 0.87). The degree of fibrosis and the presence of angiogenesis were significantly higher (both p < 0.001) with increasing inflammation score, which significantly decreased with patient age (est = - 0.015/year, p = 0.017). No significant differences in inflammation, fibrosis or angiogenesis were seen for ruptured (vs. intact), acute (vs. elective), male (vs. female) of diabetic (vs. non) patients, while current smoking was associated with more chronic inflammation (p = 0.007) and a higher degree of fibrosis (p = 0.03). Aneurysm geometric morphology (n=252) or differing annual growth rates (n=142) were not significantly associated with histologic characteristics. Conclusion: Type and degree of inflammation are the most distinguishable histologic characteristics in the AAA wall between individual patients. Despite the association to age and smoking status, no significant correlation to any patient or aneurysm specific feature, especially not diameter or rupture exists.

Iron Overload and Abdominal Aortic Aneurysm

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Full-text available

Oct 2024
REV CARDIOVASC MED

Abdominal aortic aneurysm (AAA) is a chronic vascular degenerative disease characterized by progressive segmental dilation of the abdominal aorta. The rupture of an AAA represents a leading cause of death in cardiovascular diseases. Despite numerous experimental and clinical studies examining potential drug targets and therapies, currently there are no pharmaceutical treatment to prevent AAA growth and rupture. Iron is an essential element in almost all living organisms and has important biological functions. Epidemiological studies have indicated that both iron deficiency and overload are associated with adverse clinical outcomes, particularly an increased risk of cardiovascular events. Recent evidence indicates that iron overload is involved in the pathogenesis of abdominal aortic aneurysms. In this review, we provide an overview of the role of iron overload in AAA progression and explore its potential pathological mechanisms. Although the exact molecular mechanisms of iron overload in the development of AAA remain to be elucidated, the inhibition of iron deposition may offer a promising strategy for preventing these aneurysms.

Extravascular administration of IGF1R antagonists protects against aortic aneurysm in rodent and porcine models

Article

Full-text available

May 2024
Sci Transl Med

An abdominal aortic aneurysm (AAA) is a life-threatening cardiovascular disease. We identified plasma insulin-like growth factor 1 (IGF1) as an independent risk factor in patients with AAA by correlating plasma IGF1 with risk. Smooth muscle cell– or fibroblast-specific knockout of Igf1r , the gene encoding the IGF1 receptor (IGF1R), attenuated AAA formation in two mouse models of AAA induced by angiotensin II infusion or CaCl 2 treatment. IGF1R was activated in aortic aneurysm samples from human patients and mice with AAA. Systemic administration of IGF1C, a peptide fragment of IGF1, 2 weeks after disease development inhibited AAA progression in mice. Decreased AAA formation was linked to competitive inhibition of IGF1 binding to its receptor by IGF1C and modulation of downstream alpha serine/threonine protein kinase (AKT)/mammalian target of rapamycin signaling. Localized application of an IGF1C-loaded hydrogel was developed to reduce the side effects observed after systemic administration of IGF1C or IGF1R antagonists in the CaCl 2 -induced AAA mouse model. The inhibitory effect of the IGF1C-loaded hydrogel administered at disease onset on AAA formation was further evaluated in a guinea pig-to-rat xenograft model and in a sheep-to-minipig xenograft model of AAA formation. The therapeutic efficacy of IGF1C for treating AAA was tested through extravascular delivery in the sheep-to-minipig model with AAA established for 2 weeks. Percutaneous injection of the IGF1C-loaded hydrogel around the AAA resulted in improved vessel flow dynamics in the minipig aorta. These findings suggest that extravascular administration of IGF1R antagonists may have translational potential for treating AAA.

Correcting mitochondrial loss mitigates NOTCH1-related aortopathy in mice

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Jan 2025

Molekulare Therapieansätze beim AAA mit klinischem PotenzialMolecular treatment approaches for AAA with clinical potential

Article

Dec 2024
Gefässchirurgie

The treatment of abdominal aortic aneurysms (AAA) depends on the diameter and is primarily performed as surgical or endovascular repair. In recent years interventional studies on conservative stabilization of aneurysms failed to show a positive effect. Based on a systematic presentation previous studies on the topic are discussed and potential limitations are shown. Based on a scoping review the authors present their own research approaches on the molecular pathogenesis of AAA. Due to the heterogeneous pathobiology a patient-specific consideration is necessary. In the past the treatment with sartans, doxycycline, macrolides, propranolol, statins and angiotensin-converting enzyme (ACE) inhibitors did not lead to a relevant reduction in aneurysm growth; however, there is promising evidence from the use of metformin in diabetic patients with AAA. Furthermore, drugs with pleiotropic effects have shown promising results in small and large animal models as well as approaches for targeted inhibition of platelet function. Stabilization of the aneurysm by local treatment with non-coding RNA equivalents or an endovascular device in the aneurysm neck with a so-called circumferential aortic stiffening device (CASD) also showed a preclinical reduction of the increase in diameter. Drug trials on controlling AAA progression must take patient-specific pathophysiological aspects, a sufficient number of patients and duration of follow-up into account. Several approaches for drug-based AAA treatment are currently being pursued with agents already in clinical use for other indications. Clinical trials on metformin in non-diabetic patients with AAA are the most advanced.

Disruption of PCSK9 Suppresses Inflammation and Attenuates Abdominal Aortic Aneurysm Formation

Article

Nov 2024
ARTERIOSCL THROM VAS

BACKGROUND Abdominal aortic aneurysm (AAA) is a chronic vascular inflammatory disease without effective medications. PCSK9 (proprotein convertase subtilisin/kexin 9), a serine protease from the proprotein convertase family, has recently been associated with AAA in human genome-wide association studies. However, its role in AAA is unknown. METHODS Transcriptional and histological expression of PCSK9 was examined in AAA tissues and healthy controls. The impact of PCSK9 deletion and inhibition on AAA formation was assessed in mice with hyperlipidemia and Ang II (angiotensin II) overproduction. AAA lesion morphology was assessed by tissue staining. MMP (matrix metalloproteinase) activity was evaluated by gelatin zymography, and leukocyte-vessel wall interaction was monitored by intravital microscopy. RNA sequencing was used to characterize the downstream signaling of PCSK9. RESULTS PCSK9 expression was upregulated and colocalized with macrophages in human and mouse AAAs. Pcsk9 deletion attenuated AAA formation, improved survival, and decreased systemic inflammation, without altering circulating cholesterol levels. Pcsk9 deficiency reduced aortic infiltration of macrophages and elastin degradation, without affecting vascular smooth muscle cell apoptosis and proliferation. Mechanistically, PCSK9 was essential in leukocyte-endothelium adhesion and expression of proinflammatory cytokines and MMP9 by macrophages. RNA sequencing of stimulated macrophages revealed that Pcsk9 deficiency upregulated histone deacetylase SIRT1 (sirtuin-1) and suppressed NF-κB (nuclear factor-κB) inflammatory signaling. SIRT1 inhibition attenuated the proinflammatory actions of PCSK9. Furthermore, administration of PCSK9 small interfering RNA or antibody constrained AAA formation/progression and inhibited vascular inflammation. CONCLUSIONS PCSK9 critically mediates macrophage inflammation and elastin degradation, promoting AAA formation. PCSK9 inhibitors bear a promise to curtail AAA, beyond being used as cholesterol-lowering drugs.

Innovation in pathogenesis and management of aortic aneurysm

Article

Jun 2024

Aortic aneurysm (AA) refers to the persistent dilatation of the aorta, exceeding three centimeters. Investigating the pathophysiology of this condition is important for its prevention and management, given its responsibility for more than 25000 deaths in the United States. AAs are classified based on their location or morphology. various pathophysiologic pathways including inflammation, the immune system and atherosclerosis have been implicated in its development. Inflammatory markers such as transforming growth factor β, interleukin-1β, tumor necrosis factor-α, matrix metalloproteinase-2 and many more may contribute to this phenomenon. Several genetic disorders such as Marfan syndrome, Ehler-Danlos syndrome and Loeys-Dietz syndrome have also been associated with this disease. Recent years has seen the investigation of novel management of AA, exploring the implication of different immune suppressors, the role of radiation in shrinkage and prevention, as well as minimally invasive and newly hypothesized surgical methods. In this narrative review, we aim to present the new contributing factors involved in pathophysiology of AA. We also highlighted the novel management methods that have demonstrated promising benefits in clinical outcomes of the AA.

Epigenetic modifications in abdominal aortic aneurysms: from basic to clinical

Article

Full-text available

Jun 2024

Abdominal Aortic Aneurysm (AAA) is a disease characterized by localized dilation of the abdominal aorta, involving multiple factors in its occurrence and development, ultimately leading to vessel rupture and severe bleeding. AAA has a high mortality rate, and there is a lack of targeted therapeutic drugs. Epigenetic regulation plays a crucial role in AAA, and the treatment of AAA in the epigenetic field may involve a series of related genes and pathways. Abnormal expression of these genes may be a key factor in the occurrence of the disease and could potentially serve as promising therapeutic targets. Understanding the epigenetic regulation of AAA is of significant importance in revealing the mechanisms underlying the disease and identifying new therapeutic targets. This knowledge can contribute to offering AAA patients better clinical treatment options beyond surgery. This review systematically explores various aspects of epigenetic regulation in AAA, including DNA methylation, histone modification, non-coding RNA, and RNA modification. The analysis of the roles of these regulatory mechanisms, along with the identification of relevant genes and pathways associated with AAA, is discussed comprehensively. Additionally, a comprehensive discussion is provided on existing treatment strategies and prospects for epigenetics-based treatments, offering insights for future clinical interventions.

Therapeutic potential of natural products and underlying targets for the treatment of aortic aneurysm

Article

Apr 2024
PHARMACOL THERAPEUT

SURGICAL TREATMENT OF ABDOMINAL AORTIC ANEURYSM

Article

Full-text available

Jan 2018

The article analyzed the results of surgical treatment of 140 patients with surgery of abdominal aortic aneurism. The comparison group consisted of 80 patients with aortic aneurism more than 4,5 cm, who didn’t undergo surgery. The conventional method of Khardi-Pokrovskiy resection was complemented by a number of surgical methods in these cases. The results of surgery were improved due to application of these methods. All the patients (100%), who didn’t undergo surgery, passed away during 5 years, though 70% of them died because of aneurysm rupture. The early postoperative lethality was 5% in the main group, but 5-year survival was 81%.

Diabetes Mellitus: Is It Protective against Aneurysm? A Narrative Review

Article

Full-text available

Dec 2018
CARDIOLOGY

Objectives: In the course of extensive clinical aortic surgery, we noticed that the aorta was quite thick and fibrotic in diabetic patients. We thought the diabetic aortic aorta might be inimitable to aortic dissection. On this basis, we set out to review information in the literature regarding aortic growth and dissection in diabetic patients. Methods: We used a 2-step search approach to the available literature on diabetes and aneurysm. Firstly, databases including PubMed, Cochrane, Embase and TRIP were searched. Secondly, relevant studies were identified through secondary sources including references of initially selected articles. We address the relationship between diabetes and the incidence, prevalence, growth, mortality and rupture of an aneurysm. Results: Diabetes is thought to exert a protective role in both thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA). Diabetics were shown to have a slower aneurysm growth rate, lower rupture rate, delayed (> 65 years) age of rupture, decreased rate of mortality from an aneurysm and a decreased length of hospital stay. There was also noted a decreased rate of incidence and prevalence of TAA and AAA in diabetics, smaller aneurysm diameter, reduction in matrix metalloproteinases and an increased aortic wall stress in diabetics. Antidiabetic agents like metformin, thiazolidinediones and dipeptidyl peptidase-4 inhibitors may protect against an aneurysm. Conclusion: Our literature review provides strong (but often circumstantial) evidence that diabetic patients exhibit slower growth of aortic aneurysms and a lower rate of aortic dissection. Furthermore, clinical and experimental studies indicate that common antidiabetic medications on their own inhibit growth of aortic aneurysms. These findings indicate a paradoxically beneficial effect of the otherwise highly detrimental diabetic state.

Randomized Placebo‐Controlled Trial Assessing the Effect of 24‐Week Fenofibrate Therapy on Circulating Markers of Abdominal Aortic Aneurysm: Outcomes From the FAME‐2 Trial

Article

Full-text available

Oct 2018

Background There is no drug therapy for abdominal aortic aneurysm (AAA). FAME‐2 (Fenofibrate in the Management of Abdominal Aortic Aneurysm 2) was a placebo‐controlled randomized trial designed to assess whether administration of 145 mg of fenofibrate/d for 24 weeks favorably modified circulating markers of AAA. Methods and Results Patients with AAAs measuring 35 to 49 mm and no contraindication were randomized to fenofibrate or identical placebo. The primary outcome measures were the differences in serum osteopontin and kallistatin concentrations between groups. Secondary analyses compared changes in the circulating concentration of AAA‐associated proteins, and AAA growth, between groups using multivariable linear mixed‐effects modeling. A total of 140 patients were randomized to receive fenofibrate (n=70) or placebo (n=70). By the end of the study 3 (2.1%) patients were lost to follow‐up and 18 (12.9%) patients had ceased trial medication. A total of 85% of randomized patients took ≥80% of allocated tablets and were deemed to have complied with the medication regimen. Patients’ allocated fenofibrate had expected reductions in serum triglycerides and estimated glomerular filtration rate, and increases in serum homocysteine. No differences in serum osteopontin, kallistatin, or AAA growth were observed between groups. Conclusions Administering 145 mg/d of fenofibrate for 24 weeks did not significantly reduce serum concentrations of osteopontin and kallistatin concentrations, or rates of AAA growth in this trial. The findings do not support the likely benefit of fenofibrate as a treatment for patients with small AAAs. Clinical Trial Registration URL: http://www.anzctr.org.au. Unique identifier: ACTRN12613001039774.

Creation of Murine Experimental Abdominal Aortic Aneurysms with Elastase

Article

Jul 2009
JoVE

Lower Extremity Aneurysms

Chapter

Jan 2010

Arterial Aneurysms

Chapter

Jan 2010

Survival After Elective Endovascular or Open AAA Repair: A Systematic Review and Meta-analysis

Article

Dec 2019
EUR J VASC ENDOVASC

Endovascular aneurysm repair (EVAR) has become the preferred strategy for elective repair of abdominal aortic aneurysm (AAA) for many patients. However, the superiority of the endovascular procedure has recently been challenged by reports of impaired long-term survival in patients who underwent EVAR. A systematic review of long-term survival following AAA repair was therefore undertaken. METHODS: A systematic review was performed according to PRISMA guidelines. Articles reporting short- and/or long-term mortality of EVAR and open surgical repair (OSR) of AAA were identified. Pooled overall survival estimates (hazard ratios (HRs) with corresponding 95 per cent c.i. for EVAR versus OSR) were calculated using a random-effects model. Possible confounding owing to age differences between patients receiving EVAR or OSR was addressed by estimating relative survival. RESULTS: Some 53 studies were identified. The 30-day mortality rate was lower for EVAR compared with OSR: 1·16 (95 per cent c.i. 0·92 to 1·39) versus 3·27 (2·71 to 3·83) per cent. Long-term survival rates were similar for EVAR versus OSR (HRs 1·01, 1·00 and 0·98 for 3, 5 and 10 years respectively; P = 0·721, P = 0·912 and P = 0·777). Correction of age inequality by means of relative survival analysis showed equal long-term survival: 0·94, 0·91 and 0·76 at 3, 5 and 10 years for EVAR, and 0·96, 0·91 and 0·76 respectively for OSR. CONCLUSION: Long-term overall survival rates were similar for EVAR and OSR. Available data do not allow extension beyond the 10-year survival window or analysis of specific subgroups.

Systematic review Meta-analysis of long-term survival after elective endovascular or open repair of abdominal aortic aneurysm

Article

Mar 2019

Background Endovascular aneurysm repair (EVAR) has become the preferred strategy for elective repair of abdominal aortic aneurysm (AAA) for many patients. However, the superiority of the endovascular procedure has recently been challenged by reports of impaired long‐term survival in patients who underwent EVAR. A systematic review of long‐term survival following AAA repair was therefore undertaken. Methods A systematic review was performed according to PRISMA guidelines. Articles reporting short‐ and/or long‐term mortality of EVAR and open surgical repair (OSR) of AAA were identified. Pooled overall survival estimates (hazard ratios (HRs) with corresponding 95 per cent c.i. for EVAR versus OSR) were calculated using a random‐effects model. Possible confounding owing to age differences between patients receiving EVAR or OSR was addressed by estimating relative survival. Results Some 53 studies were identified. The 30‐day mortality rate was lower for EVAR compared with OSR: 1·16 (95 per cent c.i. 0·92 to 1·39) versus 3·27 (2·71 to 3·83) per cent. Long‐term survival rates were similar for EVAR versus OSR (HRs 1·01, 1·00 and 0·98 for 3, 5 and 10 years respectively; P = 0·721, P = 0·912 and P = 0·777). Correction of age inequality by means of relative survival analysis showed equal long‐term survival: 0·94, 0·91 and 0·76 at 3, 5 and 10 years for EVAR, and 0·96, 0·91 and 0·76 respectively for OSR. Conclusion Long‐term overall survival rates were similar for EVAR and OSR. Available data do not allow extension beyond the 10‐year survival window or analysis of specific subgroups.

Losartan Versus Atenolol for Prevention of Aortic Dilation in Patients With Marfan Syndrome

Article

Oct 2018
J AM COLL CARDIOL

Background: Beta-blockers are the standard treatment in Marfan syndrome (MFS). Recent clinical trials with limited follow-up yielded conflicting results on losartan's effectiveness in MFS. Objectives: The present study aimed to evaluate the benefit of losartan compared with atenolol for the prevention of aortic dilation and complications in Marfan patients over a longer observation period (>5 years). Methods: A total of 128 patients included in the previous LOAT (LOsartan vs ATenolol) clinical trial (64 in the atenolol and 64 in the losartan group) were followed up for an open-label extension of the study, with the initial treatment maintained. Results: Mean clinical follow-up was 6.7 ± 1.5 years. A total of 9 events (14.1%) occurred in the losartan group and 12 (18.8%) in the atenolol group. Survival analysis showed no differences in the combined endpoint of need for aortic surgery, aortic dissection, or death (p = 0.462). Aortic root diameter increased with no differences between groups: 0.4 mm/year (95% confidence interval: 0.2 to 0.5) in the losartan and 0.4 mm/year (95% confidence interval: 0.3 to 0.6) in the atenolol group. In the subgroup analyses, no significant differences were observed considering age, baseline aortic root diameter, or type of dominant negative versus haploinsufficient FBN1 mutation. Conclusions: Long-term outcome of Marfan syndrome patients randomly assigned to losartan or atenolol showed no differences in aortic dilation rate or presence of clinical events between treatment groups. Therefore, losartan might be a useful, low-risk alternative to beta-blockers in the long-term management of these patients.

Metformin prescription status and abdominal aortic aneurysm disease progression in the U.S. veteran population

Article

Sep 2018
J VASC SURG

Background: Identification of a safe and effective medical therapy for abdominal aortic aneurysm (AAA) disease remains a significant unmet medical need. Recent small cohort studies indicate that metformin, the world's most commonly prescribed oral hypoglycemic agent, may limit AAA enlargement. We sought to validate these preliminary observations in a larger cohort. Methods: All patients with asymptomatic AAA disease managed in the Veterans Affairs Health Care System between 2003 and 2013 were identified by International Classification of Diseases, Ninth Revision codes. Those with a concomitant diagnosis of diabetes mellitus who also received two or more abdominal imaging studies (computed tomography, magnetic resonance imaging, or ultrasound) documenting the presence and size of an AAA, separated by at least 1 year, were included for review. Maximal AAA diameters were determined from radiologic reports. Further data acquisition was censored after surgical AAA repair, when performed. Comorbidities, active smoking status, and outpatient medication records (within 6 months of AAA diagnosis) were also queried. Yearly AAA enlargement rates, as a function of metformin treatment status, were compared using two statistical models expressed in millimeters per year: a multivariate linear regression (model 1) and a multivariate mixed-effects model with random intercept and random slope (model 2). Results: A total of 13,834 patients with 58,833 radiographic records were included in the analysis, with radiology imaging follow-up of 4.2 ± 2.6 years (mean ± standard deviation). The average age of the patients at AAA diagnosis was 69.8 ± 7.8 years, and 39.7% had a metformin prescription within ±6 months of AAA. The mean growth rate for AAAs in the entire cohort was 1.4 ± 2.0 mm/y by model 1 analysis and 1.3 ± 1.6 mm/y by model 2 analysis. The unadjusted mean rate of AAA growth was 1.2 ± 1.9 mm/y for patients prescribed metformin compared with 1.5 ± 2.2 mm/y for those without (P < .001), a 20% decrease. This effect remained significant when adjusted for variables relevant on AAA progression: metformin prescription was associated with a reduction in yearly AAA growth rate of -0.23 mm (95% confidence interval, -0.35 to -0.16; P < .001) by model 1 analysis and 0.20 mm/y (95% confidence interval, -0.26 to -0.14; P < .001) by model 2 analysis. A subset analysis of 7462 patients with baseline AAA size of 35 to 49 mm showed a similar inhibitory effect (1.4 ± 2.0 mm/y to 1.7 ± 2.2 mm/y; P < .001). Patients' factors associated with an increased yearly AAA growth rate were baseline AAA size, metastatic solid tumors, active smoking, chronic obstructive pulmonary disease, and chronic renal disease. Factors associated with decreased yearly AAA growth rates included prescriptions for angiotensin II type 1 receptor blockers or sulfonylureas and the presence of diabetes-related complications. Conclusions: In a nationwide analysis of diabetic Veterans Affairs patients, prescription for metformin was associated with decreased AAA enlargement. These findings provide further support for the conduct of prospective clinical trials to test the ability of metformin to limit progression of early AAA disease.

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