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THE PRESENT AND FUTURE

STATE-OF-THE-ART REVIEW

Changing Pathology of the ThoracicAorta From Acute to Chronic DissectionLiterature Review and Insights

Sven Peterss, MD,a,b Ahmed M. Mansour, BS,a Julia A. Ross, MD, PHD,c Irena Vaitkeviciute, MD,d

Paris Charilaou, MD,a Julia Dumfarth, MD,a Hai Fang, PHD,a,e Bulat A. Ziganshin, MD,a,f John A. Rizzo, PHD,a,g

Adebowale J. Adeniran, MD,c John A. Elefteriades, MDa

ABSTRACT

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We review current knowledge regarding the natural transition of aortic dissection from acute to chronic stages. As this is

not well understood, we also bring to bear new data from our institution. Type A dissection rarely transitions naturally into

the chronic state; consequently, information is limited. Type B dissections are routinely treated medically and indeed

undergo substantial changes during their temporal course. General patterns include: 1) the aorta dilates and, absent

surgical intervention, aortic enlargement may cause mortality; 2) continued false lumen patency, particularly with an

only partially thrombosed false lumen, increases aortic growth, whereas calcium-channel blockers affect aortic dilation

favorably; 3) aortic dilation manifests a temporal dynamic, with early rapid growth and deceleration during transition;

4) the intimal flap dynamically changes over time via thickening, straightening, and loss of mobility; and 5) temporal

remodeling, on the cellular level, initially shows a high grade of wall destruction; subsequently, significant fibrosis ensues.

(J Am Coll Cardiol 2016;68:1054–65) © 2016 by the American College of Cardiology Foundation.

T he incidence of aortic dissection is 3 to 6 per100,000 people/year (1–3). Dissections arecommonly classified by anatomic patterns

in the DeBakey classification (types I, II, and III) (4),or by prognosis and therapeutic consequences in theStanford classification (types A and B) (5,6).

Aortic dissections undergo temporal changes afterinitial occurrence (mostly defined by the onset ofsymptoms). Generally, temporal phases have beendivided into acute, subacute, and chronic. The recentgradation considers up to 2 weeks since onset asacute, 2 weeks to 3 months as subacute, and 3 months

m the aAortic Institute at Yale-New Haven Hospital, Yale University Sch

nt of Cardiac Surgery, University Hospital Munich, Ludwig-Maximilian

logy, Yale University School of Medicine, New Haven, Connecticut; dDep

dicine, New Haven, Connecticut; eChina Center for Health Development

nt of Surgical Disease #2, Kazan State Medical University, Kazan, Russia; a

ventive Medicine, Stony Brook University, Stony Brook, New York. Dr. Pe

m the Deutsche Forschungsgemeinschaft/German Research Foundation. D

d has served on the Data and Safety Monitoring Board for Jarvik Heart and

y have no relationships relevant to the contents of this paper to disclose.

th Annual Scientific Sessions of the American College of Cardiology; Marc

nuscript received March 1, 2016; revised manuscript received April 25, 20

and above as a chronic state, as per the currentEuropean Society of Cardiology guidelines (7).

However, what is the natural history of this processfrom an acute to a chronic dissection over time? Dothese processes have implications regarding clinicaldecisions? This transition from acute to chronicdissection is poorly characterized.

The aim of this state-of-the-art paper is to sum-marize recent published reports regarding the naturalacute-to-chronic transition of aortic dissection. Due toa relative signal void in published reports on thisnatural process, we call upon new data from our

ool of Medicine, New Haven, Connecticut; bDepart-

-University, Munich, Germany; cDepartment of Pa-

artment of Anesthesiology, Yale University School of

Studies, Peking University, Beijing, China; fDepart-

nd the gDepartment of Economics and Department of

terss has received a research fellowship (PE 2206/1-1)

r. Elefteriades has served as principal for CoolSpine;

the Salus Trial. All other authors have reported that

The paper was presented as an invited lecture at the

h 2015; San Diego, California.

16, accepted May 24, 2016.

AB BR E V I A T I O N S

AND ACRONYM S

CI = confidence interval

CT = computed tomography

OR = odds ratio

regression coefficient

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Aortic Institute at Yale–New Haven Hospital to sup-plement the published data review.

To this end, we retrospectively reviewed recentconsecutive patients admitted to Yale–New HavenHospital with the diagnosis of aortic dissection(Online Tables 1 and 2). To characterize these pro-cesses of transition, we focused on traditional flapdissections, and included only patients who transi-tioned into the chronic state without any surgical orendovascular intervention. Three methodologies,computed tomography (CT), echocardiography, andhistopathology, were used to assess anatomic andhistopathological changes and their dynamics overtime. (Details regarding patient cohorts and materialsand methods of analysis for new Yale data are incor-porated into the Online Appendix.)

STANFORD TYPE B DISSECTION

AORTIC ENLARGEMENT. Uncomplicated dissectionsaffecting the descending aorta are preferentiallytreated with medical therapy alone, and thus theynaturally transition into the chronic state (8–11).Although medical treatment achieves acceptableearly survival (9,12,13), about one-quarter to one-third of early survivors expire within the first 5years (10,14,15). Aortic expansion remains the crucialfactor determining long-term survival, despiteoptimal medical treatment. The estimated freedomfrom aneurysm formation in patients with type Baortic dissection is only 65.5% at 3 years and 26.7% at5 years of follow-up, according to data from the IRAD(International Registry of Acute Aortic Dissection)(16), and also confirmed by earlier studies (17).

After type B aortic dissection, dilation occurs pre-dominantly in the upper descending aorta (18). Re-ported rates of diameter enlargement of the dissecteddescending aorta vary in the published reports(probably reflecting inhomogeneity of the pop-ulations studied, variations in the methodology ofgrowth rate calculation, length of observation period,and selection and number of the evaluated aorticsegments). In 2012, Jonker et al. (19) analyzed datafrom the IRAD registry and reported a growth rate of3.11 mm/year in isolated flap dissection (follow-up:2.0 years). Asian race was found to be protectiveagainst aortic enlargement, whereas white race wasan independent risk factor for growth (regressioncoefficient [RC]: 4.6). Interestingly, an aorticdiameter <40 mm showed a significantly higher rateof enlargement than larger diameters (RC: 6.3). In arecent multicenter study, Tolenaar et al. (20) identi-fied predominantly morphological characteristicsinfluencing the rate of aortic enlargement (patency of

false lumen and saccular type formation [see“False Lumen Patency” section], number ofentry tears, false lumen localization accord-ing to curvature, and circularity of truelumen). They noted a growth rate in thedescending aorta between 3.0 � 7.3 mm/yearat the upper descending aorta and 3.4 � 7.5

mm/year at the midportion (20). Another multicenterstudy (with contribution from our institute) calcu-lated rates of 2.3 and 3.8 mm/year at levels 2 and 20cm below the left subclavian origin, with differencesalso according to false lumen patency (21). In theirrecent study, Sueyoshi et al. (22) analyzed aorticenlargement in a Japanese population and found amean growth rate of 4.1 � 4.5 mm/year using thefastest growing aortic segment for calculation.FALSE LUMEN PATENCY. Continued patency of thefalse lumen has an essential adverse influence onaortic enlargement and long-term survival (7,19–27).Multiple, but not all, studies noted a significantbeneficial effect of a completely thrombosed falselumen in comparison with a patent false lumenregarding dilation and outcome (21,23,28–31). In 2007,Tsai et al. (31) from the IRAD registry investigated thepathological effect of only partial thrombosis of thefalse lumen. They found that a false lumen in whichboth flow and thrombosis were present was associ-ated with an increased mortality during the chronicstate (by a factor of 2.7). They hypothesized thateither the occlusion of a distal re-entry tear mightlead to increased wall tension within the false lumen(saccular type formation), or that thrombus-relatedhypoxia of the adjacent aortic wall might causelocalized wall weakening. Recent studies observingthe predictors of aortic dilation confirm the effect ofpartially thrombosed or saccular-type false lumenformation (20–22). Besides the patency status of thefalse lumen, localization was also shown to have aneffect on outcomes, with worse results from falselumen localization at the inner curvature (concavity)of the aorta (20,32).

In terms of false lumen patency, there are publishedreports of 44% to 59% for patent, 23% to 47.6% forpartially thrombosed, and 8.3% to 19.5% forcompletely thrombosed false lumen (9,19,21,24,31,33).Reviewing our institutional data, we found, respec-tively, 60.2%, 38.2%, and 1.5% of the patients withpatent false lumen, partial, and complete thrombosisin patients transitioned into the chronic state(Figure 1). However, in 23.5% of those, a change of falselumen patency was noted over time (20.0 � 27.9months follow-up), which is consistent with publisheddata noting patency changes in 18% to 25%within 10 to15 years (31).

RC =

FIGURE 1 False Lumen Status in Type B Dissection

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False Lumen Status

58% 63% 53% 52% 47% 41%

42% 37% 44% 48% 47% 57%

2% 6% 2%

Day 0-14 Week 2-6 Week 6-26 Month 6-12 Year 1-3 > Year 3acute subacute chronic

Patent Partial thrombosed Complete thrombosed

The degrees of the false lumen patency according to the cumulative images (n ¼ 294) are

presented. Of the patients (n ¼ 68), 60.2%, 38.2%, and 1.5% initially presented with

patent false lumen, partial, and complete thrombosis, respectively. Among those, 23.5%

changed their status during follow-up.

FIGURE 2 Temporal Dynamic of Aortic Dilation in Type B Dissection Over Time

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Type B - Dynamic of Aortic Dilation

Exponential Decay R2 = 0.420

The figure displays how the growth rate changes post-dissection. The dynamic followed an

exponential decay function, with rapid growth in the acute state, deceleration in the

subacute (after 25 days from onset) state, and a plateau in the chronic state (after 88 days

from onset). Note that the growth rates in this chart are mm/day.

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EFFECT OF COMORBIDITIES AND MEDICATIONS ON

ANEURYSM FORMATION AND SURVIVAL. Besidesfalse lumen patency, other factors have been sus-pected to effect outcome during follow-up. In 2010,Trimarchi et al. (34) demonstrated the negative effecton survival of refractory hypertension and/or re-fractory pain (but only as a composite variable) (oddsratio [OR]: 3.31). International guidelines have forsome time recommended that refractory and/orrecurrent hypertension or pain be interpreted per seas indications for surgical intervention (7,35). How-ever, some studies have doubted this generalization,having shown no effect on aortic enlargement andsurvival (10,19,23,36,37).

Arterial hypertension, 1 of the key causative factorsof type B aortic dissection, has an incidence at pre-sentation of 66.7% to 91.7% (3,9,10,12,15,19,34,38,39).However, about 90% of patients are normotensiveunder anti-impulsive therapy at discharge, achievingrecommended values for systolic blood pressure ofbetween 100 and 120mmHg (40). No definite evidenceexists regarding the use and effectiveness of variousdrug classes (7,35,41,42). Guidelines recommendbeta-blockers as mainstay first-line therapy (7,35) (formodulation of dP/dt), a recommendation confirmedby single-center results (43,44). However, recentstudies failed to show a beneficial effect on aorticenlargement and survival (19,38,40,41). The samelack of evidence relates to medications approachingthe renin-angiotensin system (19,38,40,41). Onlycalcium-channel blockers were shown to beneficiallyaffect aortic dilation (growth rate 0.51 mm/year vs.3.9 mm/year; RC: �3.39) and mortality (OR: 0.55)according to recent data from the IRAD registry(19,40) and other studies (OR: 0.38) (38).

In a report by Durham et al. (10), chronic renalfailure, among other factors, was identified to be anindependent predictor of medical failure in conser-vatively treated patients. Although little is knownabout the influence of chronic renal insufficiency(found in about 4% to 5% of patients [10,39]), acutefailure of renal function at time of admission and,specifically, at discharge, has been well-shown tohave an adverse effect on long-term outcomes(38,45). Other comorbidities, like smoking status(incidence 25% to 80% [3,12,15,38]), appear not to beessential predisposing factors for adverse long-termoutcome in medically-treated type B dissection ofthe thoracic aorta (46,47).

Discrepancies exist regarding the influence of sexand age on transition processes. Female sex wasshown to favor less enlargement by the IRADdata (RC: �3.8) and by a recent multicenter study(RC: �2.32) (19,20), whereas a former report found a

FIGURE 3 Absolute Flap Thickness and Temporal Changes of Architecture Over Time

in Type B Dissection

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0 365 730 1095 1460 1825 2190 2555 2920 3285 3650Days From Symptom Onset

0 30 60 90 120 150 180 210 240 270 300 330 360

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acute subacute

Days From Onsetchronic

Type B - Absolute Flap Thickness

Type B - Dynamic of Flap Changes

Slope = 0.095 mm/year

R2 = 0.18p < 0.001

Exponential Decay R2 = 0.500

A

B

(A) Absolute thickness and (B) thickening rate (mm/day). The flap thickens over time, also

following an exponential decay function, with a rapid drop in the rate of thickening. The

changes decelerate after 83 days from onset and plateau after 235 days from onset in the

chronic state.

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higher dilation rate in women, and female sex was anindependent predictor of long-term mortality(hazard ratio: 1.99) (23,45). Equally contradictory arethe scientific data regarding the effect of increasedage on the rate of aortic enlargement. Some studiespromote age as a protector, whereas other studiesfind age to be a contributor or to have no effect(9,10,20,21,23,39,48).

DYNAMICS OF TRANSITION. Aortic enlargement andits annual growth rate are usually estimated eitherby the differences between the initial and most recentavailable maximal diameter divided by image timeinterval (19–23) or using a regression model, asfavored at our institute (49,50). Both methods followthe hypothesis that the aorta grows uniformly andlinearly. However, aortic expansion is not at all linearover time, and there is a relative signal void in pub-lished reports regarding its dynamic over time.

Data from our institutional database, observingeach single patient’s interval growth rate duringfollow-up images, reveals that a very rapid change indiameter occurs early in the post-dissection period,which then stabilizes after 25 days and plateaus after88 days (R2 ¼ 0.420) (Figure 2). From that point on, amuch slower rate of enlargement continues forwardwithout further variation over time.

The growth rates also differ statistically betweenthe stages (p < 0.0001) (Online Table 3). By using aregression model (50), the rate of dilation was esti-mated at a mean of 9.31 mm/year (95% confidenceinterval [CI]: 5.65 to 13.58 mm/year) in the acutestage, 1.30 mm/year (95% CI: �1.98 to 4.87 mm/year)in the subacute stage, and 0.32 mm/year (95% CI: 0.30to 0.34 mm/year) in the chronic stage.

The very rapid early growth is impressive and mayplay a role in the early virulence of this disease. It isduring the early post-dissection phase that rupture,ischemia, refractory hypertension, and recurrent painare often seen. Our observation of a period of rapidenlargement within the first month exclusively inpatients in the chronic stage may correlate with asecond peak for required intervention, as noted bySteuer et al. (51). After this period, no furtherextraordinary interventional peaks were found, againpotentially correlating with our observation of alower subsequent growth rate in the chronic post-dissection period.

FLAP ARCHITECTURE AND ITS DYNAMICS. Theintimal flap separates the true and the false lumensand also changes during the transition from the acuteto the chronic stage. Although flap stiffness isaccepted as a marker for chronicity, changes overtime have not yet been systematically observed (52).

The changes in flap architecture (thickness) alsodemonstrate an exponential decay dynamic (R2 ¼0.500) over time, with markedly higher rates in theacute and subacute state (Figures 3A and 3B). Thestabilization in thickening rate is mathematicallyreached after 83 days, and the plateau after 235 days(about 8 months).

The corresponding changes in flap thicknessare estimated by regression model at a mean of1.20 mm/year (95% CI: 0.50 to 2.09 mm/year) in the

FIGURE 4 Flap Mobility

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0 7 60 120 180 240 300 360Days From Onset

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m)

Flap Mobility

Flap Movement (mm) = 0.513 - 0.116*log(dt) R2 = 0.13p = 0.01

Type BType A

Flap mobility is cumulative of type A and B dissection. The figure depicts the absolute

movement of the flap in mm at different time points (in different patients). A gradual drop

in flap mobility over time was found.

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acute stage, 0.41 mm/year (95% CI:�0.13 to 1.09 mm/year) in the subacute stage, and 0.02 mm/year (95%CI: 0.01 to 0.03 mm/year) in the chronic stage.

The mobility of the flap (Figure 4), represented bythe amplitude of the flap movement, decreased overtime (p ¼ 0.01) and also underwent exponential decay(R2 ¼ 0.119). We also found that the flap loses curva-ture and waviness, straightening over time (CentralIllustration). CT and magnetic resonance imagingstudies confirm these findings, describing a 29%decrease of the true lumen by flap motion (no corre-lation to time since onset of symptoms was shown),as well as stiffening over time (52–54).

Tang and Dake (55) discussed chronological changein the dissection flap architecture and its clinical ef-fect. They hypothesized that as the flap matures,thickens, and stabilizes within weeks after dissection,it may affect the feasibility and success of stent graftinterventions, which rely on reapproximating the flapto the aortic wall (55–59). For the surgeon choosing anopen surgical approach to the aorta, the increasedfibrosis is a welcome finding that probably correlateswith the observation that suturing of the dissecteddescending aorta is secure from the 2-week point on.

PROGRESS OF DISSECTION. Longitudinal progres-sion of a medically treated type B aortic dissection isoften a concern during the chronic state. In studyingour institutional data, we found essentially no distalextension of dissection over time (except for 1 minorextension within the iliac artery, without clinical

effect) (Table 1). This is a striking and clinicallyimportant observation, which supports the conceptthat once the “eye of the storm” is weathered earlyafter dissection, a durable stage of stability isreached. In terms of proximal extension, a priorinvestigation by Ziganshin et al. (18) from our groupfound an incidence of only 1.7% of native, non-iatrogenic retrograde type A dissection after initialtype B dissection. Furthermore, in anatomic terms, inno case in our present study did the vascular supplyof the branches of the aorta change or deteriorateover time (Table 2). Simply put, there were no newbranch occlusions in long-term follow-up.

STANFORD TYPE A DISSECTION

Acute aortic dissection involving the ascending aortararely (<10% [60]) transitions into the chronic statenaturally. About 22% of these patients initially man-ifest acutely life-threatening complications, and theremainder are expected to develop these with a highprobability. Thus, about 90% of patients with typeA dissection are treated surgically upon initial pre-sentation (45,61). This is a reflection of the diseaseitself.

However, some patients experience delayed diag-nosis of aortic dissection, correlating, inter alia, withfemale sex, initial admission at a nontertiary carehospital, atypical or no symptoms, normotension,and less longitudinal extension of the dissection(60,62). About 60% of patients with chronic type Adissection require surgery during follow-up, withobviously better post-operative results comparedwith the acutely operated cases (60,63).

However, following the surgical repair of theproximal portion of the aorta in the acute setting, thedistal portion of the aorta transitions into a chronicstate, but this should not be equated with type Bdissection (64). The false lumen is reported to becompletely thrombosed in about 23%, partiallythrombosed in about 41%, and completely patent inabout 36%, related to the distal extent of aorticresection and the surgical success of eliminatingdistal entries (65,66). A patent false lumen was shownto have an adverse effect on aortic dilation, incidenceof distal reoperation, and survival (OR: 6.484)(27,65–67). Moreover, the long-term outcome isinfluenced by multifactorial patient characteristics(e.g., atherosclerosis [45]). However, beta-blockersare the only medication found to have a verifiablybeneficial effect on mortality (hazard ratio: 0.471)after type A dissection (40). The need for secondarydistal reoperation during the chronic state is noted in4% to 41% of patients (27,65–69).

TABLE 2 Branch Involvement and Blood Supply

CENTRAL ILLUSTRATION Changing Pathology of Aortic Dissection

Peterss, S. et al. J Am Coll Cardiol. 2016;68(10):1054–65.

Changing morphology of a type B dissection over time by computed tomography in a single illustrative patient with multiple good quality images at the same aortic

level. Please note: 1) marked early increase in aortic diameter (orange arrow); 2) intimal thickening over time (orange star); 3) decreased flap motion over time (orange

triangles); 4) flap straightening over time (green star); and 5) increased false lumen thrombosis over time (yellow star).

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HISTOPATHOLOGY

Transition into the chronic state can also be studiedon a microscopic level. Within each layer of the aorta(tunica intima, tunica media, and tunica adventitia),various pathological changes take place, which canaffect overall integrity of the aorta. For example, theintima may become hyperplastic or burdened byatherosclerotic plaque. The outer adventitia andsubadventitia may experience inflammation, generalfibrosis, or even fibrosis of the vasa vasorum specif-ically (which may, in turn, lead to compromised bloodflow and oxygen exchange). The media may atrophyand become subject to a host of pathological changes,including fragmentation of elastin fibers (disruptingthe lamellar unit), along with increased fibrosis

TABLE 1 Longitudinal Extension of Dissection Flap

Type ADissection

Type BDissection

Ascending aorta/arch 17 (26) —

Descending aorta

Proximal to sixth rib 2 (3) 0 (—)

Distal to sixth rib 5 (8) 8 (9)

Suprarenal aorta 7 (11) 15 (22)

Infrarenal aorta 3 (5) 8 (9)

Iliac arteries 32 (48) 27 (54)

Changes in distal extension 0 (—) 1 (1.5)

Values are n (%). Note: the most distal extent is indicated. Over the entirety ofobservation, only 1 patient showed (minor) distal progression of dissection overtime from infrarenal to iliac extent.

(collagen deposition at the expense of smooth musclecells), medionecrosis (defined as the loss of smoothmuscle cell nuclei within the media, and not strictly“necrosis“), and increased cystic medial necrosis(deposition of basophilic ground substance, oftenseen associated with cystic spaces, although cysts arenot necessary, nor is “necrosis“) (70).

Normally, the media of the aortic wall is micro-scopically organized into lamellar units comprised ofparallel elastic fibers, which enclose smooth musclecells, ground substance, and collagen fibers. Theserepeating units provide the tensile strength andelasticity of the aorta. Some of the pathological

Type A dissection with dissection into

Innominate artery 42 (64)

Left common carotid artery 31 (47)

Left subclavian artery 25 (38)

Type B dissection with supply by false lumen

None 44 (65)

Coeliac artery 4 (6)

Separate common hepatic artery 1/1 (100)

Superior mesenteric artery 2 (3)

Right renal artery 13 (19)

Left renal artery 10 (15)

Inferior mesenteric artery 1 (2)

Changes 0 (—)

Values are n (%). False lumen supply was never observed for both the right andleft renal arteries in the same patient. During follow-up, no changes in branchvessel supply were noted.

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changes discussed earlier can be seen with normalaging (elastin fragmentation, cystic medial necrosis,medionecrosis, and fibrosis); however, these histo-logical features are also seen in aortic pathology andare thought to represent an adaptation to stress ortrauma (70). Former studies reported these micro-scopic pathologies in aortic dissection (71–76), andfound specifically increased grades of cystic medialnecrosis and elastin fragmentation compared withnondissected aneurysm specimens (77).

However, the detailed temporal pattern ofdissection-related changes has yet not been described(to our knowledge) (72,73). Therefore, we selectedoperative specimens (44 type A, 50 type B), assignedto different temporal stages (according to the onset ofsymptoms). We reviewed these temporally specificspecimens according to the classification of Schlat-mann and Becker (70) (Online Table 4).

Among the type A dissections, no statisticallysignificant differences were seen in the presence ofatheroma, intimal hyperplasia, subadventitialfibrosis, inflammation, fibrosis of vasa vasorum, ormedial atrophy over time (Table 3). Furthermore, nosignificant differences were seen in grading (grade IIIvs. grade #II) of cystic medial necrosis, medionec-rosis, elastin fragmentation, or fibrosis betweenacute, subacute, and chronic stages (Figure 5). Despitethe lack of statistical significance, a graduallyincreasing trend is grossly discernible in elastinfragmentation and medionecrosis over time. Ofcourse, with type A dissections, the temporal span inspecimens is short (days to weeks) because of thehigh need for early surgical intervention. This is incontrast to the long temporal span of our type B

TABLE 3 Histopathology

Acute

Days 1–2 Days 2–14

Type A dissection

Atheroma 5 (25) 6 (50)

Intimal hyperplasia 15 (75) 6 (55)

Medial atrophy, mm 1.278 � 0.63 0.885 � 0.442

Subadventitial fibrosis 17 (85) 12 (100)

Fibrosis of vasa vasorum 14 (70) 8 (67)

Inflammation 12 (40) 8 (27)

Type B dissection

Atheroma 8 (57)

Intimal hyperplasia 4 (31)

Medial atrophy, mm 1.054 � 0.348

Subadventitial fibrosis 9 (90)

Fibrosis of vasa vasorum 10 (91)

Inflammation 6 (55)

Values are n (%) or mean � SD. NS ¼ p < 0.05. Note: none of the observed nongraded

specimens, where long delays in the need for surgeryare common.

Similarly, for type B aortic dissection, no differencewas seen in the presence or absence of atheroma,intimal hyperplasia, subadventitial fibrosis, inflam-mation, fibrosis of vasa vasorum, or medial atrophyover time (Table 3). However, significant histopatho-logical grading increases in elastin fragmentation andfibrosis of the media were found (Figure 6). Forexample, grade III elastin fragmentation and fibrosisrepresented 64.3% and 50% of cases, respectively, inthe first 2 weeks after dissection. As time progressed,from week 7 to year 1, grade III elastin fragmentationand fibrosis both represented >90% of cases(Figures 6B and 6C). Generally, the initial grade ofpathological remodeling was high. The majority ofaortic tissues already showed destruction classified asgrade III for all graded measures (cystic medial ne-crosis 43%, medionecrosis 86%, elastin fragmenta-tion 64%, and fibrosis 50%) in the early stage.

Although the molecular biology behind the com-plex interplay of factors that results in these histo-logical features is still under investigation, our studyemphasizes the dramatically increased fibrosis andelastin fragmentation with chronicity of the dissec-tion (from time of symptom onset), particularlyamong type B dissections. Despite this being a retro-spective study (with only representative, randomly-selected sections sampled), the trend toward elastinfragmentation and subsequent increased fibrosis isabundantly clear. This microscopically demonstratedfibrosis correlates with imaging findings of thickeneddissection flaps with loss of mobility. Also, our find-ings of increased fibrosis correlate with and may

Subacute Chronic

Weeks 2–6 Weeks 6–52 >1 Yr p Value

5 (42) — NS

5 (42) — 0.055

1.275 � 0.53 — NS

9 (82) — NS

5 (46) — NS

10 (30) — NS

7 (100) 9 (82) 7 (37) NS

6 (100) 4 (36) 9 (82) NS

0.857 � 0.352 0.889 � 0.201 0.916 � 0.464 NS

5 (83) 6 (86) 12 (100) NS

3 (50) 4 (57) 9 (82) NS

2 (33) 4 (57) 3 (27) NS

histopathological parameters showed a difference over time.

FIGURE 5 Histopathology Changes in Type A Dissection Over Time

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ent

20 12 12

Day 0-1 Day 2-14 > Week 2acute subacute

n

1.0

0.8

0.6

0.4

0.2

0.0

Perc

ent

20 12 12

Day 0-1 Day 2-14 > Week 2acute subacute

n

1.0

0.8

0.6

0.4

0.2

0.0

Perc

ent

20 12 12

Day 0-1 Day 2-14 > Week 2acute subacute

n

1.0

0.8

0.6

0.4

0.2

0.0

Perc

ent

20 12 12

Day 0-1 Day 2-14 > Week 2acute subacute

n

Type A - Cystic Medial Necrosis Type A - Elastin Fragmentation

Type A - Fibrosis Type A - Medionecrosis

Grade IIIp = .5483

Grade IIIp = .1128

Grade IIIp = .8949

Grade IIIp = .2070

10%25%

8% 5% 8% 8%

17% 17% 15% 8% 8%

60%

50%

50%

30% 25% 42%

50% 42%

17%

50% 75%45%

50%

50%

50%

33%

50%

33%

33%

50%

50%

35% 42% 58%

A B

C D

Grade I Grade II Grade III

(A) Cystic medial necrosis. (B) Elastin fragmentation. (C) Fibrosis. (D) Medionecrosis. Note: no significant differences were seen in grading of

cystic medial necrosis, medionecrosis, elastin fragmentation, or fibrosis between acute, subacute, and chronic type A dissections, with the

restriction of the admittedly (and expectedly) low numbers of late operated type A dissection patients. Despite the lack of statistical signif-

icance, a gradually increasing trend is grossly discernible in elastin fragmentation and medionecrosis over time.

J A C C V O L . 6 8 , N O . 1 0 , 2 0 1 6 Peterss et al.S E P T E M B E R 6 , 2 0 1 6 : 1 0 5 4 – 6 5 Changing Pathology of Aortic Dissection

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explain the lack of longitudinal extension or addi-tional aortic branch involvement over time. One mayenvision that the aortic layers are protectively “knit-ted together” by the fibrotic process.

Although we found no significant difference overtime in cystic medial necrosis and medionecrosis,

there is still a trend toward higher grades of each overtime in aortic dissection. Other histopathologicalfeatures involving the intima (atheroma and intimalhyperplasia), as well as adventitia and subadventitialfibrosis (particularly of the vasa vasorum) andinflammation were not found to be statistically

FIGURE 6 Histopathology Changes in Type B Dissection Over Time

1.0

0.8

0.6

0.4

0.2

0.0

Perc

ent

14 7 11

Day 0-14 Week 2-6 Week 6-52n18

> Year 1acute subacute chronic

1.0

0.8

0.6

0.4

0.2

0.0

Perc

ent

14 7 11

Day 0-14 Week 2-6 Week 6-52n18

> Year 1acute subacute chronic

1.0

0.8

0.6

0.4

0.2

0.0

Perc

ent

14 7 11

Day 0-14 Week 2-6 Week 6-52n18

> Year 1acute subacute chronic

1.0

0.8

0.6

0.4

0.2

0.0

Perc

ent

14 7 11

Day 0-14 Week 2-6 Week 6-52n18

> Year 1acute subacute chronic

Type-B Cystic Medial Necrosis Type B - Elastin Fragmentation

Type B - Fibrosis Type B - Medionecrosis

Grade IIIp = .1059

Grade IIIp = .0220

Grade IIIp = .0241

Grade IIIp = .3923

57%

43% 71%

14%

14%

30%

70% 72%

6%

36%

64% 86% 91% 91%

9% 6%14%

14%7%

43%

50% 71%

14%

9%

91% 83%

17% 14% 14%

86% 86% 100% 72%

22%

6%

A B

DC

22%

(A) Cystic medial necrosis; (B) elastin fragmentation; (C) fibrosis; (D) medionecrosis. Note: the initial grade of pathological remodeling was

high. Histopathological grading of elastin fragmentation (B) and fibrosis (C) significantly increases over time. For example, grade III elastin

fragmentation and fibrosis represented 64% and 50% of cases, respectively, in the acute state after dissection. As time progressed, grade III

elastin fragmentation and fibrosis both represented >90% in the chronic state.

Peterss et al. J A C C V O L . 6 8 , N O . 1 0 , 2 0 1 6

Changing Pathology of Aortic Dissection S E P T E M B E R 6 , 2 0 1 6 : 1 0 5 4 – 6 5

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significant over time in our cohort, and may simply berepresentative of an underlying atherosclerotic state.

SUGGESTIONS FOR CLINICAL PRACTICE

Our findings of markedly accelerated aortic growth inthe acute and subacute phases of aortic dissection areconsonant with a program of more closely spacedimaging in the early post-dissection period. The pro-tocol for imaging at our institution is indicated inTable 4. This table deals with imaging after medicallytreated type B aortic dissection (type A dissections aregenerally operated immediately, but a similarlyintense early post-operative imaging approach is

suggested, mainly to follow the large segments ofdissected aorta remaining beyond the resectedascending aorta). We generally prefer CT scan imag-ing over magnetic resonance imaging because of easeof access in the acute presentation and comparabilityof later follow-up images.

CONCLUSIONS

The changes in aortic morphology and histopathologyas acute aortic dissection transitions over time tochronic aortic dissection were as follows:

� Aortic diameter increases remarkably rapidly earlyafter dissection, with a later plateau.

TABLE 4 Imaging Protocol for Medically-Treated Type B Aortic

Dissection Patients

Period Aortic Institute Protocol

Admission Baseline CT scan

Hospital stay Repeat CT scan on hospital day 5(if clinically stable)

Repeat as needed in case of clinical instability

Early follow-up Follow-up scan 1 month after hospital discharge

Follow-up scans at 6 months and 1 yr

Late follow-up Outpatient scans every 2-3 yrs

Note: our institution prefers more closely spaced imaging in the early post-dissection period.

J A C C V O L . 6 8 , N O . 1 0 , 2 0 1 6 Peterss et al.S E P T E M B E R 6 , 2 0 1 6 : 1 0 5 4 – 6 5 Changing Pathology of Aortic Dissection

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� The dissection flap thickens early and then pla-teaus, straightens, and becomes less mobile.

� The false lumen patency has an adverse effect onthe outcome, and mild progression of false lumenthrombosis is seen over time.

� Longitudinal extension of dissection or new branchvessel involvement is rare.

� The aortic wall is markedly abnormal in its histo-logical pathology initially, and becomes increas-ingly more so over time.

� Fibrosis of the aortic wall progresses over time;thus, flap thickness and stiffness (immobility) in-crease during the remodeling process.

These findings indicate that important dynamicprocesses in the acute-to-chronic transition arevigorously at play in the early period up to 3 months.According to published clinical results, most of the

natural complications like rupture are expected dur-ing this early period, where we have confirmed activeand adverse anatomic and histological worsening.Furthermore, clinical experience has long suggestedthat operations on the acutely dissected descendingaorta are dangerous (bleeding and mortality), andthat later operation may be safer. The increasedfibrosis in the media and the deceleration of remod-eling over time that we have documented correlatewith the greater safety of suturing the more maturedescending aortic dissection, which surgeons havenoted for decades.

ACKNOWLEDGMENTS The authors thank Drs. MarkDavis and David Fullerton for their insight and wis-dom in originally assigning the acute to chronicdissection progression as a presentation topic in theaortic session at the 64th Annual Scientific Sessionsof the American College of Cardiology 2015 in SanDiego, California. Drs. Davis and Fullerton recognizedthat little was known and more needed to be learnedabout this progression in the natural history ofdissection. The authors also appreciate the sugges-tion by Drs. Davis and Fullerton that a paper corre-sponding to our 2015 presentation be prepared forsubmission.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.John A. Elefteriades, Aortic Institute at Yale–NewHaven, Yale University School of Medicine, ClinicBuilding CB317, 789 Howard Avenue, New Haven,Connecticut 06510. E-mail: john.elefteriades@yale.edu.

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KEY WORDS acute/chronic aorticdissection, aortic dissection histopathology,aortic wall, growth/dilation rate, naturalhistory

APPENDIX For an expanded Methods sectionand supplemental tables, please see the onlineversion of this article.