Nakamura, Ted Feldman and Robert S. SchwartzHidehiko Hara, Wesley R. Pedersen, Elena Ladich, Michael Mooney, Renu Virmani, Masato

Percutaneous Balloon Aortic Valvuloplasty Revisited : Time for a Renaissance?

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is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation doi: 10.1161/CIRCULATIONAHA.106.657098

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Percutaneous Balloon Aortic Valvuloplasty RevisitedTime for a Renaissance?Hidehiko Hara, MD; Wesley R. Pedersen, MD; Elena Ladich, MD; Michael Mooney, MD;Renu Virmani, MD; Masato Nakamura, MD; Ted Feldman, MD; Robert S. Schwartz, MD

Case Presentation: A 92-year-old woman presented with pro-gressive heart failure in the

setting of known aortic valve stenosis.Despite aggressive medical therapy,she remained in New York Heart As-sociation functional class IV. She livedin an assisted-care facility and wantedto engage in more vigorous daily ac-tivities. She did not wish to undergosurgical aortic valve replacement. Anechocardiogram showed a left ventric-ular ejection fraction of 50%. Theaortic valve was heavily calcified andseverely stenotic, with a mean gradientof 64 mm Hg and an aortic valve areaof 0.46 cm2.

The patient was offered balloon aor-tic valvuloplasty, to which she and herfamily consented. A retrograde ap-proach with a 23-mm balloon wasused. A total of 3 inflations werecarried out across the aortic valve dur-ing simultaneous rapid ventricular pac-ing at 220 bpm. The postvalvuloplastymean gradient was reduced to28 mm Hg, and the aortic valve areaincreased to 0.98 cm2. She was seen inthe clinic 6 months later with stablefunctional class II symptoms and re-

mained quite satisfied with her im-proved lifestyle.

Calcific aortic stenosis (AS) is themost frequent expression of valvularheart disease in the Western world,with increasing prevalence expected asthe population ages. Three percent ofall adults �75 years of age have mod-erate or severe AS, and it is the leadingindication for valve replacement inEurope and the United States. Surgicalaortic valve replacement is the pre-ferred treatment strategy for patients ofall age groups, although it has limita-tions in the octogenarian and nonage-narian populations. Open heart ap-proaches are limited by higherperioperative risk, prolonged recovery,and poor quality of life after surgery.1

The surgical 30-day mortality rate forthe nonagenarian population is �17%in 1 contemporary series, with 40%mortality by 13 months.2

Less invasive percutaneous optionsare needed for poor-surgical-risk pa-tients with severe AS. Balloon aorticvalvuloplasty (BAV) is currently theonly approved catheter-based optionfor nonsurgical patients, a procedurethat has been underused in those pa-

tients relegated to medical therapyalone. This procedure fell from favorsecondary to perceived proceduralcomplexity, suboptimal initial results,and high restenosis rates in the 6 to 12months after the procedure.3 As thenumber of very elderly with this dis-ease increases, especially those inwhom surgical options are not avail-able, an effective and less invasivetreatment of severe AS is essential.About one third of patients with severeAS are not referred for valve replace-ment surgery because of the risks per-ceived by both patients and physicians.The use of BAV for palliation ofsymptoms has been undervalued inthis difficult-to-treat patient group.

Pathophysiology of ASA normal aortic valve leaflet consistsof 3 layers (Figure 1). AS is considereda form of atherosclerosis, and earlyvalve lesions show subendothelial cel-lular and extracellular lipid accumula-tion on the aortic side of leaflets, muchlike what occurs in atherosclerotic dis-ease. Such lesions include oxidizedlow-density lipoprotein, lipoprotein(a),inflammatory cells, and calcification.

From the Minneapolis Heart Institute Foundation, Abbott Northwestern Hospital, Minneapolis, Minn (H.H., W.R.P., M.M., R.S.S.); CV Path,International Registry of Pathology, Gaithersburg, Md (E.L., R.V.); Division of Cardiovascular Medicine, Toho University, Ohashi Medical Center,Tokyo, Japan (M.N.); and Evanston Northwestern Hospital, Evanston, Ill (T.F.).

Correspondence to Robert S. Schwartz, MD, Minneapolis Heart Institute and Minneapolis Heart Institute Foundation, 920 E 28th St, Ste 620,Minneapolis, MN 55407. E-mail rss@rsschwartz.com

(Circulation. 2007;115:e334-e338.)© 2007 American Heart Association, Inc.

Circulation is available at http://www.circulationaha.org DOI: 10.1161/CIRCULATIONAHA.106.657098

CLINICIAN UPDATECLINICIAN UPDATE

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Severely stenotic leaflets have promi-nent calcification with lipocalcificchanges on the aortic side of leaflet.

Active bone formation is an impor-tant component of AS.4 Early lesioninitiation results from endothelial layerdisruption caused by mechanical

forces such as shear stress and abnor-mal blood flow patterns. Lipid accu-mulation, especially with low-densitylipoprotein, begins within the leafletsubendothelial layer and is modifiedby inflammatory and cytokine interac-tions. The angiotensin-converting en-

zyme cascade also works locallywithin the aortic leaflet, causing fibro-blasts within the fibrosa layer to dif-ferentiate into myofibroblasts whereinthe angiotensin I receptor is highlyexpressed. The myofibroblast cellplays a central role in the processbecause it is believed to differentiateinto an osteoblast-like cell phenotype,which in turn promotes deposition ofcalcified nodules and bone formation.

Novel RelevantPathophysiological Insights

From In Vivo 3-DimensionalImaging

Investigations into the relationship be-tween aortic valve calcium and stenot-ic area by multislice computed tomog-raphy show causal mechanisms.5

Three-dimensional images reveal im-portant information about leaflet calci-fication and stenosis severity. Figure 2supports the observation that extraval-vular calcification affects leaflet motil-ity, especially when calcium accumu-lates in the outflow tract and aorticroot. Calcification within these loca-tions may severely restrict leaflet mo-tion and enhance stenosis severity.

Current Therapy andResults

Surgical ReplacementSurgical valve replacement should beconsidered the treatment of choice forsevere AS patients regardless of age.Moderate-to-severe AS occurs in 5%of individuals 75 to 86 years of age,and critical AS is seen in �5% ofthose �85 years of age.6 Increasingnumbers of octogenarians and nonage-narians are presenting with severe ASfor consideration of open heart sur-gery, and physicians are increasinglyconfronted by the growing dilemma offinding suitable therapy for elderly pa-tients who are often poorly suited fortraditional valve replacement surgery.Surgical success rates for these veryelderly patients are improving but re-main suboptimal. In-hospital death andstroke rates may be as high as 8.5%and 8%, respectively.1 Mean durationof postoperative hospital stay in most

Figure 1. Layered architecture of normal aortic valve leaflet. The ventricular surface hasa black-staining elastic layer (ventricularis). A dense collagenous layer (fibrosa) extendstoward the aortic surface. The spongiosa is a loose connective tissue layer rich inproteoglycan.

Figure 2. Three-dimensional volume-rendering images reveal that extravalvular calcifica-tion of the valve leaflet, especially toward the left ventricle outflow tract, may restrict themotion of the leaflet, which can be worked as a hinge point.

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reports is �2 weeks for very elderlypatients, with most being discharged tonursing care facilitates. Furthermore,many elderly patients refuse surgerydespite favorable outcomes, makingless invasive, percutaneous therapy anattractive option for enhancing theirquality of life. Moreover, disabilityoften results from aortic valve replace-ment surgery in elderly patients. Lessspecific cognitive deficits also arecommon. More than half of all octoge-narians are discharged to rehabilitationfacilities, even after minimally inva-sive approaches are used, and �20%are rehospitalized within 1 month.7

Aortic Valvuloplasty as aForgotten Therapy

Percutaneous aortic valvuloplasty wasdeveloped as a nonsurgical option inthe 1980s. It was found to have a rolein managing unstable and critically illpatients such as those in cardiogenicshock or refractory heart failure. Amean age of 78�9 years was reportedin the National Heart, Lung and BloodInstitute (NHLBI) valvuloplasty regis-try and was typical of “younger” pa-tients who underwent BAV 2 decadesago. A consistent limitation for thistherapy among younger patients withgreater longevity was the high resteno-sis rate and the need for reintervention.BAV was thus found to be of limitedutility for many of these patients whowere acceptable candidates for aorticvalve replacement.

High complication rates and in-hospital mortality also were reportedearly in the experience, suggestingcomplications in 25% of patients (167of 672) within 24 hours of the proce-dure and documenting death in 3% (17of 672).8 The most common complica-tion was transfusion in 20%, relatedpredominantly to vascular entry sitecomplications (136 of 672; Table 1).8

Cumulative cardiovascular mortalitybefore discharge was 8% in theNHLBI registry. Restenosis and recur-rent hospitalization were common, al-though survivors reported fewer symp-toms over the subsequent 1.5 years.3

Most patients who are very elderly

often are considered too frail to un-dergo BAV or aortic valve replace-ment. In a comparable patient popula-tion without AS, median expectedsurvival was only 2 years, regardlessof valve condition.9 The most impor-

tant predictor of event-free survivalafter BAV was left ventricular func-tion at baseline (ejection fraction�25%).10 BAV may be a forgottentherapy, but analysis suggests that itoffers benefits to the very elderly high-risk patient who is looking for signif-icant symptomatic improvement that isnot available from medical therapyalone. Table 2 shows informal guide-lines currently used by our institutionsto select patients suitable for BAV.

Mechanisms of DilationThe effects of BAV on the aortic valveare poorly understood, but severalmechanisms are likely. The most com-mon effect is intraleaflet fractureswithin calcified nodular deposits.These represent leaflet hinge pointsand may increase flexibility within thecalcified aortic root to improve valveopening. Other possible mechanismsinclude scattered leaflet microfrac-tures, cleavage planes along collag-enized stroma, and uncommon separa-tion of fused leaflets. Enhancedcompliance of the rigidly calcified ad-jacent aortic root, which may followBAV, may further contribute to greaterleaflet flexibility. That no single mech-anism has been proved suggests insuf-ficient data and leaves unanswered the

TABLE 1. Complications During orWithin 24 Hours After ValvuloplastyProcedure

Complication n (%)

Death 17 (3)

Patients with any severe complication 167 (25)

Type of complication

Hemodynamic

Prolonged hypotension 51 (8)

CPR required 26 (4)

Pulmonary edema 19 (3)

Cardiac tamponade 10 (1)

IABP use 11 (2)

Acute valvular insufficiency

Aortic 6 (1)

Mitral 1 (0.1)

Cardiogenic shock 15 (2)

Neurological

Vasovagal reaction 36 (5)

Seizure 15 (2)

Transient loss of consciousness 4 (0.6)

Focal neurological event 13 (2)

Respiratory

Intubation 28 (4)

Arrhythmia

Treatment required 64 (10)

Persistent bundle-branch block 34 (5)

AV block requiring pacing 30 (4)

VF or VT requiring countershock 18 (3)

Vascular

Significant hematoma 44 (7)

Vascular surgery performed 33 (5)

Systemic embolic event 11 (2)

Transfusion required 136 (20)

Ischemic

Prolonged angina 9 (1)

Acute myocardial infarction 10 (1)

Other severe complications

Pulmonary artery perforation 1 (0.1)

Acute tubular necrosis 1 (0.1)

CPR indicates cardiopulmonary resuscitation;IABP, intra-aortic balloon pump; AV, atrioventric-ular; VF, ventricular fibrillation; and VT, ventriculartachycardia. N�672.

TABLE 2. Patients in WhomPercutaneous Balloon AorticValvuloplasty Should Be Considered

Patients with symptomatic AS and any of thefollowing:

Bridge to surgical AVR in hemodynamicallyunstable patients

Increased perioperative risk,STS risk score �15%

Anticipated survival of �3 y

Age in the late 80s or 90s and prefer BAVover open thoracotomy

Severe comorbidities such as porcelain aorta,severe lung disease, and others for which theCV surgeon prefers not to operate

Severe and/or disabling neuromuscular orarthritic conditions that would limit the abilityto undergo postoperative rehabilitation

AVR indicates aortic valve replacement; STS,Society of Thoracic Surgeons; and CV, cardiovas-cular.

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question of novel strategies for valvu-lar dilation.

Silver Linings to aDark Cloud

Several technical and procedural im-provements are now available forBAV that did not exist 20 years agowhen Cribier first described theprocedure.10a Rapid ventricular pacing(200 to 220 bpm) now arrests mechan-ical systole to preserve balloon stabil-ity across the aortic valve during infla-tion. The Inoue balloon (typically usedfor mitral valvuloplasty) improves im-mediate post-BAV aortic valve areacompared with conventional and retro-grade BAV.11 Enhanced valve openingmay be achieved through leaflet hyper-extension into the broader aortic rootdiameter. The “dumbbell”-shaped In-oue balloon locks on the aortic valveand can accomplish leaflet hyperexten-sion with a rounded distal end withoutoverstretching the valve annulus en-gaged by the narrower neck.12 Further-more, inflation– deflation times arefaster, and given the required ante-grade transvenous approach, peripher-al arterial complications are less likely.Immediate post-BAV valve area is af-fected by pre-BAV severity and corre-lated with improved hemodynamiclong-term follow-up.

Investigations suggest that repeatballoon valvuloplasty in AS patientsacross multiple age groups (59 to 104years) may improve 3-year survivalrates over a single dilatation.13 RepeatBAV can be performed without addi-tional complications. Most patientshave symptomatic relief for a year ormore. The value of symptomatic palli-ation in this population cannot be un-derstated. Minimizing the need for re-peated hospitalizations for heart failurehas a large impact on quality of life forthese 80- to 95-year-old patients. Mis-conceptions often include a higher-than-reported rate of complicationssuch as perioperative stroke, post-BAV aortic insufficiency, and myocar-dial perforation. In a series of 86 pa-tients �80 years of age, no myocardialperforations occurred, and only 1 pa-

tient developed severe aortic regurgi-tation.14 Only 1 of 86 patients sufferedstroke, and the overall periproceduralmortality was 2.2%. Data from ourgroup show successful simultaneouscoronary stenting with BAV in 11patients (mean age, 87 years; range, 79to 99 years) between July 2003 andMay 2006 without complications orin-hospital mortality (unpublisheddata, Minneapolis Heart Institute BAVregistry). These data represent a favor-able trend that is important given theincidence of severe coronary arterydisease in these patients of 50%.

Valvular Restenosis andPrevention

External Beam RadiationThe Radiation Following PercutaneousBalloon Aortic Valvuloplasty to Pre-vent Restenosis (RADAR) pilot trialsuggests that external beam radiationmay significantly reduce restenosis.Restenosis in the RADAR pilot studywas 20% at 12 months in a populationwith an average age of 89 years, sug-gesting utility in elderly patients.15

This surprising benefit may occurthrough the previously demonstratedability of external beam radiation ther-apy to limit the formation of scar tissueand heterotopic ossification previouslyreported in restenotic aortic valves.

Potential for TranscatheterImplantation and

Antirestenotic Drug TherapyPercutaneous heart valve implanta-tion with stent-based valves has beenperformed in initial feasibility stud-ies in inoperable patients with severeAS. Immediate and early clinical im-provement has been achieved insmall patient numbers with this tech-nique. BAV will play a crucial rolein preparing the stenotic aortic valvefor the prosthetic implantation. Fur-ther device improvements and long-term follow-up are required in thesenovel implantation devices beforepremarket approval is obtained.

Antirestenotic drug therapy afterBAV has not been attempted, but pre-clinical studies to prevent calcification

have been investigated in surgical set-tings. Because drug-eluting stents havereplaced brachytherapy in the manage-ment of coronary artery disease andrestenosis, local drug elution into di-lated aortic valves may be possible, intheory, to prevent restenosis after BAVor work primarily to stimulate boneregression.

Conclusions and SummaryAortic valvuloplasty strategies shouldbe reevaluated, given the enhancedknowledge of vascular and valvularbiology that permits targeted therapyto prevent restenosis and to delay orreverse valve mineralization. The in-creasing numbers of poor surgical can-didates in the expanding very elderlypopulation mandate less invasivemethods such as BAV to improvequality of life. The time has arrived forballoon aortic valvuloplasty to be re-visited, and a resurgence of this proce-dure is becoming possible through im-proved knowledge and refinedtranscatheter device developments.

The patient presented in this Clini-cian Update needs to be followed upregularly to monitor for evidence ofrestenosis. If restenosis of the aorticvalve occurs and is clinically signifi-cant, a repeat BAV can be performed.

DisclosuresNone.

References1. Kolh P, Kerzmann A, Lahaye L, Gerard P,

Limet R. Cardiac surgery in octogenarians:peri-operative outcome and long-termresults. Eur Heart J. 2001;22:1235–1243.

2. Edwards MB, Taylor KM. Outcomes innonagenarians after heart valve replacementoperation. Ann Thorac Surg. 2003;75:830–834.

3. Otto CM, Mickel MC, Kennedy JW,Alderman EL, Bashore TM, Block PC,Brinker JA, Diver D, Ferguson J, HolmesDR Jr. Three-year outcome after balloonaortic valvuloplasty: insights into prognosisof valvular aortic stenosis. Circulation.1994;89:642–650.

4. Feldman T, Glagov S, Carroll JD. Reste-nosis following successful balloon valvu-loplasty: bone formation in aortic valveleaflets. Cathet Cardiovasc Diagn. 1993;29:1–7.

5. Koos R, Mahnken AH, Sinha AM, Wild-berger JE, Hoffmann R, Kuhl HP. Aortic

Hara et al Resurgence of Balloon Valvuloplasty e337

by guest on January 11, 2013http://circ.ahajournals.org/Downloaded from

valve calcification as a marker for aortic ste-nosis severity: assessment on 16-MDCT.AJR Am J Roentgenol. 2004;183:1813–1818.

6. Lindroos M, Kupari M, Heikkila J, Tilvis R.Prevalence of aortic valve abnormalities inthe elderly: an echocardiographic study of arandom population sample. J Am CollCardiol. 1993;21:1220–1225.

7. Goodney PP, Stukel TA, Lucas FL, Fin-layson EV, Birkmeyer JD. Hospital volume,length of stay, and readmission rates inhigh-risk surgery. Ann Surg. 2003;238:161–167.

8. Percutaneous balloon aortic valvuloplasty:acute and 30-day follow-up results in 674patients from the NHLBI Balloon Valvulo-plasty Registry. Circulation. 1991;84:2383–2397.

9. Horstkotte D, Loogen F. The natural historyof aortic valve stenosis. Eur Heart J. 1988;9(suppl E):57–64.

10. Kuntz RE, Tosteson AN, Berman AD,Goldman L, Gordon PC, Leonard BM,McKay RG, Diver DJ, Safian RD. Predictorsof event-free survival after balloon aorticvalvuloplasty. N Engl J Med. 1991;325:17–23.

10a.Cribier A, Savin T, Saoudi N, Rocha P,Berland J, Letac B. Percutaneous trans-luminal valvuloplasty of acquired aorticstenosis in elderly patients: an alternative tovalve replacement? Lancet. 1986;1:63–67.

11. Eisenhauer AC, Hadjipetrou P, PiemonteTC. Balloon aortic valvuloplasty revisited:the role of the Inoue balloon and transseptalantegrade approach. Catheter CardiovascInterv. 2000;50:484–491.

12. Feldman T. Transseptal antegrade access foraortic valvuloplasty. Catheter CardiovascInterv. 2000;50:492–494.

13. Agarwal A, Kini AS, Attanti S, Lee PC,Ashtiani R, Steinheimer AM, Moreno PR,

Sharma SK. Results of repeat balloon valvu-loplasty for treatment of aortic stenosis inpatients aged 59 to 104 years. Am J Cardiol.2005;95:43–47.

14. Eltchaninoff H, Cribier A, Tron C, AnselmeF, Koning R, Soyer R, Letac B. Balloonaortic valvuloplasty in elderly patients athigh risk for surgery, or inoperable:immediate and mid-term results. EurHeart J. 1995;16:1079–1084.

15. Pedersen WR, Van Tassel RA, Pierce TA,Pence DM, Monyak DJ, Kim TH, HarrisKM, Knickelbine T, Lesser JR, Madison JD,Mooney MR, Goldenberg IF, Longe TF,Poulose AK, Graham KJ, Nelson RR,Pritzker MR, Pagan-Carlo LA, Boisjolie CR,Zenovich AG, Schwartz RS. Radiation fol-lowing percutaneous balloon aortic valvulo-plasty to prevent restenosis (RADAR pilottrial). Catheter Cardiovasc Interv. 2006;68:183–192.

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