Journal of the American College of Cardiology
`© 2004 by the American College of Cardiology Foundation
`Published by Elsevier Inc.
`
`EXPEDITED REVIEW
`
`Vol. 43, No. 4, 2004
`ISSN 0735-1097/04/$30.00
`doi:10.1016/j.jacc.2003.11.026
`
`Early Experience With Percutaneous
`Transcatheter Implantation of Heart Valve
`Prosthesis for the Treatment of End-Stage
`Inoperable Patients With Calcific Aortic Stenosis
`Alain Cribier, MD, FACC,* He´le`ne Eltchaninoff, MD,* Christophe Tron, MD,* Fabrice Bauer, MD,*
`Carla Agatiello, MD,* Laurent Sebagh, MD,* Assaf Bash, PHD,§ Danielle Nusimovici, MD,§
`P. Y. Litzler, MD,† Jean-Paul Bessou, MD,† Martin B. Leon, MD, FACC‡
`Rouen, France; New York, New York; and Fort Lee, New Jersey
`OBJECTIVES
`
`METHODS
`
`RESULTS
`
`This study wad done to assess the results of percutaneous heart valve (PHV) implantation in
`non-surgical patients with end-stage calcific aortic stenosis.
`BACKGROUND Replacement of PHV has been shown to be feasible in animals and humans. We developed
`a PHV composed of three pericardial leaflets inserted within a balloon-expandable stainless
`steel stent. We report the acute and early follow-up results of the initial six PHV
`implantations.
`An anterograde approach was used in all cases. The PHV, crimped over a 22-mm diameter
`balloon, was advanced through a 24-F sheath from the femoral vein to the aortic valve and
`delivered by balloon inflation. Clinical, hemodynamic, and echocardiographic outcomes were
`assessed serially.
`All patients were in New York Heart Association functional class IV. The PHV was
`successfully delivered in five patients. Early migration with subsequent death occurred in one
`patient who presented with a torn native valve. Acute hemodynamic and angiographic results
`showed no residual gradient, mild (three patients) or severe (two patients) aortic regurgita-
`tion, and patent coronary arteries. On echocardiography, the aortic valve area was increased
`from 0.5 ⫾ 0.1 cm2 to 1.70 ⫾ 0.03 cm2 and the aortic regurgitation was paravalvular. Marked
`and sustained hemodynamic and clinical improvement was observed after successful PHV
`implants. The first three patients died of a non-cardiac cause at 18, 4, and 2 weeks,
`respectively, and the other patients are alive at 8 weeks with no signs of heart failure.
`CONCLUSIONS Implantation of the PHV can be achieved in patients with end-stage calcific aortic stenosis
`and might become an important therapeutic option for patients not amenable to surgical valve
`replacement.
`(J Am Coll Cardiol 2004;43:698–703) © 2004 by the American College of
`Cardiology Foundation
`
`Prolonged life expectancy has resulted in an aging popula-
`tion and, consequently, in an increased number of patients
`with degenerative calcific aortic stenosis. Surgical aortic
`valve replacement is the treatment of choice for a vast
`majority of patients, offering symptomatic relief and im-
`proving long-term survival (1,2). However, in a subset of
`patients, mainly elderly patients with declining overall
`health status or life-threatening comorbidities, aortic valve
`replacement is considered either too high risk or is contra-
`indicated. Balloon aortic valvuloplasty has been shown to
`provide temporary improvement of valvular function and
`relief of symptoms in this non-surgical population (3,4), but
`its use is impaired by an unacceptably high mid-term
`
`From the Departments of *Cardiology and †Cardiac Surgery, Charles Nicolle
`Hospital, University of Rouen, Rouen, France; ‡Cardiovascular Research Foundation,
`Lenox Hill Hospital, New York, New York; and §Percutaneous Valve Technologies,
`Fort Lee, New Jersey. Drs. Cribier and Leon have stock ownership in Percutaneous
`Valve Technologies Inc., the company that designed and provided the percutaneous
`valve used.
`Manuscript received October 10, 2003; revised manuscript received November 24,
`2003, accepted November 24, 2003.
`
`(within months) frequency of restenosis (5). Given the
`limited therapeutic options in this subset of patients, there
`has been interest in the development of a percutaneously
`delivered bioprosthetic aortic heart valve.
`Recent advances in stent and valve technologies have
`demonstrated that percutaneous valve replacement is feasi-
`ble in both animals and humans. The integration of a
`bioprosthetic valve and a stent was first demonstrated by
`Andersen et al. in 1992 (6) in which a porcine bioprosthesis
`attached to a wire-based stent was delivered at various aortic
`sites with satisfactory acute hemodynamic results. Since
`then, several other investigators have reported the implan-
`tation by catheter delivery techniques of prosthetic valves of
`various designs in animal models (7–11). The first clinical
`cases of percutaneous valve replacement in congenital heart
`disease were reported by Bonhoeffer et al. (12,13), who
`successfully implanted prosthetic heart valves made from
`bovine jugular vein and mounted onto a platinum-iridium
`stent and placed in stenotic right ventricle to pulmonary
`conduits with good immediate and long-term results.
`
`ENDOHEART AG, EX. 2028 Page 1
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`

`
`JACC Vol. 43, No. 4, 2004
`February 18, 2004:698–703
`
`Cribier et al.
`Percutaneous Heart Valve in Aortic Stenosis
`
`699
`
`Abbreviations and Acronyms
`PHV ⫽ percutaneous heart valve
`NYHA ⫽ New York Heart Association
`
`We developed an original percutaneous heart valve
`(PHV) that was initially composed of three bovine pericar-
`dial
`leaflets mounted within a stainless steel balloon-
`expandable stent (Percutaneous Valve Technologies Inc.,
`Fort Lee, New Jersey) with the goal of treating non-surgical
`patients with end-stage aortic stenosis. The stent is 14 mm
`in length and achieves a maximal diameter of 23 mm after
`full balloon inflation. Extensive ex-vivo testing and animal
`implantation studies have been completed (11), and we
`reported the successful
`implantation of this PHV in a
`patient with end-stage aortic stenosis (14). Since the first
`case, additional improvements to the PHV device have been
`made, and confirmatory pre-clinical testing (bench and
`animal) has been conducted with the goal of supporting
`further clinical studies. The new PHV is composed of three
`equine pericardial leaflets mounted within a reinforced stent
`frame (Fig. 1). Valve durability testing has completed 200
`million cycles (5 years). Our early clinical experiences in
`patients with PHV implantation are reported.
`
`METHODS
`
`Patients. From April 2002 to August 2003, PHV implan-
`tation was attempted in six patients, five males and one
`female, age 75 ⫾ 12 years (range 57 to 91 years) with severe
`calcific aortic stenosis and multiple comorbidities (Table 1).
`Each patient had been declined for surgery by cardiac
`surgeons owing to hemodynamic instability and/or severe
`comorbidities. Three of these patients were in cardiogenic
`shock and all were in New York Heart Association
`(NYHA) functional class IV congestive heart failure. Bal-
`loon valvuloplasty had been previously attempted in four
`cases, but either failed or led to early valve restenosis.
`Transthoracic and transesophageal echocardiography dem-
`onstrated in all cases a heavily calcified aortic valve (bicuspid
`in Patient 1 and tricuspid in all other cases), with a valve
`area ⱕ0.6 cm2 by the continuity equation, and in all but one
`patient (Patient 2), a low transvalvular gradient (⬍50 mm
`Hg) due to severe left ventricular dysfunction. Moderate to
`severe aortic regurgitation was present in four patients and
`mitral regurgitation in five patients. Detailed echocardio-
`graphic parameters are shown in Table 2. Only one patient
`(Patient 6) had associated coronary artery disease (right
`coronary occlusion at the ostium).
`Approval of our institutional ethic committee for com-
`passionate PHV implantation was obtained for each case,
`and all patients and their closest relatives gave informed
`consent.
`Procedure. Each procedure was performed under local
`anesthesia and mild sedation. Aspirin (160 mg) and clopi-
`dogrel (300 mg) were administered the day before the
`
`procedure. In all cases, the anterograde trans-septal ap-
`proach was used for PHV implantation, as previously
`described (14). Briefly, basal hemodynamic parameters,
`supra-aortic, left ventricular, and coronary angiograms were
`first obtained. Trans-septal catheterization was performed
`from the right femoral vein, and heparin 5,000 IU was
`administered intravenously. A 7-F flotation balloon catheter
`was used for anterograde crossing of the aortic valve, and a
`stiff 0.035-inch guide wire was advanced through this
`catheter to the descending aorta and externalized through
`the left femoral artery using a catheter snare. The trans-
`septal puncture site was then dilated with a 10-mm balloon
`catheter, and a 23-mm balloon catheter advanced from the
`right femoral vein was used to predilate the native aortic
`valve. Using a mechanical crimping device, the PHV was
`securely crimped over a 23- or 22-mm (last four cases)
`diameter, 30-mm length balloon catheter (Z-Med II,
`NuMed Inc., Hopkinton, New York). Through a 24-F
`sheath (Cook, Bjaeverskov, Denmark) placed into the right
`femoral vein, the PHV was advanced over the wire, across
`the interatrial septum, and within the stenotic native valve.
`The following steps of valve implantation are shown in
`Figure 2. In the antero-posterior view, the valvular calcifi-
`cation and a frozen view of a supra-angiogram were used as
`markers to position the PHV at the mid-portion of the
`native aortic valve. In the last four cases, accurate position-
`ing was further facilitated by the use of a 7-F Sones catheter
`advanced from the left femoral artery over the same guide
`wire and placed in contact with the distal end of the delivery
`balloon catheter. The Sones catheter also prevented antero-
`grade dislodgement of the delivery balloon during inflation.
`Using a 10/90 contrast/saline solution, PHV delivery was
`obtained by maximal balloon inflation followed by rapid
`deflation. To improve the precision of PHV implantation,
`in Patients 3 and 5, rapid cardiac pacing (200 to 220
`beats/min) of the right ventricle was undertaken during
`PHV delivery to decrease aortic blood flow and prevent the
`risk of PHV migration during balloon inflation. The deliv-
`ery balloon and the guide wire were withdrawn immediately
`after PHV delivery. Hemodynamic assessment and supra-
`
`Figure 1. Upper view of the percutaneous heart valve, made of three
`leaflets of equine pericardium inserted within a stainless steel stent.
`
`ENDOHEART AG, EX. 2028 Page 2
`EDWARDS LIFESCIENCES CORPORATION (PETITIONER) v. ENDOHEART AG (PATENT OWNER)
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`

`
`700
`
`Cribier etal.
`Percutaneous Heart Valve in Aortic Stenosis
`
`JACC Vol. 43, No. 4, 2004
`February 18, 2004:698–703
`
`Table 1. Clinical Characteristics of the Patients
`Patient
`Age Gender
`Cardiovascular Comorbidities
`
`1
`
`2
`
`3
`4
`
`5
`
`57
`
`80
`
`91
`63
`
`80
`
`M
`
`M
`
`M
`M
`
`F
`
`Severe PAD, aorto-bifemoral bypass, recent
`occlusion of the right limb, subacute leg ischemia
`Massive aortic regurgitation
`
`Pacemaker for syncopal complete AV block
`—
`
`Hypertension
`
`Noncardiac Comorbidities
`
`Lung cancer (left lobectomy), silicosis; chronic pancreatitis
`
`Recent stroke (⬍1 month); chronic renal failure; asbestosis;
`prostate cancer
`Cachexia (bedridden ⬎1 month, eschars); very old age (⬎90 yrs)
`Evolving rectal adenocarcinoma; severe COPD; chronic renal
`failure
`Polymetastatic (lung and bones) breast cancer with chest
`radiotherapy; COPD; kyphoscoliosis
`Chronic renal failure
`
`6
`
`77
`
`M
`
`Inferior MI (RCA occlusion), previous stroke with
`left hemispheric sequela; porcelain aorta
`AV ⫽ atrioventricular; COPD ⫽ chronic obstructive pulmonary disease; MI ⫽ myocardial infarction; PAD ⫽ peripheral artery disease; RCA ⫽ right coronary artery.
`
`aortic, left ventricular, and selective coronary angiograms (in
`the last four patients) were then performed as well as
`transthoracic and transesophageal echocardiography. The
`venous puncture sites were closed by manual compression
`whereas puncture closure devices (Angio-Seal, St. Jude
`Medical Europe, Zaventem, Belgium) were used to close
`the arterial entry sites. All patients were closely monitored
`during follow-up, including clinical assessments and se-
`quential transthoracic echocardiography and Doppler exam-
`inations at day 1 and weekly thereafter. The continuity
`equation was used to evaluate the PHV valve area during
`follow-up. Post-procedural treatment included aspirin (160
`mg) and clopidogrel (75 mg) daily. Subcutaneous low
`molecular weight heparin (enoxaparin, 40 mg/day) was
`administered during the hospitalization stay. No oral anti-
`coagulation was given.
`Statistical analysis. Comparison of echocardiographic
`variables before, after PHV implantation, and on follow-up
`was performed using the nonparametric Wilcoxon rank-
`sum test. Differences were considered significant at p ⬍
`0.05. Values are expressed as mean ⫾ standard deviation.
`
`RESULTS
`
`Immediate results. The PHV was successfully and accu-
`rately delivered in the subcoronary position in all but one
`patient. This patient (Patient 2) was in cardiogenic shock,
`and had severe aortic stenosis associated with massive aortic
`regurgitation due to a previous balloon aortic valvuloplasty-
`induced valve tear. The balloon-PHV assembly was ejected
`in the ascending aorta at the time of full balloon inflation,
`
`Table 2. Echocardiographic Characteristics of the Patients
`Mean Gradient (mm Hg)
`
`and the patient died shortly thereafter. On autopsy, the
`valve leaflets were disconnected from the annulus on one-
`third of its circumference. In all other cases, the PHV
`remained strongly anchored after delivery within the native
`valve. No residual gradient was observed on simultaneous
`aortic and ventricular pressure recordings. Post-implantation
`supra-aortic angiography revealed mild (three cases) or
`severe (two cases) aortic regurgitation and patent coronary
`arteries. Coronary ostia were consistently above the upper
`margin of the PHV on selective coronary angiography. The
`PHV function was dramatically improved on post-
`procedure echocardiographic evaluation (Table 2), with an
`increase in aortic valve area from 0.49 ⫾ 0.08 cm2 to 1.66 ⫾
`0.13 cm2 (p ⬍ 0.04) and a decrease in transvalvular gradient
`from 38 ⫾ 11 mm Hg to 5.6 ⫾ 3.4 mm Hg (p ⬍ 0.04).
`Aortic regurgitation was paravalvular in all cases. During the
`procedure, hemodynamic collapse occurred in Patients 2
`and 6 after balloon pre-dilation requiring transient external
`cardiac massage and adrenalin infusion. However, PHV
`implantation (which, in Patient 6, was performed during
`electromechanical dissociation and external cardiac mas-
`sage) could be accomplished and was instantaneously fol-
`lowed by full hemodynamic recovery. No other complica-
`tions ensued. Mean duration of the procedure was 134 ⫾ 23
`min, and mean fluoroscopy time was 28 ⫾ 14 min.
`Clinical course. The procedure was followed in all cases by
`dramatic clinical improvement, with immediate and sus-
`tained reduction of signs of heart failure. The initial three
`patients who survived the procedure (Patients 1, 3, and 4)
`died of non-cardiac complication at 18, 4, and 2 weeks,
`
`AVA (cm2)
`
`AR (0–4)
`
`EF (%)
`
`Patient
`
`Pre-
`
`Post-
`
`Follow-Up
`
`Pre-
`
`Post-
`
`Follow-Up
`
`Pre-
`
`Post-
`
`Pre-
`
`Follow-Up
`
`1.64
`1.82
`0.60
`8
`5
`35
`1
`1.65
`1.70
`0.50
`6
`4
`56
`3
`1.70
`1.74
`0.40
`4
`2
`30
`4
`1.62
`1.52
`0.43
`6
`6
`38
`5
`1.55
`1.62
`0.52
`13
`11
`31
`6
`1.63 ⫾ 0.05*
`1.66 ⫾ 0.13*
`0.49 ⫾ 0.08
`7.4 ⫾ 3.4*
`5.6 ⫾ 3.4*
`38 ⫾ 11
`Mean ⫾ SD
`Follow-up obtained at two weeks (Patient 3) and four weeks (Patients 1, 4, 5, and 6). *p ⫽ 0.04 compared to baseline.
`AR ⫽ aortic regurgitation; AVA ⫽ aortic valve area; EF ⫽ left ventricular ejection fraction; Pre- and Post- ⫽ pre- and post-implantation of percutaneous heart valve.
`
`1
`3
`1
`1
`3
`
`10
`29
`28
`34
`19
`24 ⫾ 9.5
`
`22
`40
`42
`53
`48
`41 ⫾ 12*
`
`0
`2
`0
`1
`2
`
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`

`
`JACC Vol. 43, No. 4, 2004
`February 18, 2004:698–703
`
`Cribier et al.
`Percutaneous Heart Valve in Aortic Stenosis
`
`701
`
`Figure 2. Sequential steps of implantation. (A) The percutaneous valve in position across the native calcific aortic valve before delivery. GW ⫽ extra-stiff
`guide wire; PM ⫽ pacemaker lead in the right ventricle for brief period of rapid pacing at the time of balloon inflation; Sones ⫽ Sones catheter advanced
`over the guide wire from the left femoral artery. (B) Balloon inflation for valve delivery. (C) Post-implantation supra-aortic angiogram showing mild aortic
`regurgitation. (D) Right anterior oblique-cranial view of the valve showing the circular stent frame pushing away the calcified native valve. Selective left
`(E) and right (F) coronary angiogram post-implantation showing patent coronary ostia.
`
`respectively. Causes of death were complications of leg
`amputation due to long-standing peripheral vascular disease
`(Patient 1); an acute abdominal syndrome (Patient 3; this
`91-year-old individual had been discharged at day 10
`post-procedure with no signs of heart failure); and hemor-
`rhage from rectal carcinoma (Patient 4). The most recent
`two patients were discharged at days 12 and 15, and they are
`clinically stable at 8 weeks with no symptoms of heart
`failure.
`Echocardiographic assessment. The PHV function re-
`mained normal and unchanged during follow-up with thin
`and mobile leaflets, no change in transvalvular gradient and
`valve area, and stable paravalvular aortic regurgitation (Ta-
`ble 2). From baseline to last echocardiographic evaluation,
`mean left ventricular ejection fraction increased from 24 ⫾
`9.5% to 41 ⫾ 12% (p ⬍ 0.04). The cylindrical PHV frame
`shape was maintained over time. Only mild transatrial
`shunting was observed on color flow Doppler studies in all
`cases.
`
`DISCUSSION
`
`This early experience confirms that a bioprosthetic valve can
`be implanted percutaneously within the native diseased
`stenotic aortic valve of patients with end-stage life-
`threatening calcific aortic stenosis, using standard interven-
`tional techniques under local anesthesia. This clinical appli-
`
`cation followed an animal model testing (11) in which the
`PHV could be delivered at various cardiac sites in the sheep
`with satisfactory immediate and short-term results. How-
`ever,
`implantation within the native aortic valve in the
`subcoronary position was technically difficult in this model,
`which varies considerably from humans, with limited space
`between the coronary ostia and the mitral valve (⬍6 mm),
`and a lack of calcific orfibrotic valvular lesion explaining the
`high rate of early (⬍15 days) PHV migration.
`Implantation of PHV leads to dramatic hemodynamic
`and clinical improvement with early and mid-term relief of
`signs of heart failure. The PHV can be accurately delivered
`in the subcoronary position without impairing the coronary
`ostia or the mitral valve, and attaches firmly within the
`diseased native valve. However, pre-procedure valve disrup-
`tion can impair the anchorage of the PHV, as shown in
`Patient 2. To avoid impinging of the coronary ostia at the
`time of PHV delivery, calcification of the native valve on
`fluoroscopy and the frozen selected frame of the supra-
`aortic angiogram showing the onset of
`the left main
`coronary artery were used as markers. This clinical experi-
`ence confirmed our postmortem observations that a 14-
`mm-long stent positioned at the mid-aortic valve does not
`cover the coronary ostia.
`The anterograde trans-septal approach that was used in
`all cases has several advantages over the more commonly
`
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`

`
`702
`
`Cribier etal.
`Percutaneous Heart Valve in Aortic Stenosis
`
`JACC Vol. 43, No. 4, 2004
`February 18, 2004:698–703
`
`Figure 3. Postmortem findings in Patient 3 (upper views). (Left to right) Right coronary (RCA) ostium (arrow); left coronary (LM) ostium (arrow); and
`free space between the percutaneous valve and the native valve confirming the mechanism of the paravalvular leak (PL).
`
`used retrograde approach to reach the aortic valve. This
`route allows percutaneous insertion of the PHV through a
`24-F sheath in the femoral vein under local anesthesia,
`eliminates the risk of arterial thrombosis, dissection, or
`rupture, and offers more predictable valve delivery since the
`PHV crosses the less diseased myocardial surface of the
`aortic leaflets and is coincident with the direction of blood
`flow. However, special attention must be given at each step
`of the procedure to maintain a large guide wire loop inside
`the left ventricle so as to avoid traction on the anterior
`mitral valve leaflet with subsequent severe mitral regurgita-
`tion and hemodynamic collapse. This complication occurred
`in two patients of this series when the wire was incidentally
`straightened from the mitral valve to the aortic valve.
`A brief period of rapid (200 to 220 beats/min) cardiac
`pacing causes sufficient impairment of cardiac output during
`PHV delivery to facilitate precise positioning of the device.
`This technique, previously used in our center in several
`balloon aortic valvuloplasty procedures,
`leads to optimal
`stabilization of the inflated balloon across the aortic valve.
`The 10-mm balloon used to dilate the interatrial septum did
`not create significant residual shunting as confirmed by
`echocardiography and Doppler imaging. However, in pa-
`tients with undiseased femoral arteries of suitable size for
`insertion of a 24-F sheath, the more familiar retrograde
`aortic approach might be faster and easier to manage for
`some interventional operators. Furthermore, it would avoid
`the potential risks of trans-septal catheterization and mitral
`valve crossing-induced mitral regurgitation and subsequent
`hemodynamic collapse.
`An aortic orifice valve area averaging 1.7 cm2 with
`minimal trans-PHV gradient was instantaneously obtained
`in all successful cases after PHV implantation. This repre-
`sents a ⬎3-fold improvement compared with baseline valve
`areas and was consistently associated with a striking early
`improvement of left ventricular function and subsequent
`clinical benefit. The results after PHV implantation are
`significantly better than those obtained after balloon aortic
`valvuloplasty, which rarely provides an increase in valve area
`above 0.8 cm2 (3,4). Of note, even in Patient 1, who had no
`myocardial contractility reserve, and in whom left ventric-
`
`ular ejection fraction remained severely impaired (20%),
`PHV implantation was followed by marked relief of signs of
`heart failure. Although ex-vivo studies indicate several-year
`valve durability, the stability of PHV function over time
`requires careful assessment and meticulous long-term pa-
`tient follow-up. However, in this selected population of
`dying patients in whom severe aortic stenosis is associated
`with multiple potentially fatal comorbidities, prolonged
`survival is unlikely, as shown by the post-procedure early
`deaths from non-cardiac cause in three of the patients.
`Paravalvular aortic regurgitation was noted in all patients
`post-PHV implantation. Echocardiography indicated that
`there might be imperfect apposition of the PHV stent frame
`against the diseased native valvular structures at the site of
`calcific nodules. This was confirmed on postmortem obser-
`vation in Patient 3 (Fig. 3). Although paravalvular aortic
`regurgitation did not blunt the early improvement in left
`ventricular function and clinical status after relief of the
`aortic valve blockage, severe paravalvular aortic regurgitation
`might impair long-term clinical outcomes after PHV im-
`plantation. Larger maximal stent diameters and other im-
`provements in stent design might decrease the incidence
`and severity of paravalvular aortic regurgitation in the
`future.
`Because the PHV is a bioprosthetic valve inserted within
`a stainless steel stent, the anticoagulant regimen was limited
`to antiplatelet therapy (aspirin and clopidogrel), without
`long-term oral direct thrombin inhibitors. Prophylactic
`anticoagulation with intravenous heparin in the first two
`cases, or low molecular weight heparin in the next cases, was
`added only during the hospital convalescent period.
`An ongoing pilot clinical trial in our center (I-REVIVE
`study) will allow further refinement of the technique and
`assessment of both short- and long-term clinical outcomes.
`Once the operator technique achieves consistent predictable
`results and beneficial long-term clinical outcomes can be
`demonstrated, pivotal multicenter clinical trials will be
`required to determine the role of this promising new
`therapeutic approach for patients with end-stage calcific
`aortic stenosis that is not amenable by surgical valve replace-
`ment.
`
`ENDOHEART AG, EX. 2028 Page 5
`EDWARDS LIFESCIENCES CORPORATION (PETITIONER) v. ENDOHEART AG (PATENT OWNER)
`Case No.: IPR2016-00300, U.S Patent No. 8,182,530
`
`

`
`JACC Vol. 43, No. 4, 2004
`February 18, 2004:698–703
`
`Cribier et al.
`Percutaneous Heart Valve in Aortic Stenosis
`
`703
`
`Acknowledgments
`The authors thank the entire staff of Percutaneous Valve
`Technologies Inc., Fort Lee, New Jersey: Stanton Rowe,
`Stanley Rabinovitch, Directors; Elsa Abruzzo, Research
`Coordinator; Benjamin Spencer and the whole group of
`engineers; and Raphael Amor, for their support in the
`research program and in the development of the device. We
`also thank Gerard Pontier for his help in the collection of
`data and the presentation of tables and figures, and the
`entire group of physicians, nurses, and technicians of the
`Department of Cardiology, Charles Nicolle Hospital,
`Rouen, for their help and dedication.
`
`Reprint requests and correspondence to: Dr. Alain Cribier,
`Service de Cardiologie, Hoˆpital Charles Nicolle, 1 rue de Germont,
`76 000, Rouen, France. E-mail: Alain.Cribier@chu-rouen.fr.
`
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`ENDOHEART AG, EX. 2028 Page 6
`EDWARDS LIFESCIENCES CORPORATION (PETITIONER) v. ENDOHEART AG (PATENT OWNER)
`Case No.: IPR2016-00300, U.S Patent No. 8,182,530