Content uploaded by Clif Alferness
Author content
All content in this area was uploaded by Clif Alferness on Jul 18, 2019
Content may be subject to copyright.
Feasibility and Short-Term Efficacy of Percutaneous Mitral
Annular Reduction for the Therapy of Heart
Failure–Induced Mitral Regurgitation
David M. Kaye, MBBS, PhD; Melissa Byrne, BSc, BApp Sc;
Clif Alferness, BE; John Power, BVSc, PhD
Background—Mitral regurgitation (MR) frequently accompanies congestive heart failure (CHF) and is associated with
poorer prognosis and more significantly impaired symptomatic status. Although surgical mitral valve annuloplasty has
the potential to offer benefit, concerns about the combined surgical risk and possible effects on ventricular performance
have limited progress. We evaluated the feasibility and short-term efficacy of a novel device placed in the coronary sinus
to reduce MR in the setting of CHF.
Methods and Results—CHF and MR were induced in 9 adult sheep by rapid ventricular pacing for 5 to 8 weeks. A mitral
annular constraint device was implanted percutaneously through the right internal jugular vein in the coronary sinus and
great cardiac vein to create a short-term stable reduction (24.9⫾2.5%) in the mitral annular septal–lateral dimension as
assessed echocardiographically. Right and left heart pressures and cardiac output were determined before and 15
minutes after device implantation. MR extent was examined echocardiographically and expressed as a ratio of left atrial
area (MR/LAA). After device placement, MR was substantially reduced from an MR/LAA of 42⫹6% to 4⫾3%
(P⬍0.01). In association, mean pulmonary wedge pressure was significantly reduced (26⫾3to18⫾3 mm Hg; P⬍0.01)
and mean cardiac output significantly increased (3.4⫾0.3 to 4.3⫾0.4 L/min; P⫽0.01).
Conclusions—In this model of CHF, percutaneous placement of a mitral annular constraint device in the coronary sinus
resulted in the short-term elimination or minimization of MR and was accompanied in the short term by favorable
hemodynamic effects. (Circulation. 2003;108:1795-1797.)
Key Words: regurgitation 䡲heart failure, congestive 䡲catheterization 䡲mitral valve
Mitral regurgitation (MR) frequently accompanies con-
gestive heart failure (CHF). The precise mechanism is
controversial and can relate to mitral annular dilatation or
tethering of the leaflets secondary to progressive ventricular
remodeling.
1–3
Once established, MR plays a pivotal role in
the pathophysiology of CHF. Several studies have shown that
the presence of MR in patients experiencing CHF is associ-
ated with poor outcome.
4,5
Although this observation could
suggest that MR is merely a marker of CHF severity, it is also
increasingly apparent that the development of MR hastens the
progression of CHF.
6,7
Although the precise mechanism for
the relationship between the presence of MR and CHF
progression remains somewhat uncertain, many potential
mechanisms could be proposed. These include the hemody-
namic overload imposed by MR per se, in addition to the
activation of cardiac sympathetic nerves
8
and proinflamma-
tory cytokines such as tumor necrosis factor-
␣
,
9
which could
also influence the outcome of CHF.
10,11
The presence of
functional MR in CHF also contributes substantially to the
development of symptoms. During exercise, load-dependent
increases in regurgitant fraction develop in conjunction with
substantial elevations in pulmonary arterial pressures and
blunted forward cardiac output responses.
12
In CHF without primary valvular pathology, various ther-
apeutic approaches have been used, including pharmacolog-
ical and surgical approaches. To date, the full potential role of
anatomic intervention on the mitral valve in CHF has been
limited in most centers by virtue of the relatively high
associated operative mortality rate.
13
Nevertheless, recent
data suggest that in patients with moderate to severe symp-
toms of CHF, surgical correction of MR can provide long-
term benefit.
14
Most typically, this is achieved by placement
of an annuloplasty ring in an effort to reduce the mitral valve
annulus and to improve coaptation of the valvular leaflets.
Given concerns about the mortality associated with pri-
mary mitral valve surgery in CHF, we have developed a
Received March 5, 2003; de novo received June 18, 2003; revision received August 22, 2003; accepted August 22, 2003.
From Wynn Department of Metabolic Cardiology (D.M.K.) and the Cardiac Division (D.M.K., M.B., J.P.), Baker Heart Research Institute, Melbourne,
Victoria, Australia; and Cardiac Dimensions, Inc (C.A.), Kirkland, Wash.
Drs Kaye and Power and C. Alferness are founders of and stockholders in Cardiac Dimensions, Inc, which financed this study. M. Byrne is a minor
stockholder in Cardiac Dimensions.
Correspondence to Associate Professor David Kaye, Wynn Department of Metabolic Cardiology, Baker Heart Research Institute, P.O. Box 6492, St
Kilda Rd Central, Melbourne, Victoria 8008, Australia. E-mail d.kaye@alfred.org.au
© 2003 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org DOI: 10.1161/01.CIR.0000096051.23734.28
1795
Brief Rapid Communications
Downloaded from http://ahajournals.org by on July 18, 2019
strategy for the percutaneous insertion of a device placed in
the coronary sinus (CS) and great cardiac vein that could be
used to reduce MR in the setting of CHF.
Methods
Induction of Dilated Cardiomyopathy and MR
Pacemakers, reprogrammed for high-rate pacing, (Sigma, Medtronic
Inc) and right ventricular pacing leads were implanted in 9 adult
sheep. After recovery, animals were paced at 190 bpm for between
5 and 8 weeks until MR of at least moderate severity had developed
as assessed by echocardiography (Cypress, Acuson).
Device Implantation and Hemodynamic
Assessment
On the day of device implantation, the pacemaker rate was reduced
below the underlying native rhythm. Approximately 30 minutes
later, the animals were anesthetized with bolus propofol (4 mg/kg
intravenously) followed by a continuous intravenous infusion of 15
mg/kg ketamine per hour and 30 mg/kg propofol per hour in
conjunction with positive pressure ventilation. All animals were
placed in the left lateral decubitus position and underwent transtho-
racic echocardiography. Left atrial cross-sectional area and mitral
annular dimensions were measured in the parasternal long-axis view.
The extent and area of the regurgitant jet was assessed using color
Doppler echocardiography. A 9F introducer sheath was subsequently
positioned in the right internal jugular vein. A flow-directed ther-
modilution (Swan-Ganz, Baxter-Edwards) catheter was positioned
for the determination of pulmonary arterial pressures and cardiac
output. An 8F guide sheath containing the device was subsequently
placed in the CS and advanced along the great cardiac vein to the
level of the anterior interventricular vein. A novel mitral annular
constraint device (Figure) was then placed in the CS/great cardiac
vein. The device is constructed of nitinol wire with distal and
proximal anchors connected by an intervening cable. The distal
anchor was first deployed from the guide sheath into the distal great
cardiac vein and locked in position. Tension was then applied to the
device such that there was a reduction in the underlying mitral
annular diameter of ⬇25%. The tension was maintained while the
proximal anchor was deployed into the body of the CS and locked in
position. The echocardiographic and hemodynamic assessments
were then repeated.
The investigation conforms with the Guide for the Care and Use
of Laboratory Animals published by the US National Institutes of
Health (NIH Publication No. 82-23, revised 1996).
Statistical Methods
Data are presented as mean⫾SEM. Within-subject responses were
analyzed using a paired ttest. A probability value ⬍0.05 was
considered statistically significant.
Results
The CS was successfully cannulated in all cases, allowing
placement of the annular support device in all cases. Before
device placement, the mitral regurgitant jet area exceeded
20% of the left atrial area in all animals. After device
positioning, there was a significant reduction in the mitral
annular dimension and in the extent of MR (Table). Further-
more, MR was absent in 7 of the 9 animals, with only trivial
MR in the remaining 2 animals. In conjunction, with the
echocardiographic findings, the mean cardiac output in-
creased significantly (Table), and this was accompanied by a
significant short-term reduction in pulmonary capillary
wedge pressure (Table). During the deployment period, no
atrial or ventricular arrhythmias occurred and the arterial
blood pressure remained unchanged (data not shown). No
episodes of CS perforation or dissection occurred.
Discussion
Several studies now indicate an association between the
presence of MR with poor outcome and worse functional
status for patients with CHF. Although pharmacological
15–17
and possibly biventricular pacing–based
18
strategies have
shown some capacity to alleviate MR in patients with CHF,
their effect is usually incomplete. Although surgical ap-
proaches to the reduction of MR associated with CHF have
been reported,
13,19
concern persists in relation to the high
mortality rate that accompanies surgery in patients with
severe heart failure and in relation to concerns over the
short-term hemodynamic effect of alleviating MR in the
setting of a failing ventricle.
The present study was performed in a well-characterized
model of CHF, in which the major cause of MR has been
previously shown to be annular dilatation and subsequent loss
of leaflet coaptation.
1
As a corollary, further studies will
focus on determining whether this novel approach is appli-
cable to MR that accompanies other forms of cardiomyopa-
thy, particularly that resulting from ischemic heart disease.
Study Limitations
In the present study, we only evaluated the short-term
hemodynamic effects of percutaneous mitral annular reduc-
tion in an experimental model in which MR developed
The position of the mitral annular constraint device in the CS
and its relation to the posterior aspect of the mitral valve. Ele-
ments of the device, including proximal and distal anchors and
an intervening cable, are depicted.
Echocardiographic and Hemodynamic Effect of Mitral
Annular Constraint
Parameter Baseline Implantation P
Mitral annular diameter, cm 4.17⫾0.14 3.24⫾0.11 ⬍0.001
MR:LA area, % 41.9⫾6.4 4.1⫾2.8 0.003
Cardiac output, L/min 3.4⫾0.3 4.3⫾0.4 0.01
PCWP, mm Hg 26⫾318⫾3⬍0.01
PAP mean, mm Hg 31⫾225⫾2⬍0.01
MR:LA area indicates ratio of mitral regurgitant jet to left atrial area; PCWP,
pulmonary capillary wedge pressure; and PAP, pulmonary artery pressure.
1796 Circulation October 14, 2003
Downloaded from http://ahajournals.org by on July 18, 2019
secondary to pacing-induced left ventricular dilatation. Ac-
cordingly, we cannot comment about the long-term efficacy
of this therapy alone, or in comparison to medical or surgical
therapy for heart failure–associated MR. In this study, we
used a relatively short-term model of MR, and device
deployment was accompanied by significant reductions in
both wedge pressure and pulmonary artery pressure. In the
setting of chronic severe MR, it is conceivable that chronic
increases in the pulmonary vascular resistance could limit the
reduction in pulmonary artery pressure. The significance of
this remains unclear because chronic remodeling of the
pulmonary vasculature could occur some time after reduction
of MR. Nevertheless, the hemodynamic benefit that we
observed in the present study resulted in a similar improve-
ment in cardiac output as that seen chronically with surgical
mitral annuloplasty.
20
Conclusion
We have shown for the first time that placement of a mitral
annular constraint device in the CS has the potential to
substantially reduce MR in an experimental model of dilated
cardiomyopathy. This was well tolerated in the short term and
accompanied by favorable hemodynamic effects. Further
detailed studies are required to evaluate the tolerability and
effectiveness of this novel therapy on left ventricular function
in the long term.
Acknowledgment
This study was financed by Cardiac Dimensions, Inc.
References
1. Timek TA, Dagum P, Lai DT, et al. Pathogenesis of mitral regurgitation
in tachycardia-induced cardiomyopathy. Circulation. 2001;104(suppl
I):I47–I53.
2. Hung J, Guerrero JL, Handschumacher MD, et al. Reverse ventricular
remodeling reduces ischemic mitral regurgitation: echo-guided device
application in the beating heart. Circulation. 2002;106:2594–2600.
3. Yiu SF, Enriquez-Sarano M, Tribouilloy C, et al. Determinants of the
degree of functional mitral regurgitation in patients with systolic left
ventricular dysfunction: a quantitative clinical study. Circulation. 2000;
102:1400–1406.
4. Blondheim DS, Jacobs LE, Kotler MN, et al. Dilated cardiomyopathy
with mitral regurgitation: decreased survival despite a low frequency of
left ventricular thrombus. Am Heart J. 1991;122:763–771.
5. Robbins JD, Maniar PB, Cotts W, et al. Prevalence and severity of mitral
regurgitation in chronic systolic heart failure. Am J Cardiol. 2003;91:
360–362.
6. Lamas GA, Mitchell GF, Flaker GC, et al. Clinical significance of mitral
regurgitation after acute myocardial infarction. Survival and Ventricular
Enlargement Investigators. Circulation. 1997;96:827–833.
7. Trichon BH, O’Connor CM. Secondary mitral and tricuspid regurgitation
accompanying left ventricular systolic dysfunction: is it important, and
how is it treated? Am Heart J. 2002;144:373–376.
8. Mehta RH, Supiano MA, Oral H, et al. Relation of systemic sympathetic
nervous system activation to echocardiographic left ventricular size and
performance and its implications in patients with mitral regurgitation.
Am J Cardiol. 2000;86:1193–1197.
9. Oral H, Sivasubramanian N, Dyke DB, et al. Myocardial proinflam-
matory cytokine expression and left ventricular remodeling in patients
with chronic mitral regurgitation. Circulation. 2003;107:831–837.
10. Kaye DM, Lefkovits J, Jennings G, et al. Adverse consequences of
increased cardiac sympathetic activity in the failing human heart. JAm
Coll Cardiol. 1995;26:1257–1263.
11. Rauchhaus M, Doehner W, Francis DP, et al. Plasma cytokine parameters
and mortality in patients with chronic heart failure. Circulation. 2000;
102:3060–3067.
12. Lapu-Bula R, Robert A, Van Craeynest D, et al. Contribution of exercise-
induced mitral regurgitation to exercise stroke volume and exercise
capacity in patients with left ventricular systolic dysfunction. Circulation.
2002;106:1342–1348.
13. Bolling SF. Mitral reconstruction in cardiomyopathy. J Heart Valve Dis.
2002;11(suppl 1):S26–S31.
14. Harris KM, Sundt TM III, Aeppli D, et al. Can late survival of patients
with moderate ischemic mitral regurgitation be impacted by intervention
on the valve? Ann Thorac Surg. 2002;74:1468–1475.
15. Capomolla S, Febo O, Gnemmi M, et al. Beta-blockade therapy in
chronic heart failure: diastolic function and mitral regurgitation
improvement by carvedilol. Am Heart J. 2000;139:596–608.
16. Rosario LB, Stevenson LW, Solomon SD, et al. The mechanism of
decrease in dynamic mitral regurgitation during heart failure treatment:
importance of reduction in the regurgitant orifice size. J Am Coll Cardiol.
1998;32:1819–1824.
17. Nemoto S, Hamawaki M, De Freitas G, et al. Differential effects of the
angiotensin-converting enzyme inhibitor lisinopril versus the beta-
adrenergic receptor blocker atenolol on hemodynamics and left ventric-
ular contractile function in experimental mitral regurgitation. J Am Coll
Cardiol. 2002;40:149–154.
18. Linde C, Leclercq C, Rex S, et al. Long-term benefits of biventricular
pacing in congestive heart failure: results from the MUltisite STimulation
in cardiomyopathy (MUSTIC) study. J Am Coll Cardiol. 2002;40:
111–118.
19. Alfieri O, Elefteriades JA, Chapolini RJ, et al. Novel suture device for
beating-heart mitral leaflet approximation. Ann Thorac Surg. 2002;74:
1488–1493.
20. Bolling SF. Intermediate term outcome of mitral reconstruction in car-
diomyopathy. J Thorac Cardiovasc Surg. 1998;115:381–388.
Kaye et al Therapy of Heart Failure–Induced MR 1797
Downloaded from http://ahajournals.org by on July 18, 2019
