Download Should Moderate or Greater Mitral Regurgitation Be Repaired in All

yes no Was this document useful for you?
   Thank you for your participation!

* Your assessment is very important for improving the work of artificial intelligence, which forms the content of this project

Should Moderate or Greater Mitral
Regurgitation Be Repaired in All Patients
With LVEF <30%?
Downloaded from by guest on May 12, 2017
Surgery, Mitral Regurgitation, and Heart Failure
The Valves Are All Repairable But the Patients Are Not
Edwin C. McGee, Jr, MD
espite advances in medical and surgical therapy, heart
failure continues to be a formidable problem. More than
5 million individuals are affected by heart failure in the
United States, and it is estimated that 550 000 new cases are
diagnosed annually ( Advances
have been made with medical therapy and cardiac resynchronization, but despite such measures, outcomes remain poor in
individuals with advanced heart failure.1 Cardiac transplantation, the ultimate therapy for end-stage heart failure, is
plagued by the limited supply of donor hearts and the need for
lifelong immunosuppression. It remains, and will always be,
a therapy that benefits, at best, only a few thousand individuals each year. Ventricular assist devices are improving but
are still limited by problems such as infection and thromboembolism. Although several promising ventricular assist
devices are in trial or recently approved, they are only
available for those with the most advanced heart failure.2,3
For all intents and purposes the field of mechanical assistance
remains, if not in its infancy, in its childhood.
Many patients once thought to need transplant can benefit
from conventional surgery like bypass and valve repair.
Mahon et al4 from the Cleveland Clinic demonstrated equivalent intermediate survival for transplant and conventional
surgery in a group of patients initially referred for transplant.
We have learned from the ventricular reconstruction literature
that many patients with advanced cardiomyopathy can have
excellent long-term survival after conventional surgery.5–7
Surgeons who frequently deal with ischemic cardiomyopathy
now no longer focus on left ventricular function, but rather
the degree of hibernating myocardium that can be revascularized.8 Modern surgical heart failure specialists look for
targets of opportunity which, when corrected, will help their
patients’ compromised ventricles function more efficiently
and potentially reverse remodel. Many heart failure patients
can benefit from conventional surgical repairs but it is naïve
to think that all patients with cardiomyopathy will benefit
from standard surgeries like coronary bypass and valve
repair. The critical issue is discerning those patients that will
benefit from those that will not. In other words, when is
enough, enough?
Surgeons tend to be ego driven and appreciate sports
analogies. We love to make first downs and put points on the
board. We love it when our patients do well and manifest
dramatic improvements. However, our “interceptions” do not
lead to turnovers but rather patient morbidity and sometimes
death. A key to successful conventional heart failure surgery
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. This article is Part II of a 2-part
article. Part I appears on page 281.
From the Bluhm Cardiovascular Institute, Northwestern Memorial Hospital, and Department of Surgery, Northwestern University’s Feinberg School
of Medicine, Chicago, Ill.
Correspondence to Edwin C. McGee, Jr, MD, Heart Transplantation and Mechanical Assistance, Cardiac Surgery, 201 East Huron St, Suite 11-140,
Chicago, IL 60611. E-mail [email protected]
(Circ Heart Fail. 2008;1:285-289.)
© 2008 American Heart Association, Inc.
Circ Heart Fail is available at
DOI: 10.1161/CIRCHEARTFAILURE.108.800185
Circ Heart Fail
November 2008
Downloaded from by guest on May 12, 2017
is being able to discriminate the patients that will improve from
those that will not benefit or be potentially harmed from a
surgical procedure. It is critical to recognize that in some patients
it is often wise to “punt,” to therapies such as transplant or
ventricular assist device (VAD), as opposed to trying a risky “Hail
Mary” type conventional procedure. One size does not fit all.
With these concepts in mind, how do we address the heart
failure patient with significant (3⫹/4⫹) functional mitral
regurgitation (MR)? MR is certainly an appealing target for
surgical intervention, as significant functional MR is present
in 49% of patients with heart failure.9 Functional MR is
caused either by annular dilatation (Carpentier type I) or
posterior leaflet restriction (Carpentier type IIIB).10) The
former pathology is found in dilated cardiomyopathy; the
latter is the hallmark of chronic ischemic MR. Both of these
forms of cardiomyopathy account for most cases of heart
failure in the developed world and are the leading diagnoses
of patients on our cardiac transplant waiting lists.11 In
functional MR, the leaflets are normal. Mitral repair in these
patients is easily accomplished by ring annuloplasty and is
straight forward. The question that begs is, “why not apply it
to all heart failure patients” with significant MR? If we can
fix their valves and alleviate MR, should not we do it before
resorting to other “drastic” therapies? Does not unrepaired
MR drive ventricular remodeling and thus fuel the heart
failure epidemic? Should not all of these individuals undergo
mitral valve repair (MVR) to give their ventricles a shot at
reverse remodeling?
Without question, any heart failure patient for whom mitral
repair is being considered for functional MR should be optimally
medically managed with ␤-blockers and angiotensin-converting
enzyme inhibitors. Optimal medical management is the cornerstone of modern heart failure therapy. In addition to providing a
survival benefit, pharmacological therapy may reduce the severity of functional MR.12 Furthermore, cardiac resynchronization
therapy can decrease MR in select patients.12 However, in many
patients severe functional MR persists or recurs despite the
above measures. Repair is an attractive option in these patients
but must be considered before end organ dysfunction becomes
irreversible or right ventricular function becomes impaired, as
such conditions increase the risk of operative intervention and
impact on long-term outcomes.13–15
Advanced cardiac failure impacts greatly on end organ
function. Reversible end organ dysfunction can be improved
by improving cardiac output by the short-term use of inotropes. Irreversible renal failure or hepatic failure does not
respond to improved cardiac output and conventional surgical
procedures in such patients are bound to fail. Indeed, our
group rarely offers conventional surgery to inotrope dependent heart failure patients unless they have obstructive valvular pathology or are thought to have a great deal of
hibernating myocardium.16 We generally feel that patients
with MR whose ventricles are so compromised as to require
inotropes to maintain end organ perfusion are best managed
by transplant or mechanical assistance as destination therapy.
What about the patients we can help? Is it safe to repair
mitral valves in heart failure patients? The answer to this
question is an emphatic “yes.” It was once thought that all
patients with ventricular dysfunction and MR would suffer if
their mitral valves were made competent as they would lose
their pop-off valve.17 The “pop-off” theory has been disproved. Bolling18 was the first to demonstrate that MVR
could be safely performed in patients even with the most
compromised ventricles. In landmark studies from the University of Michigan, 140 patients (New York Heart Association class III/IV) with a mean ejection fraction of 26%
underwent a downsized mitral annuloplasty with an operative
mortality of 5%.18 Reverse ventricular remodeling, as evidenced by a decreased left ventricular end-diastolic diameter
and improvement in ventricular ejection fraction, New York
Heart Association class, and sphericity index were also
demonstrated.19 Bishay et al20 at the Cleveland Clinic demonstrated an operative mortality of 2.3% in 44 patients with
severe MR and severe left ventricular dysfunction, and also
demonstrated reverse ventricular remodeling.
The Acorn trial looked at outcomes of heart failure patients
treated with and without the Acorn cardiac support device.21
Those patients with significant MR (N⫽193) underwent
mitral surgery alone or mitral surgery plus placement of the
Acorn cardiac support device.22 Again an impressively low
operative mortality of 1.3% was demonstrated in the MVR
stratum, along with concrete evidence of reverse remodeling,
and improved quality of life.23 However, it is important to
understand that the Acorn trial was not designed as a
head-to-head comparison of MVR and medical therapy. It is
also important to realize that in all of these studies the very
low operative mortality rate is in part attributed to the fact that
some of the patients required bale out with mechanical
assistance and/or transplant. For example, the MVR stratum
(control arm) of the Acorn trial with its impressively low
operative mortality had 8 patients that needed support with a
VAD and 16 ultimately required transplant.23
These studies clearly show that select patients with severe
left ventricular dysfunction and severe MR can safely undergo ring annuloplasty and that their ventricles improve and
that quality of life improves. However, none of these studies
demonstrate an improvement in survival. In fact, a propensity
matched retrospective study by Wu et al24 from the University of Michigan, showed no improvement in survival for the
patients that underwent annuloplasty when compared with
optimal medical management (Figure 1). The authors conclude that a randomized trial is needed to better ascertain
outcomes for patients with ventricular dysfunction undergoing MVR.24
Prospective randomized trials are difficult to conduct in
surgical populations. Is there anything we can do short of a
head-to-head comparison of optimal medical therapy versus
mitral repair for severe functional MR, that can be undertaken? Can we delve deeper into the current literature to see
Downloaded from by guest on May 12, 2017
Figure 1. Event-free survival for non–mitral valve annuloplasty
group (solid line) and mitral valve annuloplasty group (dotted line).24
if we can elucidate which patients derive long-term benefit
from repair and which patients stay the same or worsen?
Ischemic mitral regurgitation (IMR) results from tethering
of the posterior mitral leaflet.10 It is truly a vexing problem.
Patients with IMR have been treated with revascularization
alone or revascularization plus mitral annuloplasty. The
repair is technically straight forward but many groups have
become nihilistic about the benefits of adding mitral annuloplasty for IMR given the high prevalence of recurrent MR and
the lack of demonstrable survival benefit. A series of 585
patients with IMR that underwent mitral annuloplasty at the
Cleveland Clinic demonstrated 30% rate of recurrent significant MR (3⫹/4⫹) at 1-year follow-up25 (Figure 2). A series
of 390 patients also from the Cleveland Clinic compared the
long-term functional status and survival in patients with IMR
treated with coronary bypass alone and bypass plus mitral
annuloplasty. Despite improved rates of early MR in the
group receiving annuloplasty,26 no difference either in terms
of 5-year functional status or survival was demonstrated26
(Figure 3). How do we explain this lack of benefit?
Recurrent functional MR is often explained away as being
the result of a “ventricular problem.” Valvular regurgitation
in these patients is secondary to annular dilatation or leaflet
tethering and is not caused by leaflet pathology per say. When
these patients do poorly their bad ventricles and the lack of
effective therapy for said bad ventricle is given as the
response. Certainly for some patients that is the case but then
why do some patients with functional MR manifest a benefit
from alleviating their MR. We are faced with the question of
whether the lack of benefit purely is the result of recurrence
or is the recurrence of significant MR a marker for a ventricle
that has passed the point of no return.
In terms of the issue of recurrent MR, are we doing all that
we can do to prevent recurrence? Are some methods of ring
Functional Mitral Regurgitation in Heart Failure
Figure 2. Recurrent ischemic MR and the effect of annuloplasty
type on return of 3⫹ or 4⫹ MR. The number of echocardiograms available at various time points is indicated, with the
number of patients in parentheses. Symbols represent crude
estimates of grouped raw data. Carpentier indicates CarpentierEdwards classic annuloplasty ring; Cosgrove, CosgroveEdwards annuloplasty system; Peri-Guard, bovine pericardial
annuloplasty more prone to recurrence than others? It was
long thought that only the posterior annulus dilates. The
intertrigonal or anterior annulus was thought to be fixed.
Recent human cadaveric studies have shown that proportional
dilatation occurs about the entire annulus and that the
intertrigonal distance is not fixed.27 Miller’s28 group at
Stanford has demonstrated intertrigonal dilation in an ovine
model of chronic IMR and recommend that IMR is best
managed by fixation of the intertrigonal and septal lateral
dimension with a complete annuloplasty ring.29 Spoor et al30
from the University of Michigan, in a study looking at risks
of recurrent MR in patients with functional MR and heart
failure, identified the use of flexible rings as a risk factor for
recurrent MR. Although ring type was not identified as a risk
for recurrent MR in the Cleveland series, most patients in that
series received partial, flexible rings.25 I think it is fair to
argue that at least some of the high recurrence rate in this
study was due to an annuloplasty technique that many feel is
not adequate by today’s standards; conversely, many patients
in this series were likely past the point of no return in terms
of their ventricular pathology. At any rate, it is not fair or
accurate to blame the high recurrence rate in this series
completely on the underlying pathology.
A recent study by Braun et al31 from the Netherlands may
shed some light on when patients pass the point of no return.
One hundred consecutive patients with IMR underwent coronary revascularization plus mitral annuloplasty with downsized complete rings.31 Only 1 of 75 patients available for late
follow-up had ⬎2⫹ MR,31 which is clearly an improvement
over the 20% rate of significant (3⫹/4⫹) recurrent MR in the
Cleveland Clinic series.25 In an earlier report from the group
in Leiden, a preoperative left ventricular end-diastolic diameter ⬍65 mm was predicative of reverse ventricular remod-
Circ Heart Fail
November 2008
Downloaded from by guest on May 12, 2017
Figure 3. Survival after coronary artery
bypass grafting either alone or with concomitant mitral valve annuloplasty for
functional ischemic MR.26
eling.32 In this most recent series, patients with an left
ventricular end-diastolic diameter ⬍65 mm had a 5-year
survival of 80% compared with a 49% 5-year survival in
patients with a preoperative left ventricular end-diastolic
diameter of ⬎65 mm.31
A study from Roshanali et al33 identified an interpapillary
muscle distance of ⬎20 mm as a risk factor for recurrent IMR
after repair. Calafiore et al34 identified tent height, defined as
the distance between the mitral annulus and point of leaflet
coaptation, ⬎10 mm as a risk factor for failure after annuloplasty for IMR. All of these measurements are surrogates for
large, end stage ventricles. Patients with any of these parameters should certainly undergo conventional surgery such as
mitral repair with caution.
It is important to realize that many heart failure patients
with functional MR will benefit from repair. It is equally
important to realize that not all heart failure patients will
manifest improvement after repair of functional MR. We
have ample evidence that repair can be accomplished in sick
patients with advanced heart failure with low morbidity and
mortality, but patients with severely remodeled ventricles,
right ventricular dysfunction, and end organ failure have
likely missed their therapeutic window. Despite evidence of
reverse ventricular remodeling and improved ventricular
function, retrospective studies have failed to demonstrate a
survival benefit for heart failure patients undergoing MVR, in
part because such studies are no doubt comparing apples and
oranges. Some patients are salvageable whereas others are
past the point of no return. A prospective randomized study is
needed to address the issue. Until such a study occurs,
certainly not all patients with an ejection fraction ⬍30% and
significant functional MR should undergo repair. As clinicians we need to focus on markers that identify patients that
have passed their window of opportunity. Certainly, questionable cases should be undertaken in centers that have experience in managing heart failure patients and that can offer
advanced techniques as salvage therapy. As surgeons we have
a great deal to offer heart failure patients but one size does not
fit all and sometimes a punt is better than a Hail Mary.
Functional Mitral Regurgitation in Heart Failure
Downloaded from by guest on May 12, 2017
1. Rose EA, Gelijns AC, Moskowitz AJ, Heitjan DF, Stevenson LW,
Dembitsky W, Long JW, Ascheim DD, Tierney AR, Levitan RG, Watson
JT, Meier P, Ronan NS, Shapiro PA, Lazar RM, Miller LW, Gupta L,
Frazier OH, Desvigne-Nickens P, Oz MC, Poirier VL. Long-term
mechanical left ventricular assistance for end-stage heart failure. N Engl
J Med. 2001;345:1435–1443.
2. Esmore DS, Kaye D, Salamonsen R, Buckland M, Begg JR, Negri J, Ayre P,
Woodard J, Rosenfeldt FL. Initial clinical experience with the VentrAssist
left ventricular assist device: the pilot trial. J Heart Lung Transplant. 2008;
3. Miller LW, Pagani FD, Russell SD, John R, Boyle AJ, Aaronson KD,
Conte JV, Naka Y, Mancini D, Delgado RM, MacGillivray TE, Farrar DJ,
Frazier OH. Use of a continuous-flow device in patients awaiting heart
transplantation. N Engl J Med. 2007;357:885– 896.
4. Mahon NG, O’Neill JO, Young JB, Bennett R, Hoercher K, Banbury MK,
Navia JL, Smedira NG, McCarthy PM, Starling RC. Contemporary
outcomes of outpatients referred for cardiac transplantation evaluation to
a tertiary heart failure center: impact of surgical alternatives. J Card Fail.
5. Athanasuleas CL, Buckberg GD, Stanley AW, Siler W, Dor V, Di Donato
M, Menicanti L, Almeida de Oliveira S, Beyersdorf F, Kron IL, Suma H,
Kouchoukos NT, Moore W, McCarthy PM, Oz MC, Fontan F, Scott ML,
Accola KA. Surgical ventricular restoration in the treatment of congestive
heart failure due to post-infarction ventricular dilation. J Am Coll Cardiol.
2004;44:1439 –1445.
6. O’Neill JO, Starling RC, McCarthy PM, Albert NM, Lytle BW, Navia J,
Young JB, Smedira N. The impact of left ventricular reconstruction on
survival in patients with ischemic cardiomyopathy. Eur J Cardiothorac
Surg. 2006;30:753–759.
7. Mickleborough LL, Maruyama H, Liu P, Mohamed S. Results of left
ventricular aneurysmectomy with a tailored scar excision and primary
closure technique. J Thorac Cardiovasc Surg. 1994;107:690 – 698.
8. Allman KC, Shaw LJ, Hachamovitch R, Udelson JE. Myocardial viability
testing and impact of revascularization on prognosis in patients with
coronary artery disease and left ventricular dysfunction: a meta-analysis.
J Am Coll Cardiol. 2002;39:1151–1158.
9. Koelling TM, Aaronson KD, Cody RJ, Bach DS, Armstrong WF. Prognostic
significance of mitral regurgitation and tricuspid regurgitation in patients
with left ventricular systolic dysfunction. Am Heart J. 2002;144:524–529.
10. Carpentier A. Cardiac valve surgery—the “French correction.” J Thorac
Cardiovasc Surg. 1983;86:323–337.
11. Taylor DO, Edwards LB, Boucek MM, Trulock EP, Aurora P, Christie J,
Dobbels F, Rahmel AO, Keck BM, Hertz MI. Registry of the International
Society for Heart and Lung Transplantation: twenty-fourth official adult heart
transplant report—2007. J Heart Lung Transplant. 2007;26:769–781.
12. Mehra MR, Reyes P, Benitez RM, Zimrin D, Gammie JS. Surgery for
severe mitral regurgitation and left ventricular failure: what do we really
know? J Card Fail. 2008;14:145–150.
13. Ngaage DL, Daly RC, Rosales G, Sundt TM III, Dearani JA, Mullany CJ,
McGregor CG, Orszulak TA, Puga FJ, Schaff HV. Mitral regurgitation
surgery in heart failure due to ischemic cardiomyopathy: a 24-year experience. J Heart Valve Dis. 2008;17:251–259; discussion 259 –260.
Di Mauro M, Calafiore AM, Penco M, Romano S, Di Giammarco G,
Gallina S. Mitral valve repair for dilated cardiomyopathy: predictive role
of right ventricular dysfunction. Eur Heart J. 2007;28:2510 –2516.
Szalay ZA, Civelek A, Hohe S, Brunner-LaRocca HP, Klovekorn WP, Knez I,
Vogt PR, Bauer EP. Mitral annuloplasty in patients with ischemic versus dilated
cardiomyopathy. Eur J Cardiothorac Surg. 2003;23:567–572.
McGee EC, McCarthy PM. Ventricular resconstruction and device
therapies for cardiomyopathy patients. In: McCarthy PM, Young JB, eds.
Heart Failure: A Combined Medical and Surgical Approach. Malden,
Mass: Blackwell Futura; 2007:174 –191.
Braunwald E. Heart Disease: a Textbook of Cardiovascular Medicine.
Philadelphia, Pa: Saunders; 1980:xix, 1943:cvi.
Bolling SF. Mitral reconstruction in cardiomyopathy. J Heart Valve Dis.
2002;11(suppl 1):S26 –S31.
Badhwar V, Bolling SF. Mitral valve surgery in the patient with left ventricular
dysfunction. Semin Thorac Cardiovasc Surg. 2002;14:133–136.
Bishay ES, McCarthy PM, Cosgrove DM, Hoercher KJ, Smedira NG,
Mukherjee D, White J, Blackstone EH. Mitral valve surgery in patients
with severe left ventricular dysfunction. Eur J Cardiothorac Surg. 2000;
Mann DL, Acker MA, Jessup M, Sabbah HN, Starling RC, Kubo SH. Rationale,
design, and methods for a pivotal randomized clinical trial for the assessment of
a cardiac support device in patients with New York health association class
III–IV heart failure. J Card Fail. 2004;10:185–192.
Acker MA. Clinical results with the Acorn cardiac restraint device with
and without mitral valve surgery. Semin Thorac Cardiovasc Surg. 2005;
Mann DL, Acker MA, Jessup M, Sabbah HN, Starling RC, Kubo SH.
Clinical evaluation of the CorCap Cardiac Support Device in patients
with dilated cardiomyopathy. Ann Thorac Surg. 2007;84:1226 –1235.
Wu AH, Aaronson KD, Bolling SF, Pagani FD, Welch K, Koelling TM.
Impact of mitral valve annuloplasty on mortality risk in patients with
mitral regurgitation and left ventricular systolic dysfunction. J Am Coll
Cardiol. 2005;45:381–387.
McGee EC, Gillinov AM, Blackstone EH, Rajeswaran J, Cohen G, Najam
F, Shiota T, Sabik JF, Lytle BW, McCarthy PM, Cosgrove DM.
Recurrent mitral regurgitation after annuloplasty for functional ischemic
mitral regurgitation. J Thorac Cardiovasc Surg. 2004;128:916 –924.
Mihaljevic T, Lam BK, Rajeswaran J, Takagaki M, Lauer MS, Gillinov
AM, Blackstone EH, Lytle BW. Impact of mitral valve annuloplasty
combined with revascularization in patients with functional ischemic
mitral regurgitation. J Am Coll Cardiol. 2007;49:2191–2201.
Hueb AC, Jatene FB, Moreira LF, Pomerantzeff PM, Kallas E, de
Oliveira SA. Ventricular remodeling and mitral valve modifications in
dilated cardiomyopathy: new insights from anatomic study. J Thorac
Cardiovasc Surg. 2002;124:1216 –1224.
Tibayan FA, Rodriguez F, Langer F, Zasio MK, Bailey L, Liang D,
Daughters GT, Ingels NB Jr, Miller DC. Annular remodeling in chronic
ischemic mitral regurgitation: ring selection implications. Ann Thorac
Surg. 2003;76:1549 –1554; discussion 1554 –1555.
Miller DC. Ischemic mitral regurgitation redux–to repair or to replace?
J Thorac Cardiovasc Surg. 2001;122:1059 –1062.
Spoor MT, Geltz A, Bolling SF. Flexible versus nonflexible mitral valve
rings for congestive heart failure: differential durability of repair. Circulation. 2006;114:I67–I71.
Braun J, van de Veire NR, Klautz RJ, Versteegh MI, Holman ER,
Westenberg JJ, Boersma E, van der Wall EE, Bax JJ, Dion RA.
Restrictive mitral annuloplasty cures ischemic mitral regurgitation and
heart failure. Ann Thorac Surg. 2008;85:430 – 436; discussion 436 – 437.
Braun J, Bax JJ, Versteegh MI, Voigt PG, Holman ER, Klautz RJ,
Boersma E, Dion RA. Preoperative left ventricular dimensions predict
reverse remodeling following restrictive mitral annuloplasty in ischemic
mitral regurgitation. Eur J Cardiothorac Surg. 2005;27:847– 853.
Roshanali F, Mandegar MH, Yousefnia MA, Rayatzadeh H, Alaeddini F.
A prospective study of predicting factors in ischemic mitral regurgitation
recurrence after ring annuloplasty. Ann Thorac Surg. 2007;84:745–749.
Calafiore AM, Di Mauro M, Gallina S, Di Giammarco G, Iaco AL,
Teodori G, Tavarozzi I. Mitral valve surgery for chronic ischemic mitral
regurgitation. Ann Thorac Surg. 2004;77:1989 –1997.
Surgery, Mitral Regurgitation, and Heart Failure: The Valves Are All Repairable But the
Patients Are Not
Edwin C. McGee, Jr
Downloaded from by guest on May 12, 2017
Circ Heart Fail. 2008;1:285-289
doi: 10.1161/CIRCHEARTFAILURE.108.800185
Circulation: Heart Failure is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX
Copyright © 2008 American Heart Association, Inc. All rights reserved.
Print ISSN: 1941-3289. Online ISSN: 1941-3297
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Circulation: Heart Failure can be obtained via RightsLink, a service of the Copyright Clearance Center, not
the Editorial Office. Once the online version of the published article for which permission is being requested is
located, click Request Permissions in the middle column of the Web page under Services. Further information
about this process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
Subscriptions: Information about subscribing to Circulation: Heart Failure is online at: