Europace Advance Access originally published online on June 15, 2007
Europace 2007 9(9):757-761; doi:10.1093/europace/eum122
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
CARDIAC RESYNCHRONISATION THERAPY
Repercussion of functional mitral regurgitation on reverse remodelling in cardiac resynchronization therapy
Servicio de Cardiología, Hospital Universitario Virgen de la Victoria de Málaga, Campus de Teatinos s/n, Colonia Santa Ines, Malaga, Spain
Manuscript submitted 18 March 2007. Accepted after revision 17 May 2007.
* Corresponding author. Tel: +34 951031441; fax: +34 951032441. E-mail address: fjcabrera{at}secardiologia.es
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionConclusionReferences |
|---|
Aims Cardiac resynchronization therapy (CRT) reduces the degree of functional mitral regurgitation (FMR). However, FMR has also been associated with a lack of clinical response to CRT. We undertook this study to determine whether the presence of FMR influences the reverse remodelling induced by CRT.
Methods and results We used Doppler echocardiography to assess 20 patients with dilated cardiomyopathy before and 6 months after undergoing CRT. We evaluated the effect of reverse remodelling (reduction 
10% in end-systolic volume) according to the presence or absence of important FMR, defined as a regurgitant orifice area (ROA) of 0.20 cm2. Of the 20 patients (mean age, 64.7 ± 8.2 years, eight women), 9 had marked FMR (ROA 0.40 ± 0.12 cm2), 6 mild FMR (ROA 0.15 ± 0.02 cm2), and 5 had trivial or no FMR. CRT reduced the presence of mitral regurgitation by 33.3% and induced reverse remodelling in 60% of the patients. A ROA 0.20 cm2 was associated with a lack of reverse remodelling, despite presenting similar baseline characteristics and a reduction in asynchrony to the other patients. Reverse remodelling was produced in all the other patients, with a significant reduction in end-systolic volume (41.7 ± 21%; P = 0.003), accompanied by improvement in the ejection fraction (P = 0.003) and myocardial performance index (P = 0.027).
Conclusion CRT improved FMR, although the baseline presence of important mitral regurgitation, with a ROA 0.20 cm2, in patients undergoing CRT was associated with a lack of response in reverse remodelling.
Key Words: Cardiac resynchronization, Reverse remodelling, Mitral regurgitation
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionConclusionReferences |
|---|
Cardiac resynchronization therapy (CRT) has greatly improved the symptoms, functional capacity, and survival in patients with heart failure, and is accepted as a Class I indication for selected patients.1
,2 The lack of a clinical response to this therapy in 30% of patients has been associated with severe mitral regurgitation.3 However, despite the absence of a standardized definition of what can be considered an adequate response to CRT, medium- and long-term clinical improvement has been associated with greater left ventricular reverse remodelling.4 Moreover, reduction of the end-systolic volume strongly predicts lower mortality and fewer admissions for heart failure in the long term.5
Functional mitral regurgitation (FMR) in dilated cardiomyopathy results from an imbalance between the closing and the tethering forces that act on the mitral valve leaflets.6 Although CRT rapidly reduces the degree of FMR in the immediate7,8 and long term,9,10 little evidence exists concerning the impact of mitral insufficiency on reverse remodelling as a response to CRT.11
The aim of this study is to determine whether the presence of important FMR in patients with dilated cardiomyopathy affects left ventricular reverse remodelling when the patients undergo CRT.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionConclusionReferences |
|---|
Patients
The study included patients with dilated cardiomyopathy with an indication for CRT according to the clinical guidelines for the management of heart failure,1
,2 who successfully received a resynchronizer implant. Patients were excluded if the cardiomyopathy was of an ischaemic or valvular origin, if they were in atrial fibrillation or pacemaker rhythm, or if the echocardiographic images obtained were of insufficient technical quality for later analysis.
Protocol
The study protocol included a baseline clinical examination and a transthoracic echocardiogram, which was repeated 6 months after placement of the device. All the patients gave their informed consent.
In order to determine the repercussion of mitral regurgitation on the response to CRT, we compared the clinical and echocardiographic characteristics of the patients according to the presence or absence of moderate or severe mitral regurgitation, defined by a regurgitant orifice area (ROA) 0.20 cm2, as per the guidelines of the American Society of Echocardiography.12 A reduction of at least 10% in the end-systolic volume was considered to represent important reverse remodelling; this value has previously been identified as the optimal cut-off figure to predict long-term survival.5
Implant
The patients received their resynchronizer implants intravenously. Direct triple puncture of the left subclavian vein was performed in all cases. After creating the pocket, the right ventricular electrode was inserted and the stimulation thresholds were measured. Using a guidewire, a balloon catheter was introduced and the lumen inflated in the first part of the coronary sinus to occlude it and thus proceed to venography. The balloon catheter was then withdrawn and the left ventricular stimulation electrode was introduced via the guidewire, advancing it through a posterolateral or lateral vein (18 patients), or in some cases via the posterior middle cardiac vein (two patients). No epicardial approach was undertaken. Thresholds were measured of cardiac stimulation and phrenic nerve stimulation. Finally, the right atrial electrode was placed in the appendage and the thresholds measured. The guidewire was withdrawn from the coronary sinus and the device was connected to the three electrodes and placed in the pocket, which was sutured by layers.
After implantation, the atrioventricular interval was optimized for maximal diastolic filling using Doppler echocardiography.
Echocardiogram
Doppler echocardiography (Acuson CV70, Siemens Co.) was performed by an expert cardiologist during the month before and 6 months after implantation of the device. Each study included the same parameters: the dimensions of the atrium and the left ventricle were measured in M-mode in the parasternal long axis, and the volumes and ejection fraction were quantified by the Simpson method. Functional mitral regurgitation was defined as secondary to mitral annulus enlargement with restricting leaflet motion. Mitral regurgitation was quantified by calculating the ROA using the flow convergence method, as described previously.13 The diastolic sphericity index (DSI) and the systolic sphericity index (SSI) were calculated as the ratio between the end-diastolic volume or the end-systolic volume and the volume of a sphere with the diameter of the end-diastolic long axis or the end-systolic long axis, respectively, obtained in the four-chamber apical view.14 Interventricular dyssynchrony was calculated as the difference in time between the aortic and the pulmonary pre-ejection delay (from the QRS to the onset of flow). Intraventricular dyssynchrony was calculated from the difference in time in the contraction peak of the septum and the lateral wall of the left ventricle in M-mode, with the time between the onset of the QRS complex and the onset of aortic ejection in pulsed Doppler, and with the difference in time between the septal and lateral peak velocities in spectral DTI analysis. Atrioventricular dyssynchrony was assessed by the ratio of the diastolic filling time to the cycle length. The myocardial performance index was also analysed.15
Statistical analysis
The continuous variables were expressed as means ± SD and the categorical variables as percentages. The normal distribution of the variables was confirmed by the Shapiro–Wilks test. In the event of normality, the Levene test was used to compare the variance; if the variances were the same, the Student's t-test was used to compare the means and if the variances differed, the Welch test was used. In the event of lack of normality, the Mann–Whitney test was used to compare the means. The 
2 test was used to compare the qualitative variables. Statistical significance was set at a P < 0.05 for two ways. All the statistical analyses were carried out with SPSS (version 11.0, SPSS Inc., Chicago, IL, USA).
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionConclusionReferences |
|---|
Patients
The study included 20 patients (eight women, 40%) with a mean age of 64.7 ± 8.2 years. The aetiology in all cases was dilated cardiomyopathy in New York Heart Association (NYHA) functional class III. All 20 patients were receiving diuretics, 19 (95%) ACE-inhibitors or angiotensin II receptor blockers, 14 (70%) beta-blockers, and 15 (75%) spironolactone. All were in sinus rhythm and the mean duration of the QRS was 165.6 ± 18.3 ms.
The baseline echocardiographic evaluation showed severe ventricular dysfunction with a mean ejection fraction of 22.7 ± 6.45%. Nine patients had moderate or severe mitral regurgitation (mean ROA, 0.40 ± 0.12 cm2), six patients had mild mitral regurgitation (mean ROA, 0.15 ± 0.02), and five had trivial or no regurgitation.
Echocardiographic evolution after CRT
Echocardiographic follow-up study of the whole group of patients 6 months after placement of the resynchronizer (Table 1) showed a significant normalization of the parameters of intraventricular, interventricular, and atrioventricular asynchrony. This was associated with a reduction in the left ventricular end-systolic diameter and volume, accompanied by an increase in the ejection fraction, improvement of the myocardial performance index, and a reduction in the diastolic and systolic indices of sphericity. Also noted at the follow-up study was a 33% reduction in the presence of important mitral regurgitation, with a significant reduction in the ROA. Reverse remodelling, considered as a reduction of at least 10% in the end-systolic volume, was seen in 12 patients (60%), with a mean relative reduction of 34.7 ± 23.0%.
|
Comparative effect of mitral regurgitation on CRT
Comparison was made between the group of patients with severe mitral regurgitation with a ROA
0.20 cm2 (SMR group, n = 9 patients) and the other patients, with mild or trivial regurgitation (NoSMR group, n = 11 patients). The programming of the devices was similar in both groups of patients, with no significant differences in the reduction of the QRS (Table 2).
|
At baseline, both groups had a similar degree of dyssynchrony, with no significant differences in ejection fraction, myocardial performance index, atrial size or sphericity indices (Table 3).
|
Analysis of the evolution of the two groups (Table 3) showed that the SMR patients experienced a significant improvement in baseline dyssynchrony, but no reduction was detected in the ventricular diameters and volumes, nor improvements in the ejection fraction or myocardial performance index, although there was a significant reduction in the ROA (P = 0.038). However, important mitral regurgitation persisted in 66.6% of the patients (two patients moderate and four severe).
The NoSMR group of patients experienced a similar improvement in the parameters of asynchrony to the SMR group. However, the NoSMR patients experienced a significant reduction in ventricular diameter (–6.3 ± 8.1% end-diastolic diameter, P = 0.032 and –13.5 ± 11.7% end-systolic diameter, P = 0.011), volume (–22.4 ± 26.6% end-diastolic volume, P = 0.016 and –41.7 ± 21.5% end-systolic volume, P = 0.003), and sphericity indices (–32.5 ± 32.2% DSI, P = 0.010 and –50.0 ± 19.5% SSI, P = 0.003). An improvement was also noted in the ejection fraction (P = 0.003) and myocardial performance index (P = 0.027) as compared with baseline levels.
The presence of a ROA < 0.20 cm2 prior to implantation was associated with a significant reduction in end-systolic volume (–41.7 ± 21%, P < 0.0001). This association remained if reverse remodelling after CRT was considered to be a reduction of at least 10% in the end-systolic volume (100% of the patients, P < 0.001). Using this cut-off point, the presence of a ROA 0.20 cm2 in this series was associated with 100% sensitivity and 90% specificity for the prediction of lack of reverse remodelling.
Clinical outcome
After a follow-up of 6 months (Table 4), NYHA functional class improved in 14 patients (3.0 vs. 2.1 ± 7.1 NYHA class; P = 0.001). No statistical difference was observed in the improvement of NYHA class between patients with/without FMR.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionConclusionReferences |
|---|
This initial series of patients with dilated cardiomyopathy who were candidates for resynchronization therapy showed that the baseline presence of important mitral regurgitation, defined here as a ROA
0.20 cm2, was associated with slight reverse remodelling after biventricular stimulation. On the other hand, those patients who had no, or just mild mitral regurgitation responded significantly to this therapy, not only with a reduction in left ventricular dimensions (with reverse remodelling in 100% of the patients) and improvement in systolic function, though with no tendency to restoring ventricular geometry, as witnessed by the reduction in the sphericity indices. This is of note, since in both groups of patients the device programming, reduction in the QRS width, and the reduction in asynchrony showed no significant differences. Nevertheless, we noticed that CRT reduced the ventricular volumes and systolic function in the group as a whole, as reported in earlier studies.9,16
Another important point is that, despite the differences detected in the subgroup analysis, the degree of mitral regurgitation was significantly reduced in both groups. However, although the SMR group experienced a significant decrease in the ROA, and in one-third of the patients the regurgitation ceased to be severe or moderate, only one patient had a reduction in the end-systolic volume of at least 10%. This all supports the idea that the medium-term effect of resynchronization therapy on FMR could depend to a greater extent on a more synchronous contraction than on ventricular remodelling, as has been suggested.17,18
Left ventricular remodelling in this series might be limited, at least in the medium term, by the presence of important mitral regurgitation. Nevertheless, reverse remodelling has been suggested to be progressive and continuous over time,4 and it is not known whether mitral regurgitation acts just as a slowing factor of this phenomenon, or whether the degree of mitral regurgitation is reduced in the longer term.
These results and observations support earlier studies that identified the presence of mitral regurgitation as a cause of the lack of response to CRT,3,11 as well as establishing a highly sensitive and specific cut-off point of a ROA 0.20 cm2, as it was significantly associated with the absence of medium-term reverse remodelling, a parameter that is associated not only with the clinical response4 but also with mortality and the rate of admissions due to heart failure.5 Our results could hypothesize that the presence of FMR would identify a more advanced stage in patients with dilated cardiomyopathy. Furthermore, a high proportion of patients continued to present a significant degree of mitral regurgitation after CRT, which has important prognostic implications, as it is associated with a high rate of mortality.19 Perhaps surgical or percutaneous correction of mitral regurgitation should be considerated as a potential alternative treatment in patients with FMR and advance heart failure.
Limitations
This was a small series which did not include patients with ventricular dysfunction of ischaemic origin, an aetiology with a different mechanism to explain the FMR and associated with a lack of response to CRT and, though this does make the sample more homogeneous.
Large studies done using gross indexes of mitral regurgitation11 indicate that greater MR at baseline is associated with less reverse remodelling. Thus, the present study supports these observations, using superior quantitative measures of mitral regurgitation, in a homogeneous cohort of dilated cardiomyopathy patients.
Though in our study FMR was not found to be in relation with clinical outcome, sample size does not look appropriate to analyse clinical outcomes. Anyway, the prognosis of patients after CRT looks to be more related with reverse remodelling than with clinical improvement.5
The results were those seen in the medium term, and we are unaware of whether these differences would be maintained in the longer term, or whether they would vary after biventricular stimulation.
|
Conclusion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionConclusionReferences |
|---|
The baseline presence of important mitral regurgitation, with a ROA
0.20 cm2, in patients with dilated cardiomyopathy who undergo CRT is associated with a lack of response in terms of reverse remodelling. Conflict of interest: none declared.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionConclusionReferences |
|---|
[1] Swedberg K, Cleland J, Dargie H, Drexler H, Follath F, Komajda M, et al. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): the Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardilogy. Eur Heart J (2005) 26:1115–40.
[2] Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, et al. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: summary article: a report from the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation (2005) 112:1825–52.
[3] Diaz-Infante E, Mont L, Leal J, García-Bolao I, Fernández-Lozano I, Hernández-Madrid A, et al. Predictors of lack of response to resynchronyzation therapy. Am J Cardiol (2005) 95:1436–40.[CrossRef][Web of Science][Medline]
[4] Vidal B, Sitges M, Marigliano A, Diaz-Infante E, Azqueta M, Tamborero D, et al. Relation of response to cardiac resynchronization therapy to left ventricular reverse remodelling. Am J Cardiol (2006) 97:876–81.[CrossRef][Web of Science][Medline]
[5] Yu CM, Bleeker GB, Fung JWH, Schalij MJ, Zhang Q, van der Wall EE, et al. Left ventricular reverse remodelling but not clinical improvement predicts long-term survival after cardiac resynchronization therapy. Circulation (2005) 112:1580–6.
[6] Otsuji Y, Handschumacher MD, Schwammenthal E, Jiang L, Song JK, Guerrero JL, et al. Insights from three-dimensional echocardiography into the mechanism of functional mitral regurgitation: direct in vivo demonstration of altered leaflet tethering geometry. Circulation (1997) 96:1999–2008.
[7] Breithardt OA, Sinha AM, Schwammenthal E, Bidaoui N, Markus KU, Franke A, et al. Acute effects of cardiac resynchronization therapy on functional mitral regurgitation in advanced systolic heart failure. J Am Coll Cardiol (2003) 41:765–70.
[8] Kanzaki H, Bazaz R, Schwartzman D, Dohi K, Sade LE, Gorcsan J 3rd. A mechanism for immediate reduction in mitral regurgitation after cardiac resynchronization therapy: insights from mechanical activation strain mapping. J Am Coll Cardiol (2004) 44:1619–25.
[9] Cleland J, Daubert J, Erdmann E, Freenatle N, Gras D, Kappenberger L, et al. for the cardiac resynchronization-heart failure (CARE-HF) study investigators. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med (2005) 352:1539–49.
[10] Brandt RR, Reiner C, Arnold R, Sperzerl J, Pitschner HF, Hamm CW. Contractile response and mitral regurgitation after temporary interruption of long-term cardiac resynchronization therapy. Eur Heart J (2006) 27:187–92.
[11] Cappola TP, Harsch MR, Jessup M, Abraham WT, Young JB, Petersen-Stejskal S, et al. Predictors of remodelling in the CRT era: influence of mitral regurgitation, BNP, and gender. J Card Fail (2006) 12:182–8.[CrossRef][Web of Science][Medline]
[12] Zoghbi WA, Enriquez-Sarano M, Foster E, Grayburn PA, Kraft CD, Levine RA, et al. Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr (2003) 16:777–802.[CrossRef][Web of Science][Medline]
[13] Enriquez-Sarano M, Millar FA Jr, Hayes SN, Bailey KR, Seward JB. Effective mitral regurgitant orifice area: clinical use and pitfalls of the proximal isovelocity surface area method. J Am Coll Cardiol (1995) 25:703–9.[Abstract]
[14] Tischler MD, Niggel J, Borowski DT, LeWinter MM. Relation between left ventricular shape and exercise capacity in patients with left ventricular dysfunction. J Am Coll Cardiol (1993) 22:751–7.[Abstract]
[15] Tei C, Ling LH, Hodge DO, Bailey KR, Oh JK, Rodeheffer RJ, Tajik AJ, et al. New index of combined systolic and diastolic myocardial performance: a simple and reproducible measure of cardiac function—a study in normals and dilated cardiomyopathy. J Cardiol (1995) 26:357–66.[Medline]
[16] Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, et al. for the MIRACLE Study Group. Cardiac resynchronization in chronic heart failure. N Engl Med (2002) 346:1845–53.
[17] Porciani MC, Macioce R, Demarchi G, Chiostri M, Musilli N, Cappelli F, et al. Effects of cardiac resynchronization therapy on the mechanisms underlying functional mitral regurgitation in congestive heart failure. Eur J Echocardiogr (2006) 7:31–9.
[18] Karvounis HI, Dalamaga EG, Papadopoulos CE, Karamitsos TD, Vassilikos V, Paraskevaidis S, et al. Improved papillary muscle function attenuates functional mitral regurgitation in patients with dilated cardiomyopathy after cardiac resynchronization therapy. J Am Soc Echocardiogr (2006) 19(9):1150–7.[CrossRef][Web of Science][Medline]
[19] Robbins JD, Maniar PB, Cotts W, Parker MA, Bonow RO, Gjeorghiade M. Prevalence and severity of mitral regurgitation in chronic systolic heart failure. Am J Cardiol (2003) 91:360–2.[CrossRef][Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  U. Bildirici, A. Vural, A. Agacdiken, T. Sahin, U. Celikyurt, T. Kilic, and D. Ural Comparison of the effects of left vs. right ventricular pacing on left ventricular remodelling Europace, December 1, 2008; 10(12): 1387 - 1391. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||