CORRESPONDENCE: LETTER TO THE EDITOR
Reply
Marc Vanderheyden, MD*,
Wilfried Mullens, MD and
Jozef Bartunek, MD, PhD
* OLV-Clinic, Cardiovascular Center Aalst, Cardiovascular Center, Moorselbaan 164, Aalst, 9300, Belgium (Email: marc.vanderheyden{at}olvz-aalst.be).
We thank Dr. Aiba and colleagues for discussing the pivotal findings described in our article (1) with regards to the effects of chronic cardiac resynchronization therapy (CRT) on myocardial gene expression. They question the magnitude of the effect of CRT in our study. The effect in responders is indeed robust and may be related to the prudent definition of responders. In fact, patients were categorized as responders only if they exhibited a relative increase in left ventricular ejection fraction (LVEF) of  25% together with an improvement in New York Heart Association functional class score >1 (2). This categorization may account for the rather large improvements in LVEF and left ventricular (LV) dimensions compared with other studies that did not include both reverse remodeling and clinical improvement as an indicator of response.
We acknowledge their concern about the paradoxically greater change in ejection fraction as well as in end-diastolic volumes in the whole study population compared with the responders group. After reviewing the data, we noticed typing errors in Table 3 of our article (1) that were responsible for the concern. The individual LVEF and end-diastolic volume at baseline and follow-up in all patients, responders, and nonresponders are summarized in Figure 1. In the whole study population, LV end-diastolic volume and ejection fraction at follow-up were 215 ± 20 ml and 31 ± 3%, respectively. This error is truly regretful, and we apologize. Nevertheless, we would like to point out that the error does not alter the data on the functional or molecular comparisons between the responders and nonresponders. In this regard, we respectfully point out that the magnitude of specific changes in LV dyssynchrony and phospholamban as being reported in the entire population is not greater than in any subgroup.
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Figure 1 LVEF and LVEDV at Baseline and Follow-Up In All Patients, Responders, and Nonresponders
BL= baseline; FU = follow-up; LVEDV = left ventricular end-diastolic volume; LVEF = left ventricular ejection fraction.
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A recent study also corroborated our finding that mechanical dyssynchrony itself might not favorable predict a successful response to CRT, but merely acts as an indicator for the presence of "hemodynamic reserve" in the setting of advanced heart failure (3). Therefore, less mechanical dyssynchrony, as evidenced in the nonresponders in our study, would indicate a more advanced degree of myocardial remodeling, less prone to favorably respond to CRT.
In addition, the paradox between the CRT effect on mechanical resynchronization and different impact on LV remodeling and function in responder versus nonresponder groups has been described previously (4). Similarly in the current study, although interventricular dyssynchrony decreased in both groups, baseline intraventricular LV dyssynchrony was greater in responders and decreased only in this group. This observation supports the hypothesis that although mechanical resynchronization may be required to reverse chamber dilation, the extent of the resynchronization alone does not always correlate with the therapeutic effect (5). Other contributing factors may be related to underlying disease, fibrosis, scar tissue, or the severity of molecular abnormalities governing excitation-contraction coupling (1,6). Therefore, it is interesting to emphasize that nonresponders had a greater baseline gene expression of  and /β major histocompatibility complex ratio as well as a trend toward greater gene expression of sarcoendoplasmatic reticulum Ca2+ ATPase. Thus, despite a similar degree of LV dysfunction, dyssynchrony, and clinical heart failure class, and a comparable extent of resynchronization, nonresponders were deemed "less sick" in terms of "molecular remodeling" and less likely to be responsive to CRT therapy. We do acknowledge this to be a provocative hypothesis; it obviously requires prospective validation in a larger cohort of patients in addition to the application of a more comprehensive assessment of transcriptional and translational changes before and after CRT.
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References
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1. Vanderheyden M, Mullens W, Delrue L, et al. Myocardial gene expression in heart failure patients treated with cardiac resynchronization therapy: responders versus nonresponders J Am Coll Cardiol 2008;51:129-136.[Abstract/Free Full Text]2. Penicka M, Bartunek J, De Bruyne B, et al. Improvement of left ventricular function after cardiac resynchronization therapy is predicted by tissue Doppler imaging echocardiography Circulation 2004;109:978-983.[Abstract/Free Full Text] 3. Mullens W, Borowski A, Curtin R, Grimm RA, Thomas JD, Tang WH. Mechanical dyssynchrony in advanced decompensated heart failure: relation to hemodynamic responses to intensive medical therapy Heart Rhythm 2008;5:1105-1110.[CrossRef][Web of Science][Medline] 4. Bleeker GB, Mollema SA, Holman ER, et al. Left ventricular resynchronization is mandatory for response to cardiac resynchronization therapy: analysis in patients with echocardiographic evidence of left ventricular dyssynchrony at baseline Circulation 2007;116:1440-1448.[Abstract/Free Full Text] 5. Kass DA. Highlighting the R in CRT Circulation 2007;116:1434-1436.[Free Full Text] 6. Ypenburg C, Schalij MJ, Bleeker GB, et al. Impact of viability and scar tissue on response to cardiac resynchronization therapy in ischaemic heart failure patients Eur Heart J 2007;28:33-41.[Abstract/Free Full Text]
Related Article
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Deciphering Gene Expression Profiling in Cardiac Resynchronization Therapy
- Takeshi Aiba, Andreas Barth, and Gordon F. Tomaselli
J. Am. Coll. Cardiol. 2008 52: 1177.
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