Europace Advance Access originally published online on December 4, 2008
Europace 2009 11(1):86-88; doi:10.1093/europace/eun326
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Pacing and Cardiac Resynchronization Therapy
Cardiac resynchronization therapy may improve symptoms of congestive heart failure in patients without electrical or mechanical dyssynchrony
Department of Cardiology, Texas Heart Institute at St Luke’s Episcopal Hospital, Houston, 6624 Fannin, Suite 2480, Houston, TX, USA
Manuscript submitted 26 August 2008. Accepted after revision 7 November 2008.
* Corresponding author. Tel: +1 832 355 8305; fax: +1 713 796 8186. E-mail address: mehdirazavi1{at}gmail.com/atodensky{at}heart.thi.tmc.edu
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Abstract |
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Aims: Cardiac resynchronization therapy (CRT) has reportedly not been effective in the absence of electrical or mechanical dyssynchrony. We present six patients with severe left ventricular (LV) dilation, mitral regurgitation (MR), and non-ischaemic cardiomyopathy who underwent CRT. We assessed the effects of CRT on LV ejection fraction (EF), LV dimensions, mitral valve regurgitant fraction (RF), pulmonary arterial pressures (PAP), and serum levels of B-natriuretic peptide (BNP).
Methods and results: All patients had severe LV dilation (
6.8 cm) and no electrical or mechanical dyssynchrony. All patients underwent CRT-D (with defibrillator) without complications. Average echocardiographic follow-up was 4.6 months. Mean LVEF increased significantly from 20.8 ± 3.4 to 28.3 ± 2.9% after CRT (P < 0.01). Mean LV end-diastolic dimension decreased significantly from 6.9 ± 0.15 to 6.45 ± 0.33 cm after CRT (P = 0.03); mean BNP serum level decreased from 1738 ± 526 to 1040 ± 768 pg/mL (P = 0.07). Baseline RF decreased from 45 ± 12.2 to 20 ± 10.9% after CRT-D (P = 0.009). Mean PAP decreased from 48.5 ± 5.8 to 42.6 ± 5.2 (P = 0.03). In five patients, New York Heart Association class symptoms improved by at least one level. No patients required assist devices or transplantation. One patient was hospitalized during follow-up.
Conclusion: We describe six patients with severe LV dilation without evidence of electrical or mechanical dyssynchrony who improved with CRT, possibly due to improvement in MR.
Key Words: Cardiac resynchronization therapy, Dyssynchrony, Heart failure
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Introduction |
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Cardiac resynchronization therapy (CRT), with or without defibrillation (-D), improves quality and length of life in patients with cardiomyopathy, severe refractory congestive heart failure (CHF), and electrical dyssynchrony.1
–3 A recent study has indicated that this finding cannot be conclusively extended to those patients who have mechanical but not electrical dyssynchrony.4 Other recent studies have shown that the mechanism for improvement in CRT may be the reduction of mitral regurgitation (MR).5–9 This finding has not been extended to patients without electrical or mechanical dyssynchrony. We report a series of six patients with severe, symptomatic non-ischaemic cardiomyopathy without electrical or mechanical dyssynchrony who underwent CRT-D to prevent further deterioration in their condition. Despite the absence of established indications for CRT, their symptoms significantly improved.
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Methods |
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This retrospective study comprised a series of six patients representing our experience in CRT in patients without dyssynchrony. All patients provided a written informed consent for the procedure.
Patient characteristics
The patients represent our experience of CRT in patients without documentation of electrical or mechanical dyssynchrony between June 2006 and January 2008. All patients met the indications for implantation of a cardiac defibrillator for primary prevention of arrhythmic death based on a chronically depressed ejection fraction (EF) and moderately severe symptoms of CHF. None of the patients had evidence of electrical (QRS duration <110 ms)1,2 or mechanical dyssynchrony (echocardiography with tissue Doppler imaging using the criteria of septal to posterior wall delay of > 130 ms).5 All patients had non-ischaemic cardiomyopathy with severe left ventricular (LV) dilation (LV end-diastolic dimension 6.8 cm), which was the primary criterion for implantation. Patients were either referred or considered for referral for heart transplantation. The option of CRT was discussed in detail with all patients and was considered as a last resort before consideration for transplantation or use of an assist device. All patients had been on a stable pharmacologic regimen (see Results) for at least 3 months before implantation.
Cardiac resynchronization therapy-D implantation
The patients underwent left-sided implantation of the CRT device in a left axillary approach. The coronary sinus was cannulated using either a quadripolar 5-Fr electrophysiology catheter or an Amplatz II catheter. A mid- or posterolateral LV branch was successfully targeted in all patients. We implanted an atrial pacing lead and a dual-coil right ventricular lead, which was placed in an apical position. We used the manufacturer’s settings for atrioventricular sensed and paced delays (100 and 130 ms, respectively) and interventricular delays (0 ms); no optimization studies were performed.
Assessment of clinical outcome
The patient’s response was assessed based on the improvements in clinical symptoms. We performed follow-up echocardiograms at 
3 and 6 months visits (with variability). Patients’ medication requirements were reassessed at each visit. Echocardiograms were interpreted by cardiologists blinded to the pacing modality. MR was quantified as the regurgitant fraction (RF) and was defined as follows: forward flow through mitral valve—forward flow through aortic valve/forward flow through the mitral valve. The value was rounded to the nearest 5%. Mean pulmonary arterial pressures (PAP) were measured at baseline and after CRT-D. When available, we noted pre- and post-implantation levels of B-natriuretic peptide (BNP).
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Results |
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All patients (five men and one woman; mean age, 47.5 ± 3.6 years) underwent CRT-D without complications. The cause of cardiomyopathy was idiopathic in all patients. All patients had at least moderate MR. Mean QRS duration was 102 ± 6.4 ms. Two patients had first-degree atrioventricular conduction delay (220 and 230 ms). The mean PR interval was 184 ± 12 ms.
At the time of implantation, all patients had New York Heart Association (NYHA) Class III to IV symptoms of CHF and had been on angiotensin-converting enzyme (ACE) inhibitors and diuretics for at least 3 months. All but one patient had been taking carvedilol for at least 2 months before undergoing CRT.
The average echocardiographic follow up was 4.6 months (range, 3–8 months). The mean LVEF increased significantly from 20.8 ± 3.4% before CRT to 28.3 ± 2.9% after CRT (P < 0.01) (Table 1). The mean LV end-diastolic dimension decreased significantly from 6.9 ± 0.15 cm before CRT to 6.45 ± 0.33 cm after CRT (P = 0.03). There was no change in left atrial diameter (4.6 ± 1.3 cm before vs. 4.8 ± 0.9 cm after CRT; P = 0.32). The baseline RF was 45 ± 12.2% before CRT-D and 20 ± 10.9% after CRT-D (P = 0.009). Furthermore, the mean PAP decreased from 48.5 ± 5.8 to 42.6 ± 5.2 mmHg (P = 0.03). The mean BNP serum level was 1738 ± 526 pg/mL before and 1040 ± 768 pg/mL after CRT (P = 0.07). BNP levels were not available for one patient.
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In five patients, NYHA status improved by at least one class after CRT. No patient required an assist device or transplantation. Only a single instance of hospitalization occurred in the follow-up period. The dose of carvedilol was increased in three patients during the follow-up period, presumably due to increased blood pressure allowing more aggressive use of this agent. Two patients had their dose of diuretics decreased. There were no changes in ACE-I regimens. The one patient who did not show improvement after CRT had the smallest change in MR (10% decrease in RF).
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Discussion |
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To our knowledge, this report is the first to describe symptomatic and echocardiographic improvement after CRT therapy in patients with cardiomyopathy and CHF who have no evidence of electrical or mechanical dyssynchrony. This improvement is further supported by the finding of reduced serum levels of BNP after CRT. All patients in our study had markedly severe LV dilation, at least moderate MR, and non-ischaemic cardiomyopathy.
The cause of improvement in our patients cannot be definitively established. The changes in echocardiographic parameters and MR and the trend of decreasing BNP do not support a placebo effect. Our study comprised a selective group of patients who had greatly enlarged LV cavities. This severe enlargement may have limited synchronization of contraction of all LV segments. Symptomatic improvement seen after CRT therapy may have been associated with improvement of MR.5 In this population, MR is frequently due to annular dilation and delayed activation of the papillary muscles.6–8 Furthermore, the reduction of MR by CRT may relate to timing of the activation of the papillary muscles.9 Such delay may be possible without gross electrical or mechanical dyssynchrony in which case MR improvement would be seen without dyssynchrony. All patients in our study had at least moderate MR, and the one patient who did not show improvement after CRT was the only one who had no significant change in the degree of MR.
Another explanation for the improvement seen is that our patients may have had exercise-induced dyssynchrony without resting dyssynchrony. In a recent report, one-third of patients with severe heart failure without resting dyssynchrony showed evidence of mechanical dyssynchrony during bicycle exercise.10 Although possible, this explanation is less likely in our study because we noted improvement in all but one patient.
Moreover, the clinical benefit seen in our study may have been due to atrioventricular synchrony created by implantation of an atrial lead. Although we cannot definitively rule out this possibility, none of our patients had evidence of sinus node dysfunction. There was evidence of only mild atrioventricular conduction delay in two patients. In a series of 16 patients with severe non-ischaemic cardiomyopathy, Hochleitner et al.11 demonstrated that dual-chamber pacing can lead to symptomatic improvement. Nishimura et al.12 have shown that in patients with LV dysfunction dual-chamber pacing can lead to haemodynamic improvement. There was no correlation between baseline PR interval and degree of improvement in our patients. Pharmacologic therapy probably cannot be cited as the cause of improvement because all patients had been prescribed the optimal regimen on a long-term basis. Spontaneous regression is also possible but less likely given the chronic nature of the disease in all patients.
In a recent study, CRT therapy provided no benefit in patients who had mechanical but not electrical dyssynchrony.4 However, the authors of that study did not use LV cavity size as an inclusion criterion; the average LV end-diastolic dimension in their study was 6.5 cm in the control group and 6.6 cm in the CRT group, and 55% of patients had no or mild MR at baseline. In our study, all patients had at least moderate MR, and the smallest measurement for LV end-diastolic dimension was 6.8 cm. These differences in baseline patient characteristics may account for the discrepancies in results and the improvement seen in our patients.
Limitations
This is a retrospective, observational case series and has the limitations inherent to such studies. The number of patients is small, and we cannot offer a definitive mechanism for our observations. Assessment of mechanical dyssynchrony can be challenging.13 It is possible our patients had mechanical dyssynchrony that was not detected by our methods. Nevertheless, we found that CRT dramatically affected clinical outcome in our patients.
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Conclusion |
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We present a series of patients with severe LV dilation and non-ischaemic cardiomyopathy who had no evidence of electrical or mechanical dyssynchrony but who improved with CRT. Future studies are warranted to assess the reproducibility and possible mechanisms of our findings.
Conflict of interest: none declared.
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References |
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[1] Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, et al. MIRACLE Study Group. Multicenter InSync Randomized Clinical Evaluation: cardiac resynchronization in chronic heart failure. N Engl J Med (2002) 346:1845–53.
[2] Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, et al. Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Investigators: Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med (2004) 350:2140–50.
[3] Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, et al. 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.
[4] Beshai JF, Grimm RA, Nagueh SF, Baker JH 2nd, Beau SL, Greenberg SM, et al. RethinQ Study Investigators: cardiac-resynchronization therapy in heart failure with narrow QRS complexes. N Engl J Med (2007) 357:2461–71.
[5] St John Sutton MG, Plappert T, Abraham WT, Smith AL, DeLurgio DB, Leon AR, et al. Multicenter InSync Randomized Clinical Evaluation (MIRACLE) Study Group: Effect of cardiac resynchronization therapy on left ventricular size and function in chronic heart failure. Circulation (2003) 107:1985–90.
[6] Ypenburg C, Lancellotti P, Tops LF, Bleeker GB, Holman ER, Piérard LA, et al. Acute effects of initiation and withdrawal of cardiac resynchronization therapy on papillary muscle dyssynchrony and mitral regurgitation. J Am Coll Cardiol (2007) 50:2071–7.
[7] Ypenburg C, Lancellotti P, Tops LF, Boersma E, Bleeker GB, Holman ER, et al. Mechanism of improvement in mitral regurgitation after cardiac resynchronization therapy. Eur Heart J (2008) 29:757–65.
[8] 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) 19:1150–7.[CrossRef][Web of Science][Medline]
[9] 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.
[10] D’Andrea A, Caso P, Cuomo S, Scarafile R, Salerno G, Limongelli G, et al. Effect of dynamic myocardial dyssynchrony on mitral regurgitation during supine bicycle exercise stress echocardiography in patients with idiopathic dilated cardiomyopathy and ‘narrow’ QRS. Eur Heart J (2007) 28:1004–11.
[11] Hochleitner M, Hortnagl H, Ng CK, Hortnagl H, Gschnitzer F, Zechmann W. Usefulness of physiologic dual-chamber pacing in drug-resistant idiopathic dilated cardiomyopathy. Am J Cardiol (1990) 66:198–202.[CrossRef][Web of Science][Medline]
[12] Nishimura RA, Hayes DL, Holmes DR Jr, Tajik AJ. Mechanism of hemodynamic improvement by dual-chamber pacing for severe left ventricular dysfunction: an acute Doppler and catheterization hemodynamic study. J Am Coll Cardiol (1995) 25:281–8.[Abstract]
[13] Chung ES, Leon AR, Tavazzi L, Sun JP, Nihoyannopoulos P, Merlino J, et al. Results of the Predictors of Response to CRT (PROSPECT) trial. Circulation (2008) 117:2608–16.
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