European Heart Journal

European Heart Journal Advance Access originally published online on May 15, 2007
European Heart Journal 2007 28(17):2134-2141; doi:10.1093/eurheartj/ehm126

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Early and late effects of cardiac resynchronization therapy on exercise-induced mitral regurgitation: relationship with left ventricular dyssynchrony, remodelling and cardiopulmonary performance

Juraj Madaric¹, Marc Vanderheyden¹, Christophe Van Laethem¹, Katia Verhamme^2,3, Ann Feys¹, Marc Goethals¹, Sofie Verstreken¹, Peter Geelen¹, Martin Penicka¹, Bernard De Bruyne¹ and Jozef Bartunek^1,*

¹ Cardiovascular Center, OLV Ziekenhuis, Moorselbaan 164, BE-9300 Aalst, Belgium
² Department of Epidemiology, OLV Hospital, Aalst, Belgium
³ Pharmaco-Epidemiology Unit, Department of Medical Informatics, Erasmus MC, Rotterdam, The Netherlands

Received 10 August 2006; revised 6 February 2007; accepted 13 March 2007; online publish-ahead-of-print 15 May 2007.

^* Corresponding author. Tel: +32 53 72 4439; fax: +32 53 72 4185. E-mail address: jozef.bartunek{at}olvz-aalst.be

See page 2055 for the editorial comment on this article (doi:10.1093/eurheartj/ehm283)

	Abstract

Top Abstract Introduction Methods Results Discussion Supplementary material Acknowledgements References

 
Aims: Exercise-induced mitral regurgitation (MR) bears a poor prognosis in patients with congestive heart failure (CHF). Cardiac resynchronization therapy (CRT) is associated with improved clinical outcome but its effects on exercise-induced MR remain undetermined. We investigated serial changes in functional MR in relation to left ventricular (LV) remodelling and cardiopulmonary performance after CRT.

Methods and results: Twenty-eight patients with CHF (LV ejection fraction 25 ± 7%), broad QRS complex (171 ± 27 ms), and at least mild MR [effective regurgitant orifice (ERO) 0.25 ± 0.12 cm²] were studied with quantitative exercise echocardiography and cardiopulmonary exercise testing prior, within 1 week, and 3 months after CRT. Early after CRT, a decrease in LV dyssynchrony (from 54 ± 21 to 19 ± 7 ms, P < 0.001) and in MR at rest (ERO from 0.25 ± 0.12 to 0.20 ± 0.10 cm², P = 0.047) was observed. However, no change in exercise-induced increase in MR was observed (ERO from 0.34 ± 0.12 to 0.31 ± 0.16 cm², NS). Three months after CRT, a decrease in the mitral valve tenting area (from 3.3 ± 1.2 to 2.0 ± 0.6 cm², P < 0.001) and an increase in LV sphericity index (from 1.5 ± 0.3 to 1.8 ± 0.5, P < 0.001) were paralleled by an attenuation of exercise-induced MR (ERO 0.19 ± 0.06 cm², P = 0.001 vs. prior CRT). This was associated with an increase in LV ejection fraction (from 25 ± 7 to 35 ± 9%, P < 0.001), peak oxygen uptake (from 11.7 ± 2.4 to 13.7 ± 3.8 mL/kg/min, P = 0.001), and a decrease in Nt-pro-BNP (from 2777 ± 1681 to 1963 ± 1361 pg/mL, P = 0.067).

Conclusion: CRT is associated with acute decrease in resting MR but does not immediately attenuate exercise-induced MR. In contrast, only late, CRT-induced reversed LV remodelling and reduced mitral apparatus deformation are associated with a reduction in both resting and exercise-induced MR and with an improvement in cardiopulmonary performance.

Key Words: Cardiac resynchronization • Heart failure • Exercise • Mitral insufficiency • Cardiopulmonary performance

	Introduction

Top Abstract Introduction Methods Results Discussion Supplementary material Acknowledgements References

 
Chronic left ventricular (LV) dysfunction is frequently associated with functional mitral regurgitation (MR) caused by leaflets malcoaptation and negative chamber remodelling.¹ Furthermore, in patients with congestive heart failure (CHF), the exercise-induced MR adversely affects cardiopulmonary performance² and is associated with poor clinical prognosis.³ In patients with inducible MR, the poor prognosis appears to be related to the extent of exercise-induced MR rather than resting MR or severity of LV dysfunction.³ Cardiac resynchronization therapy (CRT) improves exercise tolerance, LV function,^4,5 and survival in patients with CHF and cardiac dyssynchrony.^6,7 Previous studies indicated that CRT is associated with acute improvement in resting MR.^4–10 However, the effects of CRT on exercise-induced MR are not understood. In the present study, we postulated that CRT improves both resting and exercise-induced MR in parallel to LV remodelling and that the reduction in exercise-induced MR contributes to the better cardiopulmonary performance. Accordingly, we studied serial changes in MR and LV remodelling at rest and during exercise in parallel to cardiopulmonary performance early and late after CRT.

	Methods

Top Abstract Introduction Methods Results Discussion Supplementary material Acknowledgements References

 
Patients
Among 37 consecutive patients undergoing CRT according to conventional criteria,¹¹ 28 were selected for the study based on the following inclusion criteria: presence of at least mild MR at rest, no echocardiographic evidence for organic mitral valve pathology, no previous history of mitral valve surgery, absence of aortic regurgitation > 1 grade, and presence of sinus rhythm.

Biventricular pacemaker implantation
Biventricular pacing devices were implanted as previously described.¹² The LV pacing electrode was positioned by transvenous approach through the coronary sinus into the lateral (eight patients) or posterolateral cardiac vein (20 patients). The device was programmed in DDD mode with a fixed short atrioventricular delay (115 ± 24 ms) to avoid pre-systolic MR. In nine patients, biventricular ICD devices were implanted because of episodes of sustained ventricular tachycardia and/or inducible ventricular arrhythmias at electrophysiological examination. The AV delay was optimized within 1 week after implantation using the Ritter method. The VV delay was not optimized during the study protocol.

Doppler echocardiography
Two-dimensional Doppler echocardiography was performed with a commercially available system (Accuson, Sequoia C512, USA) at baseline, within 1 week and at 3 months after CRT. Images were acquired in semi-supine position at rest and at peak exercise. Following morphological and functional analyses were performed from digitally and video-stored images off-line. First, LV end-diastolic and end-systolic volumes and LV ejection fraction were calculated using the biplane Simpson's formula.¹³ LV systolic sphericity index, defined as the ratio of length to width of the LV at end-systole was used as an index of LV remodelling.^14,15 Second, mitral valve deformation was assessed from changes in tenting area and mitral annulus diameter. Tenting area was defined as the area between the annulus and the mitral valve leaflets from the parasternal long-axis view at mid-systole.¹⁶ Mitral annular diameter was measured in apical four-chamber view at end-diastole. Third, the degree of MR was assessed using proximal isovelocity surface area method and quantitative Doppler method and quantified as effective regurgitant orifice (ERO) and regurgitant volume.^17,18 The results of these two methods were averaged and used for further analyses. In addition, pulsed-wave tissue Doppler imaging was used to assess LV dyssynchrony and interventricular dyssynchrony from regional time intervals between the onset of QRS complex and the onset of systolic myocardial velocity in basal segments of the left and right ventricles.¹⁹ LV dyssynchrony was defined as the maximum delay between basal LV segments. Interventricular dyssynchrony was determined as the difference between the most delayed basal segment of the LV and free right ventricular wall delay. Finally, the myocardial systolic velocity (Sm) from the lateral annulus was acquired. LV contractile reserve was assessed as the difference between resting and exercise-induced increase in Sm (Sm).

Exercise protocol
Patients underwent symptom-limited exercise test in semi-supine position with initial workload of 25 W for 2 min and with 10 W load increments each minute. Blood pressure was measured at rest, at the end of the each load increment, and at peak exercise. Doppler echocardiography recordings were taken during peak exercise and within 1 min after its termination. At peak exercise, LV morphology and recordings of MR were obtained in all patients. Tissue doppler imaging (TDI) recordings of time interval for assessment of LV dyssyncrhony in basal segments were successfully obtained in all but five patients. In these patients, LV dyssynchrony was assessed only from the time intervals measured in basal LV septal, posterolateral, and right ventricular segments.

Cardiopulmonary exercise testing
The oxygen uptake (VO₂), VCO₂, and VE were continuously measured with a computerized breath-by-breath analyzer. Peak VO₂ was defined as the highest value recorded during the last 30 s of exercise. Ventilatory anaerobic threshold was calculated using the V-slope method.

The peak VO₂ was expressed in mL/kg/min. Exercise tests were always performed at the same period of the day. All patients performed a maximal exercise test as evidenced by a respiratory exchange ratio at peak exercise > 1.10. An increase in peak VO₂ 1.1 mL/kg/min was considered as clinically meaningful improvement.⁵

Brain natriuretic peptide measurement
Venous levels of Nt-pro-BNP (Elecsys 2010 -Roche diagnostics, GmbH, 68298 Mannheim, Germany) were determined from blood samples collected prior and after CRT.²⁰

Statistics
On the basis of the data of Lancellotti et al.,⁹ we expected a change in exercise ERO from baseline to 3 months follow-up of 0.18 cm² with a standard deviation of 0.14 cm². Using a power of 0.80, we calculated a sample size of 17 for a significance level of 0.05 and a sample size of 26 for a significance level of 0.025 (for the Bonferroni adjustment for multiple comparisons). All data are presented as mean ± SD. Gaussian distribution of data was tested by means of the Kolmogorov–Smirnov test. A two-sided non-paired, paired t-test and Fisher's exact test were used as appropriate. In the case of non-normality, the Wilcoxon paired test or the Mann–Whitney U test (for non-paired observations) was used. Bonferroni's method for multiple comparisons was used where needed. A repeated measures ANOVA followed by Bonferroni correction was used for comparison of respective conditions early and late CRT effects when compared with baseline. The Huynh–Feldt correction was used if the sphericity assumption was not met. Post hoc comparisons were performed using the Bonferroni adjustment for multiple comparisons. The Pearson or Spearman correlation coefficients were used to measure the linear association between various parameters as appropriate.

	Results

Top Abstract Introduction Methods Results Discussion Supplementary material Acknowledgements References

 
Out of 28 patients enrolled in the study, one patient died 2 days after CRT due to progression of heart failure. One patient was unable to exercise within 1 week after CRT due to worsening of heart failure. In one patient, the pacemaker was removed because of infection complication after 2 months. Three months after CRT, one additional patient was not able to exercise due to a hip fracture.

Baseline characteristics
Baseline demographic and clinical characteristics are given in Table 1. In all patients, medical treatment with beta-blockers or ACE/AT1-inhibitors remained unchanged between baseline and 3 months follow-up. Baseline echocardiography characteristics prior to CRT are given in Table 2. As shown in Figure 1, in the entire study population, exercise was associated with variable changes in LV dyssynchrony and the extent of LV dyssynchrony did not change when compared with rest. On the other hand, exercise testing was associated with an increase in ERO in all but five patients, and overall, ERO and regurgitant volume of MR increased when compared with rest. Note, a significant relationship was observed between the exercise-induced LV dyssynchrony and exercise-induced ERO (Figure 1). In addition, exercise was associated with an increase in tenting area, but no significant changes in mitral annulus diameter or sphericity index. Finally, an increase in Sm and global LV ejection fraction was noted when compared with rest. No new, exercise-induced regional wall motion abnormalities were observed.

View this table: [in this window] [in a new window]   Table 1 Baseline characteristics

 

View this table: [in this window] [in a new window]   Table 2 Left ventricular morphology, function, and Doppler quantification of mitral regurgitation at rest and during exercise echocardiography at baseline, early, and later after cardiac resynchronization therapy

 

View larger version (21K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 1 Functional mitral regurgitation (left panel) and left ventricular dyssynchrony (mid-panel) at rest and at peak exercise before cardiac resynchronization. Right panel: relationship between peak left ventricular dyssynchrony and mitral regurgitation at maximal exercise. ERO, effective regurgitant orifice of mitral regurgigation.

 
Early and late effects of cardiac resynchronization therapy on left ventricular remodelling, function, and mitral regurgitation
Serial changes in Doppler echocardiography parameters at rest and exercise early and late after CRT are given in Table 2. As shown in Figure 2, CRT resulted in an immediate reduction in LV dyssynchrony at rest with no further change at 3 months. Early after CRT, exercise was associated with a moderate increase in LV dyssynchrony. Nevertheless, no exercise-induced increase in LV dyssynchrony was noted late after CRT. Figure 3 shows an example of changes in MR early and late after CRT. In the entire population, functional MR at rest significantly decreased immediately after CRT and was further reduced 3 months later (Figure 3). In contrast, the extent of exercise-induced MR remained unchanged early after CRT and was proportional to the extent of persistent exercise-induced LV dyssynchrony at this time point (r = 0.58, P = 0.02). Nevertheless, exercise-induced MR was significantly attenuated late after CRT as evidenced from a reduction in ERO, regurgitant volume, and regurgitant fraction (Table 2). This was paralleled by a reduction in the tenting area and mitral annulus diameter when compared with baseline. Note, the extent of improvement in functional MR at rest was related to exercise-induced LV dyssynchrony (r = – 0.57, P = 0.03) and LV contractile reserve before the CRT (Sm, r = – 0.56, P = 0.02). On the other hand, the extent of improvement in exercise-induced MR late after CRT was related to changes in LV sphericity index (r = – 0.47, P = 0.04) and reduction in the tenting area (r = 0.57, P = 0.02). Finally, these changes were also associated with improved LV filling pattern as characterized by the decrease in early mitral filling and prolongation of early deceleration time at 3 months after CRT when compared with baseline.

View larger version (13K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 2 Serial changes in left ventricular dyssynchrony and mitral regurgitation at rest and at peak exercise: before cardiac resynchronization therapy, early after cardiac resynchronization therapy, and late (3 months) after cardiac resynchronization therapy. Abbreviations as in Figure 1.

 

View larger version (61K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 3 Example of changes in rest and exercise induced mitral regurgitation at baseline, early, and later after cardiac resynchronization therapy. Upper panel shows the resting conditions with colour-flow mapping of the mitral regurgitation, lower panel shows the changes in the mitral regurgitation at peak exercise. Early after cardiac resynchronization therapy, the extent of exercise-induced mitral regurgitation was comparable to baseline, despite a reduction in the resting mitral regurgitation. Significant attenuation of exercise-induced mitral regurgitation was noted only later after cardiac resynchronization therapy. Note that attenuation of exercise-induced mitral regurgitation was paralleld by reduction in left ventricular dimenstions.

 
Clinical characteristics and cardiopulmonary performance
CRT was associated with a decrease in NYHA class (Table 3). Nt-pro-BNP levels at 3 months strongly tended to be lower when compared with baseline. Maximal workload and peak VO₂ also significantly improved late after CRT when compared with baseline. At late follow-up, 14 patients showed a clinical significant increase in peak VO₂ 1.1 mL/kg/min (peak VO₂ +2.7 ± 1.7 mL/kg/min) and 10 patients showed non-significant change in peak VO₂ (peak VO₂–0.3 ± 1.1 mL/kg/min). As shown in Supplemenatry material online, Figure S1, patients with a clinically significant increase in peak VO₂ had similar LV morphology or function at 3 months follow-up when compared with patients with no significant change. Yet, in patients with a higher peak VO₂ increase, exercise-induced MR was markedly lower when compared with patients without peak VO₂ improvement. This was associated with a strong trend towards the lower Nt-pro-BNP levels in patients with a larger increase in peak VO₂ when compared with patients with no or minimal increase. Furthermore, change in peak VO₂ correlated inversely with the extent of exercise-induced MR at late follow-up (r = – 0.49, P = 0.015). No significant relationship was noted between change in peak VO₂ and Nt-pro-BNP or Doppler-echocardiographic parameters at follow-up.

View this table: [in this window] [in a new window]   Table 3 Early and late effects of cardiac resynchronization therapy on cardiopulmonary performance

 

	Discussion

Top Abstract Introduction Methods Results Discussion Supplementary material Acknowledgements References

 
The present study investigated the effects of CRT on resting and exercise-induced MR early and late after resynchronization. The main findings can be summarized as follows: (i) a reduction in LV dyssynchrony by CRT is associated with acute improvement in resting MR, but no change in exercise-induced MR. (ii) In contrast, exercise-induced MR is significantly attenuated later in parallel to reversed mitral and LV remodelling; (iii) reduction in exercise-induced MR appears to be associated with improved cardiopulmonary performance.

Left ventricular dyssynchrony and exercise-induced mitral regurgitation
Functional MR is a critical factor in symptomatology of patients with CHF.¹⁶ The extent of exercise-induced MR adversely affects cardiopulmonary performance² and is associated with poor clinical outcome.³ Earlier studies indicated that rest and exercise-induced MR are related to mitral deformation given by greater mitral tenting area and coaptation height resulting in increased transmitral pressure gradient.^21,22 In addition, more recent studies demonstrated that changes in MR from rest to exercise are closely related to the extent of LV dyssynchrony at rest^23,24 supporting the role of functional MR in QRS widening and progression of heart failure in patients with LV dyssynchrony.²⁵ Our observation of a close relationship between the LV dyssynchrony and MR at peak exercise is consistent with these findings and supports the role of LV dyssynchrony in the pathophysiology of exercise-induced MR.

Exercise-induced mitral regurgitation and cardiopulmonary performance after cardiac resynchronization therapy
In patients with CHF and dyssynchrony, CRT improves LV function, exercise tolerance,^4,5 and survival.^6,7 Although the majority of studies suggested cardiac resynchronization with subsequent LV remodelling^{14,15,19,26–28} as major underlying mechanism, a number of studies indicate that acute improvement in resting MR could also mediate beneficial effects of CRT upon LV remodelling.^4–9 However, it remains unknown whether and how CRT attenuates exercise-induced MR. The present exercise echocardiography study provides several novel insights into the serial changes of MR and mechanisms underlying benefit of CRT (Figure 4). First, improvement in MR at rest occurred immediately after CRT and was related to the extent of exercise-induced LV dyssynchrony and contractile reserve prior to implantation. This is consistent with previous studies indicating acute improvement in MR as a result of reduced dyssynchrony and increased closing force of the mitral valve.^8–10 These data suggest improved synchronization and acute recruitment of contractility as underlying mechanisms of immediate attenuation of functional MR by CRT. Nevertheless, in our study, CRT failed to attenuate immediately exercise-induced MR. Likewise, CRT induced only a moderate effect on exercise-induced LV dyssynchrony. In fact, the extent of exercise-induced LV dyssynchrony remained proportional to the extent of exercise-induced MR. On the other hand, 3 months later, CRT led to a significant reversed remodelling and entirely abolished exercise-induced LV dyssynchrony. This was paralleled by a decrease in the tenting area leading to a further reduction in MR at rest as well as to a significant attenuation of exercise-induced MR. Hence, attenuation of exercise-induced MR by CRT is gradual and related to several synergistic mechanisms. Early reduction of LV dyssynchrony and recruitment of contractile reserve are primary effects. They trigger reversed LV remodelling which together with mitral deformation further improves resting MR and attenuates exercise-induced functional MR. Reduction in exercise-induced MR in parallel to reversed LV remodelling translates into improved LV function and cardiopulmonary performance. It is of note that patients with improved cardiopulmonary performance had lower extent of exercise-induced MR when compared with patients with no or minimal increase cardiopulmonary performances. Though this may be related to differences in effects of CRT on mitral deformation between both subgroups, identification of factors responsible for greater reduction of exercise-induced MR in patients with improved peak VO₂ requires further studies. Nevertheless, mechanistic observations into serial changes in exercise-induced MR support the hypothesis that its reduction may underlie improved cardiopulmonary performance and improved survival after CRT.

View larger version (19K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 4 Cardiac resynchronization and proposed mechanisms contributing to early and late effects of cardiac resynchronization therapy on mitral regurgitation at rest and during exercise. For details, see Discussion. Abbreviations as in Figure 1.

 
Limitations
In patients with ischaemic cardiomyopathy, exercise-induced ischaemia could have been responsible for exercise-induced MR. However, similar to the study of Lancellotti et al.,²⁹ none of our patients developed exercise-induced angina or new wall motion abnormalities. Likewise, there were no differences in the extent of exercise-induced MR between patients with ischaemic and idiopathic cardiomyopathy. Nevertheless, this is a mechanistic study and the postulate that CRT improves prognosis by attenuation of exercise-induced MR requires future prospective studies. Several limitations related to pulsed-tissue Doppler-derived assessment, such as angle-dependency or sole analysis of basal segments, should be also acknowledged and novel methods such as speckle tracking or three-dimensional-derived assessment could be used as an alternative to track more reliably changes in LV dyssynchrony during the exercise. To minimize pitfalls of the MR quantification by using single method,¹⁸ MR was quantified using two methods as previously recommended.^3,8,9,17 Furthermore, changes in ERO were paralleled by similar changes in mitral regurgitant volume and regurgitant fraction. While inherent limitations of Doppler assessment of LV dyssynchrony or MR may be an issue for the comparative studies, their choice should not invalidate the principle findings of the current study as to mechanism underlying improvements in MR and cardiopulmonary performance.

Clinical implications
CRT is associated with acute improvement in MR, but it does not attenuate exercise-induced increase in MR early after CRT. In contrast, after 3 months, CRT results in the LV and mitral reversed remodelling in parallel to a reduction in both exercise-induced LV dyssynchrony and exercise-induced MR. Reduction in exercise-induced MR could represent the main mechanism contributing to the beneficial effects of CRT on survival of patients with CHF.

	Supplementary material

Top Abstract Introduction Methods Results Discussion Supplementary material Acknowledgements References

 
Supplementary material is availbale at European Heart Journal online.

	Acknowledgements

Top Abstract Introduction Methods Results Discussion Supplementary material Acknowledgements References

 
Technical assistance of the staff of the Echocardiography laboratory is greatly appreciated. We are also thankful to Mrs Josefa Cano for the secretarial assistance. There are no conflicts of interest related to this article. J.M. was a recipient of the training fellowship awarded by the Slovak Society of Cardiology.

Conflict of interest: none declared.

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When and how does cardiac resynchronization therapy reduce dynamic mitral regurgitation?

Luc A. Piérard and Patrizio Lancellotti
EHJ 2007 28: 2055-2056. [Extract] [Full Text]  

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