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European Heart Journal Advance Access originally published online on December 16, 2005
European Heart Journal 2006 27(6):679-683; doi:10.1093/eurheartj/ehi682
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© The European Society of Cardiology 2005. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Myocardial asynchronism is a determinant of changes in functional mitral regurgitation severity during dynamic exercise in patients with chronic heart failure due to severe left ventricular systolic dysfunction

Pierre V. Ennezat1,2,*, Sylvestre Maréchaux1, Thierry Le Tourneau1, Nicolas Lamblin1, Christophe Bauters1, Eric Van Belle1, Benjamin Gal1, Salem Kacet1, Philippe Asseman1, Ghislaine Deklunder1, Thierry H. LeJemtel2 and Pascal de Groote1

1Cardiology Hospital, Lille, France
2Department of Medicine, Tulane University, New Orleans, LA, USA

Received 9 October 2005; revised 17 November 2005; accepted 24 November 2005; online publish-ahead-of-print 16 December 2005.

* Corresponding author: Intensive Care Unit, University Hospital, Bd Pr Jules Leclercq, 59 000 Lille, France. E-mail address: ennezat{at}yahoo.com

See page 638 for the editorial comment on this article (doi:10.1093/eurheartj/ehi741)


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
Aims Functional mitral regurgitation (MR) and myocardial asynchronism occur commonly in patients with dilated cardiomyopathy and affect adversely their prognosis and symptoms. The aim of this study was to evaluate the mechanisms of changes in MR severity during dynamic exercise in patients with chronic heart failure (CHF).

Methods and results Seventy patients with CHF due to left ventricular (LV) systolic dysfunction [LV ejection fraction (EF) <40%] and functional MR were studied. All were in sinus rhythm. Medications were left unchanged for the study. Each patient performed a maximal symptom-limited exercise test with continuous 2D-Doppler echocardiography. Mitral regurgitant volume (RV) and effective regurgitant orifice (ERO) were determined at rest and during exercise. LV asynchrony using Doppler tissue imaging and interventricular asynchrony using conventional pulsed-Doppler were evaluated at rest.

Resting LV EF averaged 25±8%. Mean resting LV and interventricular mechanical delays were 56±50 and 43±37 ms, respectively. The overall median values for mitral ERO and RV did not significantly change during dynamic exercise (11 [7–16] vs. 11 [6–21] mm2 and 14 [10–22] vs. 12 [9–23] mL, respectively). However, changes in mitral ERO and RV were individually variable and significantly correlated with the degree of LV asynchronism (r=0.66, P<0.0001 and r=0.66, P<0.0001, respectively).

Conclusion Changes in MR are variable during dynamic exercise. LV asynchronism at rest substantially contributes to worsening of functional MR during dynamic exercise in patients with CHF due to LV systolic dysfunction.

Key Words: Chronic heart failure • Exercise echocardiology • Mitral regurgitation • Myocardial asynchronism


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusion
 References
 
Increased tenting area resulting from left ventricular (LV) remodelling has been identified as a determinant of the severity of resting1 and exercise functional mitral regurgitation (MR) in patients with LV systolic dysfunction.2–4

Besides reducing cardiac performance, myocardial asynchronism may decrease mitral valve closing forces, thereby exacerbate functional MR during dynamic exercise in patients with chronic heart failure (CHF).

To test the hypothesis that myocardial asynchronism contributes to worsening of functional MR during exercise, we evaluated myocardial asynchronism at rest and functional MR at rest and during exercise in patients with CHF due to LV systolic dysfunction.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusion
 References
 
Study population
Seventy consecutive CHF patients with dilated ischaemic or non-ischaemic cardiomyopathy, low LV ejection fraction (EF) (LV EF<40%), and functional MR were included in this study. Ischaemic cardiomyopathy was considered in the presence of a documented previous myocardial infarction or a significant coronary artery disease (CAD) (luminal narrowing >50%) at coronary arteriography. Optimal revascularization was performed in those patients. Non-ischaemic cardiomyopathy was considered only in the presence of angiographically normal coronary arteries. Peak oxygen consumption (VO2) was assessed the day before or the day after the echocardiographic study. From march 2003 to march 2005, 86 ambulatory CHF patients with known LV systolic dysfunction and MR were referred to our echocardiographic laboratory. Patients with atrial fibrillation (n=7), orthopaedic limitation (n=3), inducible myocardial ischaemia (n=2), or poor echocardiographic window (n=3) and improved LV EF>45% (n=1) were ineligible for the study. No patients refused to give their consent. The remaining 70 patients were able to perform a maximal symptom-limited exercise. The study was approved by the local Ethics Committee.

Exercise echocardiography
Symptom-limited (fatigue or dyspnoea) exercise was performed on a semi-recumbent and tilting bicycle ergometer with a 20 W/3 min step protocol starting from 25 W. Blood pressure was measured every 2 min. A 12-lead ECG was continuously monitored. Medical therapy was left unchanged for the study.

Echocardiography analysis
Continuous 2D-Doppler echocardiographic monitoring was performed with a scanner (ATL 5000, Philips) equipped with a 2–4 MHz transducer. At least three cardiac cycles were used for each measurement, and the average value was taken.

LV volumes and EF were calculated using the Simpson biplane method. The proximal flow convergence (PFC) technique has been validated as a quantitative Doppler method to calculate regurgitant volume (RV) of flow and orifice area [effective regurgitant orifice (ERO)] at rest5 and during exercise.6 The regurgitant flow is measured as 2{pi}xr2xVr, where r is the radius of the hemispheric PFC region and Vr is the aliasing velocity. The following parameters are calculated: ERO=regurgitant flow/maximal regurgitant velocity, and RV=EROxRTVI, where RTVI being the regurgitant time–velocity integral. The systolic mitral annular diameter was measured in apical two- and four-chamber views. Interventricular mechanical delays were assessed at rest using standard pulsed-Doppler. Interventricular asynchrony was evaluated on the basis of the difference between the aortic and pulmonary ejection delays. Pulsed-tissue Doppler imaging was used to evaluate intraventricular synchronism at rest as previously described.7 The explored areas were the basal segments of the septum, lateral wall, inferior wall, and anterior wall. Parietal delay was measured between the onset of the QRS and the onset of the S-wave. Intraventricular mechanical delays were calculated from the difference between the earliest and most delayed sites.

Statistical analysis
Continuous variables are expressed as mean ±SD except for mitral ERO and RV presented as median (25–75th percentile). Categorical variables are summarized in percentage. Comparisons between rest and peak exercise measurements were performed using the paired Student's t-test. For mitral ERO and RV values that were not normally distributed, the non-parametric paired test of Wilcoxon was used to compare resting and exercise values. Comparison of durations of exercise between groups was performed using the Mann–Whitney U test. The relationships between exercise-induced changes in MR severity and echocardiographic parameters were analysed by Pearson's correlation coefficients. To identify independent echocardiographic factors associated with changes in MR severity, all variables that correlated with a P-value less than 0.1 in univariate analysis were submitted to a complete instead of stepwise multiple-regression analysis. No prior sample size was calculated because of the absence of the previously published data testing the hypothesis that myocardial asynchronism could contribute to worsening of MR during exercise. A two-tailed P-value less than 0.05 was required for statistical significance. All analyses were conducted using SPSS 11.0 software (SPSS Inc., Chicago, IL, USA).


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusion
 References
 
The study population comprised 70 patients. Demographic and clinical characteristics are summarized in Table 1. Thirty-six patients (51%) had ischaemic cardiomyopathy. Optimal revascularization was performed in ischaemic patients. These patients were severely symptomatic as demonstrated by the mean absolute value of peak VO2 of 12±3 mL/kg/min and 43 patients (62%) were in NYHA functional class 3 or 4. In addition, 17 patients (24%) were in NYHA functional class 4. The duration of exercise was significantly shorter in these patients in comparison with the others (4[3–5] vs. 8[6–10] min; P=0.001). All patients were receiving ACE-inhibition and beta-adrenergic blockade except for eight patients who could not tolerate beta-adrenergic blockade because of excessive bradycardia or clinical deterioration. Width of QRS was ≥0.12 s in 48 patients (68%) and <0.12 s in the remaining 22 patients. At rest, LV diameter and volume were enlarged (65±9 mm/221±75 mL) and mean LV EF was severely depressed at 25±8%. Averaged inter- and intraventricular mechanical delays were 43±37  and 56±50 ms, respectively. During exercise (Table 2), heart rate and systolic blood pressure increased significantly, whereas LV end-diastolic volume decreased. The transtricuspid pressure gradient increased significantly from rest to peak exercise. LV EF remained unchanged. However, exercise-induced changes in MR were extremely variable (Figure 1). MR worsened in 59% of the population. Those changes were not correlated neither with exercise duration (r=0.08, P=0.56) nor with peak VO2 (r=0.02, P=0.9). Exercise-induced changes in MR ERO and RV did correlate with resting intra-LV mechanical delays (r=0.66, P<0.0001 and r=0.66, P<0.0001, respectively) (Figure 2), interventricular mechanical delays (r=0.32, P=0.022 and r=0.31, P=0.03, respectively), QRS width (r=0.53, P<0.0001 and r=0.47, P<0.0001, respectively), and end-diastolic LV volume (r=0.438, P=0.001 and r=0.32, P=0.03, respectively). The changes in mitral ERO and RV also did correlate with those in systolic mitral annular diameter (r=0.40, P=0.004 and r=0.46, P=0.001, respectively) and transmitral pressure gradient (r=0.593, P<0.0001 and r=0.44, P=0.001, respectively). Intra-LV mechanical delays and changes in systolic mitral annular diameter were the two independent determinants of exercise-induced changes in functional MR (Table 3). In the group of patients with ischaemic cardiomyopathy, intra-LV mechanical delays were independently associated with changes in MR severity. The same findings were observed in patients with non-ischaemic cardiomyopathy (Table 3).


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  		Table 1 Demographic and clinical characteristics of the study population
 

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  		Table 2 Exercise echocardiography results of the study population (n=70)
 

Figure 6821
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  		Figure 1 Individual changes in mitral ERO between rest and peak exercise.

 

Figure 6822
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  		Figure 2 Relationships between intra-LV asynchrony and exercise-induced changes in mitral ERO (left panel) and RV (right panel).

 

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  		Table 3 Results of multivariate linear-regression analysis for exercise-induced changes in mitral ERO and RV in overall population and according to aetiology of cardiomyopathy
 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusion
 References
 
The present data clearly indicate that (1) the changes in functional mitral RV and ERO are variable during dynamic exercise and (2) LV asynchronism is a strong independent determinant of changes in functional MR during dynamic exercise.

Exercise induced-changes in functional MR were extremely variable. Exercise decreased functional MR in some patients, whereas it substantially aggravated MR in the others. Changes in functional MR did not correlate with exercise duration or peak oxygen uptake, demonstrating that the alterations in skeletal muscle metabolism, mass, and vasculature may primarily limit the peak functional capacity in ambulatory patients with CHF.8 The severity of functional MR at rest and during exercise has been related to mitral deformation (i.e. differences in systolic mitral tenting area, systolic annular area, and coaptation height), resulting in changes in ERO in patients with LV systolic dysfunction.1,3,4 In addition, the systolic pressure gradient across the mitral orifice is an important determinant of functional MR at rest9 and during exercise. Exercise induced-changes in mitral RV and maximal velocity correlated closely in our patients.

Myocardial asynchronism resulting in a decrease in LV ejection phase efficiency may reduce transmitral force closure and thereby exacerbating functional MR in patients with dilated left ventricles. LV asynchrony assessed by EKG and by myocardial tissue Doppler was linearly related to changes in functional MR brought by exercise in our patients. In addition, the changes in MR maximal velocity during exercise were inversely correlated with resting LV asynchrony (r=–0.50, P<0.0001), demonstrating that exercise myocardial contractile reserve decreases when myocardial asynchronism increases. Conversely, by producing a more efficient LV contraction, cardiac resynchronization therapy (CRT) may reduce the severity of functional MR not only at rest10 but also in its dynamic component.11 However, other mechanisms may be involved. In an elegant study, Kanzaki et al.12 demonstrated, using strain mapping, that CRT improved discoordinated timing of mechanical activation of papillary muscle insertion sites associated with left bundle branch block and thereby reduced MR.

There is strong evidence that MR worsens when LV function decreases as in exercise-induced myocardial ischaemia.13 However, in our series, patients with CAD were optimally revascularized. Patients with clinical, electrocardiographic, or echocardiographic evidence of inducible myocardial ischaemia were excluded.

Surprisingly, changes in transtricuspid pressure gradient were not correlated with those in MR during exercise (r=0.22, P=0.15). However, multiple intricate factors at rest and during exercise account for the variability of the degree of pulmonary hypertension in patients with LV systolic dysfunction. In LV systolic dysfunction, pulmonary pressures depend not only on the severity of MR but also on the LV diastolic function,14 pulmonary vascular resistance, loading conditions, and right ventricular function. A potential explanation for these contrasting results with previous reports3,6 is that in our study we included patients with CHF, whereas others studied essentially patients with myocardial infarction and subsequent LV remodelling.

Study limitations
Assessment of myocardial asynchrony during exercise may allow to better characterize how does myocardial asynchrony contributes to worsen functional MR during dynamic exercise. However, concomitant quantification of functional MR and myocardial asynchrony were technically impossible during exercise.


   Conclusion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
References
 
In summary, myocardial asynchrony is an independent determinant of changes in functional MR during dynamic exercise in patients with CHF due to LV systolic dysfunction. Attenuation of exercise-induced worsening of functional MR may be in part responsible for the clinical benefits of CRT in patients with CHF.15

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 

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  2. Lapu-Bula R, Robert A, Van Craeynest D, D'Hondt AM, Gerber BL, Pasquet A, Melin JA, De Kock M, Vanoverschelde JL. Contribution of exercise-induced mitral regurgitation to exercise stroke volume and exercise capacity in patients with left ventricular dysfunction. Circulation 2002;106:1342–1348.[Abstract/Free Full Text]
  3. Lancellotti P, Lebrun F, Pierard L. Determinants of exercise-induced changes in mitral regurgitation in patients with coronary artery disease and left ventricular dysfunction. J Am Coll Cardiol 2003;42:1921–1928.[Abstract/Free Full Text]
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  5. Enriquez-Sarano M, Miller F, Hayes S, Bailey K, Tajik A, Seward J. Effective mitral regurgitant orifice area: clinical use and pitfalls of the proximal isovelocity surface area method. J Am Coll Cardiol 1995;25:703–709.[Abstract]
  6. Lebrun F, Lancellotti P, Pierard L. Quantitation of functional mitral regurgitation during bicycle exercise in patients with heart failure. J Am Coll Cardiol 2001;38:1685–1692.[Abstract/Free Full Text]
  7. Bader H, Garrigue S, Lafitte S, Reuter S, Jais P, Haissaguerre M, Bonnet J, Clementy J, Roudaut R. Intra-left ventricular electromechanical asynchrony. A new independent predictor of severe cardiac events in heart failure patients. J Am Coll Cardiol 2004;43:248–256.[Abstract/Free Full Text]
  8. Jondeau G, Katz SD, Zohman L, Goldberger M, McCarthy M, Bourdarias JP, LeJemtel TH. Active skeletal muscle mass and cardiopulmonary reserve. Failure to attain peak aerobic capacity during maximal bicycle exercise in patients with severe congestive heart failure. Circulation 1992;86:1351–1356.[Abstract/Free Full Text]
  9. He S, Fontaine A, Schwammenthal E, Yoganathan A, Levine R. Integrated mechanism for functional mitral regurgitation. Leaflet restriction vs coapting force: in vitro studies. Circulation 1997;96:1826–1834.[Abstract/Free Full Text]
  10. Breithardt O, Sinha A, Schwammenthal E, Bidaoui N, Markus KU, Franke A, Stellbrink C. Acute effects of cardiac resynchronization therapy on functional mitral regurgitation in advanced systolic heart failure. J Am Coll Cardiol 2003;41:765–770.[Abstract/Free Full Text]
  11. Lancellotti P, Melon P, Sakalihasan P, Waleffe A, Dubois C, Bertholet M, Pierard LA. Effect of cardiac resynchronization therapy on functional mitral regurgitation in heart failure. Am J Cardiol 2004;94:1462–1465.[CrossRef][ISI][Medline]
  12. 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. J Am Coll Cardiol 2004;44:1619–1625.[Abstract/Free Full Text]
  13. Peteiro J, Freire E, Montserrat L, Castro-Beiras A. The effect of exercise on ischemic mitral regurgitation. Chest 1998;114:1075–1082.[Abstract/Free Full Text]
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  15. Cleland J, Daubert J, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539–1549.[Abstract/Free Full Text]

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