|
|
||||||||||
|
J Am Coll Cardiol, 2003; 41:765-770, doi:10.1016/S0735-1097(02)02937-6 © 2003 by the American College of Cardiology Foundation |

* Department of Cardiology, University Hospital, Aachen, Germany
Heart Institute, Sheba Medical Center, Tel Hashomer, Israel
Manuscript received August 13, 2002; revised manuscript received October 25, 2002, accepted November 11, 2002.
* Reprint requests and correspondence: Dr. Ole A. Breithardt, Department of Cardiology, University Hospital Aachen, Pauwelsstrasse 30, D-52057 Aachen, Germany.
olebreithardt{at}gmx.de
| Abstract |
|---|
|
|
|---|
BACKGROUND: Both a decrease in left ventricular (LV) closing force and mitral valve tethering have been implicated as mechanisms for functional mitral regurgitation (FMR) in dilated hearts. We hypothesized that an increase in LV closing force achieved by CRT could act to reduce FMR.
METHODS: Twenty-four HF patients with LBBB and FMR were studied after implantation of a biventricular CRT system. Acute changes in FMR severity between intrinsic conduction (OFF) and CRT were quantified according to the proximal isovelocity surface area method by measuring the effective regurgitant orifice area (EROA). Results were compared with the changes in estimated maximal rate of left ventricular systolic pressure rise (LV+dP/dtmax) and transmitral pressure gradients (TMP), both measured by Doppler echocardiography.
RESULTS: Cardiac resynchronization therapy was associated with a significant reduction in FMR severity. Effective regurgitant orifice area decreased from 25 ± 19 mm2 (OFF) to 13 ± 8 mm2 (CRT). The change in EROA was directly related to the increase in LV+dP/dtmax (r = 0.83, p < 0.0001). Compared with OFF, TMP increased more rapidly during CRT, and a higher maximal TMP was observed (OFF 73 ± 24 mm Hg vs. CRT 85 ± 26 mm Hg, p < 0.01).
CONCLUSIONS: Functional mitral regurgitation is reduced by CRT in patients with HF and LBBB. This effect is directly related to the increased closing force (LV+dP/dtmax). The results support the hypothesis that an increase in TMP, mediated by a rise in LV+dP/dtmax due to more coordinated LV contraction, may facilitate effective mitral valve closure.
| ||||||||||||||||||||||||||||||||||||||||||
| Methods |
|---|
|
|
|---|
Echocardiography protocol. Transthoracic echocardiography was performed in the first week after implantation of the CRT system or before the onset of active CRT. All patients underwent a standard two-dimensional and Doppler echocardiographic examination at rest in the left lateral supine position during intrinsic conduction, no pacing (OFF) and CRT. Left ventricular end-diastolic volume (ml), end-systolic volume (ml), and EF (%) were measured by biplane Simpsons rule during OFF. Reprogramming of the pacemakers to each mode (OFF and CRT) was performed during the echocardiography examination without patient movement. The examinations were performed with broadband transducers and second harmonic imaging on different ultrasound scanners (Sonos 5500, Agilent, Andover, Massachusetts; Vivid V and Vivid VII, GE Vingmed Ultrasound, Horten, Norway). All results represent averages of three measurements in different cardiac cycles.
Echocardiographic analysis.
The proximal isovelocity surface area (PISA) method is based on the principle of flow convergence and assumes that flow proximal to the regurgitant orifice is equal to the flow through the regurgitant orifice (7). Progressive acceleration of the regurgitant blood produces shells of identical velocities proximal to the orifice. The radius of a discrete shell (r) can be measured after a baseline shift of the color flow to decrease the aliasing velocity (Valias). The baseline was shifted to achieve a Valias near 40 cm/s. Assuming a hemispherical shape, regurgitant flow (RegFlow, cm3/s) was calculated as:
The EROA (mm2) is an index of regurgitation severity (8) and was calculated by: EROA (mm2) = RegFlow/maximal mitral regurgitant velocity ([MRVmax] m/s), where MRVmax was defined as the maximal velocity of the mitral regurgitant jet obtained by CW Doppler. Changes in EROA between OFF and CRT were expressed as the percent difference from OFF (
EROA, %). Additional measurement of the CW mitral regurgitant velocity time integral ([MRVTI] cm) allows calculation of regurgitant volume ([RegVol] ml) by:
The TMP was defined as the LV to left atrial pressure drop across the mitral valve. During systole, the rise in TMP counteracts the tethering forces of the papillary muscles and leads to mitral valve closure. In the presence of mitral regurgitation, maximal TMP (TMPmax) can be estimated from CW Doppler tracings of the mitral regurgitant jet using the simplified Bernoulli equation as 4 x (MRVmax)2. To further quantify the dynamic changes with CRT, we measured the transmitral pressure gradient 100 ms after onset of the FMR jet (TMP100) and the total duration of FMR, excluding any presystolic mitral regurgitation.
The LV+dP/dtmax was used as an index for LV systolic function and estimated noninvasively from the steepest rising segment of the CW Doppler mitral regurgitation velocity curve as described previously (9). The change in LV+dP/dtmax between OFF and CRT was expressed as the percent difference from OFF (
LV+dP/dtmax, %) (Fig. 1).
|
Statistical analysis.
Continuous data are expressed as mean values ± SD. Paired data were analyzed with Wilcoxon signed rank test. A p value of <0.05 was considered significant for all comparisons. The relation between
EROA and
LV+dP/dtmax was analyzed with linear regression analysis. Reproducibility of Doppler time interval measurements and PISA radius was assessed in the first 10 consecutive patients as the mean difference between two independent measurements performed on different occasions by one observer (intraobserver variability) and between two independent observers (interobserver variability). The results were expressed as percentages of the first measurement (± SD). The analysis was performed using StatsDirect v.1.605 (CamCode, Ashwell, United Kingdom).
| Results |
|---|
|
|
|---|
EROA was directly related to the increase in
LV+dP/dtmax (Fig. 3). The improved LV+dP/dtmax resulted in an increase of TMPmax from 73 ± 24 mm Hg (OFF) to 85 ± 26 mm Hg (CRT, p < 0.01 vs. OFF) and of TMP100 from 41 ± 17 mm Hg (OFF) to 61 ± 18 mm Hg (CRT, p < 0.0001 vs. OFF). A significant, although weak, linear correlation was found between
EROA and
TMP100 (
EROA = 0.54 x
TMP100 24.8, r = 0.44, p = 0.03), but not between
EROA and
TMPmax (
EROA = 0.57 x
TMPmax 33.8, r = 0.2, p = NS). The duration of FMR decreased from 478 ± 77 ms (OFF, 62 ± 12% of cycle length) to 444 ± 57 ms (CRT, 57 ± 8% of cycle length, p = 0.02 vs. OFF).
|
|
|
|
EROA (DCM: 48 ± 21% vs. CAD: 31 ± 25%, p = NS) and for
LV+dP/dtmax (DCM: 46 ± 28% vs. CAD: 40 ± 28%, p = NS). Increased LV chamber sphericity was documented by a sphericity index of 0.56 ± 0.13, but was not significantly affected by CRT (0.58 ± 0.14, p = NS vs. OFF). Midsystolic mitral leaflet tenting area was smaller during CRT (6.21 ± 2.04 cm2 [OFF] vs. 5.52 ± 1.72 cm2 [CRT], p = 0.02). There was no significant correlation between the mitral leaflet tenting area and EROA. Inter- and intraobserver variability. The mean percent errors for measurements of Doppler time intervals and velocities were 3 ± 2% and 4 ± 2% for the same observer and 5 ± 3% and 5 ± 4% between two blinded observers. For measurement of the PISA radius, the intra- and interobserver variabilities were 6 ± 5% and 7 ± 5%, respectively.
| Discussion |
|---|
|
|
|---|
Mechanistic insights. Prior studies demonstrated that the presence of FMR in heart failure is strongly dependent on alterations in LV shape, as the tethering forces that act on the mitral leaflets are higher in dilated, more spherical ventricles (14). These geometric changes alter the balance between tethering and closing forces and impede effective mitral valve closure. Under these conditions, the mitral regurgitant orifice area will be largely determined by the phasic changes in TMP (1517), and worsening of LV dysfunction with a delayed LV rate of pressure rise will further increase FMR severity due to the impaired closing force. Consequently, it has been suggested that therapeutic interventions aimed to improve TMP should be able to reduce FMR severity (17). Our study represents a direct therapeutic application of this concept and demonstrates that an increase in TMP, mediated by a rise in LV+dP/dtmax, may oppose the increased mitral leaflet tethering forces in DCM and facilitate more effective mitral valve closure. Cardiac resynchronization therapy caused both an increase in peak transmitral closing force (TMPmax) as well as an accelerated rise in TMP during the isovolumic contraction phase, as reflected by the increase in TMP100. The accelerated rise in TMP effectively counteracted the increased tethering forces that impair mitral valve competence (Fig. 4) and decreased acutely midsystolic mitral leaflet tenting area.
|
Influence of LV geometry on FMR severity. The fact that LV sphericity, which was pathologic in all our patients, was not acutely affected by CRT further underscores the notion that the reduction in EROA was independent of a change in LV geometry. However, such a reverse remodeling process may be observed chronically and, thus, may contribute to a further decrease in FMR severity by CRT (2).
Although systolic mitral valvular tenting is a major determinant of EROA, we found no significant correlation between mitral deformation and FMR severity in our patient population, which is in contrast with previous reports (2). This apparent disagreement might be explained by the high prevalence of ventricular asynchrony in our study as we included only patients with significant electrical conduction delays, which show a large degree of ventricular wall motion asynchrony (19). The individual degree of ventricular asynchrony might, independently of the LV geometry, alter the leaflet tethering forces and aggravate FMR. As experimental studies convincingly demonstrate, it is not isolated papillary muscle dysfunction per se that causes FMR (20,21), but altered papillary displacement by dysfunction and remodeling of the underlying myocardium (22,23). Thus, asynchronous activation of the medial and lateral segments supporting the papillary muscles might independently contribute to FMR severity in heart failure. Whether resynchronization of this disturbed activation sequence would favorably affect FMR independently of an associated increase in LV+dP/dtmax requires further investigations.
Clinical implications. Several trials demonstrated successful treatment of FMR in patients with heart failure and suggested that EROA reduction is the main mechanism for improvement. Beside pharmacologic afterload reduction (24), surgical mitral annuloplasty has been shown to be effective in correcting mitral regurgitation in end-stage cardiomyopathy (25). Other groups demonstrated that surgical reduction of ventricular dilation may reduce FMR, even without concomitant mitral valve repair (26). Our present results confirm earlier suggestions that LV systolic function plays a crucial role in the pathogenesis of FMR (1,17,27) and that the restoration of an adequate closing force is as relevant as surgical correction of ventricular geometry and mitral annular dimensions.
| Study limitations |
|---|
|
|
|---|
Estimation of LV dP/dtmax with the described CW Doppler technique tends to underestimate true LV+dp/dtmax because it calculates the mean rise in LV pressure during the isovolumic contraction phase rather than the true maximum instantaneous pressure rise (31). Despite this small systematic error, the method is reproducible and even valuable for the prediction of prognosis in patients with dilative cardiomyopathy and CRT (32).
We did not systematically measure arterial blood pressure in this study, and, thus, no direct conclusions can be made on the possible changes in left atrial pressure. However, it is most likely that the measured increase in TMPmax reflects the previously observed increase in systolic arterial blood pressure with CRT (5,6). Our study is, furthermore, limited to acute measurements, and no conclusions can be drawn concerning the long-term effects of CRT on FMR severity. This has been studied by previous researchers, who demonstrated that long-term CRT may reduce FMR severity (33,34).
| Conclusions |
|---|
|
|
|---|
| References |
|---|
|
|
|---|
This article has been cited by other articles:
![]() |
2006 WRITING COMMITTEE MEMBERS, R. O. Bonow, B. A. Carabello, K. Chatterjee, A. C. de Leon Jr, D. P. Faxon, M. D. Freed, W. H. Gaasch, B. W. Lytle, R. A. Nishimura, et al. 2008 Focused Update Incorporated Into the ACC/AHA 2006 Guidelines for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): Endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons Circulation, October 7, 2008; 118(15): e523 - e661. [Full Text] [PDF] |
||||
![]() |
R. O. Bonow, B. A. Carabello, K. Chatterjee, A. C. de Leon Jr, D. P. Faxon, M. D. Freed, W. H. Gaasch, B. W. Lytle, R. A. Nishimura, P. T. O'Gara, et al. 2008 Focused Update Incorporated Into the ACC/AHA 2006 Guidelines for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease) Endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons J. Am. Coll. Cardiol., September 23, 2008; 52(13): e1 - e142. [Full Text] [PDF] |
||||
![]() |
G. Buckberg, A. Mahajan, S. Saleh, J. I.E. Hoffman, and C. Coghlan Structure and function relationships of the helical ventricular myocardial band J. Thorac. Cardiovasc. Surg., September 1, 2008; 136(3): 578 - 589. [Abstract] [Full Text] [PDF] |
||||
![]() |
R Gradaus, V Stuckenborg, A Loher, J Kobe, F Reinke, S Gunia, C Vahlhaus, G Breithardt, and C Bruch Diastolic filling pattern and left ventricular diameter predict response and prognosis after cardiac resynchronisation therapy Heart, August 1, 2008; 94(8): 1026 - 1031. [Abstract] [Full Text] [PDF] |
||||
![]() |
E. Donal, C. De Place, G. Kervio, F. Bauer, R. Gervais, C. Leclercq, P. Mabo, and J.-C. Daubert Mitral regurgitation in dilated cardiomyopathy: value of both regional left ventricular contractility and dyssynchrony Eur J Echocardiogr, June 26, 2008; (2008) jen188v1. [Abstract] [Full Text] [PDF] |
||||
![]() |
N. C. Wang, A. P. Maggioni, M. A. Konstam, F. Zannad, H. B. Krasa, J. C. Burnett Jr, L. Grinfeld, K. Swedberg, J. E. Udelson, T. Cook, et al. Clinical Implications of QRS Duration in Patients Hospitalized With Worsening Heart Failure and Reduced Left Ventricular Ejection Fraction JAMA, June 11, 2008; 299(22): 2656 - 2666. [Abstract] [Full Text] [PDF] |
||||
![]() |
C. Ypenburg, P. Lancellotti, L. F. Tops, E. Boersma, G. B. Bleeker, E. R. Holman, J. D. Thomas, M. J. Schalij, L. A. Pierard, and J. J. Bax Mechanism of improvement in mitral regurgitation after cardiac resynchronization therapy Eur. Heart J., March 2, 2008; 29(6): 757 - 765. [Abstract] [Full Text] [PDF] |
||||
![]() |
E. Agricola, M. Oppizzi, M. Pisani, A. Meris, F. Maisano, and A. Margonato Ischemic mitral regurgitation: mechanisms and echocardiographic classification Eur J Echocardiogr, March 1, 2008; 9(2): 207 - 221. [Abstract] [Full Text] [PDF] |
||||
![]() |
P. W.M. Fedak, P. M. McCarthy, and R. O. Bonow Evolving Concepts and Technologies in Mitral Valve Repair Circulation, February 19, 2008; 117(7): 963 - 974. [Full Text] [PDF] |
||||
![]() |
J. I. Fann, N. B. Ingels Jr., and D. C. Miller Pathophysiology of Mitral Valve Disease Card. Surg. Adult, January 1, 2008; 3(2008): 973 - 1012. [Full Text] |
||||
![]() |
P. Lancellotti, E. Donal, B. Cosyns, G. Van Camp, J.-L. Monin, E. Brochet, A. Berrebi, P. Pibarot, C. Chauvel, C. Hassager, et al. Effects of surgery on ischaemic mitral regurgitation: a prospective multicentre registry (SIMRAM registry) Eur J Echocardiogr, January 1, 2008; 9(1): 26 - 30. [Abstract] [Full Text] [PDF] |
||||
![]() |
C. Ypenburg, P. Lancellotti, L. F. Tops, G. B. Bleeker, E. R. Holman, L. A. Pierard, M. J. Schalij, and J. J. Bax Acute Effects of Initiation and Withdrawal of Cardiac Resynchronization Therapy on Papillary Muscle Dyssynchrony and Mitral Regurgitation J. Am. Coll. Cardiol., November 20, 2007; 50(21): 2071 - 2077. [Abstract] [Full Text] [PDF] |
||||
![]() |
G. B Bleeker, C.-M. Yu, P. Nihoyannopoulos, J. de Sutter, N. Van de Veire, E. R Holman, M. J Schalij, E. E van der Wall, and J. J Bax Optimal use of echocardiography in cardiac resynchronisation therapy Heart, November 1, 2007; 93(11): 1339 - 1350. [Abstract] [Full Text] [PDF] |
||||
![]() |
Z.-Z. Song 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., October 2, 2007; 28(20): 2554 - 2554. [Full Text] [PDF] |
||||
![]() |
A. D'Andrea and R. Calabro Effect of dynamic myocardial dyssynchrony on mitral regurgitation during supine bicycle exercise stress echocardiography in patients with idiopathic dilated cardiomyopathy and 'narrow 'QRS: reply Eur. Heart J., October 2, 2007; 28(20): 2554 - 2555. [Full Text] [PDF] |
||||
![]() |
J. Madaric, M. Vanderheyden, C. Van Laethem, K. Verhamme, A. Feys, M. Goethals, S. Verstreken, P. Geelen, M. Penicka, B. De Bruyne, et al. Early and late effects of cardiac resynchronization therapy on exercise-induced mitral regurgitation: relationship with left ventricular dyssynchrony, remodelling and cardiopulmonary performance Eur. Heart J., September 1, 2007; 28(17): 2134 - 2141. [Abstract] [Full Text] [PDF] |
||||
![]() |
L. A. Pierard and P. Lancellotti When and how does cardiac resynchronization therapy reduce dynamic mitral regurgitation? Eur. Heart J., September 1, 2007; 28(17): 2055 - 2056. [Full Text] [PDF] |
||||
![]() |
P. A. Gould, G. Kong, V. Kalff, S. J. Duffy, A. J. Taylor, M. J. Kelly, and D. M. Kaye Improvement in cardiac adrenergic function post biventricular pacing for heart failure Europace, September 1, 2007; 9(9): 751 - 756. [Abstract] [Full Text] [PDF] |
||||
![]() |
F. Cabrera-Bueno, J. M. Garcia-Pinilla, J. Pena-Hernandez, M. Jimenez-Navarro, J. J. Gomez-Doblas, A. Barrera-Cordero, J. Alzueta-Rodriguez, and E. de Teresa-Galvan Repercussion of functional mitral regurgitation on reverse remodelling in cardiac resynchronization therapy Europace, September 1, 2007; 9(9): 757 - 761. [Abstract] [Full Text] [PDF] |
||||
![]() |
C.-M. Yu, F. Fang, Q. Zhang, G. W.K. Yip, C. M. Li, J. Y.-S. Chan, L. Wu, and J. W.-H. Fung Improvement of Atrial Function and Atrial Reverse Remodeling After Cardiac Resynchronization Therapy for Heart Failure J. Am. Coll. Cardiol., August 21, 2007; 50(8): 778 - 785. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. N. Kirkpatrick, M. A. Vannan, J. Narula, and R. M. Lang Echocardiography in Heart Failure: Applications, Utility, and New Horizons J. Am. Coll. Cardiol., July 31, 2007; 50(5): 381 - 396. [Abstract] [Full Text] [PDF] |
||||
![]() |
L. A Pierard and P. Lancellotti Stress testing in valve disease Heart, June 1, 2007; 93(6): 766 - 772. [Full Text] [PDF] |
||||
![]() |
F. B. Tournoux, C. Alabiad, D. Fan, A. A. Chen, M. Chaput, E. K. Heist, T. Mela, M. Mansour, V. Reddy, J. N. Ruskin, et al. Echocardiographic measures of acute haemodynamic response after cardiac resynchronization therapy predict long-term clinical outcome Eur. Heart J., May 1, 2007; 28(9): 1143 - 1148. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. D. Burkhardt and B. L. Wilkoff Interventional Electrophysiology and Cardiac Resynchronization Therapy: Delivering Electrical Therapies for Heart Failure Circulation, April 24, 2007; 115(16): 2208 - 2220. [Abstract] [Full Text] [PDF] |
||||
![]() |
L. A. Pierard Left ventricular dyssynchrony and functional mitral regurgitation: two dynamic conditions Eur. Heart J., April 12, 2007; (2007) ehm079v1. [Full Text] [PDF] |
||||
|
|