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CLINICAL STUDY: HEART FAILURE

Acute effects of cardiac resynchronization therapy on functional mitral regurgitation in advanced systolic heart failure

Ole A. Breithardt, MD^*,*, Anil M. Sinha, MD^*, Ehud Schwammenthal, MD, FESC, Nadim Bidaoui, BSc^*, Kai U. Markus, MD^*, Andreas Franke, MD^* and Christoph Stellbrink, MD, FESC^*

^* 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

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OBJECTIVES: We studied the acute effects of cardiac resynchronization therapy (CRT) on functional mitral regurgitation in heart failure (HF) patients with left bundle branch block (LBBB).

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/dt_max) 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/dt_max (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/dt_max). The results support the hypothesis that an increase in TMP, mediated by a rise in LV+dP/dt_max due to more coordinated LV contraction, may facilitate effective mitral valve closure.

Abbreviations and Acronyms   CAD   coronary artery disease   CRT   cardiac resynchronization therapy   CW   continuous wave   DCM   dilated cardiomyopathy   EF   ejection fraction   EROA   effective regurgitant orifice area   FMR   functional mitral regurgitation   LBBB   left bundle branch block   LV   left ventricle/ventricular   LV+dP/dtmax   maximal rate of left ventricular systolic pressure rise   MRVmax   maximal velocity of the mitral regurgitant jet obtained by continuous wave Doppler   MRVTI   mitral regurgitant velocity time integral   OFF   intrinsic conduction, no pacing   PISA   proximal isovelocity surface area   RegFlow   regurgitant flow   RegVol   regurgitant volume   TMP   transmitral pressure gradient   TMP100   transmitral pressure gradient 100 ms after onset of the functional mitral regurgitation jet   TMPmax   maximal transmitral pressure gradient   Valias   aliasing velocity

	Methods

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Patients.   We studied 24 consecutive patients presenting with severely impaired LV systolic function (transthoracic biplane ejection fraction [EF] <30%), LBBB (QRS >120 ms), and FMR measured by color Doppler echocardiography. All patients received a biventricular pacing device for CRT with a right ventricular apical lead and LV pacing electrodes implanted through the coronary sinus and positioned in an LV epicardial vein. Informed consent was obtained from all patients before the echocardiographic examination with acute reprogramming of the pacemakers.

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 Simpson’s 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 (V_alias). The baseline was shifted to achieve a V_alias 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 ([MR_Vmax] m/s), where MR_Vmax 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 ([MR_VTI] 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 (TMP_max) can be estimated from CW Doppler tracings of the mitral regurgitant jet using the simplified Bernoulli equation as 4 x (MR_Vmax)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/dt_max 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/dt_max between OFF and CRT was expressed as the percent difference from OFF (LV+dP/dt_max, %) (Fig. 1).

View larger version (81K): [in this window] [in a new window]   Figure 1 Continuous wave (CW) Doppler regurgitant jet in a study patient before (left) and after cardiac resynchronization therapy (CRT) (right). Maximal rate of left ventricular systolic pressure rise (LV+dP/dtmax) is estimated by measuring the time interval between 1 m/s and 3 m/s on the downslope of the CW Doppler spectrum (solid lines). Estimated LV+dP/dtmax rises from approximately 510 mm Hg/s (approximately 63 ms) to approximately 720 mm Hg/s (approximately 44 ms), and transmitral pressure gradient peak occurs earlier in systole (arrows). Duration of functional mitral regurgitation (excluding the presystolic component) decreases from 435 ms (OFF) to 382 ms (CRT).

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/dt_max 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

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Clinical patient characteristics are presented in Table 1. All patients were in stable sinus rhythm. Ventricular pacing was performed in an atrial triggered mode with a mean atrioventricular delay of 109 ± 18 ms. Biventricular pacing acutely decreased mitral regurgitation severity and improved LV systolic function as measured by LV+dP/dt_max and EF, with no change in heart rate (Table 2). In 23 of 24 patients, EROA decreased (Fig. 2), and EROA was directly related to the increase in LV+dP/dt_max (Fig. 3). The improved LV+dP/dt_max resulted in an increase of TMP_max 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 TMP_max (EROA = –0.57 x TMP_max –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).

View larger version (18K): [in this window] [in a new window]   Figure 2 Individual changes in effective regurgitant orifice area (EROA) (mm3) between baseline (OFF) and cardiac resynchronization therapy (CRT); EROA showed a wide range during OFF and decreased with CRT in 23 patients. A small increase in EROA was observed in one patient with mild regurgitation during OFF (dashed line).

View larger version (13K): [in this window] [in a new window]   Figure 3 The decrease in effective regurgitant orifice area (EROA), displayed as the percent change between OFF and cardiac resynchronization therapy (CRT), was directly correlated to the increase in left ventricular systolic function, as measured by the percent increase in maximal rate of left ventricular systolic pressure rise (LV+dP/dtmax): EROA = –0.7 x LV+dP/dtmax –7.6, r = –0.83, p < 0.0001.

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

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The present study demonstrates that CRT can acutely reduce the severity of FMR in heart failure patients with an LBBB, irrespective of the potential long-term reverse remodeling effect on LV shape and size (12,13). Furthermore, the reduction in FMR is quantitatively related to an increase in LV+dP/dt_max and TMP. We observed an immediate reduction in mean EROA and RegVol of about 40% by CRT.

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 (15–17), 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/dt_max, 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 (TMP_max) 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.

View larger version (42K): [in this window] [in a new window]   Figure 4 Schematic representation of the relationship between the increase in transmitral pressure gradient (TMP) (the instantaneous difference between left ventricular and left atrial pressure) and the decrease in effective regurgitant orifice area (EROA). During OFF (top panel), left ventricular (LV) contractility is low and results in a slow rise in the LV pressure curve and TMP with a relatively late systolic maximum. Due to the slow LV pressure rise with delayed development of an effective transmitral closing force (approximately TMP), EROA remains large for a relatively long period until it finally reaches its minimal value. In contrast, during cardiac resynchronization therapy (CRT) (bottom panel), LV contractility improves, TMP rises faster and to a higher maximal value, which is also reached earlier. Consequently, the reduction in EROA occurs earlier, EROA reaches lower values and for a prolonged period of time. The shaded area represents the time in systole during which EROA is below 50% of its initial value. Note that, in the chosen example, the reduction in the height of the V-wave after a decrease in the initial mitral regurgitation will contribute to a preserved TMP during the latter half of systole. Solid line = left atrial (LA) and LV pressure; dotted line = EROA. Adapted from Hung et al. (15).

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/dt_max 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

Top Abstract Methods Results Discussion Study limitations Conclusions References

 
The applied PISA method assumes that the convergence zone is hemispherical. Recent studies have demonstrated that mitral valve orifice shape is rather elliptic or slit-like (28). Although a hemielliptical formula may, therefore, be more suitable to describe this situation than a simplified hemispherical formula, the current method has been extensively validated in the clinical setting and found to be both accurate and reproducible (29). Moreover, because we focused on the intraindividual changes in FMR with CRT, this limitation is unlikely to have affected the principle results of the study. Although the mitral regurgitant orifice is dynamic (15,16), midsystolic EROA appears to be a robust surrogate of mean EROA (30).

Estimation of LV dP/dt_max with the described CW Doppler technique tends to underestimate true LV+dp/dt_max 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 TMP_max 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

Top Abstract Methods Results Discussion Study limitations Conclusions References

 
Cardiac resynchronization therapy in selected patients with advanced heart failure and electrical conduction delay acutely reduces the severity of FMR by decreasing the EROA. This effect is directly related to an improvement in LV systolic function causing an accelerated rise in TMP, which effectively counteracts the increased tethering forces that impair mitral valve competence. The acute effect is independent from geometrical changes (reverse remodeling) and may exert further beneficial effects on FMR severity.

	References

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