Improvement of Atrial Function and Atrial Reverse Remodeling After Cardiac Resynchronization Therapy for Heart Failure

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1 Journal of the American College of Cardiology Vol. 50, No. 8, by the American College of Cardiology Foundation ISSN /07/$32.00 Published by Elsevier Inc. doi: /j.jacc Improvement of Atrial Function and Atrial Reverse Remodeling After Cardiac Resynchronization Therapy for Heart Failure Cheuk-Man Yu, MD, FRCP, FRACP,* Fang Fang, MM, PHD, Qing Zhang, MM, PHD,* Gabriel W. K. Yip, MD,* Chun Mei Li, BM,* Joseph Yat-Sun Chan, FHKAM,* LiWen Wu, BM,* Jeffrey Wing-Hong Fung, FRCP* Hong Kong and Beijing, China Objectives Background Methods Results Conclusions We sought to examine whether cardiac resynchronization therapy (CRT) improves atrial function and induces atrial reverse remodeling. Cardiac resynchronization therapy is an established therapy for advanced heart failure with prolonged QRS duration, which improves left ventricle (LV) function and is associated with LV reverse remodeling. A total of 107 heart failure patients (66 11 years) who received CRT and were followed up for 3 months were studied. Atrial function was assessed by M-mode, 2-dimensional echocardiography, transmitral Doppler, tissue Doppler velocity, and strain ( ) imaging. Left atrial (LA) emptying fraction based on the change in areas (LAA-EF) and volumes (LAV-EF) were calculated. The LV reverse remodeling was defined by a reduction of LV end-systolic volume 10%. In the responders of LV reverse remodeling (n 62), LAA-EF and LAV-EF were significantly increased (p 0.001). Responders also had significant decrease in LA size area and volumetric measurements, both before (p 0.05) and after atrial systole (p 0.001). However, these parameters were unchanged in the nonresponders (n 45, p NS). In the responders, tissue Doppler velocity analysis showed improvement of contraction velocity in both left (p 0.005) and right atria (p 0.018), whereas in both atria were increased in all the phases of cardiac cycle, namely ventricular end-systole (p 0.001), early diastole (p 0.001), and late diastole (p 0.007). Cardiac resynchronization therapy improves both left and right atrial pump function. The increase in atrial throughout the cardiac cycle is likely reflecting the improvement of atrial compliance. These changes lead to LA reverse remodeling with reduction of LA size before and after atrial systole. (J Am Coll Cardiol 2007;50: ) 2007 by the American College of Cardiology Foundation Cardiac resynchronization therapy (CRT) is now an established treatment for patients with advanced heart failure with prolonged QRS duration. Apart from clinical benefits, improvement of left ventricular (LV) systolic function and associated LV reverse remodeling have been well reported (1 6). Recently, improvement of right ventricular function also has been reported (7). Despite the extensive evidence of the benefits of CRT on ventricular function, whether the From the *Li Ka Shing Institute of Health Sciences, Division of Cardiology, Department of Medicine and Therapeutics, Prince of Wales Hospital and Institute of Vascular Medicine, S.H. Ho Cardiovascular and Stroke Centre, Shatin, N.T., Hong Kong, China; and Ultrasound Department, Beijing AnZhen Hospital, Capital Medical University, Beijing, China. This study was supported by a research grant from Li Ka Shing Institute of Health Sciences. Manuscript received December 22, 2006; revised manuscript received April 10, 2007, accepted April 16, use of CRT benefits patients with atrial function has not been evaluated. With improvement of LV function and reduction of mitral regurgitation, left atrial (LA) size could be reduced. Furthermore, the pressure unloading effect in the atrium may result in the improvement of atrial function. Atrial function is relatively complex. Apart from active atrial pump function as a direct result of atrial systole, atrial compliance is an important determinant of atrial reservoir and conduit functions (8). With the advancement of echocardiographic technology, it is now possible to assess regional atrial function, in particular by tissue Doppler velocity and strain ( ) imaging. Tissue Doppler velocity is useful to assess regional atrial active contractile function, whereas tissue Doppler strain is a good measure of myocardial deformation (9,10). Therefore, in the present study we combined the use

2 JACC Vol. 50, No. 8, 2007 August 21, 2007: Yu et al. Improved Atrial Function After CRT 779 of conventional and advanced echocardiographic tools of tissue Doppler velocity and strain to examine atrial function and determined whether atrial reverse remodeling occurred and atrial function improved after CRT. Furthermore, whether such changes were different between responders and non-responders of LV reverse remodeling were also explored. Methods Patients. The study population consisted of 120 consecutive patients with advanced congestive heart failure who had received CRT. The inclusion criteria of CRT included symptomatic heart failure despite optimal pharmacological therapy, New York Heart Association (NYHA) functional class III or IV heart failure, ejection fraction 40% and QRS duration 120 ms in the form of bundle branch block or intraventricular conduction delay. They were followed up at 3 months after the therapy, at which point 3 patients had died and 1 patient had dropped out before follow-up. Serial standard echocardiography with tissue Doppler imaging and clinical assessment were performed at baseline and 3 months after CRT. Nine patients whose major echocardiographic parameters could not be obtained because of poor image quality were excluded from the study. As a result, 107 patients (66 11 years, 75% males) were included in the analysis. Among them, 11 patients had permanent atrial fibrillation, but the ablation of atrioventricular node was only attempted in 3 patients with uncontrolled ventricular rate. The study protocol was approved by the Ethics Committee of The Chinese University of Hong Kong Abbreviations and Acronyms strain 3ch 3-chamber 4ch 4-chamber CRT cardiac resynchronization therapy IAS interatrial septum LA left atrial LAA-EF left atrial emptying fraction based on the change in areas LAV-EF left atrial emptying fraction based on the change in volumes LV left ventricular NYHA New York Heart Association RA right atrial and written informed consent was obtained from each participant. Biventricular device implantation. Biventricular devices were implanted as previously described (4,6). The LV pacing lead was inserted by a transvenous approach through the coronary sinus to target lateral or posterolateral cardiac vein. Choices of CRT devices included biventricular pacemaker in 97 patients (InSync, InSync III from Medtronic Inc., Minneapolis, Minnesota; Contak TR or Contak TR II from Guidant Inc., St. Paul, Minnesota) and biventricular defibrillator in 10 patients (InSync ICD, InSync Marquis or InSync Sentry from Medtronic Inc., Minneapolis, Minnesota; Contak CD or Contak Renewal from Guidant Inc., St. Paul, Minnesota). Echocardiographic assessment of atrial size and function. Echocardiography with tissue Doppler imaging was performed (Vivid 5 or Vivid 7, Vingmed-General Electric, Horten, Norway) serially before and 3 months after CRT. The atrioventricular interval was optimized by Ritter s method at day 1 after implantation to reach maximal transmitral diastolic filling and maximal biventricular capture. The adjustment of interventricular interval was not performed and, therefore, all patients were Comparison Parameters at of Baseline Clinical andechocardiographic After CRT for 3 Months Table 1 Comparison of Clinical and Echocardiographic Parameters at Baseline and After CRT for 3 Months Baseline CRT p Value NYHA functional class, % patients (Z 8.2) Class I 0 4 Class II 4 66 Class III Class IV min hall walk, m Exercise capacity, METs Quality of life score LV end-systolic volume, cc LV end-diastolic volume, cc Ejection fraction, % End-systolic sphericity index End-diastolic sphericity index Myocardial performance index Mitral regurgitation, % LA area LV filling time, ms Diastolic dysfunction, % patients 0.05 (Z 3.3) Abnormal relaxation pattern Pseudonormal filling pattern Restrictive filling pattern CRT cardiac resynchronization therapy; LA left atrial; LV left ventricular; METs metabolic equivalents; NYHA New York Heart Association.

3 780 Yu et al. JACC Vol. 50, No. 8, 2007 Improved Atrial Function After CRT August 21, 2007: having simultaneous biventricular pacing at the default setting. The LV volumes and ejection fraction were assessed by biplane Simpson s equation using the apical 4-and 2-chamber views where the length of the ventricular image was maximized. Patients who had a reduction of LV end-systolic volume of 10% were defined as volumetric responders of CRT, whereas those with a lesser degree of reduction of 10% were called nonresponders (11). Diastolic dysfunction was graded as abnormal relaxation, pseudonormal, and restrictive filling patterns, as previously described (12). Atrial function was assessed at apical 4-chamber (4ch) and 3-chamber views (3ch) (13). In the LA, the long-axis diameter at end-diastole was measured at 4-ch view. The LA areas were then measured at 4ch and 3ch views at the Comparison That and After Measured CRT of for Echocardiographic Atrial 3 Months Function at Baseline Parameters Table 2 Comparison of Echocardiographic Parameters That Measured Atrial Function at Baseline and After CRT for 3 Months Baseline CRT p value LA LAX diameter, mm LAA-max-4ch, cm LAA-pre-4ch, cm LAA-post-4ch, cm LAA-EF-4ch, % LAA-max-3ch, cm LAA-pre-3ch, cm LAA-post-3ch, cm LAA-EF-4ch, % LAV-max, cm LAV-pre, cm LAV-post, cm LAV-EF, % V-LA, cm/s V-IAS, cm/s V-RA, cm/s s-la, % s-ias, % s-ra, % e-la, % e-ias, % e-ra, % a-la, % a-ias, % a-ra, % MV-A, cm/s NS a-la maximal left atrial strain during atrial contraction; a-ias maximal inter-atrial septum strain during atrial contraction; a-ra maximal right atrial strain during atrial contraction; e-la maximal left atrial strain during ventricular early diastole; e-ias maximal inter-atrial septum strain during ventricular early diastole; e-ra maximal right atrial strain during ventricular early diastole; s-la maximal left atrial strain during ventricular systole; s-ias maximal inter-atrial septum strain during ventricular systole; s-ra maximal right atrial strain during ventricular systole; CRT cardiac resynchronization therapy; LA LAX left atrial diameter in parasternal long-axis view; LAA-max-3ch maximal left atrial area in apical 3-chamber view; LAA-max- 4ch maximum left atrial area in apical 4-chamber view; LAA-post-3ch left atrial areas after atrial systole in 3-chamber view; LAA-post-4ch left atrial areas after atrial systole in 4-chamber view; LAA-pre-3ch left atrial areas just before atrial systole in 3-chamber view; LAA-pre-4ch left atrial area just before atrial systole in 4-chamber view; LAV-EF left atrial emptying fraction based on the change in volumes; LAV-max maximum left atrial volume; LAV-post left atrial volume after atrial systole; LAV-pre left atrial volume just before atrial systole; MV-A transmitral atrial velocity; NS not significant; V-IAS Peak inter-atrial septum contraction velocity (after P-wave); V-LA peak left atrial contraction velocity (after P-wave); V-RA peak right atrial contraction velocity (after P-wave). following phases of the cardiac cycle: the maximal LA areas at ventricular end-systole where LA size is maximal (LAAmax-4ch and -3ch), LA areas just before atrial systole (LAA-pre-4ch and -3ch), and the minimal LA areas after atrial systole (LAA-post-4ch and -3ch). Atrial emptying fraction was calculated based on the change of areas before and after atrial systole (LAA-EF-4ch and -3ch). Using the modified Simpson rule, the atrial volume at ventricular end-systole, just before and after atrial systole and atrial emptying fraction (LAV-EF) also were calculated (13). Tissue Doppler imaging was performed at the apical 4ch view for the long-axis motion of the heart as previously described (14,15). Two-dimensional echocardiography with color tissue Doppler imaging was performed. The imaging angle was adjusted to ensure a parallel alignment of the sampling window with the myocardial segment of interest. Gain settings, filters, pulse repetitive frequency, sector size, and depth were adjusted to optimize color saturation. At least 3 consecutive beats were stored, and the images were digitized and analyzed off-line with EchoPac-PC (Vingmed- General Electric). Atrial Doppler velocity profile signals were reconstituted off-line by placing a 3 12-mm sampling window at the mid levels of LA, interatrial septum (IAS), and RA, respectively. The peak regional atrial contraction velocities at atrial systole (after the onset of P wave of electrocardiogram) were measured. Atrial was measured in the same atrial locations and was calculated by the formula: (L L 0 )/L 0 100%, in which L denotes the instantaneous length, and L 0 denotes the original length. The following parameters of atrial function by tissue Doppler velocity and imaging were measured: Left atrial contraction velocity during atrial systole; Inter-atrial septum contraction velocity during atrial systole; Right atrial contraction velocity during atrial systole; Left atrial during ventricular end-systole; Interatrial septum during ventricular end-systole; Right atrial during ventricular end-systole; Left atrial during ventricular early diastole; Inter-atrial septum during ventricular early diastole; Right atrial during ventricular early diastole; Left atrial during ventricular late diastole; Interatrial septum during ventricular late diastole; and Right atrial during ventricular late diastole The intraobserver and interobserver variability for atrial myocardial velocity measurement were 3.2% and 4.7%, and for atrial strain measurement, they were 7.1% and 8.4%, respectively. Statistical analyses. For comparison of continuous parametric variables between baseline and 3 months after CRT, a paired sample t test was used. The nonparametric Wilcoxon test was adopted for comparison of ordinal variables, including NYHA functional class and pattern of diastolic dysfunction. The comparison of echocardiographic param-

4 JACC Vol. 50, No. 8, 2007 August 21, 2007: Yu et al. Improved Atrial Function After CRT 781 eters between volumetric responders and nonresponders was performed with the unpaired t test. All parametric data were expressed as mean SD. A p value 0.05 was considered statistically significant. Results The optimal atrioventricular delay programmed was ms. Medications for heart failure were kept unchanged throughout the study period, except intravenous diuretics with/without subsequent increase in dosage of oral diuretics in case of acute decompensation. Heart rate was decreased slightly at 3 months when compared with baseline (67 12 beats/min vs beats/min, p 0.02). Clinical status and ventricular function. There was a favorable improvement of clinical status in the whole group, namely NYHA functional class, Minnesota Living With Heart Failure Quality of Life score, and 6-Minute Hall- Walk distance after CRT for 3 months (all p 0.001) (Table 1). Left ventricular function was improved with the evidence of LV reverse remodeling, increase in sphericity indices, reduction of mitral regurgitation, decrease in myocardial performance index, as well as increase in diastolic filling time and favorable change in LV diastolic filling pattern (all p 0.001) (Table 1). Comparison That Measured of Echocardiographic Atrial Function for Parameters Responders and Nonresponders of CRT Table 3 Comparison of Echocardiographic Parameters That Measured Atrial Function for Responders and Nonresponders of CRT Atrial remodeling and atrial function after CRT. The use of CRT resulted in significant reduction of LA area before and after atrial contraction at both 4ch and 3ch views, resulting in a significant increase in LA emptying fraction (i.e., LAA-EF-4ch and -3ch; both p 0.001) (Table 2). Similarly, the LA emptying fraction by volumetric measurement, i.e., LAV-EF, was increased significantly (p 0.001). However, the maximal LA area and volume at ventricular end-systole were unchanged. There also was no change in LA diameter observed. Transmitral Doppler measurement of peak atrial velocity showed no difference between baseline and 3 months after CRT. Left and right atrial function was further examined by tissue Doppler velocity and strain imaging. It was observed that atrial contraction velocities in all the 3 atrial sites were improved significantly (Table 2). Atrial strain at ventricular end-systole, after early-diastole, as well as at end-diastole, were improved. Atrial remodeling, atrial function, and CRT response. There were 62 responders (58%) and 45 (42%) nonresponders of LV reverse remodeling. There were 5 patients with permanent AF in the nonresponder group and 6 in the responder group. The changes in atrial structure and function were divergent in the 2 groups (Table 3). In the Nonresponders Responders Baseline CRT p Value Baseline CRT p Value LA LAX diameter, mm NS NS LAA-max-4ch, cm NS NS LAA-pre-4ch, cm NS LAA-post-4ch, cm * NS LAA-EF-4ch, % NS LAA-max-3ch, cm NS NS LAA-pre-3ch, cm * NS LAA-post-3ch, cm NS LAA-EF-4ch, % NS LAV-max, cm * NS NS LAV-pre, cm * NS LAV-post, cm * NS LAV-EF, % NS V-LA, cm/s * NS V-IAS, cm/s NS V-RA, cm/s s-la, % NS s-ias, % s-ra, % * NS e-la, % NS e-ias, % e-ra, % * NS a-la, % NS NS a-ias, % NS a-ra, % * NS MV-A, cm/s * NS NS *p 0.05, p 0.01, p 0.01 comparing responders and nonresponders of corresponding parameters. Abbreviations as in Table 2.

5 782 Yu et al. JACC Vol. 50, No. 8, 2007 Improved Atrial Function After CRT August 21, 2007: Figure 1 Apical 4-Chamber View Showing the Changes of Left Atrial Size After CRT In a responder of left ventricular reverse remodeling, the LA size after atrial contraction was significantly reduced when compared between baseline (A) and 3-month follow-up (B), in contrast to a nonresponder in whom the LA size remained unchanged between baseline (C) and 3-month follow-up (D). CRT cardiac resynchronization therapy. nonresponders, there was no evidence of reduction in LA area or volume in all the 3 phases of the cardiac cycle (Fig. 1). As a result, no improvement of atrial emptying fraction was observed (both calculated by area or by volume), in contrast to the responders that the LA area and volume before and after atrial contractions were significantly reduced (Table 3, Fig. 1). As a result, LA emptying fraction by LAA-EF-4ch, LAA-EF-3ch, and LAV-EF were significantly improved (all p 0.001). By tissue Doppler velocity and strain imaging, it was observed that improvement of LA contraction velocity was only observed in the responders, though RA and IAS contraction velocity was improved in both groups (Table 3, Fig. 2). Furthermore, improvement of LA and RA strain during ventricular end-systole and early diastole were only observed in the responders (Table 3, Fig. 3). There was no significant change in transmitral peak atrial velocity in both responders and non-responders of LV reverse remodeling. There was reduction in mitral regurgitation in both responders (32 19% vs %, p 0.001) and nonresponders (34 22% vs %, p 0.005) of reverse remodeling, though the magnitude was similar in both groups ( 10 13% vs. 8 18%, p NS). Furthermore, when those patients with atrial fibrillation were excluded and the analyses were repeated, the above observations remained unchanged. Discussion This study examined atrial function and atrial remodeling in heart failure patients who received CRT by the combined use of conventional and new echocardiographic imaging tools. It was observed that active atrial contractile function was significantly improved in both atria, in particular the LA. Furthermore, atrial remodeling is evident by the reduction of atrial area and volume before and after atrial systole. These findings corroborated with the improvement of atrial function, including the increase of atrial emptying

6 JACC Vol. 50, No. 8, 2007 August 21, 2007: Yu et al. Improved Atrial Function After CRT 783 Figure 2 Assessment of Regional Left Atrial Velocity by Tissue Doppler Imaging at Apical 4-Chamber View The sampling window was placed at the midatrial level. In a responder of left ventricular reverse remodeling, there was improvement of atrial contraction velocity (arrows) when compared between baseline (A) and 3 months after cardiac resynchronization therapy (B). On the other hand, the nonresponder showed no improvement of atrial contraction velocity (arrows) between baseline (C) and 3-month follow-up (D). fraction, peak atrial contraction velocity by tissue Doppler velocity, and atrial. There was also improvement of atrial during ventricular end-systole and early diastole, which may suggest the improvement of atrial compliance. Of note, these changes were mainly observed in responders of LV reverse remodeling. Improvement of atrial function and atrial reverse remodeling after CRT. Atrial function is an integral part of cardiac function, as at least one-third or more of the LV filling is dependent on active atrial pump function, especially in the elderly population (8). In heart failure patients who received CRT, a number of studies have confirmed the improvement of LV systolic function, LV reverse remodeling, as well as reduction of LV mass (5,6,11,16). However, atrial function and atrial reverse remodeling have not been explored. This study examined atrial function by the combined use of conventional and new echocardiographic technologies. It appeared that LA active contractile function is improved in the responders of LV reverse remodeling after CRT, as suggested by the increase in LA emptying fraction by all the 3 methods. Furthermore, tissue Doppler imaging revealed the increase in atrial contraction velocity and atrial during ventricular end-diastole. In fact, the atrial contraction velocities by tissue Doppler imaging were also increased in IAS and RA, which reflect the improvement of biatrial contractile function after CRT. Our analysis also observed the impact of LV reverse remodeling response on atrial size and function. In fact, the favorable changes in LA size and contractile function were only observed in responders of LV reverse remodeling but not the nonresponders. As shown in previous studies, responders of LV reverse remodeling had evidence of more efficient diastolic filling (4,5), favorable change in geometry (high sphericity index that reduced LV wall tension) (16), reduction of mitral regurgitation (17,18), lower LV diastolic filling pressure (19), as well as regression of LV mass (6). This will favor pressure and volume-unloading effects in the LA, which facilitate atrial emptying. Furthermore, a recent study also suggested the favorable improvement of RV

7 784 Yu et al. JACC Vol. 50, No. 8, 2007 Improved Atrial Function After CRT August 21, 2007: Figure 3 Assessment of Atrial Strain at Mid Level of Left Atria in the Same Patients as in Figure 2 In a responder of left ventricular reverse remodeling, left atrial strain at ventricular end-systole ( s), early diastole ( e) as well as after atrial contraction ( a) was increased when compared with baseline (A) and 3 months after cardiac resynchronization therapy (B). On the other hand, the nonresponder showed no improvement of atrial strain between baseline (C) and 3-month follow-up (D). function and reduction of tricuspid regurgitation in CRT responders, which may lead to favorable change in RA function (7). As the magnitude of reduction in mitral regurgitation after CRT was similar between the 2 groups, reduction volume overload caused by functional mitral regurgitation is unlikely to be the major contributing factor for atrial reverse remodeling after CRT. Improvement of atrial strain after CRT and its implication. It is also important to note that the maximal LA area and volume at end-systole remain unchanged despite the improvement of active atrial contractile function. Nevertheless, left and right atrial were increased during ventricular systole and early diastole. Strain is a measure of regional deformity, which is dependent on the ultrastructural components of the atrium, such as the extent of atrial myocyte hypertrophy and amount of interstitial fibrosis (20). Therefore, our results suggest that the atria are more elastic and compliant when subjected to passive stretching. In other words, this reflects improvement of both reservoir (increased atrial during ventricle systole) and conduit functions (increased atrial during early diastole). Therefore, although the maximal atrial size remained unchanged in the responders, the more dynamic changes in atrial throughout the cardiac cycle may possibly reflect structural changes leading to better atrial compliance. Study limitations. Regarding the possible mechanism of beneficial changes in atrial function after CRT, it will be more comprehensive if factors other than LV reverse remodeling were also taken into consideration, such as assessment of severity and change in mitral regurgitation. However, the present study aimed at investigating the changes of atrial remodeling and function as the primary objective. Furthermore, more quantitative methods are needed to explore the relationship between the changes of mitral regurgitation and LA functional improvement, such as the use of proximal isovelocity surface area method, which might not be applicable in some patients with less than mild-to-moderate or eccentric mitral regurgitation. It will also be interesting to explore whether atrial reverse remodeling is associated with reduction of atrial arrhythmias, which was not examined in the present

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