Effect of Cardiac Resynchronization Therapy on Reverse Remodeling and Relation to Outcome
Multicenter Automatic Defibrillator Implantation Trial: Cardiac Resynchronization Therapy
Background— Cardiac resynchronization therapy (CRT) plus implantation of an implantable cardioverter defibrillator (ICD) reduced the risk of death or heart failure event in patients with mildly symptomatic heart failure, left ventricular dysfunction, and wide QRS complex compared with an ICD only. We assessed echocardiographic changes in patients enrolled in the MADIT-CRT trial (Multicenter Automatic Defibrillator Implantation Trial: Cardiac Resynchronization Therapy) to evaluate whether the improvement in outcomes with CRT plus an ICD was associated with favorable alterations in cardiac size and function.
Methods and Results— A total of 1820 patients were randomly assigned to CRT plus an ICD or to an ICD only in a 3:2 ratio. Echocardiographic studies were obtained at baseline and 12 months later in 1372 patients. We compared changes in cardiac size and performance between treatment groups and assessed the relationship between these changes over the first year, as well as subsequent outcomes. Compared with the ICD-only group, the CRT-plus-ICD group had greater improvement in left ventricular end-diastolic volume index (−26.2 versus −7.4 mL/m2), left ventricular end-systolic volume index (−28.7 versus −9.1 mL/m2), left ventricular ejection fraction (11% versus 3%), left atrial volume index (−11.9 versus −4.7 mL/m2), and right ventricular fractional area change (8% versus 5%; P<0.001 for all). Improvement in end-diastolic volume at 1 year was predictive of subsequent death or heart failure, with adjustment for baseline covariates and treatment group; each 10% decrease in end-diastolic volume was associated with a 40% reduction in risk (P<0.001).
Conclusions— CRT resulted in significant improvement in cardiac size and performance compared with an ICD-only strategy in patients with mildly symptomatic heart failure. Improvement in these measures accounted for the outcomes benefit.
Clinical Trial Registration Information— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180271.
Received March 21, 2010; accepted June 15, 2010.
Cardiac resynchronization therapy (CRT) has been shown to improve measures of left ventricular (LV) size and function in appropriately selected patients.1–5 Moreover, in several large outcome studies in patients with moderate to severely symptomatic heart failure, CRT has been shown to reduce the likelihood of death or heart failure hospitalization.6,7 It has been presumed that the improvement in outcomes associated with CRT has been directly due to the improvement in cardiac size and performance,8–10 although the relationship between changes in cardiac size and function and subsequent outcomes has not been explored in a large multicenter trial. In addition, the effect of CRT on other measures of cardiac size and function has been assessed only in relatively small, mostly single-center studies without outcomes data available.11–13
Clinial Perspective on p 992
The MADIT-CRT trial (Multicenter Automatic Defibrillator Implantation Trial: Cardiac Resynchronization Therapy) was designed to test the hypothesis that CRT would reduce the risk of death or heart failure events in patients with mild cardiac symptoms (New York Heart Association class I or II), reduced ejection fraction, and widened QRS complex, and it demonstrated a significant 34% reduction in the primary end point of death or heart failure event in patients randomized to the CRT plus implantable cardioverter defibrillator (ICD) group (CRT-D group).14 To test the hypothesis that CRT would improve measures of cardiac size and function in association with improvement in outcomes, we assessed echocardiographic changes in patients enrolled in MADIT-CRT and related these changes to outcomes.
The MADIT-CRT trial enrolled 1820 patients from December 22, 2004, through April 23, 2008, at 110 centers in the United States, Canada, and Europe. Details of the study protocol and the primary results have been reported previously.14,15 All patients provided written informed consent, which included consent for the echocardiographic analyses. Included patients were >21 years of age and had mildly symptomatic heart failure (New York Heart Association class I or II if ischemic, New York Heart Association class II if nonischemic), ejection fraction of 30% or less as determined by the enrolling site, and a QRS width of at least 130 ms. Additional details on inclusion and exclusion criteria have been published previously.14,15 This research protocol was approved by individual institutional review boards, and all patients enrolled provided written informed consent.
Patients were randomly assigned in a 3:2 ratio to receive CRT-D therapy or ICD-only therapy. Details of device implantation have been provided previously. In the ICD-only group, the programmed pacing mode was VVI for single-chamber units and DDI for dual-chamber units, with lower rates of 40 bpm and hysteresis off in both single- and dual-chamber units. In the CRT-D group, the programmed mode was DDD with a lower rate of 40 bpm and hysteresis off. Randomization was stratified by clinical center and ischemic status. Echocardiograms were obtained according to a study-specific protocol at baseline, which was before device implantation (n=1809), and at 1 year (n=626 in ICD-only group, n=752 in CRT-D group). The Food and Drug Administration originally requested that all follow-up echocardiograms be performed with the CRT device turned off; after the first 201 patients had undergone follow-up testing under these conditions, the protocol was amended with the consent of the Food and Drug Administration so that follow-up studies would be performed with the CRT device turned on. Paired echocardiograms from baseline and at 12 months with the device turned on were available in 1372 patients, and these patients were included in the present analysis.
Investigators and sonographers from enrolling sites participated in investigator meetings at which the echocardiographic protocol was reviewed and the details of the echocardiographic views and techniques were demonstrated. Echocardiograms were sent on videotape or digital storage media to the echocardiographic core laboratory at Brigham and Women’s Hospital, where they were screened for quality, and LV, right ventricular (RV), and left atrial measurements were made in all patients at baseline and in patients who had on-device echocardiograms available at 12 months. To maximize efficiency in the performance of multiple echocardiographic measurements, mitral regurgitation and Doppler analyses were performed in a second core laboratory at the University of California, San Francisco, which has expertise in these measurements, in a random subset of patients (100 pairs from the ICD-only arm and 235 pairs from the CRT-D arm). Echocardiographic parameters were measured by a single technician at each core laboratory according to established American Society of Echocardiography protocols.16,17 LV volumes were measured by Simpson’s method of discs in the apical 4-chamber and 2-chamber views and averaged. LV ejection fractions were calculated according to standard methods. Left atrial volumes were measured by Simpson’s method of discs in the apical 4-chamber view. RV fractional area change was calculated as the difference in RV diastolic and systolic area divided by diastolic area, in the apical 4-chamber view.16 Ventricular and atrial diameters were measured according to standard methods. Mitral regurgitation was graded according to standard criteria.17 Additional quantitative measures of mitral regurgitation, including regurgitant jet width and proximal isovelocity surface area diameter, were made in a subset of patients when feasible. Technicians performing measurements were not aware of intention-to-treat randomization assignments or patient outcomes, although they were not blinded to the presence of devices, QRS complexes, or temporal sequence. Reproducibility of the primary volumetric measures was assessed by having the primary observer reanalyze 101 random studies. The coefficients of variation for end-diastolic volume, end-systolic volume, and ejection fraction were 5.2%, 6.2%, and 5.5% respectively. To determine the amount of RV pacing in the ICD-only group, we performed interrogation analysis on a random sample of 90 ICD-only patients.
The MADIT-CRT echocardiographic study was designed to test the hypothesis that CRT would improve LV size and function to a greater extent than ICD therapy alone and to assess the relationship between changes in cardiac size and function and outcomes. Because echocardiograms were obtained at baseline on all patients enrolled in MADIT-CRT, the echocardiographic study had >99% power to detect a 5-point absolute change in ejection fraction on the basis of an SD determined by prior studies.
Differences in baseline characteristics between treatment groups were assessed by χ2 testing for categorical variables and by t tests for continuous variables. Between-treatment-group differences in the change in echocardiographic measures from baseline to 12-month follow-up were assessed in ANCOVA with adjustment for treatment group, ischemic cause, and baseline measure. The effect of treatment on ventricular end-diastolic volume was compared in the subgroups of age less than 65 or greater than or equal to 65, male or female gender, ischemic status, QRS width less than 150 ms or greater than or equal to 150 ms, New York Heart Association class I or II, diabetic status, and presence of left bundle-branch block, and the interaction between subgroup and treatment effect with respect to change in end-diastolic volume was assessed.
The primary outcome of the overall study was the first occurrence of death due to any cause or nonfatal heart failure event; this end point was adjudicated by an independent end-points committee unaware of treatment assignment and required signs and symptoms consistent with congestive heart failure responsive to intravenous decongestive therapy on an outpatient basis or augmentation of oral or parenteral decongestive regimen during an in-hospital stay.15 The relationship between echocardiographic changes from baseline to follow-up and the primary outcome subsequent to the 1-year echocardiogram (landmark-type analysis) was assessed by Cox proportional hazards methods, either adjusted for ischemic status and treatment status or in a more fully adjusted model that included age; gender; ischemic status; diabetes; estimated glomerular filtration rate; QRS width; baseline New York Heart Association class; use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, diuretics, or statins; and treatment group. The primary event rate subsequent to 1 year was calculated in each quartile of percent change of LV end-diastolic volume between baseline and the 1-year echocardiogram in each of the treatment groups. All analyses were performed at Brigham and Women’s Hospital by the primary author and confirmed at the University of Rochester.
Baseline demographic characteristics were similar between patients enrolled in the ICD-only and CRT-D groups (Table 1), with the exception of systolic and diastolic blood pressure, which were slightly higher in the CRT-D group. Baseline echocardiographic characteristics were also similar between treatment groups (Table 1). Baseline end-diastolic volume index (124.8±27.7 mL/m2), end-systolic volume index (88.7±22.4 mL/m2), and LV ejection fraction (29.2±3.3%) were consistent with substantial ventricular enlargement and reduction in systolic function. Of note, patients with nonischemic causes of heart failure had higher LV end-diastolic volume (254±70.9 versus 243±52.8 mL, P=0.0002) and higher end-systolic volume (182±57.4 versus 173±42.4 mL, P=0.0002). Random interrogation of pacemaker data from patients in the ICD-only arm revealed that in the single-chamber units, 83% of patients had no RV pacing, an additional 15% had ≤5% RV pacing, and only 2% had >5% LV pacing, and in patients with dual-chamber units, 87% had no RV pacing, an additional 7% had ≤5% RV pacing, and 6% had >5% RV pacing.
A total of 1372 patients (623 patients in the ICD-only group and 749 in the CRT-D group) had paired echocardiographic data available. Of the 448 patients who did not undergo the 12-month device-on echocardiogram, 40 patients died before 12 months, and 201 patients underwent CRT-off echocardiograms only at 12 months. Patients who underwent the 12-month echocardiogram differed from those who did not with respect to several baseline characteristics, including fewer patients with diabetes mellitus (29% versus 35%, P=0.02), greater QRS width (159 versus 155 ms, P=0.001), greater end-diastolic volume index (124.8 versus 119.5 mL/m2, P=0.001), and greater ejection fraction (29% versus 28%, P=0.001).
Changes in echocardiographic parameters are shown in Table 2. We observed substantially greater reduction in end-diastolic volume index (−26.2±16.5 versus −7.4±7.2 mL/m2, P=0.0001) and end-systolic volume index (−28.7±15.5 versus −9.1±8.2 mL/m2, P=0.0001) in association with greater improvement in LV ejection fraction (11±5% versus 3±3%, P=0.0001) in the CRT-D group than in the ICD-only group. We observed >15% reduction in LV end-diastolic volume in 68% of patients in the CRT-D group compared with 5.1% of patients in the ICD-only group, as well as a >10-point absolute increase in ejection fraction in 58% of patients in the CRT-D arm compared with 2.1% in the ICD-only arm. LV ejection fraction improved to ≥45% in 24% of patients in the CRT-D group compared with 0% in the ICD group and to ≥50% in 7% of patients in the CRT-D group compared with none in the ICD group. LV diameters were similarly reduced to a greater extent in the CRT-D group (Table 2), as was left atrial volume (−25.1±12.0 vs. −9.1±7.8, P=0.0001). Likewise, RV fractional area change was similarly improved in the CRT-D group (8.1±5.5 versus 5.4±4.8 cm2, P=0.0001). Tricuspid regurgitant velocity, a measure of the gradient between RV and right atrial pressure and a surrogate for pulmonary artery systolic pressure, was also reduced to a greater extent in the CRT-D group (P=0.0026). Changes in chamber volumes and function are summarized in Figure 1.
We observed greater improvement in end-diastolic volume, end-systolic volume, and ejection fraction in the CRT-D group within all subgroups studied; however, significantly greater improvement in these parameters was observed in patients with nonischemic cardiomyopathy (interaction P<0.001), in female patients (interaction P=0.001), in those with QRS width >150 ms (interaction P<0.001), and in those with left bundle-branch block (interaction P<0.001; Figure 2).
Of the patients with mitral regurgitation assessed at baseline and at 12 months, mitral regurgitation was graded as “none” in 2%, “mild” in 83%, “moderate” in 13%, and “severe” in 2% of patients at baseline (Table 3). The majority of patients in each group had no change in mitral regurgitation grade (84% in the ICD-only group versus 82% in the CRT-D group), although a greater number of patients worsened in the ICD-only group and improved in the CRT-D group (P=0.016). Mitral regurgitation improved by 1 category or more in 15.3% of patients in the CRT-D group compared with 8.3% in the ICD-only group (P=0.02). Mitral regurgitant jet width, available in a smaller subset of patients, was reduced to a greater extent in patients in the CRT-D group (Table 2; P=0.004).
The primary outcome of death or heart failure event occurred after the 1-year echocardiogram in 98 patients (16.8%) in the ICD-only group and in 55 (7.8%) in the CRT-D group, with a median postyear follow-up of 16.2 months. In an analysis that explored the relationship between changes in echocardiographic measures over the first year and the primary MADIT-CRT end point of death or heart failure event that occurred subsequently, the extent of improvement in echocardiographic measures was directly related to the likelihood of death or heart failure event after 1 year (Figure 3). This relationship was similar in both treatment groups, although the distributions of change in end-diastolic volume were substantially different in the 2 treatment groups. In a multivariable model that adjusted for baseline demographic characteristics, medication use, laboratory data, and treatment group, each 10% decrease in end-diastolic volume over the 12-month period was associated with a 40% reduction in the primary outcome; each 10% decrease in end-systolic volume was associated with a 28% reduction in the primary outcome; and each 5-point absolute increase in ejection fraction was associated with a 40% reduction in the primary outcome (Table 4). Similar reductions in the outcome of all-cause mortality were observed with improvements in cardiac size and function (Table 4). There was no interaction between treatment group and the relationship between changes in echocardiographic measures and outcome.
MADIT-CRT demonstrated improvement in the primary outcome of death or heart failure event in patients with mildly symptomatic heart failure, LV dysfunction, and wide QRS treated with CRT compared with ICD-only therapy.14 In the present analysis of the echocardiographic data from MADIT-CRT, we observed marked improvements in LV volumes and ejection fraction, RV function, left atrial volumes, and mitral regurgitation. These improvements were similar across subgroups, although females, patients with nonischemic heart failure, those with wider QRS complexes, and those with left bundle-branch block benefited to a greater extent. Decreases in ventricular sizes and improvement in ventricular function over the first year of therapy were predictive of a reduction in subsequent cardiac events, even after adjustment for baseline covariates and treatment group, which suggests that improvements in ventricular size and performance may be among the most important contributors to improved outcomes in patients receiving CRT.
Approximately two thirds of patients receiving CRT in MADIT-CRT demonstrated improvement in ventricular size and function, a proportion similar to that seen in other studies.10 A small number of patients derived substantial benefit, with marked changes in ventricular size and performance even into the near-normal range. Although the proportion of patients who should be considered responders is dependent in part on the definition of “response,” these data suggest that even though the majority of patients who fulfilled the entry criteria for MADIT-CRT benefited from CRT, determination of predictors of response remains an important goal in CRT.
The benefits of CRT on LV size and function are well established. We observed similar benefits of changes in ventricular size to those observed in the REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction (REVERSE) trial,5 although we saw even greater benefits with respect to improvement in ejection fraction. One possible reason for this difference may be that the longer QRS duration required for enrollment in MADIT-CRT (QRS ≥130 ms) than in REVERSE (QRS ≥120 ms) may have resulted in a population with more dyssynchrony and thus patients who were more likely to benefit from this therapy. We further observed substantial improvement in RV function and left atrial volumes, as well as improvement in tricuspid regurgitant velocity, which is directly related to pulmonary systolic pressure. These measures, which have been shown to be independent and incremental predictors of outcome in heart failure patients and after myocardial infarction,18–20 suggest that some of the benefits of CRT may be to reduced LV filling pressures, which are then reflected by improvements in atrial size, pulmonary pressures, or RV function.
The degree of mitral regurgitation in patients enrolled in MADIT-CRT was substantially more mild than that observed in prior studies of more symptomatic patients undergoing CRT.21,22 Although greater improvement in mitral regurgitation was observed in the CRT-D group in MADIT-CRT, the present data suggest that reduction in mitral regurgitation severity played a limited role in the improved outcomes observed, in contrast to other studies of more symptomatic patients in which CRT has been associated with substantial improvement in mitral regurgitation.22 These findings were similar to those in the recently reported REVERSE study of a similar population.5,10,23
Although the benefit of CRT on outcomes and measures of ventricular size and function was observed across subgroups, the greater benefit observed in female patients, those with nonischemic status, those with wider QRS complexes, and those with left bundle-branch block was concordant with the effects observed on outcomes, and the observation that women may derive greater benefit than men is novel. Indeed, exploratory analyses suggest a complex interaction between gender and QRS width with regard to degree of reverse remodeling, with females showing benefit across the spectrum of enrolled QRS values. Similarly, the higher proportion of women enrolled who had left bundle-branch block may also have contributed to these findings.
Although substantial changes in ventricular size and function in some patients receiving CRT have been observed in multiple smaller studies, MADIT-CRT is the first large multicenter study to be able to explore the relationship between improvements in cardiac size and function and subsequent outcomes, because we had substantial follow-up time after the second echocardiogram. We performed this analysis to directly link changes in ventricular size and performance to outcomes benefit. Reverse ventricular remodeling during the first year of resynchronization therapy was predictive of fewer future events, even after adjustment for baseline covariates. Indeed, nonfatal events even during the first 12 months were reduced in patients who demonstrated improvement in ventricular size and function during that period (data not shown). These data underscore the important relationship between changes in ventricular size and function and outcomes, which we observed even in the ICD-only group, although the distribution of this relationship was markedly shifted compared with the CRT-D group. It is likely that improvement in ventricular size and performance in the ICD-only group, albeit substantially less than in the CRT-D group, was in part secondary to the excellent background therapy of enrolled patients, with 96% receiving an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, 93% receiving β-blockers, and 31% receiving aldosterone antagonists. Those patients in the ICD-only group who demonstrated improvement in ventricular size and function derived proportional benefit with respect to subsequent events. These data also provide strong support for the use of ventricular size and function as a surrogate end point in assessment of heart failure therapies.
A number of limitations of the present analysis should be noted. As with all echocardiographic studies, the quality of data is dependent on acquired images and image quality. Because echocardiograms were obtained only at baseline and 12 months, we cannot determine how rapidly these changes in ventricular size and function occurred. In addition, 201 patients who underwent 12-month echocardiograms with devices turned off, in response to an early Food and Drug Administration request, were not included in the present analysis. Once the Food and Drug Administration agreed that follow-up echocardiograms should be obtained with the device turned on, the remainder of the 12-month echocardiograms were performed this way. We cannot assess the relationship between changes in ventricular size and function and outcomes in those patients who died or did not undergo the 12-month on-therapy echocardiogram. Many parameters, including severity of mitral regurgitation, were only analyzed in a subset of patients but nevertheless showed significant changes similar to those in previous studies. Finally, we cannot exclude potential reader bias given the inability to blind readers as to QRS complexes or temporal sequence. Nevertheless, the strong relationship between echocardiographic changes and blinded subsequent outcomes argues against systematic bias.
In summary, we observed substantial improvement in LV size and function, RV function, left atrial size, and mitral regurgitation severity in patients treated with CRT compared with ICD alone. These findings were concordant with and predictive of the primary outcome of death or heart failure event and suggest a compelling cardiac structural and functional mechanism by which CRT improves outcomes.
Sources of Funding
The MADIT-CRT trial was funded by Boston Scientific through a research grant to the University of Rochester, which in turn provided funding for core laboratories, including the echocardiography core laboratories.
Drs Solomon, Foster, Hall, and Moss have received research support for the conduct of the MADIT-CRT trial from Boston Scientific through a grant to the University of Rochester. Drs Solomon and Pfeffer have served as consultants to Boston Scientific. The remaining authors report no conflicts.
Saxon LA, De Marco T, Schafer J, Chatterjee K, Kumar UN, Foster E; VIGOR Congestive Heart Failure Investigators. Effects of long-term biventricular stimulation for resynchronization on echocardiographic measures of remodeling. Circulation. 2002; 105: 1304–1310.
St John Sutton MG, Plappert T, Abraham WT, Smith AL, DeLurgio DB, Leon AR, Loh E, Kocovic DZ, Fisher WG, Ellestad M, Messenger J, Kruger K, Hilpisch KE, Hill MR; Multicenter InSync Randomized Clinical Evaluation (MIRACLE) Study Group. Effect of cardiac resynchronization therapy on left ventricular size and function in chronic heart failure. Circulation. 2003; 107: 1985–1990.
Rao RK, Kumar UN, Schafer J, Viloria E, De Lurgio D, Foster E. Reduced ventricular volumes and improved systolic function with cardiac resynchronization therapy: a randomized trial comparing simultaneous biventricular pacing, sequential biventricular pacing, and left ventricular pacing. Circulation. 2007; 115: 2136–2144.
St John Sutton M, Ghio S, Plappert T, Tavazzi L, Scelsi L, Daubert C, Abraham WT, Gold MR, Hassager C, Herre JM, Linde C; REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction (REVERSE) Study Group. Cardiac resynchronization induces major structural and functional reverse remodeling in patients with New York Heart Association class I/II heart failure. Circulation. 2009; 120: 1858–1865.
Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, Carson P, DiCarlo L, DeMets D, White BG, DeVries DW, Feldman AM; Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Investigators. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004; 350: 2140–2150.
Yu CM, Bleeker GB, Fung JW, Schalij MJ, Zhang Q, van der Wall EE, Chan YS, Kong SL, Bax JJ. Left ventricular reverse remodeling but not clinical improvement predicts long-term survival after cardiac resynchronization therapy. Circulation. 2005; 112: 1580–1586.
Daubert C, Gold MR, Abraham WT, Ghio S, Hassager C, Goode G, Szili-Török T, Linde C; REVERSE Study Group. Prevention of disease progression by cardiac resynchronization therapy in patients with asymptomatic or mildly symptomatic left ventricular dysfunction: insights from the European cohort of the REVERSE (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction) trial. J Am Coll Cardiol. 2009; 54: 1837–1846.
Moss AJ, Hall WJ, Cannom DS, Klein H, Brown MW, Daubert JP, Estes NA III, Foster E, Greenberg H, Higgins SL, Pfeffer MA, Solomon SD, Wilber D, Zareba W; MADIT-CRT Trial Investigators. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med. 2009; 361: 1329–1338.
Moss AJ, Brown MW, Cannom DS, Daubert JP, Estes M, Foster E, Greenberg HM, Hall WJ, Higgins SL, Klein H, Pfeffer M, Wilber D, Zareba W. Multicenter automatic defibrillator implantation trial-cardiac resynchronization therapy (MADIT-CRT): design and clinical protocol. Ann Noninvasive Electrocardiol. 2005; 10: 34–43.
Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton MS, Stewart WJ; Chamber Quantification Writing Group; American Society of Echocardiography’s Guidelines and Standards Committee; European Association of Echocardiography. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr. 2005; 18: 1440–1463.
Zoghbi WA, Enriquez-Sarano M, Foster E, Grayburn PA, Kraft CD, Levine RA, Nihoyannopoulos P, Otto CM, Quinones MA, Rakowski H, Stewart WJ, Waggoner A, Weissman NJ; American Society of Echocardiography. Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr. 2003; 16: 777–802.
Zornoff LA, Skali H, Pfeffer MA, St John Sutton M, Rouleau JL, Lamas GA, Plappert T, Rouleau JR, Moyé LA, Lewis SJ, Braunwald E, Solomon SD; SAVE Investigators. Right ventricular dysfunction and risk of heart failure and mortality after myocardial infarction. J Am Coll Cardiol. 2002; 39: 1450–1455.
Anavekar NS, Skali H, Bourgoun M, Ghali JK, Kober L, Maggioni AP, McMurray JJ, Velazquez E, Califf R, Pfeffer MA, Solomon SD. Usefulness of right ventricular fractional area change to predict death, heart failure, and stroke following myocardial infarction (from the VALIANT ECHO Study). Am J Cardiol. 2008; 101: 607–612.
Meris A, Amigoni M, Uno H, Thune JJ, Verma A, Køber L, Bourgoun M, McMurray JJ, Velazquez EJ, Maggioni AP, Ghali J, Arnold JM, Zelenkofske S, Pfeffer MA, Solomon SD. Left atrial remodelling in patients with myocardial infarction complicated by heart failure, left ventricular dysfunction, or both: the VALIANT Echo study. Eur Heart J. 2009; 30: 56–65.
Solis J, McCarty D, Levine RA, Handschumacher MD, Fernandez-Friera L, Chen-Tournoux A, Mont L, Vidal B, Singh JP, Brugada J, Picard MH, Sitges M, Hung J. Mechanism of decrease in mitral regurgitation after cardiac resynchronization therapy: optimization of the force-balance relationship. Circ Cardiovasc Imaging. 2009; 2: 444–450.
St John Sutton MG, Plappert T, Hilpisch KE, Abraham WT, Hayes DL, Chinchoy E. Sustained reverse left ventricular structural remodeling with cardiac resynchronization at 1 year is a function of etiology: quantitative Doppler echocardiography evidence from the Multicenter InSync Randomized Clinical Evaluation (MIRACLE). Circulation. 2006: 113; 266–272.
Linde C, Abraham WT, Gold MR, St John Sutton M, Ghio S, Daubert C; REVERSE (REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction) Study Group. Randomized trial of cardiac resynchronization in mildly symptomatic heart failure patients and in asymptomatic patients with left ventricular dysfunction and previous heart failure symptoms. J Am Coll Cardiol. 2008; 52: 1834–1843.
Cardiac resynchronization therapy has been shown to reduce the risk of death or heart failure in patients with class III or IV heart failure. The Multicenter Automatic Defibrillator Implantation Trial: Cardiac Resynchronization Therapy (MADIT-CRT) study extended these results to patients with class I and II heart failure. In this echocardiographic substudy of MADIT-CRT, we observed substantial improvement in cardiac size and function in patients who received combined therapy with cardiac resynchronization and an implantable cardioverter defibrillator versus those receiving implantable cardioverter defibrillator therapy only. We observed reductions in end-diastolic volume, end-systolic volume, and left atrial volume and improvement in left ventricular ejection fraction and right ventricular fractional area change. These findings were concordant with the improvement in outcomes, and outcomes after 1 year were directly related to the extent of improvement in ventricular size and function between baseline and 1 year. These data provide a direct link between the improvement in cardiac size and function with CRT and improvement in outcomes.
Guest Editor for this article was Buddhadeb Dawn, MD.