Author + information
- Julius M. Gardin, MD, MBA∗ ()
- Hackensack University Medical Center, Hackensack, New Jersey; and Rutgers New Jersey Medical School, Newark, New Jersey
- ↵∗Reprint requests and correspondence:
Dr. Julius M. Gardin, Hackensack University Medical Center and Rutgers New Jersey Medical School, 30 Prospect Avenue, Hackensack, New Jersey 07601.
- cardiac resynchronization therapy
- implantable cardioverter defibrillator
- left ventricle
- relative LV wall thickness
- sudden cardiac death
- ventricular arrhythmias
Ventricular arrhythmia (VA) and sudden cardiac death (SCD) remain important problems in patients with heart failure (HF), despite the reduction in VA-associated deaths attributable to implantable cardioverter-defibrillators (ICDs) (1). The MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy) study demonstrated that in patients with mild HF, left ventricular ejection fraction (LVEF) of ≤30%, and QRS duration ≥130 ms, the primary endpoint of HF or all-cause mortality occurred in 17.2% of the CRT-ICD group versus 25.3% in the ICD-only group (p = 0.001), a difference driven primarily by a 41% reduction in HF events in the CRT group (2). Interestingly, there was no difference in benefit in patients with ischemic versus nonischemic cardiomyopathy, even though myocardial scar and LVEF are both associated with increased risk of VA and SCD (1).
In this issue of the Journal, Biton et al. (3) retrospectively evaluated 1,260 MADIT-CRT patients (70% of the original cohort) who had mild ischemic (New York Heart Association functional class I or II) or nonischemic cardiomyopathy (New York Heart Association functional class II), left bundle branch block (LBBB), and LVEF ≤30% (3). They aimed to determine the value of echocardiographic LV relative wall thickness (RWT: the ratio of twice LV diastolic posterior wall thickness to left ventricular end-diastolic dimension [LVEDD]) versus other transthoracic echocardiographic measurements in predicting risk of VA or VA-associated death. Additionally, they compared the association of CRT-D versus ICD-alone therapy with respect to the change in RWT (i.e., LV remodeling) at 1 year and the relationship of this change to VA and VA death.
The researchers found that patients in the lowest RWT tertile (<0.24) had an 83% increased risk for VA and 68% increase in VA death (both p < 0.001) compared with patients with higher RWT values. In multivariable analyses, RWT was the best echocardiographic predictor for VA risk. Specifically, each 0.01-unit decrease in RWT was associated with 12% and 10% increases in risk of VA and VA death, respectively (both p < 0.001). Perhaps more important, when the investigators compared echocardiographic RWT in the CRT-D versus ICD-only groups after 1 year of therapy, CRT-D was associated with a greater increase in RWT. Remarkably, every 10% increase in RWT in CRT-D patients was associated with 34% (p = 0.027) and 36% (p = 0.009) reductions, respectively, in risk of VA and VA death.
In population studies, LV geometry assessed by echocardiographic or cardiac magnetic resonance has shown prognostic value for HF and death (4,5). An RWT cut point has been used to differentiate those with increased LV mass who have concentric hypertrophy (RWT of >0.42 in the current study  and American Society of Echocardiography Guidelines  and >0.45 in other studies [4,7]) versus eccentric LV hypertrophy (LVH). In the current study, almost all patients had an RWT of <0.32 (eccentric hypertrophy). Of interest, in the Framingham and Framingham Offspring population studies, RWT added little prognostic value to traditional cardiovascular disease risk factors once LV mass was known (4) or LVH or LV enlargement was present (5). Conversely, in patients with hypertension, Koren et al. (7) reported that those with concentric LVH had the greatest mortality risk, followed by eccentric hypertrophy and concentric remodeling (normal LV mass and increased RWT).
In contrast to Koren et al. (7), the current study demonstrated that in patients with HF, increases in RWT were associated with improved prognosis and incremental predictive benefit when added to other echocardiographic predictors, such as LV mass, LVEF, and left atrial, LV end-systolic, and LV end-diastolic volumes (LVEDV). The difference in these findings may relate partly to there being few patients with concentric LVH in the current study. Alternatively, a recent study in 127 patients with LVEF of ≤0.45 and an ICD demonstrated that ventricular tachycardia/fibrillation (VF) was most frequent in patients with eccentric LVH (43%), followed by those with concentric remodeling/hypertrophy (30%), and lowest (12%) with normal geometry (all p < 0.02) (8). A previous MADIT-CRT study publication in patients with LBBB reported that at 1 year, decreases in LV mass, correlating directly with LVEDV change, were greater in CRT-D versus ICD patients (9). In CRT-D patients, ventricular tachycardia/VF/death occurred 3 times less often in patients with versus without a 25% LV mass decrease. The current study extended these observations by demonstrating incremental VA risk with RWT decreases in the eccentric hypertrophy group, the graded benefit of RWT increases, and the benefit of CRT-D over ICD-alone therapy in increasing RWT.
The investigators suggest several plausible mechanisms to explain the association of decreased RWT and VA risk: 1) fibrosis and scar formation can serve as a substrate for reentry circuits, early after-depolarizations, and VA; 2) fibrosis enhances the ability of oxidative stress to induce spontaneous VF; and 3) LV wall thickness, a measure of wall fibrosis, and LVEDD, a measure of remodeling, are independently associated with VA risk.
The researchers performed additional analyses that enhanced their findings. A model including RWT demonstrated better fit for predicting VA risk compared with RWT’s 2 components, increased LVEDD and lower LV wall thickness, both being associated with higher risk. Also, RWT demonstrated better fit in a prognostic VA risk model than did the LV mass/LVEDV ratio. Furthermore, RWT had significant predictive benefit even after adjustment for significant baseline clinical differences.
The researchers appropriately acknowledged important study limitations, including: 1) the retrospective, nonrandomized, post-hoc design potentially introduced confounder bias; 2) exclusion of patients without LBBB, potentially limiting generalizability; and 3) not presenting a model including clinical as well as echocardiographic predictors for VA risk. Additionally, their use of linear dimensional measurements (LV wall thickness and LVEDD) introduced potential measurement errors (6,10), including missing important areas of LV dilation and wall thinning/scar (Figure 1). Furthermore, by studying a cohort with RWT values at the lower end of the population spectrum, a repeat (1-year) echocardiogram might have revealed higher RWT merely because of random measurement fluctuation, a statistical artifact known as “regression to the mean” (10). The current study did demonstrate a graded (inverse) relationship between RWT and VA/VA death at baseline and post-therapy, suggesting the relationships reported are not artifactual.
It remains to be seen whether additional predictive value may be gained using a 3-dimensional imaging technique or imaging slice technology that can identify and quantify extent of myocardial fibrosis, providing a more complete picture of myocardial thickness/scar and volume. In this regard, Gulati et al. (11) studied 472 patients with dilated cardiomyopathy by cardiac magnetic resonance of the LV. After adjustment for LVEF and conventional risk factors, both presence and extent of myocardial midwall fibrosis were independently and incrementally associated with all-cause mortality, SCD, or aborted SCD; the addition of fibrosis to LVEF improved risk reclassification for these endpoints.
Biton et al. (3) are to be congratulated for providing insights into patients with mild HF and LBBB regarding the graded relationship of LV geometry to VA risk, as well as the role of CRT in improving LV geometry and decreasing VA risk. Additional follow-up data in 2 to 3 years or longer would be of interest.
The author gratefully acknowledges the assistance of Barbara Reich and Deborah Magnan for performing library searches, and Laura Alumbaugh for typing this paper.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Gardin has reported that he has no relationships relevant to the contents of this paper to disclose.
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