Risk and predictors of dyssynchrony cardiomyopathy in left bundle branch block with preserved left ventricular ejection fraction

Abstract Background Left bundle branch block (LBBB) and left ventricular (LV) dyssynchrony likely contribute to progressive systolic dysfunction. The evaluation of newly recognized LBBB includes screening for structural heart abnormalities and coronary artery disease (CAD). In patients whose LV ejection fraction (EF) is preserved during initial testing, the incidence of subsequent cardiomyopathy is not firmly established. Hypothesis The risk of developing LV systolic dysfunction among LBBB patients with preserved LVEF is high enough to warrant serial imaging. Methods We screened records of 1000 consecutive patients with LBBB from our ECG database and identified subjects with an initially preserved LVEF (≥45%) without clinically relevant CAD or other cause for cardiomyopathy. Baseline imaging, clinical data, and follow‐up imaging were recorded to determine the risk of subsequent LV systolic dysfunction (LVEF ≤40%). Results (Data are mean + SD) 784 subjects were excluded, the majority for CAD or depressed LVEF upon initial imaging. Of the remaining 216, 37 (17%) developed a decline in LVEF(≤40%) over a mean follow‐up of 55 ± 31 months; 94% of these patients had a baseline LVEF≤60% and LV end systolic diameter (ESD) ≥ 2.9 cm indicating that these measures may be useful to define which patients warrant longitudinal follow‐up. The negative predictive value of a LVEF>60% and LVESD <2.9 cm was 98%. Conclusions Seventeen percent of patients with LBBB and initial preserved LVEF develop dyssynchrony cardiomyopathy. We believe the risk of developing dyssynchrony cardiomyopathy is high enough to warrant serial assessment of LV systolic function in this high‐risk population.


| INTRODUCTION
The prevalence of left bundle branch block (LBBB) in the general population ranges from approximately 0.1% to 1.0%, the incidence increasing with age. [1][2][3][4][5] LBBB is strongly associated with structural heart and/or coronary artery disease. 3,[5][6][7][8] Patients with a newly recognized LBBB are at increased risk of cardiovascular events including heart failure, myocardial infarction, and sudden death. 3,6,8 The evaluation of patients with incidental, newly recognized LBBB therefore, necessitates assessments for structural heart disease and coronary artery disease (CAD) in appropriate candidates, an approach that is supported by current guidelines. 9 Clinical and experimental data support that dyssynchronous left ventricular (LV) contraction (ie, early septal activation with delayed lateral wall contraction) itself may lead to a decline in LV systolic function. [10][11][12][13] In patients with LBBB and a reduced LV ejection fraction (LVEF), cardiac resynchronization therapy (CRT) improves survival, and reduces heart failure hospitalizations. [14][15][16] Among patients treated with CRT, reports describe "superresponders" whereby LVEF normalizes with resolution of heart failure symptoms. 17,18 These observations have led to the notion that LBBB with resultant dyssynchrony may play a causative role in the development or progression of LV systolic dysfunction. This putative syndrome is now commonly designated "dyssynchrony cardiomyopathy" or "LBBB-associated cardiomyopathy." 19,20 Among patients with LBBB and preserved LV systolic function upon initial imaging, the likelihood of developing a dyssynchrony-induced cardiomyopathy, and whether such patients require longitudinal follow-up is not well established. The purpose of our study was to determine the risk of and explore predictors of developing a cardiomyopathy by examining a population of patients with LBBB, an initially preserved LVEF, without clinically relevant coronary artery disease, or other potential cause of LV systolic dysfunction.

| Patient population
This study was approved by the Institutional investigational review board. We obtained subjects by screening our ECG database from September 2011 to September 2012 for all studies in which LBBB was included in the official interpretation. This time period represents the earliest computerized tracings for review in our database to assure as long a follow-up period as possible. The ECG was analyzed for evidence of a left bundle branch block using conventional criteria that included native QRS duration ≥120 ms, broad R waves in leads I, aVL, V5, or V6, and absent q waves in leads I, V5, and V6. 21 Among those with a confirmed LBBB, we reviewed all prior available ECGs to establish the earliest date in which the LBBB was identified for a given subject. This served as time point zero or the start of the follow-up period.
Patients were included if they demonstrated an initially preserved LVEF prospectively defined as ≥45% by any imaging modality obtained after the earliest identified LBBB tracing with at least one follow-up assessment of LV function. Transthoracic echocardiography was the imaging method used for 205 out of 216 subjects (95%). A LVEF of 45% was chosen as the lower limit because dyssynchrony alone acutely lowers the EF in patients with rate-related LBBB and no other structural heart abnormalities. 11,22 Moreover, 2D echocardiography has been shown to underestimate LVEF in subjects with and without LBBB compared with quantitative 3D modalities. 23,24 To reduce selection bias inherent in the need for repeated, follow-up imaging, we included patients with only one assessment of LV function if their ejection fraction was preserved (≥45%) and measured more than 1 year after the LBBB was identified. Patients whose LBBB was noted to be intermittent or rate-related were excluded. Subjects were also excluded if they had no assessment of LV function. Subjects who demonstrated an initial LVEF of <45% or whose medical history noted any other potential cause of cardiomyopathy or LV systolic dysfunction were also excluded as were patients with severe aortic or mitral valve disease. Subjects with clinically relevant coronary artery disease were excluded. This was defined as a history of a myocardial infarction, prior coronary angiogram demonstrating a ≥ 75% stenosis of a major epicardial coronary artery, percutaneous coronary intervention on a major epicardial vessel or previous coronary artery bypass surgery. Patients were excluded, if they had a pacemaker or were censored at the time of pacemaker implant though they remained in the study population, if pacemaker interrogations were available and demonstrated less than 10% right ventricular pacing. The follow-up period was defined as the date starting with the earliest ECG demonstrating a LBBB through the date of the latest echocardiogram.

| Assessment of variables
Medical records were reviewed whereby clinical data were recorded at the time of initial diagnosis including age, gender, comorbid conditions (eg, hypertension, diabetes mellitus), and laboratory data (BUN, creatinine, hemoglobin, BNP/NT-proBNP when available). The initial and follow-up EKGs were reviewed for underlying rhythm, QRS axis, and duration. We obtained echocardiographic measurements (LVEF, end diastolic dimension, and end systolic dimension) from echocardiographic reports. Chamber dimensions were only available for those patients whose initial LVEFs were assessed by echocardiography and whose reports were available for review (N = 152 for patients with retained preserved LVEF-Group 1; N = 31 for patients whose LVEF deteriorated-Group 2). Our institution follows the chamber quantification guidelines for these measures. 25 End diastolic and end systolic dimensions were not available in patients whose LVEF assessment was performed by another modality (eg, ventriculogram, gated myocardial perfusion imaging, MRI).

| Statistical analysis
Two groups were compared: patients whose LVEF remained preserved (≥45) upon subsequent imaging-Group 1; and those who exhibited a decline in LVEF (≤40%) on subsequent imaging-Group 2. Continuous variables were expressed as mean ± SD. Comparisons were made with the student t test. Chi square analysis was used to compare differences in the frequencies of categorical variables between the two groups. Differences were considered statistically significant if the P-value was less than .05. Odds ratio, sensitivity, specificity, and negative predictive values were calculated using standard formulas. We utilized Kaplan-Meyer analysis to chart the time course of the development of LV systolic dysfunction among those patients who developed a cardiomyopathy during the follow-up period. The Symstat software (version 13.2) was used for these analyses.

| RESULTS
We reviewed a total of 1000 consecutive subjects within our ECG  Table 1 demonstrates the demographic and clinical variables pertaining to these groups. We observed a female predominance (70%) among those patients who maintained a preserved LVEF compared with 51% females among those who developed a decline in their LVEF. The incidence of cardiovascular risk factors, such as, diabetes mellitus, hypertension, and dyslipidemia were statistically similar between the two groups. Body mass index (not shown), baseline renal function, and hemoglobin were also similar between these groups.
Among those with available BNP levels, Group 2 (N = 24) demonstrated significantly higher BNP levels than Group 1 (N = 91) though the standard deviations were wide. Table 2 shows the ECG and echocardiographic data. A smaller percentage of patients in Group 2 were in sinus rhythm on the earliest LBBB ECG (84% vs 96% in Group 1, P < .01). The baseline mean QRS durations and QRS axes were similar. The follow-up QRS durations in the decline in EF group, Group 2, were slightly and significantly higher than those in the preserved LVEF group, Group 1. The initial assessments of LVEF differed significantly with a statistically lower mean LVEF in those with subsequent deterioration of LV systolic function vs those who maintained a preserved LVEF. Coinciding with the LVEF F I G U R E 1 Study populationreasons for exclusion. Flow chart depicting the subjects screened for this analysis with excluded patients and reason for exclusion shown on the right. 24 patients were excluded (not shown) because the LBBB was found to be intermittent (n = 22) or the ECG did not meet criteria for LBBB (n = 2) measures, the initial LVEDD and LVESD measurements were higher in the group whose LVEF declined. Data pertaining to baseline LVEFs and LVESDs are shown graphically as scatter plots in Figure 2.
Although there is a great deal of overlap between Group 1 and Group 2, no patient in Group 2 (decline in LVEF) exhibited an initial EF of more than 60% or an initial LVESD of less than 2.5 cm. In fact, among patients with an LVESD≥2.9 cm, the odds ratio for developing a decline in LVEF was 14.5 (95% confidence interval 3.3-62.9). Combining the variables of LVESD≥2.9 cm and LVEF ≤60%, the odds ratio for developing a decline in LVEF was 18.4 (95% Confidence interval 4.2-79.8). The sensitivity of these combined parameters in identifying those who subsequently developed dyssynchrony cardiomyopathy is 94% with a specificity of 56%. Accordingly, the negative predictive value of having an LVESD of <2.9 cm and an LVEF of >60% was 98%.

| DISCUSSION
Significant interest has been placed on dyssynchrony cardiomyopathy 20 following the recognition of "super responders" who demonstrate normalization of LV systolic function following CRT lending great support to the hypothesis that dyssynchrony itself plays a causative role in progressive LV systolic dysfunction in patients with LBBB. 17,18 However, the risk of developing dyssynchrony cardiomyopathy among patients with LBBB and initial preserved LVEF is not well established. Indeed, the purpose of the present study was to address this question and identify predictive variables for the development of dyssynchrony cardiomyopathy.
Because of the need for sequential imaging to document an initially preserved LVEF with subsequent deterioration, retrospective analyses are wrought with selection bias. To reduce this bias, we included patients with a single assessment of LV systolic function if that subject's LVEF was preserved and the assessment occurred more than 1 year following the earliest LBBB ECG. By identifying the   demonstrated an initial LVESD of ≥2.9 cm whereas slightly more than half of the preserved LVEF group had an initial LVESD ≥2.9 cm. No patients who developed a cardiomyopathy had an initial LVEF above 60%. In patients with an LVESD of ≥2.9 cm and an LVEF ≤60%, the relative risk of developing a cardiomyopathy was 18.4. The negative predictive value for an LVESD <2.9 cm and LVEF >60% was 98% Accordingly, we propose that patients with a LBBB and an initial preserved LVEF undergo annual clinical assessment coupled with imaging to evaluate LV systolic function.

| LIMITATIONS
Since inclusion within our database required serial assessments of LVEF after the diagnosis of LBBB, the possibility of selection bias remains. Moreover, despite screening 1000 subjects with LBBB, over 75% were excluded from the data reducing our sample size. We were also unable to include morbidity or mortality assessments within our population as these data could not be obtained reliably. Moreover, medication data were only inconsistently available; it is possible; therefore, that differences in background medical therapy (eg, betaadrenergic blocker or ACE-inhibitor therapy) may have influenced our findings. Finally, echocardiographic data were extracted from written reports and were not subjected to core-lab verification.

| CONCLUSIONS
Dyssynchrony cardiomyopathy occurs in 17% of patients with LBBB and preserved LVEF on initial assessment over a mean follow-up period of 55 months. An initial LVEF between 45% and 60% and an LVESD ≥2.9 cm are associated with much greater risk of developing LV systolic dysfunction among patients with LBBB. Our findings support that patients with LBBB and a preserved LVEF undergo serial imaging and clinical assessments.