Cardiac Resynchronization Therapy in Adult Patients with Repaired Tetralogy of Fallot and Left Ventricular Systolic Dysfunction FAISAL M. MERCHANT, M.D., DANESH KELLA, M.D., WENDY M. BOOK, M.D., JONATHAN J. LANGBERG, M.D., and MICHAEL S. LLOYD, M.D. From the Emory University School of Medicine, Atlanta, Georgia
Background: Although left ventricular (LV) systolic dysfunction is known to occur in adults with repaired Tetralogy of Fallot (TOF), the effects of cardiac resynchronization therapy (CRT) are not well characterized. Methods: We retrospectively divided all patients with repaired TOF and impaired LV ejection fraction (LVEF ≤ 40%) undergoing CRT at our institution (n = 10) into two groups: de novo CRT (group A, n = 6) or upgrade from existing device (group B, n = 4). Echocardiograms were reviewed at baseline, medium-term (>6 months post-CRT), and long-term follow-up. CRT response was defined as reduction in LV end-systolic volume (LVESV) ≥15% at medium term. Results: Age at surgical repair was 13.1 ± 16.0 years, age at CRT was 44.4 ± 12.5 years, and baseline LVEF was 24.0 ± 10.5%. Group A demonstrated a preponderance of right ventricular (RV) conduction delay, whereas all patients in group B demonstrated RV pacing at baseline. At medium-term followup, patients in group A showed significant improvements in LVEF, LV end-diastolic volume (LVEDV), and LVESV. Group B also demonstrated a significant improvement in LVEF with favorable trends in LV volumes. Of nine patients with complete data at medium term, eight showed evidence of CRT response. Average long-term follow-up was 53.4 ± 29.3 months. At long-term follow-up, LVEF, LVEDV, and LVESV remained numerically better than baseline, although the results were no longer significant. Conclusions: Adult patients with repaired TOF and LV systolic dysfunction demonstrate significant medium-term response to CRT, even among those with RV conduction delay. The long-term impact of CRT in this population requires further characterization. (PACE 2014; 37:321–328) cardiac resynchronization therapy, Tetralogy of Fallot, left ventricle dysfunction, congestive heart failure
Introduction Early surgical repair for Tetralogy of Fallot (TOF) has significantly improved outcomes and resulted in a rapidly growing population of patients surviving to adulthood.1 Although progressive heart failure in adults with surgically repaired TOF is often due to worsening right ventricular (RV) and/or right-sided valve function,2 it has been estimated that approximately 20% of adult patients with repaired TOF will develop at least mild left ventricular (LV) systolic dysfunction3 and 5–10% will develop moderate or severe dysfunction.3,4 LV dysfunction following surgical repair of TOF has been associated with increased Financial disclosures: None. Address for reprints: Michael S. Lloyd, M.D., Emory University School of Medicine, 1364 Clifton Road NE, Suite F424, Atlanta, GA 30322. Fax: 404-712-4374; e-mail: [email protected] Received February 4, 2013; revised August 3, 2013; accepted August 14, 2013. doi: 10.1111/pace.12284
risk of life-threatening arrhythmias/sudden cardiac death,5–7 and worsening heart failure status.4,5,8 Management of LV dysfunction in this setting is largely extrapolated from data in patients with other forms of left-sided heart failure, including ischemic and nonischemic cardiomyopathy, and includes the use of β-adrenergic blockers and renin-angiotensin-aldosterone antagonists. Cardiac resynchronization therapy (CRT) has a well-established role in the treatment of LV systolic dysfunction with interventricular dyssynchrony, either due to left bundle branch block9,10 or due to chronic RV pacing.11,12 Although patients with repaired TOF demonstrate evidence of both mechanical13–15 and electrical15,16 interventricular dyssynchrony, RV conduction delay and right bundle branch block (RBBB) is almost always present in adults. Data in other forms of cardiomyopathy suggest that CRT is not usually beneficial in the setting of RBBB; however, the anatomic level of block differs significantly between patients with repaired TOF and other forms of nonoperative RBBB.17,18 Acute
©2013, The Authors. Journal compilation ©2013 Wiley Periodicals, Inc. PACE, Vol. 37
March 2014
321
MERCHANT, ET AL.
hemodynamic data, predominantly in patients with preserved LV systolic function, suggest that CRT may be beneficial in patients with repaired TOF.15,16 However, the response to CRT has not been assessed in patients with significant baseline LV systolic impairment. Therefore, we sought to describe the clinical response to CRT in adult patients with repaired TOF and at least moderate LV systolic dysfunction. Methods Study Population The protocol for this study was reviewed and approved by the Emory University Institutional Review Board. Patients were retrospectively identified from a database of the Emory University Hospital Cardiac Electrophysiology Lab from 2003 to 2010. All patients with a diagnosis of TOF with LV systolic dysfunction, defined as LV ejection fraction (LVEF) ≤40% by echocardiogram, referred for CRT were included in the cohort. All patients included in the cohort were being followed primarily in the Emory Adult Congenital Heart Center and the decision to refer for CRT along with decisions about medication regimen and the timing of baseline and follow-up echocardiograms were made by the primary cardiologist. Demographic data, baseline covariates, and clinical history were obtained from review of medical records. Technical aspects of the CRT implant procedure, including positioning of the LV lead, were performed at the discretion of the implanting physician. All LV leads were implanted with a transvenous approach via the coronary sinus. The choice of concomitant implantable cardioverter defibrillator (ICD) implantation (i.e., cardiac resynchronization therapy-pacemaker vs cardiac resynchronization therapy-defibrillator) was made by the implanting physician in consultation with the referring cardiologist. Echocardiography The most recent echocardiogram prior to CRT implant served as the baseline. The first echocardiogram obtained at least 6 months after CRT was used for medium-term follow-up and the most recent available echocardiogram was used for long-term follow-up. All echocardiogram images were re-reviewed for the purpose of this study to measure left ventricle volumes (end-diastolic volume [LVEDV] and end-systolic volume [LVESV]) using the biplane method of discs from the apical four- and two-chamber views. Original echo images were also re-reviewed for assessment of LV diastolic function based on mitral inflow E:A ratio for patients in sinus rhythm
322
Table I. Baseline Characteristics (n = 10) Age, at surgical repair (years) Age, at CRT implantation (years) Male gender Concomitant ICD therapy QRS duration Medical Therapy β-blockers ACE inhibitors/ARBs Aldosterone antagonists Amiodarone
13.1 ± 16.0 44.4 ± 12.5 7 (70%) 9 (90%) 181.5 ± 35.1 10 (100%) 7 (70%) 2 (20%) 3 (30%)
Data are presented as mean ± standard deviation or n (%). ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; CRT = cardiac resynchronization therapy; ICD = implantable cardioverter defibrillator.
and mitral E/E ratio for noninvasive assessment of LV filling pressure. Quantitative LVEF and semiquantitative assessment of RV size/function and valvular regurgitation were obtained from the clinical echocardiogram reports based on the judgment of the original reviewing echocardiographer. Right ventricle size, right ventricle systolic function, and valvular regurgitation were graded on a semiquantitative scoring system: 0 = normal, 1 = mildly enlarged/impaired/regurgitant, 2 = moderately enlarged/impaired/regurgitant, and 3 = severely enlarged/impaired/regurgitant. Statistical Analysis On the basis of recent trials assessing CRT outcomes in other forms of cardiomyopathy, the primary endpoint for this study was CRT response defined as a reduction in LVESV ≥ 15% at medium-term follow-up.19 Continuous variables are presented as mean ± standard deviation and categorical data are summarized as frequencies and percentages. Comparisons within and between groups were performed using a twotailed, paired or unpaired Student’s t-test, χ 2 test, or Fisher’s exact test, as applicable. A P value of < 0.05 was considered significant. Results Ten patients with a diagnosis of surgically repaired TOF and at least moderate LV systolic dysfunction underwent CRT implantation from 2003 to 2010. Baseline characteristics of the study cohort are presented in Table I. Age at surgical repair was 13.1 ± 16.0 years and age at CRT was 44.4 ± 12.5 years. Baseline LVEF was 24.0 ± 10.5% and New York Heart Association
March 2014
PACE, Vol. 37
CRT IN TETRALOGY OF FALLOT P=0.53
LeŌ ventricle ejecƟon fracƟon (%)
A
P
Background: Although left ventricular (LV) systolic dysfunction is known to occur in adults with repaired Tetralogy of Fallot (TOF), the effects of cardiac resynchronization therapy (CRT) are not well characterized. Methods: We retrospectively divided all patients with repaired TOF and impaired LV ejection fraction (LVEF ≤ 40%) undergoing CRT at our institution (n = 10) into two groups: de novo CRT (group A, n = 6) or upgrade from existing device (group B, n = 4). Echocardiograms were reviewed at baseline, medium-term (>6 months post-CRT), and long-term follow-up. CRT response was defined as reduction in LV end-systolic volume (LVESV) ≥15% at medium term. Results: Age at surgical repair was 13.1 ± 16.0 years, age at CRT was 44.4 ± 12.5 years, and baseline LVEF was 24.0 ± 10.5%. Group A demonstrated a preponderance of right ventricular (RV) conduction delay, whereas all patients in group B demonstrated RV pacing at baseline. At medium-term followup, patients in group A showed significant improvements in LVEF, LV end-diastolic volume (LVEDV), and LVESV. Group B also demonstrated a significant improvement in LVEF with favorable trends in LV volumes. Of nine patients with complete data at medium term, eight showed evidence of CRT response. Average long-term follow-up was 53.4 ± 29.3 months. At long-term follow-up, LVEF, LVEDV, and LVESV remained numerically better than baseline, although the results were no longer significant. Conclusions: Adult patients with repaired TOF and LV systolic dysfunction demonstrate significant medium-term response to CRT, even among those with RV conduction delay. The long-term impact of CRT in this population requires further characterization. (PACE 2014; 37:321–328) cardiac resynchronization therapy, Tetralogy of Fallot, left ventricle dysfunction, congestive heart failure
Introduction Early surgical repair for Tetralogy of Fallot (TOF) has significantly improved outcomes and resulted in a rapidly growing population of patients surviving to adulthood.1 Although progressive heart failure in adults with surgically repaired TOF is often due to worsening right ventricular (RV) and/or right-sided valve function,2 it has been estimated that approximately 20% of adult patients with repaired TOF will develop at least mild left ventricular (LV) systolic dysfunction3 and 5–10% will develop moderate or severe dysfunction.3,4 LV dysfunction following surgical repair of TOF has been associated with increased Financial disclosures: None. Address for reprints: Michael S. Lloyd, M.D., Emory University School of Medicine, 1364 Clifton Road NE, Suite F424, Atlanta, GA 30322. Fax: 404-712-4374; e-mail: [email protected] Received February 4, 2013; revised August 3, 2013; accepted August 14, 2013. doi: 10.1111/pace.12284
risk of life-threatening arrhythmias/sudden cardiac death,5–7 and worsening heart failure status.4,5,8 Management of LV dysfunction in this setting is largely extrapolated from data in patients with other forms of left-sided heart failure, including ischemic and nonischemic cardiomyopathy, and includes the use of β-adrenergic blockers and renin-angiotensin-aldosterone antagonists. Cardiac resynchronization therapy (CRT) has a well-established role in the treatment of LV systolic dysfunction with interventricular dyssynchrony, either due to left bundle branch block9,10 or due to chronic RV pacing.11,12 Although patients with repaired TOF demonstrate evidence of both mechanical13–15 and electrical15,16 interventricular dyssynchrony, RV conduction delay and right bundle branch block (RBBB) is almost always present in adults. Data in other forms of cardiomyopathy suggest that CRT is not usually beneficial in the setting of RBBB; however, the anatomic level of block differs significantly between patients with repaired TOF and other forms of nonoperative RBBB.17,18 Acute
©2013, The Authors. Journal compilation ©2013 Wiley Periodicals, Inc. PACE, Vol. 37
March 2014
321
MERCHANT, ET AL.
hemodynamic data, predominantly in patients with preserved LV systolic function, suggest that CRT may be beneficial in patients with repaired TOF.15,16 However, the response to CRT has not been assessed in patients with significant baseline LV systolic impairment. Therefore, we sought to describe the clinical response to CRT in adult patients with repaired TOF and at least moderate LV systolic dysfunction. Methods Study Population The protocol for this study was reviewed and approved by the Emory University Institutional Review Board. Patients were retrospectively identified from a database of the Emory University Hospital Cardiac Electrophysiology Lab from 2003 to 2010. All patients with a diagnosis of TOF with LV systolic dysfunction, defined as LV ejection fraction (LVEF) ≤40% by echocardiogram, referred for CRT were included in the cohort. All patients included in the cohort were being followed primarily in the Emory Adult Congenital Heart Center and the decision to refer for CRT along with decisions about medication regimen and the timing of baseline and follow-up echocardiograms were made by the primary cardiologist. Demographic data, baseline covariates, and clinical history were obtained from review of medical records. Technical aspects of the CRT implant procedure, including positioning of the LV lead, were performed at the discretion of the implanting physician. All LV leads were implanted with a transvenous approach via the coronary sinus. The choice of concomitant implantable cardioverter defibrillator (ICD) implantation (i.e., cardiac resynchronization therapy-pacemaker vs cardiac resynchronization therapy-defibrillator) was made by the implanting physician in consultation with the referring cardiologist. Echocardiography The most recent echocardiogram prior to CRT implant served as the baseline. The first echocardiogram obtained at least 6 months after CRT was used for medium-term follow-up and the most recent available echocardiogram was used for long-term follow-up. All echocardiogram images were re-reviewed for the purpose of this study to measure left ventricle volumes (end-diastolic volume [LVEDV] and end-systolic volume [LVESV]) using the biplane method of discs from the apical four- and two-chamber views. Original echo images were also re-reviewed for assessment of LV diastolic function based on mitral inflow E:A ratio for patients in sinus rhythm
322
Table I. Baseline Characteristics (n = 10) Age, at surgical repair (years) Age, at CRT implantation (years) Male gender Concomitant ICD therapy QRS duration Medical Therapy β-blockers ACE inhibitors/ARBs Aldosterone antagonists Amiodarone
13.1 ± 16.0 44.4 ± 12.5 7 (70%) 9 (90%) 181.5 ± 35.1 10 (100%) 7 (70%) 2 (20%) 3 (30%)
Data are presented as mean ± standard deviation or n (%). ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; CRT = cardiac resynchronization therapy; ICD = implantable cardioverter defibrillator.
and mitral E/E ratio for noninvasive assessment of LV filling pressure. Quantitative LVEF and semiquantitative assessment of RV size/function and valvular regurgitation were obtained from the clinical echocardiogram reports based on the judgment of the original reviewing echocardiographer. Right ventricle size, right ventricle systolic function, and valvular regurgitation were graded on a semiquantitative scoring system: 0 = normal, 1 = mildly enlarged/impaired/regurgitant, 2 = moderately enlarged/impaired/regurgitant, and 3 = severely enlarged/impaired/regurgitant. Statistical Analysis On the basis of recent trials assessing CRT outcomes in other forms of cardiomyopathy, the primary endpoint for this study was CRT response defined as a reduction in LVESV ≥ 15% at medium-term follow-up.19 Continuous variables are presented as mean ± standard deviation and categorical data are summarized as frequencies and percentages. Comparisons within and between groups were performed using a twotailed, paired or unpaired Student’s t-test, χ 2 test, or Fisher’s exact test, as applicable. A P value of < 0.05 was considered significant. Results Ten patients with a diagnosis of surgically repaired TOF and at least moderate LV systolic dysfunction underwent CRT implantation from 2003 to 2010. Baseline characteristics of the study cohort are presented in Table I. Age at surgical repair was 13.1 ± 16.0 years and age at CRT was 44.4 ± 12.5 years. Baseline LVEF was 24.0 ± 10.5% and New York Heart Association
March 2014
PACE, Vol. 37
CRT IN TETRALOGY OF FALLOT P=0.53
LeŌ ventricle ejecƟon fracƟon (%)
A
P
