Who Are the Super-Responders to Cardiac Resynchronization Therapy?

Eduardo Arrais Rocha Francisca Tatiana Moreira Pereira Ana Rosa Pinto Quidute José Sebastião Abreu José Wellington Oliveira Lima Carlos Roberto M Rodrigues Sobrinho Maurício Ibrahim Scanavacca About the authors

Abstract

Background:

Patients submitted to cardiac resynchronization may develop response patterns that are higher than expected, with normalization of clinical and echocardiographic parameters.

Objective:

To analyze the clinical and echocardiographic characteristics of this population of super-responders, comparing them with the other patients submitted to cardiac resynchronization therapy.

Methods:

A prospective, observational cohort study involving 146 patients consecutively submitted to cardiac resynchronization implants. Fisher's exact test and Mann-Whitney test were performed to compare the variables. Patients with ejection fraction > 50% and functional class I/II (New York Heart Association) were considered super-responders after 6 months of cardiac resynchronization therapy.

Results:

Mean age was 64.8 ± 11.1 years, with 69.8% of males, with a median ejection fraction of 29%, 71.5% with left bundle-branch block, 12% with right bundle-branch block associated with hemiblocks; 16.3% wearing a definitive cardiac pacemaker, 29.3% with ischemic cardiomyopathy, 59.4% with dilated cardiomyopathy, and 11.2% with Chagasic cardiomyopathy. Twenty-four (16.4%) super-responders were observed, and 13 (8.9%) showed normalization of the ejection fraction, left ventricular diastolic diameters and functional class. When compared to the non-super-responder patients, in relation to the pre-implantation characteristics, the super-responders were more often females (58.3% vs. 22.8%, p = 0.002), had higher body mass index (26.8 vs. 25.5, p = 0.013), higher baseline ejection fraction (31.0 vs. 26.9, p = 0.0003), and lower left ventricular diastolic diameters (65.9 mm vs. 72.6 mm, p = 0.0032). Ten patients (41.6% of super-responders) with right bundle-branch block and hemiblock progressed to super-responders, although there was only one patient with Chagas' disease among them, and only at the first assessment.

Conclusions:

Super-responders had less advanced heart disease at baseline and no differences regarding the type of conduction disorder at baseline. Patients with right bundle-branch block and hemiblock, but without Chagasic heart disease may also progress as super-responders.

Keywords:
Heart Failure; Cardiac Resynchronization Therapy; Echocardiography; Defibrillators, Implantable

Resumo

Fundamento:

Pacientes submetidos à ressincronização cardíaca podem evoluir com padrões de resposta acima do esperado, com normalização dos parâmetros clínicos e ecocardiográficos.

Objetivo:

Analisar as características clínicas e ecocardiográficas desta população de super-respondedores, comparando-as com os demais pacientes submetidos à terapia de ressincronização cardíaca.

Métodos:

Estudo de coorte observacional, prospectivo, envolvendo 146 pacientes, consecutivamente submetidos a implantes de ressincronizador cardíaco. Para comparação das variáveis, foram realizados o teste exato de Fisher e o teste de Mann-Whitney. Foram considerados super-respondedores os pacientes com fração de ejeção > 50 % e classe funcional I/II (New York Heart Association) após 6 meses da terapia de ressincronização cardíaca.

Resultados:

A idade média foi de 64,8 ± 11,1 anos, sendo 69,8% do sexo masculino, com mediana da fração de ejeção de 29%, sendo 71,5% com bloqueio de ramo esquerdo, 12% com bloqueio de ramo direito associado a bloqueios divisionais; 16,3% com marca-passo cardíaco definitivo, 29,3% com miocardiopatia isquêmica, 59,4% com miocardiopatia dilatada e 11,2% com miocardiopatia chagásica. Foram observados 24 (16,4%) super-respondedores, sendo que 13 (8,9%) apresentaram normalização da fração de ejeção, dos diâmetros diastólicos do ventrículo esquerdo e da classe funcional. Quando comparados com os pacientes não super-respondedores, em relação às características pré-implante, os super-respondedores apresentaram-se mais no sexo feminino (58,3% vs. 22,8%; p = 0,002), maior índice de massa corporal (26,8 vs. 25,5; p = 0,013), maior fração de ejeção basal (31,0 vs. 26,9; p = 0,0003) e menores diâmetros diastólicos do ventrículo esquerdo (65,9 mm vs. 72,6 mm; p = 0,0032). Dez pacientes (41,6% dos super-respondedores) com bloqueio de ramo direito e bloqueio divisional evoluíram como super-respondedores, entretanto apenas um paciente com doença de Chagas e apenas na primeira avaliação.

Conclusões:

Os super-respondedores apresentaram cardiopatia de base menos avançada e sem diferenças em relação ao tipo de distúrbio de condução basal. Pacientes com bloqueio de ramo direito e bloqueio divisional, mas sem cardiopatia chagásica podem também evoluir como super-respondedores.

Palavras-chave:
Insuficiência Cardíaca Congestiva; Terapia de Ressincronização Cardíaca; Ecocardiografia; Desfibriladores Implantáveis

Introduction

Cardiac Resynchronization Therapy (CRT) has shown good results in the treatment of Congestive Heart Failure (CHF) in patients with conduction disorders, marked left ventricular dysfunction and outpatient New York Heart Association (NYHA) functional classes (FC) II, III and IV, being included as class I and higher level of scientific evidence in the several guidelines for cardiac device implants and CHF.11 Tracy CM, Epstein AE, Darbar D, Dimarco JP, Dunbar SB, Estes NA 3rd, et al. 2012 ACCF/AHA/HRS focused update of the 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2012;60(14):1297-313.

However, 30 to 40% of the patients may not have a good outcome after CRT, thus being called non-responders. The classification of responders and non-responders is very heterogeneous in the several performed studies.22 Yu CM, Bleeker GB, Fung JW, Schalij MJ, Zhang Q, van der Wall EE, et al. Left ventricular reverse remodeling but not clinical improvement predicts long-term survival after cardiac resynchronization therapy. Circulation. 2005;112(11):1580-6. The fact is, the criteria for the definition of an adequate CRT response is still in question and it is not possible to define response predictors with precision and consensus.22 Yu CM, Bleeker GB, Fung JW, Schalij MJ, Zhang Q, van der Wall EE, et al. Left ventricular reverse remodeling but not clinical improvement predicts long-term survival after cardiac resynchronization therapy. Circulation. 2005;112(11):1580-6.,33 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(16):2136-44.

Some authors have described groups of patients that progressed with higher responses than the expected ones, with normalization of left ventricular function, FC, and ventricular diameters, thus being called hyper-responders or Super-Responders (SR), ranging from 9 to 21% in several studies.44 Castellant P, Fatemi M, Bertault-Valls V, Etienne Y, Blanc JJ. Cardiac resynchronization therapy:" nonresponders" and" hyperresponders". Heart Rhythm. 2008;5(2):193-7.

5 Castellant P, Fatemi M, Orhan E, Etienne Y, Blanc JJ. Patients with non-ischaemic dilated cardiomyopathy and hyper-responders to cardiac resynchronization therapy: characteristics and long-term evolution. Europace. 2009;11(3):350-5.
-66 António N, Teixeira R, Coelho L, Lourenço C, Monteiro P, Ventura M, et al. Identification of 'super-responders' to cardiac resynchronization therapy: the importance of symptom duration and left ventricular geometry. Europace. 2009;11(3):343-9. The characteristics of these patients have been assessed, and the super-response is interpreted as a possible cardiomyopathy induced by cardiac dyssynchrony, caused by the intra-ventricular conduction disorder.77 Blanc JJ, Fatemi M, Bertault V, Baraket F, Etienne Y. Evaluation of left bundle branch block as a reversible cause of non-ischaemic dilated cardiomyopathy with severe heart failure. A new concept of left ventricular dyssynchrony-induced cardiomyopathy. Europace. 2005;7(6):604-10. Predictors of super-response are the female gender, non-ischemic heart disease (Chagas cardiomyopathy not included) and Left Bundle-Branch Block (LBBB).88 Hsu JC, Solomon SD, Bourgoun M, McNitt S, Goldenberg I, Klein H, et al; MADIT-CRT Executive Committee. Predictors of super-response to cardiac resynchronization therapy and associated improvement in clinical outcome: the MADIT-CRT (multicenter automatic defibrillator implantation trial with cardiac resynchronization therapy) study. J Am Coll Cardiol. 2012;59(25):2366-73.

This study aimed to analyze the clinical and echocardiographic characteristics of a cohort of patients submitted to cardiac resynchronization implants that progressed as SR, comparing them with other patients implanted in the same period.

Methods

This was a prospective, observational, and single-center study of a cohort of 146 consecutive patients submitted to cardiac resynchronization implants at a tertiary university hospital during a 3-year period. Only patients who failed to successfully receive an electrode implant in the coronary sinus were excluded from the analysis. Implant indications comprised patients with Ejection Fraction (EF) ≤ 35%, outpatient FC III or IV (NYHA), intraventricular conduction disorder with QRS width ≥ 120 ms and optimized CHF treatment.

Patients were divided into two groups after clinical and echocardiographic analysis in the first year. Group I comprised SR and Group II, Non-Super-Responders (NSR). Patients who died before the protocol was finished were considered as Group II. Patients who did not maintain the pattern defined as SR during the second year of assessment were kept in Group I and their characteristics were analyzed. There was no loss to follow-up in either group. Patients in FC I or II and EF ≥ 50% after 6 months of implantation were considered SR.55 Castellant P, Fatemi M, Orhan E, Etienne Y, Blanc JJ. Patients with non-ischaemic dilated cardiomyopathy and hyper-responders to cardiac resynchronization therapy: characteristics and long-term evolution. Europace. 2009;11(3):350-5.

The patients were submitted to clinical and echocardiographic assessment in the first year (6 to 12 months after the implantation) and in the second year (18 to 24 months after), as well as clinical consultations every 4 months for therapeutic optimization and programming of the implanted devices. The characteristics of patients included in the study are shown in Table 1.

Table 1
Description of baseline variables

Analyzed variables

The following clinical, electrocardiographic and echocardiographic variables were analyzed: clinical variables - age, gender, Body Mass Index (BMI), presence of cardiac cachexia, NYHA-FC, baseline heart disease, cardiac vein in which the LV electrode was placed, plasma creatinine levels, systolic blood pressure, diastolic blood pressure, use of high dose-loop diuretics (≥ 80 mg/day of furosemide), hospitalizations from CHF; Electrocardiographic variables - presence of atrial fibrillation, type of block, cardiac pacing, presence of first-degree atrioventricular block (AVB), QRS duration, QRS narrowing after implantation (QRS delta), QRS axis in the frontal plane, before and after implantation; Echocardiographic variables: LV diastolic and systolic diameters, EF measured by the Simpson method, diastolic dysfunction degree from I to IV, degree of mitral regurgitation from I to III, presence of right ventricular dysfunction, presence and type of cardiac dyssynchrony.

The American Society of Echocardiography guidelines were followed for the analysis of echocardiographic and dyssynchrony parameters.99 Gorcsan J 3rd, Abraham T, Agler DA, Bax JJ, Derumeaux G, Grimm RA, et al; American Society of Echocardiography Dyssynchrony Writing Group. Echocardiography for cardiac resynchronization therapy: recommendations for performance and reporting - a report from the American Society of Echocardiography Dyssynchrony Writing Group endorsed by the Heart Rhythm Society. J Am Soc Echocardiogr. 2008;21(3):191-213.,1010 Gottdiener JS, Bednarz J, Devereux R, Gardin J, Klein A, Manning WJ, et al; American Society of Echocardiography. American Society of Echocardiography recommendations for use of echocardiography in clinical trials. J Am Soc Echocardiogr. 2004;17(10):1086-119. Recommendations for clinical studies involving echocardiography were strictly followed, in accordance with this specific North-American guideline.1010 Gottdiener JS, Bednarz J, Devereux R, Gardin J, Klein A, Manning WJ, et al; American Society of Echocardiography. American Society of Echocardiography recommendations for use of echocardiography in clinical trials. J Am Soc Echocardiogr. 2004;17(10):1086-119. The GE, Vivid 7® model (GE Healthcare, Fairfield, CT, USA) echocardiography equipment was used. The physicians performing the examinations were blinded for the patients' previous clinical and echocardiographic findings, and had experience in evaluating patients, such as those included in the study.

The variables selected to constitute the models represented relevant, practical and conventional parameters in the electrocardiographic and echocardiographic evaluation of patients with cardiomyopathy - several already showing a positive association with clinical and / or prognostic improvement.1111 Yu CM, Hayes DL. Cardiac resynchronization therapy: state of the art 2013. Eur Heart J. 2013;34(19):1396-403.

The systolic function analysis was performed using the Simpson method, in two- and four-chamber two-dimensional mode, followed by the mean. Ventricular diameters were obtained in M mode according to the standardization of the guidelines.1010 Gottdiener JS, Bednarz J, Devereux R, Gardin J, Klein A, Manning WJ, et al; American Society of Echocardiography. American Society of Echocardiography recommendations for use of echocardiography in clinical trials. J Am Soc Echocardiogr. 2004;17(10):1086-119. Right ventricular function was qualitatively analyzed, differentiated between the presence or absence of any degree of dysfunction.

The diastolic function analysis was performed by assessing mitral flow (at rest and after the Valsalva maneuver), tissue Doppler, and the flow propagation velocity in the M mode with color, being classified into four different diastolic dysfunction degrees (I for Mild, II for moderate or pseudonormal, III for severe or restrictive, and IV for severe or irreversible restrictive pattern).

The degree of mitral regurgitation was assessed using color Doppler, according to the percentage of left atrial filling. In mild regurgitation, the percentage was less than 20%; in the moderate, between 20% and 40%, and values above this percentage were considered important. In this practical context, the Coanda effect was interpreted as moderate reflux, when restricted to the lateral atrial wall and, as marked, when it extended through the upper pole of the left atrium.

Statistical Analysis

The Shapiro-Wilks normality test was performed to classify the normal variables. The variables creatinine, diastolic blood pressure, R wave length, QRS width, EF and left ventricular diastolic diameter (LVDD) were not normally distributed.

The behavior of the variables of interest was compared through the Mann-Whitney test for ordinal, discrete and continuous variables, and Fisher's exact test and its extensions for the categorical variables, with a significance level of 5% to determine the statistically different behaviors in the two groups. The data were analyzed using Stata / SE, version 12.1 (StataCorp LP, College Station, TX, USA) and R software (R Foundation for Statistical Computing, Vienna, Austria).

The study was approved by the Ethics and Clinical Research Committee of the university hospital, and all patients signed the free and informed consent form. The study protocol followed the ethical standards of the Helsinki Declaration.

Results

There were 30 deaths during the follow-up of 34.0 ± 17.9 months, which represents 23.1% of overall mortality. Analyzing all patients together, 88.6% improved at least one degree in FC (NYHA); 51.7% reduced the number of hospitalizations from CHF; 50% improved more than 5% in absolute EF values and 87% decreased more than 5 mm in the LVDD. Of the 46 patients evaluated for the presence of dyssynchrony, 37 (80.4%) had some degree of previous dyssynchrony; 35 (76%) intraventricular, 16 (34.7%) interventricular, 15 (32.6%) atrioventricular and 9 (19.5%) had no dyssynchrony.

There were twenty-four (16.3%) SR (Group I) and 13 (8.8%) patients had EF, LV diastolic diameters and FC normalization. Compared with the NSR patients (Group II) in relation to baseline, pre-implantation characteristics, Group I patients had more women (58.3% vs. 22.8%, p = 0.002), higher BMI (26.8 vs. (p < 0.05), higher baseline EF (31.0% vs. 26.9%, p = 0.0003) and lower LVDD (65.9 mm x 72.6 mm, p = 0.0032) (Tables 2 and 3).

Table 2
Comparison of numerical variables between Group I, Super-Responders (SR), and Group II, Non-Super-Responders (NSR), pre-implantation
Table 3
Comparison of the categorical variables in Group I, Super-Responders (SR), and Group II, Non-Super-Responders (NSR) pre-implantation

The SR had a higher incidence of pre-implantation dyssynchronization at the 10% level of significance (p = 0.072) and a lower percentage of patients using high-dose loop diuretics (p = 0.087). Regarding the type of cardiopathy, no differences were observed when comparing the three types simultaneously (dilated cardiomyopathy - DCM, Chagasic cardiomyopathy and ischemic cardiomyopathy). When DCM vs. other cardiomyopathies were analyzed together, the SR showed a higher incidence of DCM (p = 0.035).

Ten patients (41.6% of total SR) with Right Bundle-Branch Block (RBBB) and Hemiblock (HB) became SR, with no difference in relation to patients with self-LBBB or LBBB induced by stimulation. When we analyze LBBB vs. RBBB/HB and induced LBBB, the SR showed a lower incidence of LBBB alone (p = 0.043).

In the group of patients with Chagas cardiomyopathy (11.2%) submitted to CRT, only 15.3% had RBBB /HB; 30.7% had artificial stimulation rhythm and 54% had LBBB. Only one patient with Chagas' disease evolved as SR and it occurred temporarily, limited to the first evaluation.

One patient from the SR group lost control of the coronary sinus electrode in the third year after implantation, showing clinical worsening and hemodynamic deterioration. After implantation of a new epicardial electrode, a new normalization of left ventricular function and diastolic diameters occurred at 4 months.

Of the 15 patients with complete clinical and echocardiographic normalization, only two were observed late (in the second year of evaluation), whereas of the other nine SR patients, it occurred late in five, but without complete normalization of all parameters and in two, it occurred transiently and limited to the first year of evaluation.

Regarding the diastolic function, two patients developed grade II diastolic dysfunction and the others, grade I. All SR progressed to grade I of mitral regurgitation. No patient with complete normalization of EF, LVDD and FC migrated to Group II during follow-up.

Three patients in SR group died: one due to breast cancer, the other due to respiratory infection and another was transplanted due to persistent ventricular arrhythmia and died postoperatively.

Discussion

The SR were predominantly female patients, with a likely better nutritional status, higher EF and lower LVDD. Patients receiving lower amounts of high-dose loop diuretics (≥ 80 mg furosemide a day), and with a higher degree of pre-implant dyssynchrony showed a trend towards statistically significant results when compared to NSR.

Less advanced heart disease has shown better results with CRT, disclosing good results in recent studies with patients in FC II, and unsatisfactory results in subanalyses of patients with FC IV, particularly when hospitalized or dependent on vasoactive drugs. The results of this study corroborate that of others who also demonstrated hyper-responsive patterns in patients with less advanced heart disease.55 Castellant P, Fatemi M, Orhan E, Etienne Y, Blanc JJ. Patients with non-ischaemic dilated cardiomyopathy and hyper-responders to cardiac resynchronization therapy: characteristics and long-term evolution. Europace. 2009;11(3):350-5.,66 António N, Teixeira R, Coelho L, Lourenço C, Monteiro P, Ventura M, et al. Identification of &apos;super-responders&apos; to cardiac resynchronization therapy: the importance of symptom duration and left ventricular geometry. Europace. 2009;11(3):343-9.,1212 Zaroui A, Reant P, Donal E, Mignot A, Bordachar P, Deplagne A, et al. Identification and characterization of super-responders to cardiac resynchronization therapy: an echocardiographic study. Circulation. 2008;118:S-781.

In the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy) study, in patients with mild symptoms of heart failure, the female gender, absence of infarction, LBBB, QRS > 150 ms, BMI < 30 kg/m2 and reduced left atrial volume were predictors of SR.88 Hsu JC, Solomon SD, Bourgoun M, McNitt S, Goldenberg I, Klein H, et al; MADIT-CRT Executive Committee. Predictors of super-response to cardiac resynchronization therapy and associated improvement in clinical outcome: the MADIT-CRT (multicenter automatic defibrillator implantation trial with cardiac resynchronization therapy) study. J Am Coll Cardiol. 2012;59(25):2366-73. Our study included a group of patients with very symptomatic CHF, with 64% of patients having been previously hospitalized for recently decompensated CHF. These differences in the population characteristics may explain some differences in the observed results.

Patients with RBBB + HB showed super-response with no difference in relation to LBBB or patients with LBBB induced by cardiac stimulation. When we analyzed the conventional LBBB in relation to the other electrocardiographic patterns (right branch and LBBB induced by the PM), we observed a lower chance of SR with conventional LBBB. These results show differences in comparison to the literature, which demonstrates a clear advantage of classic RBBB in the CRT results. However, in relation to hyper-responsiveness or super-response, the studies do not attain a consensus in their conclusions. We believe that the patients in our study with RBBB, because they had associated HB and a wider QRS (median of 160 ms), should have a significant degree of dyssynchrony, which could justify the absence of differences. Another reason may be due to the lower number of patients analyzed in our study, determining a statistical limitation.

However, in a study of 200 patients with CHF, Haghjoo et al.1313 Haghjoo M, Bagherzadeh A, Farahani MM, Haghighi ZO, Sadr-Ameli MA. Significance of QRS morphology in determining the prevalence of mechanical dyssynchrony in heart failure patients eligible for cardiac resynchronization: particular focus on patients with right bundle branch block with and without coexistent left-sided conduction defects. Europace. 2008;10(5):566-71. evaluated 110 patients with RBBB with or without Left Anterior-Superior Hemiblock (LASHB) and 90 patients with LBBB. Mechanical dyssynchrony was investigated through tissue Doppler echocardiography. Patients with isolated RBBB had a lower prevalence (33%) of interventricular dyssynchrony (defined as a delay of more than 40 ms in the aortic and pulmonary pre-ejection intervals) than patients with LBBB (54%) or RBBB plus LASHB (50%), with statistical significance. As for the intraventricular dyssynchrony (defined by standard deviation of 12-segment pre-ejection intervals greater than 34 ms), it was more prevalent in patients with LBBB (58%) than in those with RBBB (28%) or RBBB with LASHB (42%), with p < 0.001. The presence of intraventricular dyssynchrony, in this case considered an important predictor of resynchronization response, could not be correlated to the presence of HB: patients with RBBB, with or without LASHB, did not show statistical difference.1313 Haghjoo M, Bagherzadeh A, Farahani MM, Haghighi ZO, Sadr-Ameli MA. Significance of QRS morphology in determining the prevalence of mechanical dyssynchrony in heart failure patients eligible for cardiac resynchronization: particular focus on patients with right bundle branch block with and without coexistent left-sided conduction defects. Europace. 2008;10(5):566-71.

To date, most of the information that has accumulated regarding the role of CRT in the treatment of CHF comes from studies that evaluated patients predominantly with LBBB. Patients with RBBB were less representative in clinical trials (less than 15%) and, therefore, little can be definitively inferred regarding the efficacy of resynchronization in this scenario.1414 Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, et al; 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(21):2140-50.,1515 Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, et al; MIRACLE Study Group Multicenter InSync Randomized Clinical Evaluation. Cardiac resynchronization in chronic heart failure. N Engl J Med. 2002;346(24):1845-53. Our study shows that RBBB patients when associated with HB can also become as hyper-responders, especially in the absence of Chagasic heart disease.

Even though the changes induced by dyssynchrony are proposed as an essential condition for the resynchronization response, the effect of this therapy can be mediated by other pathways, such as the previous degree of diastolic dysfunction and ventricular dilatation.1616 Tang WH, Mullens W, Borowski AG, Tong W, Shrestha K, Troughton RW, et al. Relation of mechanical dyssynchrony with underlying cardiac structure and performance in chronic systolic heart failure: implications on clinical response to cardiac resynchronization. Europace. 2008;10(12):1370-4. The multicenter study, PROSPECT (Predictors of Response to Cardiac Resynchronization Therapy) was unable to correlate the different types of dyssynchronization, evaluated by 12 echocardiographic parameters, with the response to CRT, having as justifications the variabilities in the techniques used and the method interpretations.1717 Chung ES, Leon AR, Tavazzi L, Sun JP, Nihoyannopoulos P, Merlino J, et al. Results of the Predictors of Response to CRT (PROSPECT) Trial. Circulation. 2008;117(20):2608-16. However, in the SR subgroup, the PROSPECT study showed a higher incidence of previous dyssynchrony, in addition to a larger group of women, non-ischemic heart disease and wider QRS.1818 Van Bommel RJ, Bax JJ, Abraham WT, Chung ES, Pires LA, Tavazzi L, et al. Characteristics of heart failure patients associated with good and poor response to cardiac resynchronization therapy: a PROSPECT (predictors of response to CRT) sub-analysis. Eur Heart J. 2009;30(20):2470-7.

LV reverse remodeling has been used as a standard to define response in most new studies.22 Yu CM, Bleeker GB, Fung JW, Schalij MJ, Zhang Q, van der Wall EE, et al. Left ventricular reverse remodeling but not clinical improvement predicts long-term survival after cardiac resynchronization therapy. Circulation. 2005;112(11):1580-6.,1919 Cleland JG, Ghio S. The determinants of clinical outcome and clinical response to CRT are not the same. Heart Fail Rev. 2012;17(6):755-66.,2020 Ypenburg C, van Bommel RJ, Borleffs CJ, Bleeker GB, Boersma E, Schalij MJ, et al. Long-term prognosis after cardiac resynchronization therapy is related to the extent of left ventricular reverse remodeling at midterm follow-up. J Am Coll Cardiol. 2009;53(6):483-90. Patients with LV end-systolic volume shortening > 10%, in analyses of 3 to 6 months, would be considered responders; greater than 15%, hyper-responders; and below 10%, non-responders, with a sensitivity of 70% and specificity of 70% in predicting total mortality. For cardiac mortality, the sensitivity was 87% and the specificity was 69%. Other studies used the LV end-systolic volume > 30% to define the SR and, more classically, the EF normalization1212 Zaroui A, Reant P, Donal E, Mignot A, Bordachar P, Deplagne A, et al. Identification and characterization of super-responders to cardiac resynchronization therapy: an echocardiographic study. Circulation. 2008;118:S-781. associated with the reduction in FC.55 Castellant P, Fatemi M, Orhan E, Etienne Y, Blanc JJ. Patients with non-ischaemic dilated cardiomyopathy and hyper-responders to cardiac resynchronization therapy: characteristics and long-term evolution. Europace. 2009;11(3):350-5.

When DCM was compared to other heart diseases, a greater chance of hyper-responsiveness was observed in the DCM, as described in the literature. The degree of fibrosis observed in patients with ischemic and Chagasic cardiomyopathy could explain these findings. However, these patients were not previously submitted to cardiac viability assessment or nuclear magnetic resonance imaging to confirm such hypothesis. Chagasic heart disease has been associated with a lower response rate in CRT, probably related to the higher severity of this cardiopathy and higher incidence of RBBB.2121 Martinelli Filho M, de Lima Peixoto G, de Siqueira SF, Martins SA, Nishioka SAD, Costa R, et al. Cardiac resynchronization therapy in chronic chagasic cardiomyopathy: a good clinical response and the worst prognosis. RELAMPA. Rev Lat-Am Marcapasso Arritm. 2013;26(1):33-8. In our study, 15.3% of the patients with Chagas disease had RBBB, and only one became a SR and then, only transiently.

The reasons for better responses among the female patients in the group submitted to CRT and better results among males submitted to ICD implants have raised discussions in the literature, without definitive conclusions. We also observed a higher BMI in the SR group, which could reflect better nutritional status and, consequently, less advanced heart disease, but the numerical differences are clinically difficult to evaluate and may reflect small variations in volume retention.

The use of high doses of loop diuretics has been shown to be a marker of severity in cardiomyopathy, including in the group of patients submitted to CRT, when analyzed before implantation, as well as 1 year after the CRT.2222 Rocha EA, Pereira FT, Abreu JS, Lima JW, Monteiro Mde P, Rocha Neto AC, et al. Development and validation of predictive models of cardiac mortality and transplantation in resynchronization therapy. Arq Bras Cardiol. 2015;105(4):399-409. The presence of a higher incidence in the NSR group may reflect this aspect.

Regarding the cardiac function normalization time, most SR showed these results in the first year, with a small portion showing slight worsening in parameters in the second year. Therefore, the SR pattern occurs more frequently in the first 12 months after CRT, a finding also observed in other studies.2323 Zecchin M, Proclemer A, Magnani S, Vitali-Serdoz L, Facchin D, Muser D, et al. Long-term outcome of super-responder patients to cardiac resynchronization therapy. Europace. 2014;16(3):363-71.

The possibility of cardiac function normalization in 15 to 20% of patients submitted to CRT has been an intriguing and encouraging finding, considering they are severe patients, with poor prognosis in the medium and long term.77 Blanc JJ, Fatemi M, Bertault V, Baraket F, Etienne Y. Evaluation of left bundle branch block as a reversible cause of non-ischaemic dilated cardiomyopathy with severe heart failure. A new concept of left ventricular dyssynchrony-induced cardiomyopathy. Europace. 2005;7(6):604-10. Cay et al.2424 Cay S, Ozeke O, Ozcan F, Aras D, Topaloglu S. Mid-term clinical and echocardiographic evaluation of super-responders with and without pacing: the preliminary results of a prospective, randomized, single-centre study. Europace. 2016;18(6):842-50. demonstrated cardiomyopathy recurrence and ventricular function worsening in the SR group when multisite stimulation was switched off. Thus, it is necessary to analyze the group of hyper- or SR in greater depth. They may represent an important target in CRT, constituting the possibility of cure in a subgroup of patients.

Limitations

This was a single-center study, which involved a not very large population of 147 patients submitted to CRT and analyzed 24 (16.3%) SR. No intra- or inter-observer analysis was performed on electrocardiographic and echocardiographic variables. The dyssynchrony analysis was performed in only 46 patients, without the possibility of statistical analysis of subgroups. No adjustments were made for the AV interval by the echocardiogram after the implant. Feasibility and fibrosis assessments were not performed by magnetic resonance imaging prior to implantation. New echocardiographic techniques, such as strain, were not evaluated. Patients with isolated RBBB were not included in the analysis. The study did not have statistical power of mortality analysis between the studied groups.

Conclusions

The super-responders represented 16.4% of the patients submitted to cardiac resynchronization therapy, 8.9% with functional class, left ventricular diastolic diameter and ejection fraction normalization. These patients had less advanced heart disease at baseline and no differences regarding the type of baseline conduction disorder.

Patients with right bundle-branch block associated with left hemiblocks may also develop a super-response. Chagasic heart disease was less likely to be overresponsive, even in the presence of left bundle-branch block.

  • Sources of Funding
    This study was funded by CAPES e FUNCAP.
  • Study Association
    This article is part of the thesis of Doctoral submitted by Eduardo Arrais Rocha from São Paulo University and Federal University of Ceará.

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Publication Dates

  • Publication in this collection
    Jan-Feb 2017

History

  • Received
    07 Sept 2016
  • Reviewed
    11 Oct 2016
  • Accepted
    25 Jan 2017
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