European Journal of Heart Failure

DIFFERENTIAL CLINICAL CHARACTERISTICS AND PROGNOSIS OF INTRAVENTRICULAR CONDUCTION DEFECTS IN PATIENTS WITH CHRONIC HEART FAILURE
--Manuscript Draft-Manuscript Number: Full Title: DIFFERENTIAL CLINICAL CHARACTERISTICS AND PROGNOSIS OF INTRAVENTRICULAR CONDUCTION DEFECTS IN PATIENTS WITH CHRONIC HEART FAILURE Full Length Article Heart failure; Bundle branch block; Outcomes; Prognosis Juan Cinca, PhD Hospital de la Santa Creu i Sant Pau Barcelona, SPAIN

Article Type: Keywords: Corresponding Author:

Corresponding Author Secondary Information: Corresponding Author's Institution: Corresponding Author's Secondary Institution: First Author: First Author Secondary Information: Order of Authors: Juan Cinca, PhD Ana Mendez Teresa Puig Andreu Ferrero Eulalia Roig Rafael Vazquez Jose R. Gonzalez-Juanatey Luis Alonso-Pulpon Juan Delgado Josep Brugada Domingo Pascual-Figal Order of Authors Secondary Information: Manuscript Region of Origin: Abstract: SPAIN Aims Intraventricular conduction defects (IVCD) can impair the prognosis of heart failure (HF) but their specific impact is not well established. This study aimed to analyze the clinical profile and outcomes of HF patients with left bundle branch block (LBBB), right BBB (RBBB), left anterior fascicular block (LAFB), and no IVCD. Methods and Results Clinical variables and outcomes of 1,762 patients with chronic HF were analyzed according to the presence of LBBB (n=532), RBBB (n=134), LAFB (n=154), and no IVCD (n=942). LBBB was associated with more marked LV dilation, depressed LV ejection fraction (LVEF), and mitral valve regurgitation. Patients with RBBB presented overt signs of congestive HF and depressed right ventricular motion. The LAFB group presented intermediate clinical characteristics and patients with no IVCD were more often women with less enlarged LV and less depressed LVEF. Death occurred in 332 patients (interannual mortality=10.8%): cardiovascular in 257, extravascular in 61, and of unknown origin in 14 patients. Cardiac death occurred in
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Hospital de la Santa Creu i Sant Pau

Juan Cinca, PhD

230 (pump failure in 171 and sudden in 59). Adjusted Cox model showed higher 21month risk of cardiac death and pump failure death in LBBB and RBBB than in LAFB and in no IVCD groups. Conclusion LBBB and RBBB are associated with different clinical profiles and both are independent predictors of increased risk of cardiac death in patients with HF. A more favourable prognosis was observed in patients with LAFB and in those free of IVCD. Further research for HF patients with RBBB is warranted.

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*Cover Letter

Correspondig author: Juan Cinca,MD Cardiology Service Hospital de la Santa Creu i Sant Pau St. Antoni M. Claret ,167 08025 Barcelona, Spain e-mail: jcinca@santpau.cat Prof. Dr. Dirk J. van Veldhuisen Editor-in-Chief European Journal of Heart Failure Barcelona, December, 10th, 2012 Dear Prof. van Veldhuisen, We submit our paper entitled Differential clinical characteristics and prognosis of intraventricular conduction defects in patients with chronic heart failure to be evaluated for publication in the European Journal of Heart Failure. This paper is not under consideration elsewhere, none of the papers contents have been previously published, all authors have read and approved the manuscript, and we do not have disclosures of any relationship with industry. All authors have contributed to the conception and design or analysis and interpretation of data, or both. They have granted final approval of the manuscript submitted. As a novelty, this paper analyzes comparatively the clinical and mid-term (21-months) prognostic consequences of the three most common intraventricular conduction defects (left bundle branch block, right bundle branch block, and left anterior fascicular block) in a cohort of 1,762 patients with chronic heart failure. Patients were recruited prospectively by the Spanish Ministries of Health and Science Network for the Study of Heart Failure(REDINSCOR). As potential reviewers we suggest: -Prof Gnter Breithardt, MD, Med. Klinik & Poliklinik, Innere Medizin C-Universitt Mnster, E-mail: breithg@ukmuenster.de -Prof. Hein J. Wellens, Maastricht, The Netherlands, E-mail: hwellens@xs4all.nl -Prof. Michel Komajda, Lapitie Hospital, Paris. E-mail: Michelkomajda@psl.aphp.fr Looking forward to your decision Sincerely yours,

Juan Cinca, MD Professor of Medicine

*Manuscript

DIFFERENTIAL CLINICAL CHARACTERISTICS AND PROGNOSIS OF INTRAVENTRICULAR CONDUCTION DEFECTS IN PATIENTS WITH CHRONIC HEART FAILURE

Juan Cinca1*, Ana Mendez1, Teresa Puig2, Andreu Ferrero1, Eulalia Roig1, Rafael Vazquez3, Jose R.Gonzalez-Juanatey , Luis Alonso-Pulpon5, Juan Delgado6, Josep Brugada7, Domingo Pascual-Figal8 on behalf of the investigators of the Spanish Heart Failure Network (REDINSCOR)

Servicio de Cardiologa, Hospital de la Santa Creu i Sant Pau, IIb-Sant Pau, Universitat Autonoma de

Barcelona, Barcelona, Spain

2

Departmento de Epidemiologa, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain Servicio de Cardiologa, Hospital Puerta del Mar, Cdiz, Spain Servicio de Cardiologa, Hospital Clnico, Santiago de Compostela, Spain

Servicio de Cardiologa, Hospital Puerta de Hierro, Madrid, Spain Servicio de Cardiologa, Hospital 12 de Octubre, Madrid, Spain Servicio de Cardiologa, Hospital Clnic, Barcelona, Spain

Servicio de Cardiologa, Hospital Virgen de la Arrixaca, Murcia, Spain

*Corresponding author: Juan Cinca, MD, Cardiology Service, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, St. Antoni M. Claret 167, 08025 Barcelona, Spain. Phone: +34 935565940; Fax: +34 935565603; e-mail: jcinca@santpau.cat. Short title: Prognosis of bundle branch block in heart failure Word count: 3,371

ABSTRACT Aims Intraventricular conduction defects (IVCD) can impair the prognosis of heart failure (HF) but their specific impact is not well established. This study aimed to analyze the clinical profile and outcomes of HF patients with left bundle branch block (LBBB), right BBB (RBBB), left anterior fascicular block (LAFB), and no IVCD. Methods and Results Clinical variables and outcomes of 1,762 patients with chronic HF were analyzed according to the presence of LBBB (n=532), RBBB (n=134), LAFB (n=154), and no IVCD (n=942). LBBB was associated with more marked LV dilation, depressed LV ejection fraction (LVEF), and mitral valve regurgitation. Patients with RBBB presented overt signs of congestive HF and depressed right ventricular motion. The LAFB group presented intermediate clinical characteristics and patients with no IVCD were more often women with less enlarged LV and less depressed LVEF. Death occurred in 332 patients (interannual mortality=10.8%): cardiovascular in 257, extravascular in 61, and of unknown origin in 14 patients. Cardiac death occurred in 230 (pump failure in 171 and sudden in 59). Adjusted Cox model showed higher 21month risk of cardiac death and pump failure death in LBBB and RBBB than in LAFB and in no IVCD groups. Conclusion LBBB and RBBB are associated with different clinical profiles and both are independent predictors of increased risk of cardiac death in patients with HF. A more favourable prognosis was observed in patients with LAFB and in those free of IVCD. Further research for HF patients with RBBB is warranted. Keywords: Heart failure; Bundle branch block; Outcomes; Prognosis

ABBREVIATIONS LBBB: left bundle branch block RBBB: right bundle branch block LAFB: left anterior fascicular block LV: left ventricular IVCD: intraventricular conduction defects EF: ejection fraction NYHA: New York Heart Association class

INTRODUCTION Intraventricular conduction defects (IVCD) can likely impair the clinical course and outcomes of patients with chronic heart failure (HF) since delayed activation of either the right or left ventricle shortens the duration of the ventricular diastolic filling period and this in turn reduces the stroke volume and cardiac output (1,2). Moreover, the systolic and diastolic ventricular asynchrony originated by the abnormal cardiac activation sequence (3,4) will worsen the already depressed cardiac output and favor further ventricular volume remodeling (5,6). Clinical registries that have analyzed the prognostic implications of bundle branch block in patients with HF (7-12) reported distinct results. Whereas the presence of LBBB emerges as an independent prognostic marker in some studies (7,9,10) others found a higher mortality linked to the presence of RBBB) (11,12) . Differences in the length of the follow-up period (from 1 up to 5 years) (7,10) may account in some extent for the reported prognostic differences although the categorization of patients and the analysis of the causes of death would certainly play an important role. Indeed, vital status or all cause mortality instead of a more precise assessment of different causes of cardiac death were currently done in most studies. On the other hand, the clinical characteristics associated with the different IVCD can not be well established because echocardiographic data are not reported in all studies and moreover, they lack of information on relevant features such as LV and left atrial size, or mitral valve assessment (7,10,12,13) . This study was therefore undertaken to determine the clinical characteristics and 21-month follow up outcomes of chronic HF in relation to the presence of LBBB, RBBB, LAFB, and absence of IVCD.

METHODS

Study population We screened 2,254 patients with chronic HF entered in the Spanish Network for the Study of Heart Failure (REDINSCOR) (www.redinscor.og) (14). Patients were consecutively recruited between January 2007 and January 2011 at HF units in 18 hospitals. Inclusion criteria were: a) age older than 18 years, b) prior hospital admission (>24h) due to HF and at least one echocardiographic abnormality (LV EF 40 %, LV end-diastolic diameter 60 mm, altered LV relaxation indicating diastolic dysfunction, thickness of interventricular septum/ LV posterior wall 14 mm). All patients were symptomatic (functional New York Heart Association class II-IV) and were treated according to the established clinical guidelines. Exclusion criteria were: a) reversible acute HF, b) severe valvular disease amenable to surgical repair, c) right HF secondary to chronic corpulmonale, and d) concomitant terminal disease. The investigation conforms with the principles of outlined in the Declaration of Helsinki. The protocol was approved by the ethics committees of all centers and all patients gave written informed consent to participate in the study. Study variables Data were collected using purposely designed web forms and quality controls were done every month. We recorded 93 clinical variables at study inclusion: a) demographic, epidemiological and previous clinical history; b) case history and physical examination; c) chest radiography; d) electrocardiographic; e) echocardiographic; f) laboratory blood tests; and g) treatments. Standard criteria were used to define the clinical variables. Cardiovascular risk factors were eventually coded as dichotomous variables (yes/no). Central obesity was defined as abdominal perimeter 88 cm in

women and 102 cm in men (15). Body mass index (Kg/m2) was entered as a continuous variable. Anemia was defined by hemoglobin <120 g/L for women and <130 g/L for men (16). The plasma levels of N-terminal-pro brain natriuretic peptide and brain natriuretic peptide were dichotomized for a cut-off value of >118.2 pmol/L and >43.41pmol/L respectively (17). The LV mass was determined according to previously published methods (18). The estimated rate of glomerular filtration was calculated using the MDRD method (19). Plasma levels of cardiac troponin I or T were considered high as from the reference cut off value for each hospital. LBBB was defined by prolonged QRS duration of 0.12 s or more associated with broad, notched R wave without q waves in leads I, aVL, and V6 and a rS pattern in lead V1. RBBB was characterized by prolonged QRS duration of 0.12 s or more associated with an R, rSR, or qR wave in lead V1; wide , slurred S waves in leads I, aVL, V5, and V6; and a wide terminal r wave in aVR. LAFB was defined by leftward axis deviation of -45 or more associated with qR wave in leads I and aVL and a rS pattern in leads II, III, and aVF. Follow-up Follow-up data were obtained from the outpatient annual visits or from the readmission and event reports. Total mortality included all cardiac and non-cardiac deaths. Cardiac mortality included death due to pump failure and sudden death. Pump failure death included patients dying because of refractory HF and patients undergoing urgent cardiac transplantation. Sudden death was defined as an unexpected natural death with no apparent cause occurring in less than one hour after the onset of symptoms. Patients lost in the follow-up and those submitted to non emergent heart transplant were censured for the analysis. The reported deaths were reviewed by an ad hoc committee. Statistical analysis

Continuous variables were expressed as mean standard deviation and the categorical variables were presented as frequency and percentage. Differences in the categorical variables were assessed by the chi-square test or Fishers exact test and differences in continuous variables were analyzed with the ANOVA method. A multivariate analysis (Cox model) was built to assess the influence of the different intraventricular conduction defects on survival and a Cox proportional hazard regression model was used to identify independent predictors of readmissions and cardiac death for each intraventricular conduction disorder. Variables showing a significant level in the univariate model (p <0.1) were thereafter included in the multivariate Cox model following a backward stepwise approach. The final model was adjusted for those variables categorized as clinically relevant. Moreover, confounding variables were included when they carry a change of the effect on the hazard ratio greater of 10% (20) .The proportionality assumption of the models was verified using time-dependent variables. Variables with >10% of missing data were not included in the Cox models and a multivariate regression imputation was applied, whenever necessary (21).A twosided p<0.05 was considered statistically significant. All analyses were performed using SPSS (v 19.0) software.

RESULTS Clinical characteristics

Among the 2,254 patients screened, 532 (23.6%) presented LBBB; 134 (6%) RBBB; 154 (6.8%) LAFB; and 942 (41.8%) no IVCD at inclusion. The remaining 492 patients (21.8%) presented left posterior fascicular block (n=14), combined BBB (n=87), nonspecific IVC (n=131), and ventricular pacing rhythm (n=260) and they were not included in the analysis. Thus, the final study population consisted of 1,762 patients (mean age 66 years, 68% men, 57% in NYHA class III-IV, mean LVEF of 36%). As shown in Table 1, there were significant clinical differences between the study groups. Patients with LBBB had more frequent history of dilated cardiomyopathy and presented with the most dilated and weighted LV, more advanced mitral valve regurgitation, largest QRS duration, and most depressed LVEF. Patients with RBBB had more frequent history of ischemic heart disease and prior myocardial infarction, a greatest proportion of central obesity, signs of left and right heart failure, and abnormal right ventricular motion at echocardiography. Patients with LAFB presented intermediate proportion of risk factors and degree of structural and functional cardiac involvement and had a lower prevalence of previous myocardial infarction than patients with LBBB and RBBB. However, deterioration of the NYHA functional class and presence of signs of left and right HF remained highly expressed in patients with LAFB. Patients free of IVCD were more often women, with less enlarged LV and less depressed LVEF. The percentage of pharmacological drug prescription varied among the study groups. Patients with LBBB received more -blockers, whereas loop diuretics were

more used in patients with RBBB and LAFB. Cardiac resynchronization devices were more frequently implanted in patients with LBBB and LAFB.

Outcomes Patients were followed for a median of 21 months (interquartile interval 11-33) and 15 of them (0.9%) were lost in the follow-up. Non emergent heart transplant was performed in 43 patients (2.4%). There were 666 readmissions due to decompensated HF, 148 to myocardial ischemia, and 222 to arrhythmias. Death occurred in 332 patients (interannual mortality rate of 10.8 %). Causes of death were: cardiovascular in 257 (77.4%); extravascular in 61 (18.4%); and of unknown origin in 14 (4.2%) of patients. Among the cardiac deaths, 171 were due to pump failure and 59 occurred suddenly. As shown in Table 2, patients with LBBB and RBBB showed the highest rates of readmissions and mortality and were followed by patients with LAFB and finally by those free of IVCD. Cox models were adjusted for some of the following variables: age, prior myocardial infarction, diabetes, central obesity, mitral valve regurgitation, signs of left and right HF, LVEF, left atrial size, LV mass, hemoglobin, renal function, implantable defibrillator, cardiac resynchronization and drug therapy. These models showed that the presence of RBBB was associated with a higher 21-month risk of all cause readmissions. Risk for cardiac death and pump failure death was higher in patients with LBBB and RBBB than in patients with LAFB or those free of IVCD (Figure 1 and Table 3). The hazard ratio for pump failure death tended to be higher (p=0.055) in RBBB than in LBBB patients (2.62 (1.60 - 4.28, p=0.001) vs. 1.60 (1.10-2.34, p=0.015), respectively). Multivariate predictors of readmissions, cardiac death, and pump failure death are listed in the supplementary Table S1. The most powerful

predictors of these events were Diabates mellitus, prior myocardial infarction, and presence of signs of left HF and right HF. New onset of BBB during follow up was observed in 65 patients (LBBB in 26, RBBB in 20, and LAFB in 19) but these patients remained in the group free of BBB because the categorization in this study was based on the variables at admission. During the follow-up 89 patients underwent implantation of cardiac resynchronization devices and these were entered in the Cox model.

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DISCUSSION This study affords integrative information on the clinical and prognostic influence of the most frequent IVCD in a cohort of patients with chronic HF. Differences in the clinical profile and 21-month risk of readmissions and cause of death were observed among patients with LBBB, RBBB, LAFB, and without IVCD. Clinical characteristics Present data indicate that a clinical phenotype characterized by LV dilation with markedly depressed systolic function, advanced mitral valve regurgitation, and history of dilated cardiomyopathy was more often observed in patients with LBBB. In contrast, patients with RBBB presented with overt signs of right and left HF, more depressed right ventricular motion at echocardiography, and more often reported a history of coronary heart disease. On the other hand, patients with LAFB showed intermediate degrees of structural LV derangements with respect to LBBB and RBBB although they still presented marked signs of left and right HF and advanced NYHA functional class. Patients free of IVCD were more often women with less enlarged LV and less depressed LVEF. The clinical-electrocardiographic associations described in this study have not been previously recognized provided the lack of studies analyzing more than two conduction defects in the same cohort as we did in the present study. On the other hand, studies assessing the prognosis of two conduction defects namely LBBB and RBBB in the same cohort of patients (8,10-12) have not provided echocardiographic information in all and, moreover, specific data on relevant structural cardiac features such as LV mass, LV diameter or LA size, or resynchronization therapies are not reported in these studies. However, concrete features drawn from these reports such as a more advanced mitral valve regurgitation in LBBB assessed in one study (8) , or a

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higher prevalence of prior myocardial infarction in RBBB found in three (8,11,12) are in accordance with the clinical patterns observed in our study. The pharmacological regimes prescribed in our patients share a coherence with the different clinical profiles of the observed subgroups since in accordance with the predominance of LV dilation in patients with LBBB, they received more -blockers and resynchronization therapy. Moreover, patients with RBBB received more loop diuretics in consonance with their advanced signs of congestive HF. Therefore, the clinical associations observed in our study do not appear to be fortuitous because they are not at variance with the available reports and also because they share a pathophysiological plausibility. The mechanism by which an IVCD could be associated to a particular clinical phenotype is complex, but some notions can be addressed. Theoretically, bundle branch block could precede the onset of HF thus being the primary cause of cardiac dysfunction. Alternatively, the conduction defect could develop secondarily to the underlying cardiac disease and then causing a further impairment of the clinical condition. Evidence that LBBB can primarily deteriorate the LV function is provided by experimental studies inducing acute LBBB in previously healthy hearts. Indeed, radio frequency ablation of the LBBB provoked acute mechanical asynchrony with concurrent decrease of cardiac output and also delayed LV dilation with depression of EF (LV remodeling) 16 weeks after LBBB ablation in anesthetized dogs (5). Moreover, asynchronous cardiac electrical activation induced by LV free wall pacing elicited asymmetrical hypertrophy and dilation in dogs (22). These findings indicate that LBBB itself has the potential to primarily induce LV dysfunction in otherwise healthy hearts but also to induce secondary LV remodeling in previously failing hearts. Once the left or right ventricle undergo dilation, the free wall stress increases (23) and this exerts an

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overstretching of the local Purkinje fibers that may favor either the development of new ipsilateral bundle branch block or the impairment a preexisting local intraventricular conduction defect. An example of acute induction of ipsilateral block in a dilated ventricle is the occurrence of RBBB in the course of acute pulmonary thromboembolism (24). Our patients with RBBB presented overt signs of right heart failure and greater percentage of depressed right ventricular motion at echocardiography. Outcomes Present data demonstrate that either LBBB or RBBB but not LAFB, are independent predictors of increased 21-month risk of readmissions and cardiac death in patients with chronic HF. A study on the prognosis of LBBB in 5,517 patients with congestive HF (7) evidenced a higher 1-year all cause mortality and sudden death in the group of 1,391 patients with LBBB than in controls free of LBBB. Similar unfavorable prognosis of LBBB was observed 1-year after admission in a cohort of patients with acute HF (9). However, studies comparing the prognosis of two conduction defects namely LBBB and RBBB in the same cohort of patients have not afforded consistent results since some of these studies report a more unfavorable prognosis to LBBB whereas others found increased mortality risk in patients with RBBB. Indeed, in a series of 9,082 hospitalized HF patients with LBBB (n=1,480) and RBBB (n=651) followed during 5 years the adjusted risk of death was higher in patients with LBBB than in those with RBBB (10). Likewise, in a cohort of 110,000 subjects free of cardiovascular disease followed up 9.5 years, 310 subjects developed BBB (LBBB=112, RBBB=198) and those with LBBB presented increased prevalence of cardiovascular disease and higher cardiac mortality than age- and sex-matched controls (13) . By contrast, a study on 3,200 hospitalized patients with acute HF showed that rehospitalization and death

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occurred more frequently in patients with RBBB (n=118) than in those with LBBB (n=107). Likewise, in a cohort of 1,888 patients with HF and LVEF <50%, those with LBBB (n=306) had a 4-year all-cause mortality higher than patients with RBBB (n=193) (11). Finally, all cause mortality was comparable in patients with LBBB and RBBB admitted to an intensive care unit with decompensated HF 23-month after admission (8). Our study confirms that patients with either LBBB or RBBB have a higher 21month incidence of cardiac death and pump failure death than patients with LAFB and than those free of IVCD. Therefore, in addition to the advanced therapies widely applied to HF patients with LBBB (i.e. LV resynchronization devices), the risk of patients with RBBB is as high as that of LBBB and therefore search for new and more specific therapies for patients with HF and RBBB is warranted.

Study limitations Among the initially screened cohort of 2,254 patients, there were 492 (21.8%) patients who presented either combined BBB, nonspecific IVC, ventricular pacing rhythm or left posterior fascicular block. These patients were not included because the objective of the study was to analyze the specific influence of the three most common IVCD. This study was conducted in tertiary hospitals and, as compared with patients currently attended in primary care services, they likely presented with more advanced stages of the disease as suggested by more than 50% of patients in NYHA class III-IV. Therefore, our results apply to patients with well defined underlying structural derangements and not to patients still in the early stages of the disease. However,

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knowledge of prognostic risk factors detected in patients with evolved HF could guide implementation of preventive measures to slow the course of the disease.

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ACKNOWLEDGEMENTS
This work was supported by a grant from the Spanish Ministry of Science and Innovation, Redes de Investigacin del Instituto de Salud Carlos III, (REDINSCOR, RD06/0003) and FondoEuropeo de Desarrollo Regional (FEDER).

FUNDING
This work was supported by a grant from the Spanish Ministry of Science and Innovation, Redes de Investigacin del Instituto de Salud Carlos III, (REDINSCOR, RD06/0003) and Fondo Europeo de Desarrollo Regional (FEDER).

CONFLICT OF INTEREST None to be declared

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FIGURE LEGENDS
Figure 1. Adjusted Cox model survival curves for readmissions (A), cardiac death (B), and pump failure death (C) in patients with chronic heart failure with and without intraventricular conduction defects after a median follow-up of 21 months.

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APPENDICES
REDINSCOR investigators Hospital Clnic de Barcelona: J. Brugada, M. Batlle, A. Berruezo, S. Hevia, L. Mont, F. Prez-Villa,; Hospital de la Santa Creu i Sant Pau: J. Cinca, E. Roig, A. Bays de Luna, X. Borrs, F. Carreras, A. Ferrero, J.M. Guerra, L. Hove-Madsen, E. Jorge, R. Martnez, J. Padr, T. Puig, N. Ribas, X. Violas, J. Alvarez-Garcia; Hospital Clnico Universitario de Santiago de Compostela: J.R. Gonzlez-Juanatey, M. Bandn, S. Eiras, L. FernndezHernndez, J. Garca-Acua, I. Gmez-Otero, L. Grigorian-Shamagian, F. Lago, P. Manzn, M. Moure, F. Otero-Ravia, F. Otero-Santiago, B. K. Rodino Janeiro, J. Rubio, A. Salgado, A. Seoane, A. Varela, P. V. Lear; Hospital Clnico San Carlos Medicina Interna: A. Fernndez-Cruz, A. Alvarez de Arcaya Vicente, M. Avila, E. Bordiu, L. Calle, C. Fernndez-Pinilla, D. Gmez-Garre, L. Gonzlez-Rubio, J. Marco, N. Martell, P. Muoz-Pacheco, A. Ortega, R. Patio, J. Pedrajas, L. Reinares; Hospital Clnico San Carlos Inst. Cardiovascular: J. Prez-Villacastn, R. Bover, M. Cobos, J. Garca-Quintanilla, J. Moreno, N. Prez-Castellano, M. Prez-Serrano, I. Vila; Hospital 12 de Octubre: J. F. Delgado, F. Arribas, P. Escribano, A. Flox, C. Jimnez Lpez-Guarch, M. Paradina, J. Ruiz-Cano, C. Senz de la Calzada, R. Salguero, V. Snchez-Snchez, R. Tello de Meneses, M. Vicente-Hernndez; Clnica Puerta de Hierro: L. Alonso-Pulpn, I. Fernndez -Lozano, P. Garca-Pava, A. Garca-Touchard, M. Gmez-Bueno, J. Mrquez, J. Segovia, L. Silva, M. Vzquez-Mosquera; Hospital Universitario Virgen de la Arrixaca: M. Valds, A. Garca-Alberola, I. Garrido, D. A. Pascual-Figal, F. J. Pastor-Prez, J. Snchez-Ms, P. Tornel; Hospital La Fe: M. Rivera, L. Almenar, R. Corts, L. Martnez-Dolz, J. Montero, M. Portols, E. Rosell-Lleti, A. Salvador, V. Vila; Hospital Universitario Virgen de Valme: R. Vzquez, J. Cubero, A. Fernndez-Palacn, D. Garca-Medina, S. Garca-Rey, E. Laguna, J. Leal del Ojo, F. Miano, L. Pastor-Torres, R. Pavn, A. Prez-Navarro, D. Villagmez; Hospital Universitario Puerta del Mar: R. Vzquez, R. Arana, D. Bartolom, P. Cabeza, G. Calle-Prez, F. Camacho, L. Cano, A. Carrillo, E. Daz-Retamino, V. Escolar, R. Fernndez-Rivero, S. Gamaza, A. Girldes, N. Hernndez-Vicente, M. Lagares, J. Lpez-Bentez, M. Marante, E. Otero, J. Pedregal, M. Sancho-Jaldn, R. Sevillano , R. Zayas; Gerencia del mbito Territorial de Bacelona-Institut Catal Salud: J.M. Verd, S. Aguilar, M. Aizpura, F. Alguacil, J. Casacuberta, J. Cerain, M. Domingo, M. GarcaLareo, J. Herrero-Melechn, N. Lpez-Pareja, A. Mena, A. Prez-Orcero, J. RodrguezCristbal, M. Rozas, J. Sorribes, P. Torn; Hospital Universitario Arnau de Vilanova: F. Worner, L. Barta, C. Bravo, J. Cabau, J. Casanova, B. Daga, I. De la Puerta, I. Hernndez-Martn, E. Piol, E. Pueo, G. Torres, A. Troncoso, D. Viles; Hospital Universitario Joan XXIII: A. Bardaj, J. Merc, E. Sanz-Girgas, P. Valdovinos; Hospital Universitario Virgen Macarena: O. Aramburu, J. Arias; Hospital Guadarrama: C. GarcaGonzlez, M. Alonso, C. Bischofberger, G. Domnguez-De Pablos; Hospital Morales Meseguer: D. Jimnez-Cervantes, I. Urea; Hospital Son Dureta: A. Grau-Seplveda, C. Fiol, P. Pericas, M. Villalonga; Hospital Francesc de Borja de Ganda: P. Orosa, J. Agero; Hospital Municipal de Badalona: F. Planas-Aym, J. Grau-Amoros, F. Planas-Comes, L. San Vicente.

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Table 1. Baseline clinical characteristics of 1,762 patients with and without intraventricular conduction defects
LBBB Variables (n=532, 30.2%) Age, years Sex, Male Diabetes Mellitus Hypertension Prior AMI Ischemic heart disease Dilated myocardiopathy BMI, kg/m2 Central obesity NYHA class, III-IV Signs of left HF -Orthopnea -Nocturnal dyspnea -3rd sound Signs of right HF -Lower limb edema -Jugular ingurgitation -Hepatomegaly -Hepatojugular reflex -Ascites RR Interval, ms QRS duration, ms AF/Flutter LVEDD, mm IndexedLVEDD, mm/m2 RV end-diastolic D, mm* IndexedRVDD, mm/m2 LVEF, % 66.811.6 380 (71%) 209 (39%) 351 (66%) 176 (33%) 228 (43%) 210 (39%) 28.34.6 299 (56%) 316 (59%) 321 (60%) 222 (42%) 102 (19%) 95 (18%) 221 (42%) 137 (26%) 129 (24%) 76 (14%) 91 (17%) 27 (5%) 826168 148 28 125 (23%) 6510 346 317 164 2910 RBBB (n=134, 7.6%) 67.612.6 101 (75%) 58 (43%) 98 (73%) 59 (44%) 70 (52%) 21 (16%) 29.35.8 91 (68%) 75 (56%) 84 (63%) 64 (48%) 38 (28%) 23 (17%) 70 (52%) 58 (43%) 37 (28%) 32 (24%) 27 (20%) 16 (12%) 801169 135 28 44 (33%) 5710 306 328 175 3915 LAFB (n=154, 8.7%) 68.513.8 108 (70%) 53 (34%) 111 (72%) 45 (29%) 61 (40%) 49 (32%) 28.74.2 87 (56%) 98 (64%) 97 (63%) 76 (49%) 36 (23%) 14 (9%) 76 (49%) 54 (35%) 43 (28%) 17 (11%) 33 (21%) 9 (6%) 817162 111 25 37 (24%) 6111 326 327 174 3616 No IVCD (n=942, 53.5%) 64.713.7 610 (65%) 406 (43%) 639 (68%) 352 (37%) 450 (48%) 215 (23%) 29.25.4 586 (62%) 512 (54%) 492 (52%) 348 (37%) 176 (19%) 104 (11%) 367 (39%) 270 (29%) 168 (18%) 108 (11%) 124 (13%) 48 (5%) 808175 9820 260 (28%) 5810 306 317 164 3916 <0.001 0.011 0.146 0.282 0.023 0.047 <0.0001 0.011 0.025 0.081 0.002 0.004 0.042 <0.001 0.005 <0.001 <0.001 <0.001 0.011 0.013 0.223 <0.0001 0.098 <0.0001 <0.0001 0.190 0.279 <0.0001 p value

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LV Mass, g LV Mass index, g/m2 LA, mm Indexed LA, mm/m2 Septalthickness , mm LV posterior wall, mm Mitral regurgitation, III/IV Normal RV motion Abnormal LV relaxation Pseudonormal LV

404123 21262 489 255 113 112 141 (27%) 393 (74%) 157 (36%)

351103 18255 499 256 123 113 18 (13%) 93 (69%) 41 (34%)

372119 19660 487 255 123 112 20 (13%) 111 (72%) 46 (37%) 14 (11%)

348121 18164 468 245 123 112 145 (15%) 764 (81%) 337 (40%)

<0.0001 <0.0001 <0.001 <0.001 <0.0001 0.126 <0.0001 <0.001 0.351

66 (15%) relaxation Restrictive LV relaxation Hemoglobin, g/L eGFR (mL/min/1,73 m2) NT-proBNP or BNP high ACE inhibitor Angiotensin II receptor 118 (22%) blocker RAAS blockade -blockers Aldosterone antagonists Digoxin Loop diuretics Antithrombotic Anticoagulants ICD CRT 462 (87%) 442 (83%) 332 (62%) 132 (25%) 468 (88%) 271 (51%) 226 (42%) 59 (11%) 26 (5%) 101 (23%) 13120 6725 292 (70%) 356 (67%)

18 (15%)

114 (13%)

0.696

25 (21%) 13121 6829 69 (64%) 93 (69%)

25 (20%) 13018 6627 83 (72%) 107 (69%)

166 (20%) 13221 70 27 438 (60%) 618 (66%)

0.587 0.779 0.052 0.003 0.684

27 (20%)

29 (19%)

206 (22%)

0.799

117 (87%) 102 (76%) 71 (53%) 36 (27%) 116 (87%) 79 (59%) 62 (46%) 12 (9%) 4 (3%)

135 (88%) 115 (75%) 94 (61%) 43 (28%) 141 (92%) 71 (46%) 74 (48%) 13 (8%) 9 (6%)

805 (85%) 755 (80%) 467 (50%) 191 (20%) 748 (79%) 542 (58%) 368 (39%) 70 (7%) 12 (1%)

0.792 0.067 <0.0001 0.042 <0.0001 0.009 0.090 0.125 <0.001

Qualitative data are presented as absolute frequencies and percentages. Quantitative data are expressed as meanstandard deviation. ACE inhibitor: angiotensin-converting enzyme inhibitor; AF: atrial fibrillation; BBB: bundle branch block; BMI: body mass index; BNP: brain natriuretic peptide; CRT: Cardiac resynchronization therapy; eGFR: estimated glomerular filtration rate (MDRD method); ICD: Implantable cardioverter defibrillator; IVCD: Intraventricular conduction defect; LA: left atrium; LAFB: left anterior fascicular block; LBBB: left bundle branch block; LV: left ventricular; LVEDD: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; NT-proBNP:

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amino-terminal pro-brain natriuretic peptide; NYHA class: New York Heart Association class; RAAS blockade: renin-angiotensin-aldosterone system blockade; RBBB: right bundle branch block. * Valid cases: 1,054 (60%).

Valid cases: 1,054 (60%). Valid cases: 1,368 (78%).

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Table 2. Readmissions and mortality rates in heart failure patients with and without intraventricular conduction defects after a median follow-up of 21 months.
RBBB LBBB Variables (n=532, 30.2%) 7.6%) Readmissions* All cause readmission Heart failure Myocardial Ischemia Arrhythmias ICD CRT Cardiac transplantation 219 (41%) 128 (24%) 35 (7%) 102 (19%) 23 (4%) 72 (14%) 23 (4%) 52 (39%) 36 (27%) 12 (9%) 16 (12%) 4 (3%) 5 (4%) 5 (4%) 46 (30%) 37 (24%) 6 (4%) 13 (8%) 7 (5%) 2 (1%) 7 (5%) 282 (30%) 197 (21%) 59 (6%) 63 (7%) 36 (4%) 10 (1%) 23 (2%) <0.0001 0.289 0.370 <0.0001 0.873 <0.0001 0.190 8.7%) 53.5%) (n=134, (n=154, (n=942, p value LAFB No IVCD

Mortality All cause mortality Cardiovascular death Cardiac Death - Pump failure - Sudden Vascular Extravascular Unknown cause 125 (23%) 99 (19%) 94 (18%) 66 (12%) 28 (5%) 5 (1%) 21 (4%) 5 (0.9%) 36 (27%) 27 (20%) 24 (18%) 23 (17%) 1 (1%) 3 (2%) 5 (4%) 4 (3.0%) 31 (20%) 25 (16%) 21 (14%) 18 (12%) 3 (2%) 4 (3%) 6 (4%) 0 (0%) 140 (15%) 106 (11%) 91 (10%) 64 (7%) 27 (3%) 15 (2%) 29 (3%) 5 (0.5%) <0.0001 <0.001 <0.0001 <0.0001 0.019 0.308 0.750 0.037

* One or more readmissions for the same cause. BBB: bundle branch block; CRT: Cardiac resynchronization therapy; ICD: Implantable cardioverter defibrillator; IVCD: Intraventricular conduction defect; LAFB: left anterior fascicular block; LBBB: left bundle branch block; RBBB: right bundle branch block.

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Table 3. Hazard ratios for readmissions and cardiac mortality in heart failure patients with and without intraventricular conduction defects after a median follow-up of 21 months.
All cause readmission p value HR 95% CI for HR Lower LBBB vs no IVCD RBBB vs no IVCD LAFB vs no IVCD 0.123 0.018 0.459 1.172 1.433 0.887 0.958 1.063 0.646 Upper 1.433 1.930 1.218

Adjusted for: Age, ICD, CRT, Signs of left HF, Signs of right HF, LVEF, Diabetes Mellitus, Prior AMI, LV mass Index, Hemoglobin , eGFR, and loop diuretics.

Cardiac death p value HR 95% CI for HR Lower LBBB vs no IVCD RBBB vs no IVCD LAFB vs no IVCD 0.005 0.007 0.336 1.579 1.894 1.266 1.149 1.192 0.783 Upper 2.169 3.008 2.049

Adjusted for: Age, ICD, CRT, Signs of left HF, Signs of right HF, LVEF, Diabetes Mellitus, Prior AMI, LV mass index , Indexed LA diameter, Mitral valve regurgitation III/IV, Hemoglobin , -blockers, and RAAS blockade.

Pump failure death p value HR 95% CI for HR Lower LBBB vs no IVCD RBBB vs no IVCD LAFB vs no IVCD 0.015 0.0001 0.139 1.600 2.620 1.492 1.097 1.603 0.878 Upper 2.335 4.283 2.535

Adjusted for: Age, ICD, CRT, Signs of left HF, Signs of right HF, LVEF, Diabetes Mellitus, LV mass index, Indexed LA diameter, Hemoglobin , eGFR, -blockers, and RAAS blockade. BBB: bundle branch block; CRT: Cardiac resynchronization therapy; eGFR: estimated glomerular filtration rate (MDRD method); ICD: Implantable cardioverter defibrillator; IVCD: Intraventricular conduction defects; LA: left

27

atrium; LAFB: left anterior fascicular block; LBBB: left bundle branch block; LV: left ventricular; LVEF: left ventricular ejection fraction; RAAS blockade: renin-angiotensin-aldosterone system blockade; RBBB: right bundle branch block.

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Supplementary Table S1. Multivariate predictors of readmissions, cardiac death, and pump failure death in heart failure patients with and without intraventricular conduction defects after a median follow-up of 21 months.
All cause readmission p value HR 95% CI for HR Lower LBBB vs no IVCD RBBB vs no IVCD LAFB vs no IVCD ICD CRT Age Signs of left HF Signs of right HF LVEF Diabetes Mellitus Prior AMI LV Mass index, g/m2 Hemoglobin, g/L eGFR (mL/min/1,73 m2) Loop diuretics 0.123 0.018 0.459 0.963 <0.0001 0.506 0.003 0.331 0.645 <0.001 0.007 <0.0001 0.003 0.007 0.012 1.172 1.433 0.887 0.993 2.869 0.997 1.319 1.092 1.002 1.340 1.271 1.002 0.993 0.995 1.387 0.958 1.063 0.646 0.736 2.262 0.990 1.100 0.915 0.995 1.135 1.069 1.001 0.989 0.992 1.076 Upper 1.433 1.930 1.218 1.340 3.637 1.005 1.581 1.303 1.008 1.581 1.512 1.003 0.998 0.999 1.789

Cardiac death p value HR 95% CI for HR Lower LBBB vs no IVCD RBBB vs no IVCD LAFB vs no IVCD ICD CRT Age 0.005 0.007 0.336 0.112 0.052 0.036 1.579 1.894 1.266 0.636 0.580 1.014 1.149 1.192 0.783 0.364 0.335 1.001 Upper 2.169 3.008 2.049 1.111 1.004 1.027

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Signs of left HF Signs of right HF LVEF Diabetes Mellitus Prior AMI LV Mass index, g/m2 Indexed LA, mm/m2 Mitral valve regurgitation, III/IV Hemoglobin, g/L -blockers RAAS blockade

<0.0001 0.200 0.062 0.015 0.040 0.005 0.004 0.036 0.002 0.003 0.005

1.914 1.205 0.990 1.402 1.335 1.003 1.039 1.385 0.989 0.637 0.632

1.380 0.906 0.980 1.069 1.014 1.001 1.012 1.022 0.982 0.472 0.458

2.653 1.601 1.000 1.840 1.758 1.005 1.066 1.877 0.996 0.859 0.872

Pump failure death p value HR 95% CI for HR Lower LBBB vs no IVCD RBBB vs no IVCD LAFB vs no IVCD ICD CRT Age Signs of left HF Signs of right HF LVEF Diabetes Mellitus LV Mass index, g/m2 Indexed LA, mm/m2 Hemoglobin, g/L eGFR (mL/min/1,73 m2) -blockers RAAS blockade 0.015 0.0001 0.139 0.502 0.275 0.358 0.0001 0.051 0.139 0.019 0.002 <0.001 0.003 0.026 <0.001 <0.001 1.600 2.620 1.492 0.812 0.717 1.007 2.181 1.390 0.992 1.453 1.003 1.051 0.988 0.992 0.554 0.517 1.097 1.603 0.878 0.442 0.395 0.992 1.461 0.998 0.981 1.064 1.001 1.022 0.980 0.986 0.396 0.363 Upper 2.335 4.283 2.535 1.491 1.303 1.022 3.256 1.935 1.003 1.984 1.005 1.082 0.996 0.999 0.775 0.735

BBB: bundle branch block; CRT: Cardiac resynchronization therapy; eGFR: estimated glomerular filtration rate (MDRD method); ICD: Implantable cardioverter defibrillator; IVCD: Intraventricular conduction defects; LA: left atrium; LAFB: left anterior fascicular block; LBBB: left bundle branch block; LV: left ventricular; LVEF: left

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ventricular ejection fraction; RAAS blockade: renin-angiotensin-aldosterone system blockade; RBBB: right bundle branch block.

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