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European Journal of Heart Failure 2007 9(1):7-14; doi:10.1016/j.ejheart.2006.04.011
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© 2006 European Society of Cardiology

Left bundle branch block as a risk factor for progression to heart failure

Faiez Zannada,*, Etienne Huvelleb, Kenneth Dicksteinc, Dirk J. van Veldhuisend, Christoph Stellbrinke, Lars Køberf, Serge Cazeaug, Philippe Ritterg, Aldo Pietro Maggionih, Roberto Ferrarii,j and Philippe Lechatk

a CIC-INSERM-CHU de Nancy, Hospital Jeanne d'Arc Dommartin-lès-Toul, BP 303 - 54201 Toul Cedex, France
b Guidant CRM Clinical Research Department Brussels, Belgium
c Department of cardiology, Stavanger University Hospital Stavanger, Norway
d Department of Cardiology, University Hospital Groningen Groningen, the Netherlands
e Department of Cardiology, University Hospital RWTH, Aachen, Germany
f Department of Cardiology, Rigshospitalet Heart Centre Copenhagen, Denmark
g Department of Cardiology InParys, Saint-Cloud, France
h ANMCO Research Centre Florence, Italy
i Department of Cardiology, University of Ferrara Ferrara, Italy
j Cardiovascular Research Centre, Salvatore Maugeri Foundation, IRCCS Gussago, Italy
k Clinical Pharmacology Department Pitié-Salpétrière Hospital, Paris, France

* Corresponding author. Tel.: +33 3 83 65 66 25; fax: +33 3 83 65 66 19. f.zannad{at}chu-nancy.fr


   Abstract
Top
 Abstract
1. Introduction
 2. Pathophysiology of LBBB
 3. Clinical effects of...
 4. LBBB treatment
 5. Conclusions
 Acknowledgment
 References
 
The prevalence of conduction disturbances, particularly left bundle branch block (LBBB), is strongly correlated with age and with the presence of cardiovascular disease. LBBB has been reported to affect approximately 25% of the heart failure (HF) population and it is likely that the deleterious role of such conduction disorders in the progression to HF has been underestimated.

The purpose of this article is to review the data from the literature indicating that LBBB may have a causative role, mediated through the resulting intra-ventricular asynchrony, in the deterioration of cardiac function and the development of cardiac remodelling and HF. It also aims to address the potential for future clinical therapies for this conduction disorder.

Key Words: Left bundle branch block • Remodelling • Heart failure • Prevention • Cardiac resynchronisation therapy

Received May 10, 2005; Revised December 9, 2005; Accepted April 25, 2006


   1. Introduction
Top
 Abstract
 1. Introduction
2. Pathophysiology of LBBB
 3. Clinical effects of...
 4. LBBB treatment
 5. Conclusions
 Acknowledgment
 References
 
Approximately one third of patients with heart failure (HF) present with conduction disturbances that result in a QRS of greater than 120 ms. Most commonly (in approximately 25% of HF patients) this is exhibited as a left bundle branch block (LBBB) pattern [1]. This percentage is significantly higher than the estimated 1.5% prevalence of LBBB in the general patient population [2].

This article reviews the data currently available in the literature showing that LBBB deteriorates both diastolic and systolic left ventricular (LV) functions and constitutes a risk factor for the development and progression of cardiovascular diseases (CVD). As with other conduction defects, LBBB appears to be irreversible despite pharmacological treatment, but can be mitigated by cardiac resynchronisation therapy (CRT) in patients with moderate to severe HF and deteriorated LV systolic function. It is unknown whether CRT could slow or prevent emergent remodelling in non-HF patients presenting with LBBB.


   2. Pathophysiology of LBBB
Top
 Abstract
 1. Introduction
 2. Pathophysiology of LBBB
3. Clinical effects of...
 4. LBBB treatment
 5. Conclusions
 Acknowledgment
 References
 
The reduced cardiac function and/or poor clinical status observed in patients presenting with abnormal ventricular conduction patterns may support a possible cause-and-effect relationship between LBBB and HF.

2.1. LBBB and LV function
Comparing 18 patients with isolated LBBB to 10 control subjects, Grines et al. [3] identified delays in LV systolic and diastolic events in the LBBB group, as described in Fig. 1. The delays were associated with a shortening of LV diastole, abnormal septal motion with an associated decrease in regional ejection fraction and an overall reduction in global ejection fraction in the LBBB group compared to the controls. Similar findings were made in patients with isolated LBBB by other authors [4-6].


Figure 01
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  		Fig. 1 Timing of right and left ventricular events in normal individuals (A) and in subjects with LBBB (B). In normal individuals, LV events either precede or occur simultaneously with RV events. In patients with isolated LBBB, the sequence is reversed with RV events preceding LV events (reprinted from Grines et al. [3], with permission from Lippincott, Williams and Wilkins) po, to, ao, mo, time of pulmonary, tricuspid, aortic, and mitral valve opening respectively. pc, tc, ac, mc, time of respective valve closure.

 
Xiao et al. [7] reported a similar association of LBBB with deterioration of LV systolic and diastolic function in patients with cardiomyopathy of ischaemic or non-ischaemic origin. They confirmed the prolongation of pre-ejection and relaxation times that directly impairs diastolic function by shortening LV filling time to an extent likely to limit stroke volume. This effect has been quantified by Zhou et al. [8] who showed that the LBBB-dependent activation abnormalities have a dominant effect, over the presence of cardiomyopathy, on the deterioration of LV function.

While these studies show that LBBB may be associated with a deterioration of LV function, it should be acknowledged that several types of LBBB may exist and that the mechanical effect may depend upon the site of block. Auricchio et al. [9] demonstrated that, although LBBB is a complex electrical disease resulting from conduction delays located at several anatomic levels of the activation sequence, most patients with HF and LBBB have a specific "U-shaped" activation sequence that turns around the apex of the LV. Their observations substantiate the remarkable heterogeneity of LBBB and correlate well with echocardiographic observations of variable regions of mechanical delay in these patients. Interestingly, the authors show that asynchronous pacing can modify the line of block, supporting a functional basis for these lines of block rather than a fixed anatomic obstacle.

2.2. Electrical versus mechanical asynchrony
Intra-left ventricular asynchrony, observed in the majority of patients with LBBB, is an independent predictor of severe cardiac events in HF patients. This has been shown in patients with non-ischaemic cardiomyopathy either by tissue Doppler imaging [10] or by radionuclide angiography [11].

Both studies suggest that, in some patients, intra-LV electromechanical asynchrony might constitute a link between the conduction disturbance and clinical deterioration.

2.3. Right ventricular pacing
Right ventricular (RV) pacing creates a slow depolarization, conducted through the myocardium rather than the Purkinje network. As a consequence, the electrical activation and mechanical activity of the ventricles are asynchronous, the left ventricle being activated later than the right ventricle. In this aspect, RV pacing shares some common features with the depolarization and mechanical activity observed in LBBB patients. In addition the MOST [12] and DAVID [13] trials showed that, in patients with normal and depressed LV function respectively, there is a significant association between RV pacing and the risk of hospitalisation for HF.

Therefore, although RV pacing may not exactly mimic the LBBB conduction disturbance seen in dilated cardiomyopathy [14], it does create similar electrical and mechanical activation sequences and the data presented do support a general association between cardiac asynchrony and clinical deterioration.

2.4. LBBB and cardiac remodelling
There is increasing evidence suggesting that inflammation plays a pathogenic role in HF by inducing contractile dysfunction and promoting apoptosis or fibrosis, thus contributing to the myocardial remodelling process [15-17]. One can assume that the inflammatory process and the fibrosis impair both the conductive tissue and the myocardium. Fibrosis and QRS complex duration have indeed been found to be positively correlated [18,19]. Besides the inflammatory process promoting fibrosis, Shamim et al. hypothesized that the progressive increase in LV filling pressure observed in LV diseases might lead to ischaemia of the subendocardium that could then become predisposed to subendocardial fibrosis and permanent conduction disorder [20].

As well as probably being the result of similar pathophysiological mechanisms, the conduction disturbance and the cardiac remodelling seen in HF might interact to produce a deleterious feedback loop. This "vicious circle" has been proposed based on observations made in LBBB patients and on the results of animal studies where abnormal conduction was either created by ablation or ventricular pacing [21]. In addition to these observations, some of the steps of this "vicious circle" are also supported by the data from studies of CRT in HF patients with a wide QRS.

An anesthetized canine LBBB model has been developed using radiofrequency ablation of the proximal part of the left bundle branch [22,23]. The resulting LBBB causes widening of the QRS, interventricular delay, paradoxical septal motion, and haemodynamic deterioration indicating a significant impairment of LV function, observations similar to those found in LBBB patients [3].

Although this LBBB model may not mimic the diffuse distal alteration of the conduction system seen in dilated cardiomyopathy, it does support the association between loss of LV conduction and haemodynamic dysfunction.

The deterioration of haemodynamic function is known to be associated with compensatory neurohumoral mechanisms which, although initially adaptive, may be deleterious over the long-term, in part by contributing to myocyte hypertrophy and pathologic remodelling [24,25].

Prinzen et al. [26] showed in animals that asynchronous electrical activation generated by ventricular pacing is associated with a redistribution of myocardial fiber strain and a change in regional blood flow. More specifically, these authors showed that epicardial fiber strain is early and decreased in regions close to the pacing site (early-activated). In regions remote from the pacing site (late-activated), an initial positive fiber strain (stretch) is observed, most likely caused by the contraction of early-activated regions. This early stretch is followed by a late and pronounced negative strain, prolonged after the ejection phase (Fig. 2A).


Figure 02
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  		Fig. 2 (A) Ventricular pacing in animals: regional strain in regions close to (early activated) and remote from (late activated) the pacing site (reprinted from Vernooy et al. [21], with permission from Blackwell Publishing). (B) and (C) Example of TDI-derived strain curves in a LBBB heart failure patient, before (B) and after (C) CRT (reprinted from Breithardt et al. [29], with permission from the American College of Cardiology Foundation). See text for explanations. 1, 2, and 3 indicate end-diastole, begin ejection, and end ejection, respectively. IVC=isovolumic contraction time, IVRT=isovolumic relaxation time.

 
Such asynchronous activation induces LV dilatation chronically and asymmetrical hypertrophy, the late activated regions being thicker than the early-activated regions [27]. Similar asymmetric hypertrophy has been observed in patients with LBBB, the early-activated septum becoming significantly thinner than the late activated posterior wall [27]. It is possible that the resulting ventricular hypertrophy and dilatation seen in both animals and humans, may in turn, increase asynchrony by causing gap junction remodelling and modifying the conduction pathways [28].

Support is given to a causative role for LBBB in the progression of dilated cardiomyopathy by the fact that restoration of the ventricular activation sequence by CRT opposes the various mechanisms that lead to ventricular dilatation.

Breithardt et al. [29], using echocardiographic strain rate imaging in HF patients presenting with LBBB, confirmed the observations made in animals by Prinzen et al. The septal region, early-activated in LBBB patients indeed demonstrated an early maximum negative strain, while the late-activated lateral wall showed an early stretch (positive strain) followed by an intense late peak contraction (negative strain) which persisted into the post-systolic period (Fig. 2B). Moreover the abnormal myocardial fiber strain distribution seen in these patients could be reversed by CRT (Fig. 2C), allowing resumption of a physiologic pattern in which the systolic contraction occurred simultaneously in both walls. This restoration of lateral-septal synchrony, the unloading of the intrinsically late-activated region, and the reduction in abnormal myocardial stretch, may favourably affect the recovery of regional myocardial function and promote reverse remodelling by reducing the asymmetric hypertrophy and cardiac dilatation.

In addition to this direct effect on regional preload and myocardial stretch and to the effect on neurohumoral imbalance [30-32], CRT improves the inflammatory response seen in HF patients. Recent results [33] have shown that CRT in HF patients with a wide QRS, leads to a reduction in serum levels of TNF-{alpha} and interleukin-6, both of which are suspected to have a deleterious effect on cardiac function and remodelling [34].

In summary, LBBB contributes to a vicious circle of LV wall stress, asymmetric hypertrophy, and dilatation that progressively deteriorates LV function.


   3. Clinical effects of LBBB
Top
 Abstract
 1. Introduction
 2. Pathophysiology of LBBB
 3. Clinical effects of...
4. LBBB treatment
 5. Conclusions
 Acknowledgment
 References
 
3.1. LBBB and cardiovascular morbidity
The Framingham study showed that the appearance of complete LBBB on a routine ECG was usually associated with underlying hypertension, coronary artery disease (CAD) or cardiomyopathy, conditions that, if not already clinically apparent, would subsequently evolve during follow-up [35]. The study showed specifically that 28% of patients who were free from clinical HF and who developed LBBB after the first Framingham examination also developed HF coincident with, or soon after the onset of LBBB. This occurred more than seven times more frequently than the incidence of HF seen during the same time interval in control subjects (Fig. 3). The mean time interval from the onset of LBBB to the first recognition of clinical HF was 3.3 years.


Figure 03
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  		Fig. 3 Incidence of new cardiovascular abnormalities after onset of LBBB (mean FU=6 years). (*) p<0.05, (#) p<0.001 (reprinted from Schneider et al. [35], with permission from the American College of Physicians). CE=cardiac enlargement, CHD=coronary heart disease, CHF=congestive heart failure, DIAB=diabetes, HBP=high blood pressure.

 
While the Framingham study suggests that HF might develop as a result of LBBB, HF could also develop before the block and simply worsen with increasing conduction disturbances. It has been shown that QRS widening, observed during serial ECGs in patients with pre-existing moderate to severe HF, provides an independent predictor of deterioration of clinical status and need for heart transplantation [36].

3.2. LBBB and mortality risk
Table 1 summarizes several studies evaluating mortality data from patients with isolated LBBB [37], randomly sampled populations [2,38,39], sicker patients with hypertension [40], suspected [41] or existing CAD [42], post-myocardial infarction (MI) patients [43,44], and HF patients [1].


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  		Table 1 Mortality risk associated with LBBB in various patient populations

 
Most studies show that LBBB is associated with an increased mortality, whatever the control population, even in healthier individuals, although the sicker the patient population, the higher the impact of the conduction disturbance on the mortality.

The relative risk associated with the presence of LBBB in these studies varies roughly between 1.5 and 2.0, even after adjustment for covariates (Table 1).

Analysis of community sample data collected in the Framingham study [38] reveals a significant increase in cardiac mortality in patients with LBBB when compared to no BBB. While this finding was not confirmed by Eriksson et al. [2], their study had a much smaller patient population and no stratification between right and left bundle branch blocks.

In a recent study conducted by the same team in a large asymptomatic male population in Göteborg [39], the presence of LBBB (and not right BBB) was associated with an increased risk of developing HF [RR=3.73 (1.63-8.51)] within a follow up period of 28 years. LBBB was also associated with a higher risk of coronary death, acute myocardial infarction, and atrio-ventricular block.

While most studies do indicate that LBBB is associated with an increased mortality, Stenestrand et al. [44] concluded that LBBB does not appear to be an important independent predictor of 1-year mortality in MI but mainly reflects ageing, comorbid conditions, and LV dysfunction. Although it must be considered that LBBB could simply reflect comorbidity in this post-MI population, it is also possible that these data are in fact consistent with the hypothesis ascribing a causative role to LBBB in deterioration of LV function, HF evolution, and death.

The registry analyzed more than 11,000 patients with available LVEF measurements. Although the successive adjustments for multiple covariates continually identified LBBB as an independent predictor of one-year mortality, LBBB was no longer a predictor after adjustment for LVEF. Our review of the pathophysiology of LBBB indicates that the conduction disturbance induces an abnormal LV contraction pattern which results in LV dysfunction and a decrease in LVEF, leading to emerging HF and then to death. If we assume that LVEF is LBBB-dependent, this could explain why, in a multivariate analysis, the LBBB is no longer an independent predictor of mortality after the adjustment for LVEF. Only an analysis evaluating the chronological sequence of events could definitely ascribe the decrease in LVEF to LBBB and thus the increase in mortality to the low LVEF.


   4. LBBB treatment
Top
 Abstract
 1. Introduction
 2. Pathophysiology of LBBB
 3. Clinical effects of...
 4. LBBB treatment
5. Conclusions
 Acknowledgment
 References
 
The review presented here shows that there is increasing evidence that LBBB may be an early marker of cardiomyopathy and that it may have a causative role in the development of cardiac remodelling and hypertrophy. This raises the question as to the possibility of treating the conduction disorder itself and so preventing its negative impact on cardiac function and structure.

4.1. Treatment of the underlying disease
As HF and LBBB share the same aetiologies [45], the treatment of causative diseases, mainly diabetes, hypertension, and CAD, will be instrumental in the prevention of HF as well as the occurrence of the conduction defect. At present the mechanisms leading to LBBB or other conduction disturbances are poorly understood [46].

Although current drug treatments acting on neurohumoral imbalances can lead to reverse architectural or tissue remodelling (decrease in heart volumes and in LV hypertrophy), there are few data suggesting that, once LBBB occurs, these drug treatments can cause an electrical reverse remodelling and so restore a normal conduction. On the contrary, some studies that evaluated patients treated with current drug regimens, identified over a period of one or two years, a progressive lengthening of QRS duration [20,47]. The Euro Heart Failure survey showed recently in a HF population that the QRS was shorter in patients treated with beta blockers, while it was longer in those treated with ACE inhibitors, spironolactone, or digoxin [48].

Given these observations, CRT might constitute a reasonable adjuvant therapy addressing this aspect of HF pathophysiology.

4.2. Cardiac resynchronisation therapy (CRT)
Patients with mild HF have been studied in several trials, some of which are published and others ongoing. The MIRACLE ICD II trial [49] showed that in patients with mildly symptomatic HF (NYHA class II), a QRS ≥130 ms, and a LVEF ≤35%, CRT results in significant improvement in cardiac structure and function. The ongoing MADIT-CRT and REVERSE studies are larger scale trials investigating the effect of CRT on morbidity and mortality in patients with NYHA classes I-II, a wide QRS (respectively ≥130 ms and 120 ms), and a deteriorated LVEF (respectively ≤30% and 40%) [50].

Based on the observed deleterious effect of standard RV pacing, previously described in the MOST [12] and DAVID [13] trials, other studies are currently evaluating the benefit of CRT in patients who present with a standard indication for permanent ventricular pacing. While the COMBAT [51] trial is enrolling patients with indications for anti-bradycardia pacing and moderate to severe HF, the BIOPACE [50] trial is including standard brady-patients without restriction on either LVEF or baseline QRS width.

The OPSITE [52] and PAVE [53] trials compared standard RV pacing with CRT in patients undergoing atrio-ventricular node ablation for drug-refractory chronic atrial fibrillation. Both studies showed incremental improvement in functional capacity with BV pacing when compared to RV pacing although it must be considered that the overall improvement, when compared to baseline status, could have been attributed to rate control and rate regularization in these patients with refractory atrial fibrillation.

All the above-cited trials include patients with either a deteriorated ventricular function (low LVEF) or with an indication for permanent ventricular pacing.

Could the LBBB-related dyssynchrony be prevented by CRT before deterioration of LVEF and before cardiac remodelling? Although CRT has been shown to trigger a reverse remodelling process in patients with moderate to severe HF [54,55], it is not known whether CRT could slow or prevent emergent remodelling in non-HF patients. An initial answer to this question may be provided by Vernooy et al. [56] who recently presented results of CRT in non-HF animals in which a LBBB had been created by RF-ablation. This animal study showed that CRT normalized regional LV myocardial shortening and blood flow distribution and reversed LV hypertrophy and dilatation. These results lead to the conclusion that HF is not a prerequisite of the beneficial effect of CRT at the organ level in the presence of LBBB.


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Pathophysiology of LBBB
 3. Clinical effects of...
 4. LBBB treatment
 5. Conclusions
Acknowledgment
 References
 
LBBB is associated with an increased risk of cardiovascular morbidity and mortality. It may be a marker of a slowly progressing, degenerative cardiac disease, ischaemic or non-ischaemic, affecting not only the conduction system but also the myocardium.

The sequence LBBB-intra-ventricular asynchrony-reduced pump function-neurohormonal activation-asymmetric hypertrophy-dilatation, followed by emerging HF seems established. CRT can interrupt this sequence in moderate to severe heart failure patients but it is unknown whether the effects of LBBB-related dyssynchrony could be prevented before deterioration of function and cardiac remodelling. While recent animal studies suggest that HF may not be a prerequisite to see a beneficial effect of CRT at the organ level in the presence of LBBB, the identification of non-HF patient populations likely to benefit from CRT warrants further evaluation in prospective clinical trials.


   Acknowledgment
Top
 Abstract
 1. Introduction
 2. Pathophysiology of LBBB
 3. Clinical effects of...
 4. LBBB treatment
 5. Conclusions
 Acknowledgment
References
 
The authors gratefully appreciate the constructive review of the manuscript by Mr. Andrew Kramer, PhD and Mrs. Helen Reeve, PhD.


   References
Top
 Abstract
 1. Introduction
 2. Pathophysiology of LBBB
 3. Clinical effects of...
 4. LBBB treatment
 5. Conclusions
 Acknowledgment
 References
 

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