© 1999 European Society of Cardiology
Do we have reasons to be enthusiastic about pacing to treat advanced heart failure?
a Département de Cardiologie et Maladies Vasculaires, Centre Cardio-Pneumologique, Hôpital Pontchaillou Rennes 35043, France
b Association Val d'Or Saint-Cloud, France
* Corresponding author. Tel.: +33-299282525; fax: +33-299282510
Key Words: Advanced heart failure • Pacing therapy
Received April 26, 1999; Revised July 7, 1999; Accepted July 8, 1999
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1. Introduction |
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 Top 1. Introduction 2. Rationale of biventricular...3. Acute studies with...4. Technical requirements of...5. Long-term results with...6. ConclusionReferences |
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Despite pharmacological advances, the introduction of ACE inhibitors and of beta-blockers in particular, the prognosis of patients with severe heart failure (grades III and IV of the NYHA classification) remains pejorative and their quality of life is poor. A number of non-pharmacological treatments have been proposed for this type of patient: heart transplantation remains the reference treatment although its application is restricted by donor shortage, among other factors. Left ventricular support devices are still at the evaluation stage and the results of cardiomyoplasty are highly controversial. In the early 1990s, standard dual-chamber pacing with short AV delay was proposed as a supplementary treatment of drug-resistant heart failure [1,2]. Initial results were encouraging but were never confirmed [3,4]. These studies, however, made it possible to select a population of potentially responsive patients, especially those with a prolonged PR interval reflecting major atrioventricular asynchrony in the left heart [5]. That relative failure of standard dual-chamber pacing could be linked to the fact that by capturing the ventricle from the right apex, it increases, or at least it cannot correct the marked asynchrony of activation, contraction and relaxation which characterizes a number of patients with chronic left ventricular dysfunction. Such is the case in particular in patients with important QRS enlargement linked to major intraventricular conduction delay. Biventricular pacing, which simultaneously activates both ventricles, may contribute to correcting the asynchrony and thus improve cardiac performance.
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2. Rationale of biventricular pacing: electromechanical correlates in chronic heart failure |
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Top1. Introduction2. Rationale of biventricular...3. Acute studies with...4. Technical requirements of...5. Long-term results with...6. ConclusionReferences |
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The purpose of multi-site biventricular pacing is to correct the sometimes major electromechanical abnormalities that result from conduction disorders associated with chronic left ventricular systolic dysfunction.
2.1. Conduction disorders in chronic LV systolic dysfunction
Anatomoclinical studies, especially the Wilensky’s study [6], have shown the high prevalence of conduction disorders in patients with chronic LV systolic dysfunction, and their progression over time with an independent prognostic value. AV conduction and intraventricular conduction are particularly concerned. The PR interval increases progressively and is significantly prolonged (
200 ms) in 60% of patients at the end-stage of the disease. It has been shown that first or second degree AV block was an independent risk factor of cardiac death in patients with dilated cardiomyopathy [7]. In the same way significant increase of QRS duration is observed in the course of follow-up and reflects the development of progressive intraventricular conduction delay (IVCD). In Wilensky’s study [6] 27% of patients had QRS width 150 ms with peaks up to 200 ms on the last ECG recording before death. IVCD has also been shown as independent mortality risk factor in patients with chronic LV systolic dysfunction [8–11].
2.2. Electromechanical consequences
These conduction disorders have a significant impact on cardiac performance. The lengthening of the PR interval, be it apparent or concealed, induces atrio-ventricular desynchronization, hence shorter ventricular filling time and reduced or even suppressed left atrial contribution to ventricular filling, as often reflected by the single-pulse aspect of the mitral Doppler flow resulting from the superimposition of wave A and wave E [5].
The hemodynamic consequences of abnormal LV activation in patients with DCM have been explored in depth by Xiao et al. [12,13]. That study conducted in 50 patients revealed a positive correlation between QRS duration and Q wave delay at LV pressure peak and the interval between the Q wave and the peak+dp/dt. In contrast, QRS duration and the +dp/dt value were negatively correlated. These data showed that the longer the QRS duration, the longer the duration of LV isovolumetric contraction and relaxing time, hence the more altered the LV pump function was. Also, the increased isovolumetric contraction and relaxation times of the left ventricle induced a shortening of filling time in patients whose QRS duration was particularly long. Finally, abnormal activation sequence may play a role in increasing mitral regurgitation: Xiao et al. [13] and Nishimura et al. [5] found a positive correlation between mitral regurgitation time and QRS duration on the one hand, and PR interval duration on the other hand. In addition, left diastolic atrio-ventricular gradient is a common occurrence in AV conduction disorders and may result in diastolic mitral regurgitation.
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3. Acute studies with temporary pacing |
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Top1. Introduction2. Rationale of biventricular...3. Acute studies with...4. Technical requirements of...5. Long-term results with...6. ConclusionReferences |
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The first hemodynamic study of the acute effects of biventricular pacing was conducted post-operatively immediately following coronary bypass surgery in 18 patients with LVEF >40%. Biventricular pacing significantly increased cardiac output and reduced systemic arterial resistance, by comparison with no pacing or right or left ventricular single site pacing [14].
Our group [15,16] reported their experience in 18 patients in class III or IV with advanced DCM and intraventricular conduction delay (mean QRS duration=170±36 ms). All these patients were in sinus rhythm, with a mean PR interval of 224±36 ms. Biventricular pacing induced a significant decrease in QRS duration on baseline (154±18 ms vs. 170±37 ms; P<0.01). The cardiac index was significantly improved by biventricular DDD pacing, when compared with no pacing or right ventricular, single chamber DDD pacing (2.7±0.7 l/min per m2, 2±0.5 l/min per m2 and 2.4±0.6 l/min per m2, respectively; P<0.01). In parallel, a significant decrease in mean pulmonary capillary pressure was observed with biventricular pacing.
Other authors studied the effects of left ventricular pacing. Blanc et al. [17] compared biventricular pacing, single site left ventricular pacing, apical and outflow tract right ventricular pacing in 23 patients. Compared to baseline, biventricular pacing and LV pacing induced the same hemodynamic benefit, as assessed from the following criteria: systolic blood pressure, mean pulmonary capillary pressure and V-capillary wave; cardiac output was not considered in that study. Recently Kass et al. [18] published the results of extensive hemodynamic studies aimed to assess the acute effects of VDD pacing at varying sites (RV apex, RV midseptal, LV paced transvenously and biventricular) and AV delays in 18 heart failure patients. He showed that RV pacing at any site had negligible contractile/systolic effects. However, LV free-wall pacing increased dP/dt max by 23.7±19% and pulse-pressure by 18±18.4% (P<0.01). Biventricular pacing yielded less change than LV pacing alone. In the same way pressure–volume curves analysis consistently revealed minimal changes with RV pacing but increased stroke work and lowered end-systolic volumes with LV and biventricular pacing. Finally Kass et al. [18] showed that AV delay had less influence on LV function than pacing site.
3.1. Which heart failure patients could be candidates for pacing therapy?
At the present stage of knowledge, we can postulate that optimal candidates should be patients: (i) with chronic and severe heart failure (class IV or preferably III) related to LV systolic dysfunction whatever the etiology; (ii) non- or insufficiently improved by optimal drug treatment including at least diurectics, ACE inhibitors and when possible beta-blocking agents; (iii) with the clear evidence of electromechanical abnormalities linked to significant conduction disorders, especially wide QRS complex. The value of this last point was clearly shown in the Kass [18] study where a positive linear relationship was observed between the QRS duration during intrinsic conduction and the percentage of increase in LV+dp/dt during biventricular — or LV–VDD pacing as compared to baseline without pacing. Interestingly this correlation was missed above a cut-off QRS width of 150 ms. In summary this study showed that, within this limit, the wider was the QRS complex, the greater the acute hemodynamic benefit; (iv) finally the presence of a significant mitral regurgitation (grade2) seems to be an additional predictive factor of positive response to pacing (Fig. 1).
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4. Technical requirements of permanent biventricular or left-ventricular based pacing |
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Top1. Introduction2. Rationale of biventricular...3. Acute studies with...4. Technical requirements of...5. Long-term results with...6. ConclusionReferences |
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4.1. How to pace the left ventricle permanently?
Among the technical difficulties of multisite biventricular pacing, one is to chronically and safely pace the left ventricle at the optimal site.
The first pacing experiments [15,19,20] were conducted using the epicardial route, and thoracotomy or thoracoscopy. However, this method has two principal disadvantages. First, it incurs a non-negligible operative risk in such a severely diseased patient population. Second, the epicardial technique is associated with a poor quality of acute pacing thresholds and a high rate of delayed exit blocks resulting in LV pacing loss. However, this route has the theoretical advantage to place the pacing electrode at the optimal site in each patient. In a preliminary experience of acute intra-operative hemodynamic testing in 25 patients, Auricchio et al. [20] showed that the observed benefit was primarily dependent on the LV pacing site. From the different tested sites, the mid-part of the LV free wall provided the greater hemodynamic benefit in most patients.
To eliminate the need of general anesthesia and to minimize the operative risk, our group introduced from 1994 a transvenous approach using a lead inserted in a tributary vein over the LV free wall through the coronary sinus [21]. The target location was a lateral or posterolateral coronary vein. If lateral vein catheterization failed or in case of poor pacing thresholds, the LV lead was inserted into the great cardiac vein to pace the anterobasal wall, or in the mid cardiac vein to pace the inferoapical area. From the beginning of our experiment until 1996, non-specific models of unipolar ventricular leads were used. The implantation success rate was low, only 54%. Since 1996, specifically designed coronary sinus leads have been used. The implantation success rate increased at 85% in the whole experience, and up to 92% in the last 50 patients. The target location, i.e. a lateral or posterolateral vein in a mid position, could be reached in 72% of patients. No serious complications were observed during the implantation procedure, or could be related to the coronary sinus lead during the follow-up. At the end of follow-up with a mean time of 10.2±8 months, 97% of the implanted leads were fully functional.
Recently [22] LV endocardial pacing using a transeptal approach was proposed as an alternative to coronary venous pacing. This new technique is now under investigation with special focus to the potential risk of thrombo-embolism.
4.2. RV lead placement (biventricular pacing)
The optimal pacing configuration is that which best corrects electromechanical disorders. At the present stage of knowledge, our observations [16,19] encourage to try and find the best RV and LV pacing sites according to patients, i.e. sites that would ensure the shortest QRS duration as possible and optimal QRS axis normalization in each patient, during simultaneous pacing at the two ventricles. In practice, it can be suggested to position the LV lead first, if possible in a lateral or posterolateral vein, and to secondarily determine the best RV site, based on continuous surface ECG analysis during biventricular pacemapping. The best RV and LV pacing sites usually correspond to the earliest and latest activation sites during intrinsic conduction (Fig. 2) in the individual patient.
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4.3. Devices for multisite biventricular pacing
In patients with normal sinus rhythm, AV synchrony has to be preserved and the patients are usually paced in a biventricular — DDD or VDD mode. In the early clinical experience [15], standard DDDR pacemakers were used with the atrial lead conventionally placed at the high right atrium and the two ventricular leads connected to the ventricular port of the device through a Y bifurcated or a parallel adapter. Many technical problems were related to the use of this external adapter with the need to pace one of the two ventricles in an anodal configuration. That resulted in high pacing threshold with a subsequent risk of exit-block. With the introduction of new, more sophisticated pacemakers dedicated to biventricular pacing and featuring a built-in connector inside the device, the technical difficulties should be considerably reduced. In those patients with normal sinus rhythm the programmed AV delay has to be optimized individually by using echo-Doppler techniques.
Patients with chronic atrial fibrillation have to be paced in a biventricular-VVIR mode. The LV and RV leads are connected to the atrial and the ventricular ports of a standard DDDR pacemaker, respectively. The device is programmed in the DDDR mode with the shortest programmable value of AV delay (0–30 ms) in order to activate both ventricles nearly simultaneously. To ensure full and permanent biventricular capture, the AV junction is systematically ablated at the time of implantation.
In our personal experience [19], 22% of the patients implanted with a biventricular-DDD pacemaker evolved towards persistent AF after a mean follow-up time of 14 months. The pacemaker was then reprogrammed in a biventricular-VVIR mode.
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5. Long-term results with permanent biventricular pacing |
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Top1. Introduction2. Rationale of biventricular...3. Acute studies with...4. Technical requirements of...5. Long-term results with...6. ConclusionReferences |
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At that time, the results of two prospective but non-randomized studies have been reported.
The French pilot study started on 1994 in two centers, Rennes and Saint-Cloud [19]. Until December 1997, 50 patients, 45 males and five females, mean age 68±8 years, were included in the study. Inclusion criteria were chronic heart failure class III or IV with symptoms refractory to medical therapy including at least diuretics and ACE inhibitors at the maximal tolerated doses in each patient, LV systolic dysfunction as assessed on LVEF <35% and LV endiastolic diameter >60 mm, and finally intraventricular conduction delay with a QRS duration >150 ms during intrinsic conductions. At the time of inclusion 34 patients were in NYHA class IV, including 17 in terminal phase, requiring permanent IV inotropic support, and 26 were in class III. The mean LVEF was 20±6%. Heart failure was of ischemic origin in 24 patients and non-ischemic in 26. The mean QRS duration was 197±32 ms. Fourteen patients with chronic AF were implanted with a biventricular-VVIR pacemaker and had the AV junction ablated at the same time. The other 36 patients were in stable sinus rhythm and received a biventricular-DDD (R) pacemaker. The mean duration of follow-up was 15.4±10.2 months, ranging from 1 to 48 months. Twenty patients died during the follow-up period within a mean of 8±7.2 months after pacemaker implantation. All deceased patients but two were NYHA class IV at the time of biventricular pacemaker implantation. Death causes were progressive pump failure (n=11), sudden cardiac death (n=6) and non-cardiac (n=3). At the end of follow-up period, 55% patients were alive without heart transplant or any circulatory support. The survival rate differed significantly between patients who were NYHA class III or IV at the time of implantation (Fig. 3). In the course of follow-up, patient’s functional status was significantly improved by permanent biventricular pacing. One month after implantation, the mean NYHA classification value was 2.37±0.66 vs. 3.7±0.5 at the time of inclusion; P<0.001. This functional improvement persisted henceforth to the end of follow-up, when the mean functional class was 2.2±0.6. In the subgroup of 16 patients who were able to exercise before pacemaker implantation, a significant improvement in exercise tolerance was observed at 3 months, with significant increase in exercise duration (9±3.4 min vs. 6.3±1.6 min; P=0.01), in sustained workload (73±13 W vs. 56±19 W; P<0.01) and in maximal oxygen consumption (15.5±3.4 ml/kg per min vs. 11.1±3 ml/kg per min; P<0.01) when compared with the pre-implantation period. Simultaneous biventricular pacing induced a significant decrease in QRS duration (162±29 ms vs. 197±32 ms; P<0.001). The variation in QRS axis was also significant with a clear trend to normalization. Finally echocardiographic data revealed a significant improvement of LVEF under biventricular pacing (24±10% vs. 20+6%; P<0.01).
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The multicenter In-Sync study [23] involved 14 different centers in Europe and Canada, and was aimed to assess the technical feasibility, the safety and the clinical efficacy of transvenous atrioventricular–biventricular pacing in heart failure patients with stable sinus rhythm. Inclusion criteria were identical to those of the French pilot study. Over a 10-month period, 81 patients were enrolled and 68 or 84% could be successfully implanted. The study population consisted of 52 males and 16 females, with a mean age of 66±10 years. The etiology was ischemic in 28 patients and non-ischemic in 40. At the time of inclusion, 43 patients were in NYHA class III and 25 were in class IV. The mean 6-min walking distance was 299±121 m. The mean LVEF was 21±9% and the mean QRS duration was 177±29 ms.
After the implantation, serial evaluations including functional status (NYHA class), quality of life (Minnesota Living with Heart Failure questionnaire), exercise tolerance (6-min walking distance), 12-lead surface ECG recording and Doppler-echocardiography were planned at 1, 3, 6 and 12 months. During the follow-up period (1–12 months), seven patients died from cardiovascular cause between 11 and 127 days after pacemaker implantation including cardiac sudden death in four. A first analysis at 3-months follow-up (Table 1) showed that DDD biventricular pacing was associated with a significant improvement in symptoms, in quality of life and in exercise tolerance when compared with the pre-inclusion period. The mean QRS duration decreased from 177±29 ms to 143±18 ms; P<0.001, and finally there was a non-significant trend to increased LVEF.
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6. Conclusion |
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Top1. Introduction2. Rationale of biventricular...3. Acute studies with...4. Technical requirements of...5. Long-term results with...6. ConclusionReferences |
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By correcting left ventricular asynchrony as well as left atrio-ventricular asynchrony, multisite biventricular pacing appears to significantly and durably improve the functional status, the quality of life and exercise tolerance of patients with drug-refractory heart failure secondary to chronic LV systolic dysfunction, and major intraventricular conduction delay, thus corresponding to 20–30% of class III–IV patients. The technique appears highly promising as an adjuvant treatment of drug-refractory heart failure, in particular in class III patients, as mortality remains high in class IV patients. Technical advances should improve accessibility of that treatment in the near future [23]. However, controlled and randomized trials will be necessary to validate this novel concept and better define responding patients. The results of a small German study (PATH-CHF) with use of the epicardial route to pace the left ventricle, are expected soon [20]. The MUSTIC trial is ongoing in Europe, under the auspices of the European Society of Cardiology, with the primary objective to assess the actual impact of biventricular pacing on exercise tolerance and quality of life.
Inclusion was completed on April 1999 and final results are expected in early 2000. Other prospective multicenter trials were recently started both in Europe and in North America (MERIDIEN, MIRACLE, PATH-CHF II, VIGOR-CHF...). Further and larger studies will be needed after, to assess the effect on morbidity, mortality and cost-effectiveness. Technical advances should be evaluated in parallel, especially the potential interest to combine in the same implantable device multisite pacing and ICD function. The objective should be to significantly decrease the risk of sudden cardiac death which accounts for 30–50% of total mortality in class III–IV patients.
So, do we have reasons to be enthusiastic about multisite pacing? Probably yes, but there is still a long way to go before validating definitively this new concept.
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References |
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Top1. Introduction2. Rationale of biventricular...3. Acute studies with...4. Technical requirements of...5. Long-term results with...6. ConclusionReferences |
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- Hochleitner M., Hortnagl H., Choi-Keung N.g., Hortnagl M., Gschnitzer F., Zechmann W. Usefulness of physiologic dual-chamber pacing in drug-resistant idiopathic dilated cardiomyopathy. Am J Cardiol (1990) 66:198–202.[CrossRef][Web of Science][Medline]
- Brecker S.J., Xiao H.B., Sparrow J., Gibson D.G. Effects of dual-chamber pacing with short atrioventricular delay in dilated cardiomyopathy. Lancet (1992) 340:1308–1311.[CrossRef][Web of Science][Medline]
- Linde C., Gadler F., Edner M., Nordlander R., Rosenqvist M., Ryden L. Results of atrioventricular synchronous pacing with optimized delay in patients with severe congestive heart failure. Am J Cardiol (1995) 75:919–923.[CrossRef][Web of Science][Medline]
- Gold M.R., Feliciano Z., Gotdieb S.S., Fisher M.L. Dual-chamber pacing with a short atrioventricular delay in congestive heart failure: a randomized study. J Am Coll Cardiol (1995) 26:967–973.[Abstract]
- Nishimura R.A., Hayes D.L., Holmes D.R. Jr, Tajik A.J. Mechanism of hemodynamic improvement by dual-chamber pacing for severe left ventricular dysfunction: an acute Doppler and catheterization study. J Am Coll Cardiol (1995) 25:281–288.[Abstract]
- Wilensky R.L., Yudelman P., Cohen A.I., et al. Serial electrocardiographic changes in idiopathic dilated cardiomyopathy confirmed at necropsy. Am J Cardiol (1988) 62:276–283.[CrossRef][Web of Science][Medline]
- Schoeller R., Andresen D., Büttner P., Oezcelik K., Vey G., Schröder R. First or second degree atrioventricular block as a risk factor in idiopathic dilated cardiomyopathy. Am J Cardiol (1993) 71:720–726.[CrossRef][Web of Science][Medline]
- Cowburn P., Cleland J., Coast A., Komajda M. Risk stratification in chronic heart failure. Eur Heart J (1998) 19:696–710.
[Free Full Text] - Aaronson K., Schwartz S., Chen T., Wong K., Goin J., Mancini D. Development and prospective validation of a clinical index to predict survival in ambulatory patients referred for cardiac transplant evaluation. Circulation (1997) 95:2660–2667.
[Abstract/Free Full Text] - Silverman M., Pressel M., Brackett J., Lauria S., Gold M., Gottlieb S. Prognostic value of the signal-averaged electrocardiogram and a prolonged QRS in ischemic and non ischemic cardiomyopathy. Am J Cardiol (1995) 75:460–464.[CrossRef][Web of Science][Medline]
- Likoff M., Chandler S., Kay H. Clinical determinants of mortality in chronic congestive heart failure secondary to idiopathic dilated or to ischemic cardiomyopathy. Am J Cardiol (1987) 59:634.[CrossRef][Web of Science][Medline]
- Xiao H.B., Roy C., Gibson D.G. Nature of ventricular activation in patients with dilated cardiomyopathy: evidence for bilateral bundle branch block. Br Heart J (1994) 72:167–174.
[Abstract/Free Full Text] - Xiao H.B., Brecker S.J.D., Gibson D.G. Effect of abnormal activation on the time course of the left ventricular pressure pulse in dilated cardiomyopathy. Br Heart J (1992) 68:403–407.
[Abstract/Free Full Text] - Foster A.H., Gold M.R., McLaughlin J.S. Acute hemodynamic effects of atrio-biventricular pacing in humans. Ann Thorac Surg (1995) 59:294–300.
[Abstract/Free Full Text] - Cazeau S., Ritter P., Lazarus A., et al. Multisite pacing for end-stage heart failure: early experience. PACE (1996) 19(part II):1748–1757.[Medline]
- Leclercq C., Cazeau S., Le Breton H., et al. Acute hemodynamic effects of biventricular DDD pacing in patients with end-stage heart failure. J Am Coll Cardiol (1998) 32:1825–1831.
[Abstract/Free Full Text] - Blanc J.J., Etienne Y., Gilard M., et al. Evaluation of different ventricular pacing sites in patients with severe heart failure. Circulation (1997) 96:3273–3277.
[Abstract/Free Full Text] - Kass D.A., Chen C.H., Curry C., et al. Improved left ventricular mechanics from acute VDD pacing in patients with dilated cardiomyopathy and intraventricular conduction delay. Circulation (1999) 99:1567–1573.
[Abstract/Free Full Text] - Leclercq C, Cazeau S, Victor F, et al. Long-term results of permanent biventricular pacing in refractory heart failure: comparison between class III and class IV patients. Eur Heart J (1998) 19:573. abstract.
- Auricchio A., Stellbrink C., Sack S., et al. The pacing therapies for congestive heart failure (PATH-CHF) study: rationale, design and endpoints of a prospective randomized multicenter study. Am J Cardiol (1999) 83:130D–135D.[CrossRef][Web of Science][Medline]
- Daubert J.C., Ritter P., Le Breton H., et al. Permanent left ventricular pacing with transvenous leads inserted into the coronary veins. PACE (1998) 21:239–245.[Medline]
- Jaïs P., Douard H., Shah D.C., Barold S., Barat J.L., Clémenty J. Endocardial biventricular pacing. PACE (1998) 21:2128–2131.[Medline]
- Auricchio A., Klein H., Tockman B., et al. Transvenous biventricular pacing for heart failure: can the obstacles be overcome? Am J Cardiol (1999) 83:136D–142D.[CrossRef][Web of Science][Medline]
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