The European Society of Cardiology
The Bad Oeynhausen Experience
a Department of Cardiology, Heart Centre North Rhine-Westphalia, Ruhr University Bochum, Bad Oeynhausen, Germany
b Department of Thoracic and Cardiovascular Surgery, Heart Centre North Rhine-Westphalia, Ruhr University Bochum, Bad Oeynhausen, Germany
Received 3 May 2004; accepted 24 May 2004.
* Jürgen Vogt, MD, Department of Cardiology, Heart Centre North Rhine-Westphalia, Ruhr University Bochum, Georgstr. 11, 32545 Bad Oeynhausen, Germany. Tel.: +49-5731-971258; fax: 49-5731-972194
akohlstaedt{at}hdz-nrw.de
Abstract
Introduction Patients with advanced heart failure received cardiac resynchronisation therapy at our centre, if the following selection criteria were fulfilled: NYHA class 
3, left bundle branch block with QRS width 150 ms, left ventricular ejection fraction 
35%, left ventricular enddiastolic diameter 
60 mm, VO2 peak 18 ml/min/kg. Patients with atrial fibrillation and left bundle branch block were also included. Patients with a preoperative pulse pressure increase of 10% under left/biventricular stimulation were regarded "responders" and had permanent implantation of a resynchronisation device.
Patients and results 313 patients (79 women, mean age 62±10 years, 110 patients with coronary heart disease, 174 patients with dilated cardiomyopathy and 28 patients after valve replacement or with end-stage hypertrophic cardiomyopathy) underwent resynchronisation. Mean VO2 peak was 13.0±2.8 ml/min/kg, ejection fraction 23.5±7.2% with a mean left ventricular enddiastolic diameter of 79.5±10.6 mm. 32 of 251 had progressive pump failure, which was more frequent in patients with CHD and AF. 21 of 204 patients (20%) with CHD compared to 22 of 179 patients (13%) with DCM had pump failure progression after 30-month follow-up.
Conclusion The tailored implantation of the left ventricular lead and programming of the optimal pacing mode resulted in a VO2 peak increase by 2.8 ml/min/kg during follow-up. During mid-term follow-up of 18 months, DCM patients demonstrated a higher clinical benefit than patients with CHD. In the future, areas and extent of mechanical and electrical asynchrony have to be evaluated more exactly by tissue Doppler echocardiography.
Key Words: Congestive heart failure • Resynchronisation • Coronary heart disease • Dilated cardiomyopathy • Atrial fibrillation • Outcome
List of Abbreviations: AF atrial fibrillation • CHD coronary heart disease • DCM dilated cardiomyopathy • EF ejection fraction • HTX heart transplantation • LVAD left ventricular assist device • LVEDD left ventricular enddiastolic diameter • QOL quality of life (Minnesota score) • SR sinus rhythm • VO2AT oxygen consumption at anaerobic threshold • VO2peak oxygen consumption at peak exercise
This single-center experience started with the enrollment of the first patient for the PATH-CHF I study.1 Prerequisite for the routine clinical application of cardiac resynchronisation therapy beyond clinical trials was the experience that many patients with a QRS duration 150 ms, a typical or atypical left bundle branch block pattern, and severe heart failure did profit from such a therapy. The intraoperative haemodynamic tests completed for the PATH-CHF I trial and the acute tests performed in the catheterisation laboratory as part of the PATH-CHF II trial, convinced us that in the majority of patients an acute haemodynamic response accurately predicts long-term improvements of (1) quality of life, (2) peak exercise oxygen consumption, and (3) left ventricular performance.2,3,4
While still awaiting the results of the atrial fibrillation subgroup of the Mustic trial on resynchronisation, we were reluctant to use cardiac resynchronisation in patients with atrial fibrillation.5 Because of both the small number of patients and the QRS width criterion with right ventricular pacing, no statistically significant clinical improvement had been shown. Patients with atrial fibrillation underwent CRT at our centre (1) if they had a typical or atypical left bundle branch block pattern and (2) a QRS width 150 ms (3) heart failure class III to IV, and (4) if heart rates were decreased with ß blockers sufficient to allow for predominant pacing.
Especially the results of the Contak CD trial, which failed to show a statistically significant overall improvement at the composite endpoint, encouraged us to stick to more conservative implantation criteria.6 For the Contak CD trial, NYHA class II and QRS duration of 120 ms or longer was regarded sufficient for inclusion. In a higher percentage of patients the left ventricular lead was not positioned in the posterolateral target region, but in one of the anterior veins.7 A significant clinical improvement was only found by a retrospective analysis for patients with NYHA classes III and IV. Six-month and one-year published or preliminary follow-up data of the larger randomised Miracle and Companion studies, which included patients with a QRS complex width of 130 ms or longer, had not revealed any differences between underlying coronary heart disease or dilated cardiomyopathy.
Implant criteria
The inclusion criteria at our centre required all patients to be at least in NYHA class III independent of the underlying cardiac aetiology, i.e. coronary heart disease, dilated cardiomyopathy, acquired valve lesions with poor ventricular function persisting after valve surgery, and end-stage hypertrophic cardiomyopathy. For inclusion, the QRS width had to be 150 ms. Patients were included, if left ventricular ejection fraction was 35% and the left ventricular enddiastolic diameter 60 mm. We accepted patients with peak exercise oxygen consumption values of 18 ml/kg/min only. All patients were on chronic treatment with ACE inhibitors or AT-1 receptor antagonists, diuretics, and – whenever tolerated – spironolactone and digitalis. Except for those with an absolute contraindication, such as chronic obstructive pulmonary disease, all patients were meticulously titrated with ß blockers. The dose was adjusted as tolerated. All patients, except a small number with renal function being severely impaired by radiographic contrast agent, underwent acute testing in the cardiac catheterisation laboratory. If they had an acute response, defined as a pulse pressure increase 10% beyond baseline under left and/or biventricular stimulation, patients were considered candidates for resynchronisation treatment. (Fig. 1)8 Patients with atrial fibrillation underwent both left and biventricular stimulation above the intrinsic heart rate. If their pulse pressure increased by appr. 10% compared to pacing from the right ventricular apex, they were also considered acute responders and accepted for implantation.
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Patients
During the last five years, 313 patients (including 79 females) with a mean age of 62±10 years underwent resynchronisation therapy. 110 patients had coronary heart disease, 174 patients dilated cardiomyopathy, and 29 patients either valvular heart disease or end-stage hypertrophic cardiomyopathies. All patients had advanced or end-stage heart failure (Table 1). Mean VO2 peak was 13.0±2.7 ml/kg/min, ejection fraction 23.5±7.2%. The average left ventricular diameter of 79.5±10.6 mm corresponds to the severely limited functional reserve. Most patients met the criteria for transplantation. Mean follow-up at present is 17.4±12.7(1–56) months.
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Follow-up and outcome
As shown in large randomized trials, we also documented important prognostic improvement in our entire patient population (Fig. 2). This includes a significant increase of the peak exercise oxygen consumption by 2.8 ml/kg/min over a one-year period. Indicative for reverse remodeling of the left ventricle, the mean enddiastolic diameter decreased significantly from more than 80 mm (55–112) to 74 (38–119) mm.
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The corresponding data on major event-free survival (sudden cardiac death, worsening heart failure mandating transplantation, implantation of left ventricular assist devices) were convincingly high. Kaplan–Meier analysis (Fig. 3) showed a cumulative incidence for death from heart failure or need for cardiac transplantation or left ventricular assistance of 10% at one year and 20% after two years. During this time period, we lost only four patients due to sudden death occurring at different intervals from CRT. 204 of 313 patients received an implantable cardioverter defibrillator (ICD) as they had either survived sudden death, syncopes, inducible ventricular tachycardias, a primary indication in accordance with the MADIT I and II criteria, or required an ICD as bridge-to-transplant because of underlying dilated cardiomyopathy.
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We analysed the pre-implant data of 251 patients and compared the baseline data of 219 clinical responders with those of 32 patients, who developed progressive pump failure despite resynchronisation. This analysis did not reveal any significant differences regarding age, heart failure severity, QRS width, oxygen consumption at peak exercise or the anaerobic threshold, exercise tolerance, left ventricular enddiastolic diameter, distance during the 6-minute test or quality of life. Compared to long-term responders, patients with progressive pump failure were statistically more likely to have coronary artery disease (17 patients (53%) versus 70 patients (32%) of clinical responders)
. Another highly significant difference 
was the presence of persisting or intermittent atrial fibrillation in 23% of patients with progressive left ventricular failure versus 13% among responders (Table 2).
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Comparison of follow-up data of patients in sinus rhythm versus patients with atrial fibrillation
264 of our total study population of 313 patients had stable sinus rhythm throughout, and 49 patients had various types of atrial fibrillation. 26 of the latter were in chronic atrial fibrillation, 6 patients had chronic atrial fibrillation and were pacemaker dependent. 17 patients with persistent atrial fibrillation were in sinus rhythm after cardioversion, but continued to have paroxysmal atrial fibrillation.
In comparison to patients with sinus rhythm (Table 3), heart failure patients with atrial fibrillation were in a significantly higher NYHA class 
and had significantly lower peak exercise oxygen uptake 
, despite a slightly smaller left ventricular enddiastolic diameter. None of the other baseline data were significantly different.
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Analysis of peak oxygen uptake (Fig. 4) revealed a significant
increase over an 18-month period for patients in sinus rhythm. The same holds true for peak oxygen uptake at the anaerobic threshold . In comparison, the relative increase in peak oxygen uptake and oxygen uptake at the anaerobic threshold were lower in patients with a history of atrial fibrillation, but still improved significantly after three months . During the subsequent course, 35 (13.2%) of the sinus rhythm group developed progressive left ventricular failure, and 4 patients died suddenly while 11 patients (22.5%) of the atrial fibrillation group developed progressive left ventricular failure.
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Long-term course and outcome of patients with dilated cardiomyopathy versus coronary heart disease
In contrast to previously published study results, we were able to identify underlying coronary heart disease as a second marker for limited resynchronisation success. Until April 2003, we analysed 273 patients, including 169 with dilated cardiomyopathy and 104 patients with coronary heart disease (Table 4). The mean age of patients with coronary heart disease was significantly higher (65±7 years) than that of patients with dilated cardiomyopathy (60±11 years) 
. The oxygen uptake at the aerobic threshold was 10±2.4 ml/kg/min in patients with coronary heart disease, and thus significantly lower than in patients with dilated cardiomyopathy (11±2.5 ml/kg/min, 
). Compared to patients with dilated cardiomyopathy, we found lower left ventricular enddiastolic diameters in patients with coronary heart disease 
, whereas all other functional and clinical baseline parameters were not significantly different.
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As early as 2002, Lamp et al. showed that oxygen uptake, enddiastolic diameter, and quality of life take different courses, depending on the underlying pathology.9 Fig. 5 illustrates that in patients with dilated cardiomyopathy, oxygen uptake increases steadily over the 18-month follow-up period, while peak oxygen uptake does not show such a striking increase in patients with coronary heart disease. It should be noted that both peak oxygen consumption and oxygen consumption at the anaerobic threshold decrease after 12 months. This phenomenon is associated with deteriorating quality of life, although left ventricular enddiastolic diameters regress identically in both groups, an indication for reverse remodelling of the left ventricle (Fig. 6).
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Collecting follow-up data prospectively beyond a one-year period, Lamp et al. demonstrated that 21 of 104 patients with coronary heart disease (20%) but only 22 of 169 patients with dilated cardiomyopathy (13%) developed progressive pump failure. Based on Kaplan–Meier analyses, the incidence of all types of pump failure, including the need to proceed with cardiac transplantation, was significantly higher in patients with coronary heart disease after a follow-up of more than 30 months (Fig. 7). It is remarkable that despite the different underlying diseases, the curves remain parallel for 1 3/4 years, and do not diverge until later, indicating heart failure progression despite resynchronisation in patients with coronary heart disease.
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Course of resynchronisation therapy in patients after valve replacement and endstage HCM
Despite resynchronisation, four (14%) of 28 patients with endstage HCM or previous heart valve replacement (
aortic valve replacement, 
mitral valve replacement) developed progressive pump failure during the later course as compared to 13% (22 of 169 patients) with dilated cardiomyopathy and 20% (21 of 104 patients) with coronary heart disease. The three Kaplan–Meier survival curves revealed no difference during a two-year follow-up.
Discussion
A 10% incidence of progressive pump failure after one year and a 20% incidence after two years represent an excellent result in this large population of patients with initially severe heart failure followed in a large single centre series. Despite different heart failure aetiologies, the outcome of these strongly selected patients was fully comparable to that of a heart transplant population. Peak oxygen uptake increased by 2.8 ml/kg/min. Compared to other centers and to large randomized trials, we elected to include patients with more significant electrical dyssynchrony and performed CRT device implantation only if an acute response – defined as a 10% pulse pressure increase – had been demonstrated. Based on preoperative testing, the implantation was individually tailored, and the tested target vein region was used in almost 100% of cases. That may be the reason why we observed a peak oxygen uptake increase as high as 2.8 ml/kg/min, while published large outcome studies reported increases of only 1.5 ml/kg/min. In the meantime, for patients who underwent previous acute testing the PATH-CHF-II trial has shown that functional parameters do improve on the long run, even if the QRS complex width was smaller than 150 ms. The analysis of the largest study, the Companion trial, remains to be published.
Our results, which so far encompass a follow-up period of more than 30 months and an 18-month mean follow-up, substantiate a more beneficial course in patients with dilated cardiomyopathy. While patients with dilated cardiomyopathy have more diffuse cardiac fibrosis and more disseminated scarring, advanced stages of ischaemic heart failure is characterised not only by residual ischaemic areas and disseminated areas of scarring, but often also by large transmural scars, associated with subsequent remodelling of the remaining healthy heart muscle. Due to the extent of transmural scarring, resynchronisation can only reverse remodel a limited amount of healthy myocardium so that structural benefits of resynchronisation will always be limited by the underlying disease process. In addition, central and peripheral discontinuities of the specialized conduction system, arborisation, and delayed conduction in areas of scarring create a much more inhomogeneous type of dyssynchrony for which the current electrical resynchronisation approach remains too unrefined and cannot be as efficient as in cases of dilated cardiomyopathy associated with the more uniform conduction delay seen with left bundle branch block. Beyond acute haemodynamic testing of cardiac resynchronisation, it will be tissue Doppler echocardiography (TDE) that has to accomplish the task of defining the exact regions affected by asynchrony and of determining the inhomogeneous pattern of asynchronous contraction in coronary heart disease, before a more sophisticated type of electrical and mechanical resynchronisation becomes possible. TDE will also have to establish prognostic criteria for patient selection that will not only experience temporary improvement of symptoms and quality of life after resynchronisation, but have an additional survival benefit.10–15
Additionally, the analysis of our single-center experience demonstrates that patients with atrial fibrillation, especially those with chronic atrial fibrillation, ß-blocker induced rate control, and conduction delay due to typical or atypical left bundle branch block, do also benefit from resynchronization clinically. The improvement is somewhat less than that of patients in sinus rhythm. These results are only valid for patients fulfilling the implantation criteria at our centre, including a pulse pressure increase of 10% under left and/or biventricular stimulation compared to right ventricular apical stimulation.
Acknowledgments
We express our gratefulness to all surgical, cathlab, echocardiography lab, ECG, and electrophysiology personnel, and all physicians, as well as to our research secretary, Mrs. A. Kohlstädt-Klapper. Careful patient selection, medical management, implantation, and patient follow-up would not have been possible without their efforts.
Footnotes
1 These authors made equal contributions to this study. 
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