Eur J Cardiothorac Surg 2003;23:81-85
© 2003 Elsevier Science NL
Maintained benefits and improved survival of dynamic cardiomyoplasty by activity–rest stimulation: 5-year results of the Italian trial on ‘demand’ dynamic cardiomyoplasty
Gianluca Rigatellia*,
Mario Barbieroa,
Giorgio Rigatellia,
Roberto Riccardib,
Franco Cobellib,
Angelo Cotognia,
Attilio Bandelloa,
Ugo Carraroc
a Cardiomyoplasty Project Unit, Legnago General Hospital, Verona, Italy
b Montescano Medical Center, ‘Fondazione Maugeri’, Montescano, Pavia, Italy
c Department of Biomedical Science, University of Padua, Padua Medical School, Padua, Italy
Received 30 July 2002;
received in revised form 16 September 2002;
accepted 1 October 2002.
* Corresponding author. Via T Speri, 18, 37040 Legnago, Verona, Italy. Tel.: +39-044-2632-329; fax: +39-044-2632-311
e-mail: jackyheart{at}hotmail.com
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Abstract
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Objective: Latissimus dorsi (LD) muscular degeneration caused by continuous electrical stimulation has been the main cause of the poor results of dynamic cardiomyoplasty (DCMP) and its exclusion from the recent international guidelines on heart failure. To avoid full transformation of the LD and to improve results, a new stimulation protocol was developed; fewer impulses per day are delivered, providing the LD wrap with daily periods of rest (‘demand’ stimulation), based on a heart rate cut-off. The aim of this work is to report the results at 5 years of follow-up of the Italian Trial of Demand Dynamic Cardiomyoplasty and to discuss their impact on the destiny of this type of cardiac assistance. Methods: Twelve patients with dilated myocardiopathy (M/F=11/1, mean age 58.2±5.8 years, sinus rhythm/atrial fibrillation=11/1) were submitted during the period 1993–1996 to DCMP and at different intervals to demand protocol. Clinical, echocardiographic, mechanographic and cardiac invasive assessments were scheduled before initiating the demand protocol and during the follow-up at 0, 6 and every 12 months. Results: The mean duration of follow-up was 40.2±13.8 months (range 18–64). There were no perioperative deaths. The demand stimulation protocol showed a decrease in 5 years in New York Health Association (NYHA) class (3.17±0.38–1.67±0.77, P=0.0001), an improvement of left ventricular ejection fraction (22.6±4.38–32.0±7.0, P<0.001), a 5-year actuarial survival of 83.3% (one patient was switched to heart transplantation programme due to clinical worsening and another one died of massive pulmonary embolism). Conclusions: Demand DCMP maintains over time LD muscular properties, enhances clinical benefits and improves survival of DCMP, thus reopening the debate whether this type of treatment should be considered in patients with end-stage heart failure.
Key Words: Heart failure • Circulatory assist • Dynamic cardiomyoplasty
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1. Introduction
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After the early enthusiasm during 1980s [1,2] in which dynamic cardiomyoplasty (DCMP) was retained to be a real alternative to heart transplantation for the treatment of heart failure, there has a been a decline in its application. This is mainly due to the poor long-term results [3–5] caused by latissiums dorsi (LD) degeneration and has culminated in the exclusion of cardiomyoplasty form the recent ACC/AHA guidelines for the evaluation and management of chronic heart failure [6].
In order to maintain long-term partial transformation of the LD wrap avoiding excessive muscular degeneration and an extremely long contraction–relaxation cycle, fewer impulses per day than in standard clinical stimulation should be delivered. This can be obtained by providing the LD wrap with daily periods of rest (demand stimulation protocol) that are based on a heart rate cut-off [7]. The encouraging preliminary results in sheep and humans [8–10] have been recently confirmed by studies [11,12] in which systolic assistance has been measured and its correlation with the muscular and clinical status has been shown. The aim of this paper is to report the results at 5 years of the Italian trial on demand dynamic cardiomyoplasty (ITDDC) and to discuss the possibility of reopening the debate on this kind of cardiac assistance.
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2. Methods
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From 1993 to 1996, 12 patients underwent DCMP according to the original Broussais Hospital procedure, created by Carpentier et al. [13]. Informed consent to the intervention and then to demand stimulation protocol was obtained from all patients. Invasive evaluation of right cardiac chamber pressures and the baseline functional properties of the LD were obtained pre-operatively and before initiating demand protocol, respectively. Indication and exclusion criteria are shown in Table 1.
Demand stimulation was programmed at the Department of Cardiology, Cardiomyoplasty Project Unit, Center for Advanced Heart Failure, Legnago Teaching Hospital, Verona, Italy, whereas follow-up was performed in the Division of Cardiology and Rehabilitation, Montescano Medical Center, Maugeri Foundation, Montescano, Pavia, Italy.
In four patients coming from Legnago General Hospital and operated at the Cardiac Surgery Department of the University of Padua, Padua Medical School, Padua, Italy, the demand protocol was introduced early (12 months) after the procedure. In the other eight patients, coming form the Montescano Medical Center, Montescano, Pavia, Italy and operated elsewhere, because of worsening clinical conditions the demand protocol was introduced several months (36.3±18.6, range 70–17 months) after continuous standard stimulation (see Table 2 for pre-operative data of the patient population).
2.1. Demand stimulation protocol
Demand stimulation protocol was introduced [12] in order to avoid complete LD wrap transformation caused by the continuous stimulation protocol of the Federal Drug Administration (FDA) phase II trial in use by the American Cardiomyoplasty Group [9] and to homogenise patient response.
It is well established that a muscle fully transformed by continuous stimulation displays significant loss of power, generally attributed to fibre-type change or loss of type 2 myofibrils (fast contracting myofibrils). The insertion of rest periods during chronic electrical conditioning preserves myofibril cross-sectional area and produces fatigue-resistant fibre distributions; in this way, a more powerful fatigue-resistant muscle is created. The improved performance of such an LD is thought to be due to the maintenance of an intermediate level of transformation of the LD wrap, thanks to the demand regimen. The LD was stimulated with a single impulse at a synchronisation ratio of 1:3 after a healing period of 10–14 days. An impulse was then added every week at a 23 ms interval (43 Hz) for a final burst of four impulses, with a cardiac amplitude of >5 V and pulse width of 1.5 ms. After 6–12 months of this ‘light’ daily stimulation, the patients were submitted to the ‘demand regimen’, allowing the LD wrap a daily period of rest.
In order to provide the LD wrap with daily periods of rest, a 24-h Holter study was initially performed to determine the average heart rate during sleeping hours. The pacing parameters of the cardiomyostimulator (Transform, Model 4710, Medtronic, Inc., Minneapolis, MN, USA) were programmed at a rate of 70–80 beats per min, with minimum pulse amplitude (<1 V) and pulse width (<0.05 ms). Muscle output was programmed to ‘sense’, occurring only with sensed cardiac events, not with paced events. In this way, the lower rate was set just above the average nocturnal heart rate and the cardiomyostimulator worked during resting hours at an energy level well below the one required for capturing the heart. During these pacing episodes, muscle output was inhibited. The result was that muscle stimulation was inhibited during resting hours and occurred at the programmed synchronisation ratio during active hours, providing an activity–rest stimulation regimen. The differences between continuous stimulation and demand protocol are shown in Table 3.
2.2. Monitoring muscle functionality: the mechanogram
Contractile characteristics of LD wrap, such as speed of contraction and relaxation, can be monitored using a standard polygraph (MegaCart or Mingophon, Siemens Elema, Solna, Sweden). The electrocardiogram, heart sounds and pressure changes due to LD flap contraction and relaxation were recorded simulataneously as previously described [12]. The LD motion was monitored by placing the pressure transducer, which is traditionally used to monitor apical motion, at the location of the rib window through which the LD enters the thoracic cavity; this obviated to every kind of modification induced by the overlapped ventricular systole. The following parameters were determined: (1) the activation threshold, (2) the actual duration of the mechanical event of LD flap contraction and relaxation, and (3) the dynamic contractile characteristics of the LD flap.
The dynamic characteristics of the LD wrap are determined from the LD response to stimuli delivered at increasing frequency up to tetanic fusion frequency (TFF). In this way, a smooth contraction curve can be plotted; the faster the fibres, the higher the TFF. As described elsewhere[14,15], the normal value of TFF for human muscle is expected to be 43 Hz (the titanic contraction with pulses delivered at 23 ms intervals). The mechanogram also serves for synchronising cardiac and LD contraction [12].
2.3. Follow-up
Non-invasive evaluation was performed by clinical and echocardiographic examination. Invasive evaluation of right cardiac pressure was obtained during the follow-up by means of right heart catheterisation.
2.4. Statistical analysis
Paired Student's t-test was used to compare data before and after demand dynamic cardiomyoplasty (DDCMP), whereas frequencies were compared using the chi-square test. A P value of <0.05 was considered significant. Clinical and laboratory data are expressed as mean±SD or as percentage. Survival rate was expressed as mean±SEM. Patients switched to heart transplantion programme due to worsening clinical conditions were calculated as deaths, whereas death due to non-cardiovascular related causes was calculated as censored data. StatView (SAS Institute Inc., Cary, NC, USA) and GraphPad Prism 3 (GraphPad Software Inc., San Diego, CA, USA) systems were used for data analysis and graphic output.
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3. Results
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The mean duration of follow-up was 40.2±13.8 months (range 18–64). The mean NYHA class was significantly lower when compared with pre-operative values: 1.67±0.77 versus 3.17±0.38 (P<0.0001). The number of hospitalisations for congestive heart failure decreased significantly from 3.2±0.4 to 1.1±1.08 per year (P<0.0001).
The mean left ventricle ejection fraction (LVEF) at follow-up was significantly higher than pre-operative value: 32.0±7.0% versus 22.6±4.38% (P<0.001), whereas the mean end-diastolic volume did not change significantly during the follow-up (114±41.1 ml/m2 versus 104±9.9 ml/m2, P<0.67).
Right catheterisation data demonstrated a non-significant decrease in capillary wedge pressure (12.2±6.11–11.7±7.19 mmHg, P=0.83).
At mechanographic interrogation, the value of TFF was significantly higher at follow-up (33±7.86 Hz versus 15.8±11.1 Hz, P<0.0001).
There were no perioperative deaths. During the follow-up, one patient died of hepatic cancer in 36 months and another died of massive pulmonary embolism in 18 months from operation. Both were in NYHA class I, 1 month before death. One patient was implanted with a biventricular pacing system and defibrillator for the development of left bundle block and ventricular arrhythmias, with no interference with the myostimulator. Two patients, in whom continuous stimulation had been performed for several months (107 and 57 months, respectively) were switched to the heart transplantion programme, one patient for worsening clinical conditions (NYHA class III, also treated with biventricular pacing) and the other due to the dysfunction of the myostimulator, previously in NYHA class II. The actuarial 5-year survival rate was 83.3% (Fig. 1
).
In all patients, an oral therapy with personalised doses of diuretics, ace-inhibitors and beta-blockers was maintained.
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4. Discussion
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Muscular degeneration has been the main cause for the loss of interest in DCMP and its exclusion as treatment option from the recent ‘ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult’ [6]. From pathological and morphological studies, [16,17] it appears that muscle degeneration is caused by surgical dissection of the muscle and exacerbated by chronic stimulation. Moreover, the 2-week delay in stimulation after cardiomyoplasty seems to contribute to muscle atrophy and loss of function [17]. These studies lead to the concept that an intermittent stimulation may result in less muscular damage and maintain muscle viability, contributing to a more effective cardiac support [18]; these are the premises for the development of the demand protocol in order to improve the results of classic DCMP.
Two mechanisms are suggested for the beneficial effects of DCMP: first, a limitation in heart dilatation, and second, enhancement of systolic contraction. The enhancement of systolic contraction has been suggested, but not fully proven by studies revealing low-to-moderate increase in left ventricular ejection fraction (LVEF) and stroke volume [19,20].
Nevertheless, a real and notable improvement in NYHA class, usually from class III or higher to class II or lower has been reported worldwide [1,2,4,5,21–23], even though the improvement in LVEF seems to be limited to the early follow-up period.
The demand protocol used in our series, seems to give an answer to these problems. Muscular properties, as proved in previous studies [24] were maintained over time and this explains the high values of TFF measured and the good survival rate, as well as the improvement in NYHA class and LVEF value. Moreover, in the patients in whom demand protocol started later, after a period of continuous stimulation, the TFF not only maintained its initial value, but in many cases increased, this being a sign of enhanced muscular properties.
All these are, to our opinion, not to be underestimated, especially when one considers the poor expectance of life of this class of patients with sole medical therapy. Moreover, both the possibilities of performing a heart transplantation [7] or multisite electrical stimulation was preserved. In particular, it was still possible to implant a defibrillator providing an increase in indications and an improvement in survival.
In the future, a new approach, the so-called ‘vascular delay’, could be added to our protocol. This consists of a 10-day period of ischemic preconditioning of the muscle, in order to achieve assistance also in the early period of light stimulation [25].
In the era of heart transplantation and great technological advances in the field of circulatory assist devices and of the artificial heart, DCMP may, in our opinion, still play a role. In fact, unfortunately, donor organs are still scarce, transplantation itself as well as immunosuppressive therapy and its follow-up remain extremely expensive and chronic rejection limits survival to 38% at 12 years. Moreover, ventricular assist devices are also extremely expensive, carry a high incidence of complications and some contraindications.
Gene therapy, stem cell implant and passive restraint device are now in favour, but today they are not completely investigated and clear results in terms of survival, cost and availability are expected only in the future. DCMP on the other hand, does not require much high technology, extracorporeal circulation, immunosuppression, anticoagulation therapy or follow-up with endomyocardial biopsy. Moreover, our previous studies on the demand stimulation protocol demonstrated not only that this protocol can make DCMP more effective giving both passive and active girdling effects , but also that an adequate follow-up can be obtained by a simple and economic polygraph [12].
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5. Limitations
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Our study carries some limitations. Firstly, our trial is not randomised and contains a low number of patients, due to the difficulty to enrol patients to a procedure that remains experimental and to the negative opinion of cardiologists aware of the results of the old dynamic cardiomyoplasty.
Bias in patients' enrolment have been limited, although not eliminated, by strictly following the indication and exclusion criteria presented previously.
Second, in our country DCMP was performed discontinuously, in many centres, but on few patients, making recruitment of geographically dispersed patients problematic. Finally, switching patients to the heart transplantation programme after long-term continuous stimulation influenced our opinion of the global results, decreasing the impact of demand stimulation.
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6. Conclusion
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We believe that the Demand protocol is the most effective protocol for DCMP, providing an amelioration of the response to DCMP in terms of benefits and survival by preventing excessive muscle degeneration. This ‘new’ improved technique may refresh the role of DCMP and be an answer for the patients in whom, due to contraindications, absence of donors or economic resources, heart transplantation, mechanical devices and the other recent product of gene therapy cannot be applied. In light of the results described previously, a reconsideration of the role of DDCMP is not only reasonable, but also appropriate.
We hope that these results may encourage both the cardiologist community to promote further trials on the use of DDCMP and the biomedical companies to invest resources on the development of a new cardiomyostimulator with activity–rest capability.
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Acknowledgments
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This study was supported in part by funds from the Italian National Research Council to the Unit for Muscle Biology and Physiopathology. It was also supported by the Italian Ministry of University and Scientific and Technologic Research (M.U.R.S.T. n. 9806192428): Trial Italiano sulla Cardiomioplastica Dinamica a Domanda (TiCDD).
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Abstract
1. Introduction
