Ann Thorac Surg 2000;70:67-73
© 2000 The Society of Thoracic Surgeons
Original articles: Cardiovascular
Demand dynamic cardiomyoplasty: mechanograms prove incomplete transformation of the rested latissimus dorsi
Ugo Carraro, MDa,b,
Mario Barbiero, MDa,b,
Giorgio Docalib,
Angelo Cotogni, MDa,b,
Giorgio Rigatelli, MDa,b,
Dino Casarotto, MDa,b,
Claudio Muneretto, MDa,b
a National Research Council Unit for Muscle Biology and Physiopathology, Department of Biomedical Sciences, and Institute of Cardiovascular Surgery, University of Padua, Padua, Italy
b Division of Cardiology, Legnago General Hospital, Legnago (Verona), Italy
Address reprint requests to Dr Carraro, Department of Biomedical Sciences, University of Padua, Viale G. Colombo 3, I-35121 Padua, Italy
e-mail: bam{at}civ.bio.unipd.it
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Abstract
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Background. In dynamic cardiomyoplasty, standard stimulation produces high fatigue resistance but also undesirable dynamic characteristics of the latissimus dorsi (LD). Based on results of intermittent stimulation in animals we introduced demand stimulation, a lighter regimen of LD activity–rest stimulation, and the mechanogram, a noninvasive method to determine the contractile characteristics of LD wrap.
Methods. Surgery and standard stimulation was according to the technique of Carpentier and Chachques, demand stimulation and LD wrap mechanogram were as we previously described. The LD contraction is synchronized to heart systole by mechanogram and echocardiography, and extent of transformation by tetanic fusion frequency analysis. A total of 22 patients were studied to date. Data for the 8 subjects who attained 6-month follow-up are reported. Four of them were lightly stimulated from the conditioning period, whereas 4 others were converted to light and then demand stimulation after years of standard stimulation. Patients were followed up with respect to survival, functional class, hospital admission rate, medication used, cardiopulmonary exercise testing, and LD wrap mechanography.
Results. Latissimus dorsi wrap slowness reverses by the activity–rest regimen, even after years of standard stimulation (Tetanic fusion frequency of 11 ± 2 Hz after standard stimulation vs 30 ± 3 Hz after demand regimen, p < 0.0001). After demand dynamic cardiomyoplasty there are no deaths. Quality of life is substantially improved with significant reduction of heart failure symptoms (New York Heart Association class: preoperative 3.0 ± 0.0, post–demand dynamic cardiomyoplasty 1.5 ± 0.2, p < 0.0001). In the subgroup of patients lightly stimulated from LD conditioning, exercise capacity tends to increase over preoperative values more than 2 years after operation (VO2 max: preoperative 12.3 ± 0.7 vs 16.6 ± 1.7 post–demand dynamic cardiomyoplasty, p = 0.05).
Conclusions. Demand stimulation and mechanography of the LD wrap are safe procedures that could offer long-term benefits of dynamic cardiomyoplasty to patients with pharmacologically intractable heart failure.
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Introduction
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The main mechanism of action in dynamic cardiomyoplasty is thought to be the active girdling of the latissimus dorsi wrap, which limits failing heart dilation. Load-independent measurements demonstrate real improvements when preoperative and postoperative analyses are compared [1–4], but noninvasive analyses provide scarce evidence of systolic assist with cardiomyostimulator on versus off [5]. One of the factors limiting systolic assistance is the reduced muscle performance after full fast-to-slow conversion of the LD wrap. After weeks of stimulation, mitochondrial content and capillaries increase but calcium handling is less efficient and the contraction–relaxation significantly slows. When slow substitutes fast myosin, a powerful, early fatiguing LD is transformed into a slow contracting muscle that is fatigue-resistant at moderate power [6, 7]. Intermediate transformation of the LD wrap by activity–rest stimulation could couple resistance to fatigue with a maintained high speed of contraction [8, 9]. To test the hypothesis LD wrap monitoring is essential. Tetanic fusion frequency analysis by mechanogram provides the data on dynamic characteristics of LD wrap [10].
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Material and methods
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Four dilated cardiomyopathy patients (three men and one woman, 50 [41–57] years old) were operated according to Chachques and associates [4] between June 1996 and November 1997 at the Institute of Cardiovascular Surgery of the University of Padua, but the LD wrap conditioning period was shortened to 1 month ("light group"). After a healing period of 10 to 14 days the LD was stimulated with a single impulse at a 1:3 synchronization ratio. Each week, one impulse was added at 23-ms interval (43 Hz) for a final burst of four impulses, which is a stimulation regimen lighter than the standard stimulation of Carpentier and Chachques [4]. They are followed up at the Cardiology Division of the Legnago General Hospital (Verona, Italy). After 6 to 12 months of light daily stimulation, the patients were submitted to the heart rate–based demand regimen to provide the LD wrap with daily periods of rest. Holter studies were performed to determine the average heart rate during sleeping hours. Patients were considered to have no indications for bradycardia pacing. The cardiac pacing parameters of the cardiomyostimulator (Transform, Model 4710, Medtronic, Inc, Minneapolis, MN) were then programmed as previously described [10].
An additional group of subjects, operated on and stimulated according to standard procedures [4] at the Institute of Cardiac Surgery, University of Pavia, were studied in collaboration with The Cardiology Rehabilitation Centre, IRCSS Fondazione "Maugeri," Montescano (Pavia, Italy). A prudent approach was used to change the stimulation regimen from standard to demand in these long-term dynamic cardiomyoplasty subjects. Burst settings were first adapted to light stimulation, then 6 to 12 months later to demand stimulation. Table 1 shows settings of the standard stimulation, and of the "light stimulation regimen" delivered either continuously or at demand.
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Table 1. Dynamic Cardiomyoplasty: Cardiomyostimulator Settings of Either Carpentier and Chachques Protocol (Standard Stimulation) or Light (Daily or Demand) LD Stimulation
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A total of 22 subjects were included in the study, but only 8 patients attained 6 months of demand stimulation and are considered here. Tetanic fusion frequency analysis was performed in 11 long-term standard subjects.
Contractile characteristics of the LD wrap were monitored using a polygraph (MegaCart or Mingophon, Siemens Elema, Solna, Sweden). To monitor the LD wrap, the pressure transducer, which was traditionally used for apex cardiography, is placed at the location of the rib window through which the LD enters the thoracic cavity. The optimal LD–heart synchronization is determined by comparing the mechanogram event with both the mitral and the aortic valve sounds as measured by the phonogram or after connecting the polygraph to echocardiography equipment by M-mode echocardiography or echo-Doppler measurements of aortic flows.
The dynamic characteristics of the LD wrap are determined from the response to stimuli delivered at increasing frequency rate [10]. The range of pulse intervals of the cardiomyostimulator, from 8 to 242 ms (from 125 to 3 Hz), is adequate to test the fast-to-slow transitions of the LD wrap. Tetanic fusion frequency produces a smooth contraction curve. The unfused tetanus shows a rippled slope. The analysis lasts the few minutes needed to adjust parameters by telemetry.
The subjects were followed up with respect to survival, functional class, hospital admission rate, medication used, cardiopulmonary exercise testing, and dynamic characteristics of the LD wrap by mechanographic analyses. Student’s t test was used for statistical analysis; data were regarded as statistically significant when p was less than 0.05.
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Results
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Mechanogram-based synchronization of heart–latissimus dorsi wrap contraction–relaxation cycles
In dynamic cardiomyoplasty, besides palpating the left axillary region for the muscle twitch, the LD contraction can be verified by fluoroscopy [11]. Invasive techniques involving catheterization document LD activity and provide information about the optimal delay setting [1, 2]. The LD wrap synchronization within the heart cycle is routinely performed by M-mode echocardiography, but the method analyzes electrical rather than mechanical events [2–5]. Mechanogram provides for the first time a simple, noninvasive technique to couple accurately LD contraction to cardiac functions.
Figure 1 shows an LD wrap mechanogram as obtained by the polygraph. The upper trace (ECG) displays the spikes of the muscle impulses, the middle records the phonogram, and the lower the mechanogram of the LD wrap. In response to a burst of four impulses delivered at 23-ms intervals (43 Hz) the muscle contraction is recorded as a smooth peak (Fig 1A). The LD wrap stimulated at 55-ms intervals (18 Hz) shows a rippled slope, as some relaxation of the myofibers occurs in between the impulses (Fig 1B).
By connecting the polygraph to echocardiography equipment, the mechanogram of the LD can be compared better to cardiac events. With the mechanogram the LD contraction–relaxation cycle is precisely tuned with the desired phase of the cardiac cycle by M-mode echocardiography of the mitral valve (Fig 2) or by echo-Doppler measurements of aortic outflow (Fig 3).
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Fig 2. High-resolution examination of the latissimus dorsi–heart synchronization. Mechanogram of latissimus dorsi wrap contraction is obtained by combined polygraph and M-mode echocardiography.
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Fig 3. High-resolution examination of the latissimus dorsi–heart synchronization. Mechanogram is viewed simultaneously with echo-Doppler measurements of aortic outflow. (A) The mechanogram of a lightly conditioned latissimus dorsi wrap stimulated with four impulses delivered at 23-ms intervals (43 Hz) is well included in the aortic outflow period. (B) After 4 years of standard stimulation, the mechanogram lasts longer than the aortic outflow when a fully transformed LD wrap is stimulated with six impulses delivered at 31-ms intervals (32 Hz).
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Contraction and relaxation speeds of LD wrap change over time during dynamic cardiomyoplasty. Time to peak contraction of human fast muscles is about 50 ms, and increases up to 100 ms in slow-type or in slow-type–transformed muscles [6, 7, 12]. Figure 3A shows the mechanical response of the LD wrap to four impulses delivered at 23-ms intervals (43 Hz) in a patient just at the end of the LD conditioning by "light stimulation." The contraction–relaxation event of the "mechanogram-synchronized" LD wrap is well included in the aortic outflow period.
The LD wrap mechanogram of a subject after 4 years of standard stimulation is shown in Figure 3B. Under the standard stimulation settings (six impulses delivered at 31-ms intervals, ie, 32 Hz), relaxation phase of this fully transformed LD lasts longer than the aortic outflow period.
Using the mechanogram, a 50 to 100 ms synchronization delay was determined in the majority of the studied subjects to induce LD contraction after mitral valve closure, and relaxation within the ejection phase of cardiac systole [10]. In a few patients the settings identified by the mechanogram are supported by pressure–volume analysis [2].
Electrical stimulation of the latissimus dorsi wrap by cardiac rate-based demand regimen
To provide the LD wrap with daily periods of rest, 24-hour Holter studies were performed to determine the average heart rate during sleeping hours. For the patients studied to date, this rate was less than 80 beats min, whereas their average heart rate during the day was greater than 80 beats/min.
In Figure 4 two examples are shown of either an easy-to-set threshold (panel A) or the worst case in which the circadian changes are stabilized by pharmacological intervention on heart rate (panel B). In this case, the extent of demand stimulation is less predictable, and for safety the threshold is set to a value (80 beats/min) that produces sparse periods of LD wrap rest.
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Fig 4. Holter study to determine the average heart rate during sleeping hours. (A) An easy-to-set threshold. (B) A problematic case in which circadian changes are stabilized by pharmacological intervention on heart rate.
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Dynamic characteristics of the latissimus dorsi wrap
Tetanic fusion frequency is a physiologic index of muscle contraction and relaxation speed, and thus of fiber type composition [6–8]. Table 2 shows that just before conditioning tetanic fusion frequency of the LD wrap is 43 Hz, which is in the expected range of values for human LD [7]. Tetanic fusion frequency of LD wrap at the end of the conditioning period by the light-stimulation protocols (4 to 5 weeks postoperation) is between 43 and 32 Hz, but after 6-month light stimulation the LD wrap is slightly slower. Figure 5 shows an almost smooth slope produced by two impulses delivered at about 50-ms intervals (panel A, 20 Hz). As the interval between the two stimuli is increased (B, 75 ms; C, 150 ms), there comes a stage at which the LD wrap contraction record shows two distinct maxima. With still greater separation of the stimuli (D, 200 ms), the muscle responds with two distinct twitches, each lasting about 200 ms.
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Fig 5. Tetanic fusion frequency analysis of latissimus dorsi wrap. Stimulation at intervals. (A) 50 ms, 20 Hz. (B) 75 ms, 13 Hz. (C) 150 ms, 7 Hz (D to F) 200 ms, 5 Hz. (A to D) Six-month light stimulation, (E and F) Long-term standard stimulation.
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When stimulated long-term according to Carpentier and Chachques the LD wrap becomes even slower [10]. In the cohort of Italian subjects we are studying, tetanic fusion frequency is in between 5 and 20 Hz after long-term standard stimulation (Table 2). Accordingly, panels E (25 months of standard stimulation) and F (42 months of standard stimulation) of Figure 5 confirm that the muscles are far from being fully relaxed after 200 ms.
Demand stimulation of LD wrap was introduced either after several months of continuous light regimen or after years of clinical stimulation according to Carpentier and Chachques. In both cases the fast-to-slow transformation of the LD wrap shifts back to faster values during several months of the demand regimen. When long-term standard stimulation is compared to demand stimulation the difference in tetanic fusion frequency of the LD wrap is highly significant (Tables 2 and 3).
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Table 3. Dynamic Characteristics of Latissimus Dorsi Wrap After Long-Term Daily or Demand Stimulation, Tetanic Fusion Frequency Analysis (Hz)
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Demand dynamic cardiomyoplasty: follow-up
To date all patients submitted to demand stimulation are alive, and they give preference to the activity–rest regimen based on their general feeling of well-being. Table 4 shows that after demand stimulation the 8 patients maintain a sustained improvement in quality of life with a highly significant reduction in heart failure symptoms. Hospitalization is reduced in 3 of the 4 patients lightly stimulated from LD conditioning; ß-blockers therapy could be introduced in all of them, whereas it was not tolerated before operation. In the "light group" of demand dynamic cardiomyoplasty subjects the exercise capacity was increased in comparison to preoperation values, more than 2 years after operation (Table 5).
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Table 5. Demand Dynamic Cardiomyoplasty: Functional Analyses After Long-Term Continual or Demand Stimulation: VO2 Max
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Comment
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The mechanogram provides information on the contractile characteristics (speed of contraction and relaxation) of the LD wrap. The LD wrap becomes a pure slow muscle by both functional and molecular parameters during 1 year of standard stimulation [4, 10]. In the patients we are studying, conversion from standard to demand stimulation (ie, to an activity–rest regimen) reverses fast-to-slow transformation of LD wrap. The demand-stimulated LD wrap shows dynamic characteristics intermediate between those of fast and slow human muscle 3 years after operation. This result has been validated by fluoroscopic contraction analysis [13].
Our clinical results are in agreement with evidence collected in animal models of dynamic cardiomyoplasty [14, 15]. The effects of intermittent stimulation (10 hours on, 14 hours off per day) versus standard daily stimulation of LD wrap were compared in a canine model of dynamic cardiomyoplasty. Significantly larger percent increases in peak aortic pressure (+18%), left ventricular pressure (+22%), peak positive LV dP/dt (+25%), stroke volume (+38%), stroke work (+71%), and aortic flow (+64%) were observed in the intermittent stimulated LD wraps (W.P. Santamore, Temple University, Philadelphia, 1999, personal communication).
Data from long-term training and detraining experiments in rodents, rabbit, goat, sheep, and man [6–9, 12–18] support the interpretation that the increased performances are the result of the maintained intermediate transformation of the LD wrap, which produces faster, more powerful contractions. The biological bases of such an interpretation are that "intermediate" myofibers do exist in nature, and that dynamic characteristics are induced and maintained by different level of activity against load [6–10, 12]. Cessation of stimulation has a pronounced effect on gene expression leading to a rapid reversal (hours) of the stimulation-induced changes [12]. All these results support our 5-year-old hypothesis that activity–rest stimulation (demand stimulation in the present study) is superior to daily continuous stimulation, not only because it minimizes incremental activity-induced muscle damage, but because it maintains an intermediate state of fast-to-slow LD wrap conversion [8–10]. We have no histochemical or molecular analyses of the extent of muscle changes in demand dynamic cardiomyoplasty. All the subjects submitted to demand stimulation are alive, and we find it unethical to perform biopsies of the LD wrap. In this preliminary group of patients, in which the expected result could be a better quality of life, we minimized invasive analyses during follow up, although this decreases the chance to collect evidence of increased systolic performance on a nonassisted/assisted beat basis. We have no evidence that wrap power improved to the level to provide systolic assistance measurable by means of echocardiography, but we stress that the faster contraction-relaxation cycle of the demand-stimulated LD wrap is per se an evidence of increased muscle power [6–12]. Reducing by two-stage surgery muscle damage due to LD mobilization, optimizing work–rest stimulation regimes pre- and postoperation, and administrating locally anabolic and angiogenic agents might further increase power of the LD wrap.
In conclusion, the regimen we introduced into management of dynamic cardiomyoplasty (demand stimulation to avoid full transformation of the LD wrap, as assessed by mechanography) is safe, well tolerated, and by maintaining an intermediate fast-to-slow LD wrap conversion provides excellent clinical results. We hope that all together these results reinforce the concept of activity-rest stimulation, and contribute to a larger acceptance of dynamic cardiomyoplasty.
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Acknowledgments
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Supported in part by funds from the Italian National Research Council to the Unit for Muscle Biology and Physiopathology. Supported by the Italian Ministry for University and Scientific and Technologic Research (M.U.R.S.T. n. 9806192428): Italian Trial of Demand Dynamic Cardiomyoplasty (TiCDD)". The support of TELETHON-ITALY to the project n. 968 is gratefully acknowledged.
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Accepted for publication January 12, 2000.
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Abstract
Introduction
