LD-PACE II: a new cardiomyostimulator for cardiac bioassist.

The LD-PACE II was designed for use in cardiomyoplasty, aortomyoplasty, and skeletal muscle ventricles. All parameters specified as programmable can be changed in a noninvasive manner (using a programming interface wand connected to a computer using the Windows 95/98 environment). Two new functions may be very useful clinically, based on experimental research. 1. Work-rest regimen. The LD-PACE II is able to deliver alternating periods of muscle contractions and rest. Work and rest periods may be programmed independently between 1 and 120 minutes in increments of 1 minute. The work-rest regimen may be useful clinically if muscle contractions are needed for cardiac assist postoperatively. 2. Night/day regimen. This feature allows for a change in the ratio of muscle contractions according to a patient's activity level. During the day the cardiosynchronization ratio may be set from 1:1 to 1:4, and during the night it may be set for 1:8 to 1:16. This allows the muscle to have a long rest period, prevents overuse, and prolongs battery life. These two new features make this cardiomyostimulator very attractive for cardiomyoplasty in particular. The addition of the work-rest and night-day regimens allow the muscle to rest for periods during the day to prevent overuse, subsequent damage, and potential atrophy.

Age related skeletal muscle response to electrical stimulation.

We hypothesized that the conditioned muscles of elderly and growing organisms have different responses to electrical stimulation from that of young adult organisms. Five day old lambs, 1 year old sheep, and 8 year old elderly sheep were used for this investigation. The latissimus dorsi muscle (LDM) was partially mobilized and left in situ. Two electrodes were implanted and electrical stimulation (ES) was begun for 8 weeks; it was then stopped for 2 weeks. Biopsies were taken before ES, after 8 weeks of ES, and after the 2 week delay period. The LDM of old sheep has less fatigue resistance than the LDM of younger animals. Conditioned LDM of the lamb continued to be fatigue resistant after a 2 week delay compared with adult sheep. In all animals, lactate dehydrogenase (LDH) fraction five decreased and LDH-1 + 2 fractions increased after ES. After a 2 week delay, the data returned to baseline values only in adult animals. The percentage area occupied by mitochondria in old sheep was less after ES than in younger animals. In all animals, the mitochondrial area increased after ES and reverted to baseline values after the delay. The number of nuclei and fibers considerably increased after ES. Only in the lamb did the number of nuclei and fibers continue to be elevated after the delay. There are more changes in young skeletal muscle than in adult (1 year or 8 year old) muscle during ES, and they "remember" these properties. Elderly skeletal muscle does not convert to a fatigue resistant state as completely as adult skeletal muscle during a conventional 8 week ES protocol. It is necessary to change and prolong the ES protocol for elderly patients.

Effects of electrical stimulation postcardiomyoplasty in a model of chronic heart failure: hemodynamic results after daily 12-hour cessation versus a nonstop regimen.

The hemodynamic effects of cardiomyoplasty (CMP) have been investigated in many centers, but the question of whether it is necessary to stimulate the latissimus dorsi muscle (LDM) 24 hours a day has not been answered. The main goal of our investigation was to determine whether hemodynamic results after CMP were impaired when continuous electrical stimulation (ES) was off for 12 hours a day. A model of chronic heart failure was created in 12 sheep by performing an arteriovenous anastamosis and administering doxorubicin. Two weeks after the anastomosis, CMP was performed in eight sheep (experimental series); ES training was begun at 2 weeks after CMP. After completion of the initial ES conditioning (8 weeks after CMP), one group of sheep continued to receive ES 24 hours daily. Another group of sheep had only 12 hours of ES daily. Hemodynamic parameters were investigated 2 weeks later with the stimulator turned on and then off. With doxorubicin administration, arteriovenous anastamosis created a stable model of biventricular heart failure (right atrial pressure 20 +/- 3 mmHg vs 6 +/- 2 mmHg at baseline; pulmonary capillary wedge pressure 18 +/- 3 mmHg vs 9 +/- 2 mmHg; left ventricular end-diastolic area 15.2 +/- 1.2 cm2 vs 6.4 +/- 0.7 cm2; left ventricular ejection fraction 0.38 +/- 0.6 vs 0.65 +/- 0.7). Cardiomyoplasty improved hemodynamic status in all eight experimental sheep. However, when the investigation was performed with the stimulator off, this improvement was statistically insignificant. With stimulation on, there was decreased right atrial pressure, pulmonary capillary wedge pressure, left ventricular end-diastolic volume, and increased left ventricular ejection fraction. With the stimulator turned off for 12 hours daily, hemodynamic measurements did not differ from data with continuous ES for 24 hours daily. Because hemodynamic results do not seem to be impaired, we recommend daily, periodic cessation of stimulation to prevent damage to the LDM after CMP.

Angiogenesis in the latissimus dorsi muscle using different regimens of electrical stimulation and pharmaceutical support.

It is our contention that the prevention of ischemia-reperfusion injuries immediately after latissimus dorsi muscle (LDM) mobilization and enhancement of angiogenesis will be effective in improving cardiomyoplasty results. The investigations were performed on adult sheep. Three hours after LDM mobilization, various stages of leukocyte-endothelium interaction were revealed: leukocytes binding to the endothelium, leukocyte destruction of endothelium, and leukocytes leaving capillaries through gaps in the endothelium. Fifty-six days after mobilization various stages of necrosis were discernible. The area occupied by capillaries was 3.45 +/- 0.26% vs. 3.99 +/- 0.24% in control muscle; most of the endothelial cells exhibited morphologic degeneration. Electrical stimulation with 60 CPM actually decreased the capillary density to 2.15 +/- 0.7%, and most of the endothelial cells were damaged, with disrupted plasma membranes. Muscle subjected to 15 CPM increased the percent of capillaries to 5.01 +/- 0.56%, and endothelial cells appeared normal in ultrastructure. Pharmaceutical support prevented muscle damage and accelerated revascularization. After 56 days of autologous biological glue (ABG) application, the area occupied by capillaries was 5.57 +/- 0.24%. This increased to 8.47 +/- 0.72% when aprotinin (proteinase inhibitor) was added to ABG, and to 9.40 +/- 1.24% with pyrrolostatin (free radical scavenger). Both ABG application with aprotinin and electrical stimulation at 15 CPM prevent the LDM from postmobilization damage, and increase angiogenic potential.

Biodesign of a skeletal muscle flap as a model for cardiac assistance.

In using autologous muscles for cardiac assistance, it is crucial to reduce ischemia-reperfusion injury in the surgically traumatized skeletal muscle. In adult sheep, we developed a simple model of surgically designed 2 latissimus dorsi muscle leaflets by modifying the vascular supply to these leaflets. Three pockets with graded injury were established, and muscle morphology and vascular remodeling were monitored in 3 experimental groups: muscle leaflets without any treatment (Group 1, n = 6) that served as controls; muscle leaflets integrated with a fibrin interlayer (Group 2, n = 6); and leaflets integrated with fibrin and entrapped pyrrolostatin (Group 3, n = 6). We applied the fibrinogen and thrombin solutions, which polymerize to form a three-dimensional meshwork joining the tissues, creating a provisional matrix for angiogenesis, and acting as a delivery depot for agents aimed at minimizing ischemia-reperfusion lesion formation. After 2 months, the muscle leaflets biointegrated with the fibrin interface showed none of the signs of necrosis or ischemia-reperfusion lesions seen in the controls. Although no angiogenic factors were incorporated, the fibrin interlayer rapidly (<2 weeks) became a densely vascularized tissue replete with a voluminous capillary network. In contrast, controls showed poor bonding between the tissues, muscle fiber deterioration, and a compromised vascular network. Muscle structure was best preserved and angiogenesis was greatest when pyrrolostatin, a free radical scavenger, was added to the fibrin meshwork to reduce damage caused by overproduction of free radicals. This newly designed model will be useful to study many current approaches in cardiovascular biology, from pharmaceuticals to gene therapy, which might prove advantageous in muscle-designed cardiac assistance.

Multistep approach to electrical stimulation after cardiomyoplasty.

UNLABELLED: Still a controversial procedure, cardiomyoplasty (CMP) improves the failing heart's ability to contract by using a latissimus dorsi muscle (LDM), but to date, hemodynamic results correlate poorly with clinical improvement. The following two causes for apprehension bar attempting to change the conventional electrical stimulation (ES) protocol to improve CMP results: (1) fear of beginning ES for LDM-assisted contraction immediately postmobilization and CMP and (2) fear of stopping or slowing ES during sleep periods. METHODS: In ten different experimental series, I used animal models of CMP to determine how to apply ES to newly mobilized LDM, how to begin partial cardiac assist immediately post-CMP, and how to suspend ES for 12 hours daily. RESULTS: From my experimental series I noted the following three results. (1) Different ES regimens applied 1 hour postmobilization changed the contractile force (CF). After a 30-minute fatigue test, CF decreased by 34% +/- 3% with continuous ES at 30 contractions per minute (cpm), by 23% +/- 2% with continuous ES at 15 cpm, by 25% +/- 5% with ES in a work-rest regimen at 30 cpm, and by 8% +/- 3% with ES in a work-rest regimen at 15 cpm. (2) Imitation of partial cardiac assist immediately postmobilization slightly decreased CF. Sixteen days postmobilization, during a 30-minute fatigue test in animals in which ES had been started immediately after mobilization, CF decreased by only 6% +/- 3% and did not change when ES was combined with imitation of cardiac assist for 30 minutes twice daily (work-rest regimen). (3) ES cessation for 24 hours daily or 12 hours daily in CMP model created no difference in ejection fraction (EF) with ES (54% +/- 4% vs 53% +/- 5%, respectively (or in left ventricular end-diastolic volume (LVEDV, 234.3 ml +/- 1.0 ml vs 24.8 mL +/- 0.6 mL, respectively) or in LV end-systolic volume (LVESV; 12.1 mL +/- 0.7 mL vs 12.8 mL +/- 0.7 mL, respectively). CONCLUSION: For improving angiographic potential in the LDM, ES can be started safely immediately post-CMP at 15 cpm (a 1:4 or 1:5 regimen) and single impulses per burst. For partial cardiac assist and for improving LDM performance, cardiac assist can be used for 30 minutes twice daily immediately post-CMP. To rest the muscle and save it from overuse, muscle contraction can be either stopped or slowed down during hours of sleep.

Cardiomyoplasty after implantation of a pacemaker and cardioverter/defibrillator.

Presently, a combination of two surgical methods improves the survival of patients with advanced ventricular dysfunction: implantable cardioverter/defibrillator implantation (which prevents sudden cardiac death) and cardiomyoplasty (which prevents further dilatation of the heart and provides additional cardiac assistance). We report the clinical course of a patient who had cardiomyoplasty after cardioverter/defibrillator implantation and pacemaker insertion. It is a rare case in which three different devices cardioverter/defibrillator, pacemaker, and cardiomyostimulator) are functioning together without crosstalk.

Comparison of different regimens of electrical stimulation applied to nonmobilized and newly mobilized latissimus dorsi muscle.

We investigated the possibility of preventing further aggravation of muscle ischemia and necrosis in newly mobilized, unconditioned latissimus dorsi muscle (LDM) by utilizing short increments of stimulation with intervening rest periods. Adult St. Croix sheep (N = 12) weighing 30 +/- 8 kg were used in this study. Fatigue tests (30 min) using different stimulation regimens before and after LDM mobilization were performed on all animals; the length of time to return to baseline levels was also measured. Our investigation yielded results that contradict the conventional wisdom that any electrical stimulation damages newly mobilized LDM and will cause a considerable decrease in contractile force (CF). Stimulation regimens using continuous contractions at 30 and 60 contractions per minute (CPM) for 30 minutes were damaging to the LDM. CF also dropped significantly and returned slowly to baseline values: at 60 CPM, CF dropped to 50 +/- 4% and did not return to baseline even after 90 minutes of rest; at 30 CPM, CF dropped to 61 +/- 4% and baseline was restored after 80 minutes of rest. Electrical stimulation using continuous contractions at a slower rate (15 CPM) was tolerable, although a 23% decrease in CF was noted (p < 0.05 when compared to 60 CPM). These results did not satisfy us that such a regimen would be useful for cardiac assistance immediately after cardiomyoplasty. The work-rest regimen at 30 CPM also gave poor results: CF decreased to 75 +/- 2% and baseline was restored after 80 minutes of rest. Promising results were seen when utilizing a work-rest regimen at 15 CPM. The newly mobilized LDM showed no visible signs of fatigue: CF decreased minimally to 92 +/- 3% (p < 0.05 when compared to 30 CPM), and light microscopic analysis of biopsies revealed no morphological damage exceeding that typically seen after subtotal mobilization. Such results open avenues for future investigations: beginning electrical stimulation immediately after cardiomyoplasty (using a single impulse and a slow rate of contraction); decreasing the length of time necessary to obtain full cardiac assistance; and beginning partial cardiac assistance immediately after cardiomyoplasty (if needed) for approximately 30 minutes several times a day.

Biologic glue increases capillary ingrowth after cardiomyoplasty in an ischemic cardiomyopathy model.

The authors investigated the multi-step mechanism of healing after cardiomyoplasty, focusing on the process of angiogenesis. The authors contend that enhancement of angiogenesis and prevention of ischemia-reperfusion injuries immediately after muscle mobilization will be effective in improving cardiomyoplasty results. After cardiomyoplasty, autologous biologic glue (ABG) was administered between the latissimus dorsi muscle (LDM) and myocardium. By 2 months, a new pseudo interlayer was present that bridged the gap between the LDM and myocardium. Neovascularization was visible in the form of numerous small capillaries. Marked degeneration of the LDM was noted, possibly caused by muscle ischemia-reperfusion damage after mobilization. Pockets were created of ischemic and nonischemic LDM to test for angiogenesis. One was left free of ABG (control); one received ABG only; one received ABG and pyrrolostatin. Some of the capillaries were large and had erythrocytes inside. biopsy samples showed 9.4 +/- 1.9% of the sample was occupied by blood vessels (compared with 3.6 +/- 0.7% in control muscle). These preliminary studies prove the feasibility of the authors' concept and provide evidence that angiogenesis can accelerate the healing process and provide an organic bridge between the LDM and myocardium after cardiomyoplasty.

Skeletal muscle of a growing organism has a greater transformation after electrical stimulation than adult skeletal muscle.

Six adult sheep and four newborn lambs (5 days old) were implanted with stimulator leads into the latissimus dorsi muscle and connected to a Myostim 7220 pacing system (Telectronics Pacing Systems, Inc., Englewood, CO). Electrical stimulation was started immediately after the operation. After 8 weeks of electrical stimulation, contractile force (CF) in adult sheep decreased to 76-81%, and to 78-82% in lambs. After 2 weeks' delay, CF in adults was 96-98%, and only 89-93% in lambs. After a 30 min intensive stress test, unconditioned control muscle lost 39% in lambs and 43% in adults. Muscle conditioned for 8 weeks lost 7-8% CF. However, after 2 weeks' delay, CF in adult muscle lost 33%, but only 12% in lambs. After cessation of electrical stimulation, the LDH-5 and LDH-1 + 2 fractions reverted to initial levels in adults, whereas in lambs, these levels continued to follow trends established during electrical stimulation. In both adults and lambs, the percent area occupied by the mitochondria increased during electrical stimulation by 6.9% in adults and 6.5% in lambs. After electrical stimulation cessation, the percent area in adults returned to baseline levels, whereas it continued to be elevated in lambs (3.3% vs 5.1%, respectively). The transformed muscle of the lamb did not revert to baseline levels after a delay period.

Skeletal muscle used as experimental cardiac assist: Russian experience.

This manuscript presents experimental data in the area of biomechanical cardiac support obtained at the Bakulev Institute for Cardiovascular Surgery in Moscow, Russia. After creation of the left ventricular aneurysm and subsequent cardiomyoplasty, active functioning of the muscle-heart complex was observed. In the late postoperative stages (3-6 months) hemodynamic parameters did not reach original preoperative values, but were satisfactory to support decreasing heart function: Cardiac index was decreased by 9.8%, the pumping coefficient of the left heart (KLH) by 24.7%, and left ventricular stroke work index (LVSWI) fell by 25%. Acute aneurysm of the left ventricle is a good model to study the effectiveness of cardiomyoplasty. Determination of parameters for stimulation of the muscle autograft showed that from the point of view of hemodynamic parameters of the muscle-heart complex, the optimal initial training schedule is a burst of seven pulses, each from 0.07 to 0.6 ms in duration, with a frequency of 30-50 Hz an amplitude of 6 V, and a burst following frequency of 15-30 per minute.

Is it possible to perform immediate cardiac assist using untrained latissimus dorsi muscle in a work-rest regimen?

The authors investigated what contractile force (CF) could be obtained from unconditioned latissimus dorsi muscle immediately after mobilization and for the 2 week vascular period of recovery. Latissimus dorsi muscle mobilization was performed on seven adult (4 experimental and 3 control) sheep leaving only the pedicle and the peripheral muscle intact. Telectronics stimulators (Myostim 7220; Teletronics Pacing Systems, Inc, Englewood, CO) were implanted. Immediately after mobilization 11-35% of the initial CF was lost. A 30 min fatigue test was performed 1 hr after mobilization (20 g/kg preload, 10 V, 10 Hz, 15 BPM, 6 impulses per burst) using a 1 min work-1 min rest regimen. Two sheep lost 2-12% of initial CF; two increased CF by 14-24%. At the end of the fatigue test, CF consisted of 74-89% of immobilized CF. Electrical stimulation training of the muscle was then initiated with the following regimen in the experimental animals only: 15 BPM, single impulses, 5 V, 10 Hz. Every day the muscle was exercised using a work-rest regimen to mimic cardiac assist, starting with 20 min on day 2, and increasing by 2 min per day until a total of 50 min was reached on day 16. All animals were retested for CF using a 42 min fatigue test on days 6, 11, and 16. On day 6, there was no fatigue evident in the experimental group during the 42 min test. CF after testing was 59-81% (mean 67%) of initial data. In the control group (animals with no electrical stimulation training protocol), CF decreased by 11% (from 64 to 53%). On day 11, there was no fatigue evident in the experimental group; CF in all animals increased by 2-8%. On day 16, there was also no fatigue evident in the experimental group; CF increased by 0-9%. An additional 20 min of continuous contraction (15 BPM) fatigue testing was performed on the muscle without rest between the tests. No fatigue was evident at the end of testing. Light microscopic analysis of latissimus dorsi muscle biopsy specimens taken on the days of testing showed no evidence of necrotic damage. Our investigations suggest that it may be possible to start muscle transformation immediately after mobilization and use the untrained latissimus dorsi muscle for cardiac assist immediately after surgery for short periods.

Force enhancement of skeletal muscle used for dynamic cardiomyoplasty and as a skeletal muscle ventricle.

Some patients with pre end-stage congestive heart disease do not receive a significant hemodynamic benefit from dynamic cardiomyoplasty because, during prolonged preoperative immobilization, their latissimus dorsi muscle (LDM) becomes extremely weak. It is the authors' hypothesis that the local administration of an anabolic steroid into an electrically stimulated LDM will produce a thicker and stronger muscle with significant resistance to fatigue. The electrical stimulation training protocol of sheep continued for 8 weeks. For localized anabolic steroid administration an osmotic pump was placed in a subcutaneous pocket and the catheter was introduced into the LDM. The contractile force of electrically stimulated and unstimulated control muscle was studied. Control data were calculated as 100% and all other data were corrected to control. After 4 weeks there was no decrease in contractile force. The change seen was from 88 to 100% with different preloads (10, 15, and 20 g/kg) and amplitudes of impulses (5 and 10 V). After 8 weeks, the LDM was more powerful than before electrical stimulation, with a change of 97-133%. Usually after 8 weeks of electrical stimulation alone, contractile force decreases to 70-75%. During a fatigue test (30 min, 100 bursts per minute, 10-25 Hz, ripple frequency, 10 V impulse amplitude) after 4 and 8 weeks of our protocol, the LDM lost only 12% of its initial force, whereas control muscle lost 40%. Thus local anabolic steroid administration makes the LDM stronger and more useful for cardiomyoplasty.