Use of skeletal muscle grafts for cardiac assist

EMERGING TECHNOLOGIES Use of Skeletal Muscle Grafts for Cardiac Assist Hiroshi Niinami, Albert0 Pochettino, and Larry W. Stephenson

Skeletal muscle is a potential power source for cardiac assist. Two approaches have been used to harvest this power: dynamic cardiomyoplasty, which involves the application of a muscle directly to the heart to support cardiac contractile function; and the construction of skeletal muscle pouches or ventricles, which are used as separate pumps working either in parallel or in series with the heart. These techniques may represent an alternate therapeutic approach in patients with end-stage heart disease or in infants with certain congenital heart anomalies. (Trends Cardiovasc Med 199 1; 1: 122-126)

There is now considerable interest in the use of skeletal muscle for circulatory assist, but the concept itself is not new. For more than 50 years, attempts have been made to assist the failing heart with skeletal muscle (Leriche and Fontaine 1933). Much of the recent interest is due to the discovery that chronic electrical stimulation can transform skeletal muscle into a more fatigue-resistant form. Despite innovations, such as heart transplantation and mechanical assist devices, the prognosis for patients with end-stage heart failure remains grave. Autogenous skeletal muscle has several advantages over other sources of mechanical assist for the failing heart. It does not induce an immune response. There is no need for donors and no requirement for cumbersome external power sources. In addition, autologous skeletal muscle is likely to preserve the potential for growth, which may make it applicable for the correction of complex congenital heart anomalies. In a number of laboratories world-

Hiroshi Niinami, Albert0 Pochettino, and Larry W. Stephenson are at the Division of Cardiotboracic Surgery, Wayne State University, School of Medicine, Detroit, MI 48201, USA.

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wide, two methods have been developed in an attempt to use skeletal muscle for cardiac assistance. The first method involves the construction of skeletal muscle ventricles (SMVs) or pouches which act as separate pumps connected to the circulation. In the second method, termed dynamic cardiomyoplasty, skeletal muscle grafts are applied directly to the heart to support cardiac contractile function. Only dynamic cardiomyoplasty is presently being tested in clinical trials.

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Skeletal Muscle Adaptive Transformation

Skeletal muscle that is subjected to chronic electrical stimulation progressively acquires the properties of a fatigueresistant muscle. This stimulated muscle has an increase in capillary density, mitochondrial volume fraction, enzymes of oxidative metabolism, and there is a switch from the synthesis of fast to the synthesis of slow isoforms of myosin. These changes result in increased resistance to fatigue (Mannion et al. 1986~; Pette 1984; Salmons and Henriksson 1981). The above transformation (termed conditioning) is complete by 6-8 weeks. Under conditions of continuous stimulation, such histochemical and metabolic adaptations remain stable with-

out evidence of cellular damage (Acker et al. 1987a). To understand better the fatigue resistance induced by chronic stimulation, Clark et al. (1988) used phosphorus (31P) nuclear magnetic resonance spectroscopy to study the bioenergetics of conditioned canine latissimus dorsi muscle in vivo. They demonstrated that the increased resistance to fatigue is related to an increased capacity for oxidative phosphorylation, possibly due to the increased mitochondrial volume. As the capacity for oxidative phosphorylation is increased, the rate of ATP production by the muscle is able to match the sustained increase in ATP utilization due to exercise. The decline in phosphocreatine, and the accumulation of ADP and inorganic phosphate (Pi), which usually accompany muscle fatigue, are absent. Like the heart, the resistance to fatigue by the conditioned muscle is derived from an efficient recycling of ADP to ATP which prevents the accumulation of Pi. The increased ability to utilize oxygen during isometric exercise further contributes to the fatigue resistance of electrically conditioned skeletal muscle (Acker et al. 1987b). Conditioned muscle is homogeneously slow in cross-bridge cycling. As the rate of cycling of cross bridges determines the energy cost to maintain a given tension, less ATP is needed and therefore less oxygen is consumed by an electrically conditioned canine muscle than by a control muscle during identical isometric tension.

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Skeletal Muscle Ventricles

SMVs have been constructed from a numberof different muscles (Chiu 1986). We prefer the latissimus dorsi muscle. It is a large, powerful, nonessential muscle with a single main neurovascular pedicle (thoracodorsal nerve, artery, and vein), which makes surgical manipulation easy. To prepare a pedicle graft, the muscle is freed from all of its chest wall attachments. Collateral blood vessels are severed. The thoracodorsal neurovascular bundle is left intact. The muscle flap is then wrapped around a Teflon stent of a given size in a multilayered spiral fash-

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delay period allows for adhesions to form between the muscle layers and for the recovery of the normal resting and exercise-induced blood flow (Mannion et al. 1986a and b and 1989). The vascular delay period also allows for the muscle to adhere to the felt sewing ring implanted at the time of SMV construction.

Figure 1. Skeletal muscle ventricle connected to the aortic circulation and used as an arterial diastolic counterpulsator. The skeletal muscle ventricle was positioned on the chest wall with the skin and subcutaneous tissue closed over it.

ion. The muscle is usually wrapped 1.5-2.5 times around the stent. A cuff electrode is placed around the proximal thoracodorsal nerve, which is connected to an implantable

neuromuscular

lator.

stimu-

Before

the SMV

is used, the Teflon

stent must be removed, which is done after 4-5 weeks. A reduction of muscle blood flow occurs when the collateral blood supply is divided during SMV construction. This 4- to 5-week vascular

Figure 2. These are carotid and femoral arterial tracings obtained at 25.43, and 85 Hz after an SMV had been continuously pumping for 1 year in the circulation. Increasing the intensity of the burst frequency from the chronic setting of 25 Hz to 43 Hz and then 85 Hz increases diastolic augmentation. The device is activated in a 1:2 mode. The nstetik represents diastolic augmentation. Note corresponding superimposed burst pattern on ECG.

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Acker et al. (1986a) studied the pumping function of the SMVs utilizing an implantable mock circulation device. This system allows for independent control of preload (filling pressure) and afterload (resistance the SMVs pumped against), while obviating problems of thrombosis and complex cardiac synchronous burst stimulation that would have been necessary if these SMVs had been connected to the circulation. These SMVs pumped continuously against an afterload of 80 mm Hg at a preload of 40-50 mm Hg for up to 28 days. At the initiation of pumping, the mean systolic pressure was 134 mm Hg and flow was 464 mUmin. After two weeks of continuous pumping, the systolic pressure was 104 mm Hg and flow was 206 mL/min. In a subsequent study, the SMVs were constructed without electrical preconditioning. After a vascular delay period, the SMVs were connected to the same mock circulation device (Acker et al. 1987b). Systolic pressure was initially 139 + (SE) 7 mm Hg, and 107 + 7 mm Hg after 1 month. Flow was initially 5 18 + 105 mL/ min, and 224 rt:85 mL/min after 1 month. Although pressures and flows decreased during the 1 month of continuous pumping, this study indicated that canine skeletal muscle could perform continuous work while simultaneously undergoing adaptive transformation. A recent study from our laboratory showed that an extended vascular delay period results in improved SMV performance and that SMVs could generate more stroke work than the canine left ventricle

01991, Elsevier Science Publishing Co., 1050-1738/91/$2.00

at physiologic

preloads

and

123

afterloads

(Pochettino

et al. 1990).

When skeletal muscle pumps are used in the circulation, it is necessary to use a special pacemaker that is an R-wave

synchronous burst stimulator (Medtronic SP- 1005). Mannion et al. (1986a-c) demonstrated that electrically preconditioned

Figure 3. Schematic drawing of catdiomyoplasty. Latissimus dorsi is freed, leaving its neurovascular bundle intact, passed into the chest and sutured around the heart. A special pacemaker, triggered from the ECG, delivers bursts of impulses to branches of the thoracodomal nerve, causing the graft to contract in synchrony with the patient’s heart. Figure 4. Latissimus dorsi strain gauge measurement, aortic flow, carotid arterial pressure, and femoral arterial pressure tracings taken with the pacemaker ON and OFF.Despite developed skeletal muscle tension as measured by strain gauge, no hemodynamic changes are noted.

Strain Gauge

Aortic Flow

;,.. PA Pressure

:. ..:._.!_ . : 2 .:. .: ‘.,, >j,.._’ I I, .+mp..y ,&...e : :

.,. _.“.--.

tracings showing good diastolic pressure augmentation (Figure 2). This animal is

CVP (Mean) Carotid Pressure

Femoral Pressure

ECG

J---‘-T 1

II Cardiomyostimulator ON

124

SMVs connected acutely to the descending thoracic aorta as diastolic counterpulsators were able to function well in the circulation for many hours. In another acute study, Nielson et al. (1985) demonstrated an improvement in the subendocardial viability ratio when SMVs of their own design were used to power an arterial diastolic counterpulsation device. Acker et al. (1986b) demonstrated that SMVs could function chronically as diastolic counterpulsators connected directly to the circulation. These SMVs were tube shaped and lined with Gore-Tex. The device was inserted into the circulation by dividing the descending thoracic aorta and reestablishing flow through a Gore-Tex-lined SMV. These SMVs functioning as diastolic counterpulsators generated useful work in the circulation for up to 11 weeks. The two longest-surviving dogs with this device in place died from complications of renal failure. Autopsy revealed evidence of thromboembolism with multiple renal and splenic infarcts. Anderson, from our laboratory, connected canine SMVs to the descending aorta via a Gore-Tex bifurcation graft (Anderson et al. 1991). The aorta was then ligated between the two limbs of the graft, so that there was obligatory blood flow through the SMV (Figure 1). These SMVs, which were cone shaped, contracted chronically during diastole, thus augmenting diastolic pressure and unloading the heart. As of this writing, one dog remains alive after 1 year, with

J

Cardiomyostimulator OFF

active and appears to be in good health without evidence of thromboembolism. SMVs have also been used to replace the right heart fully by connecting the SMV afferent limbs to the superior and inferior vena cava and the efferent limb to the pulmonary artery (Bridges et al. 1989). When these SMVs were activated during systole, they were capable of performing the work of the right ventricle with near-physiologic filling pressures for up to 4 h. At the initiation of bypass, the systemic arterial blood pres-

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TCM Vol. 1,No.3,1991

ECG

Lv

failure model by placing the hearts into ventricular fibrillation. Cardiomyoplasty had been performed 7 months earlier. The muscle graft was stimulated at the rate of 54 contractions/min at a burst frequency of 43 Hz. There was a 15-mm Hg augmentation of arterial pressure during each skeletal muscle contraction (Figure 5). To date, experimental results by other groups have been variable, yet the consistent improvement in symptoms of patients undergoing this procedure cannot be denied. A chronic heart failure model with cardiomyoplasty has yet to be developed. When this becomes available, the mechanisms by which the latissimus dorsi assists the heart in the cardiomyoplasty configuration should become apparent.

-

.e.-

_-_

....I

Femoral Pressure

l

A

Carotid Pressure

II

I

Cardiomyostimulator OFF

4 Cardiomyostimulator ON

Figure5. Thesetracings were taken during agonal idioventricular rhythm. Note that the heart generates no pressure during this rhythm. Shown here are ECG, pulmonary arterial, carotid, and femoral arterial pressures with pacer OFFand ON. Note the augmentation of femoral and carotid arterial pressures with the pacemaker ON.

sure was 100-l 10 mm Hg, and the peak SMV output was > 5 L/min. After 4 h, the systemic pressure was still > 100 mm Hg, with peak SMV output at = 4 Urnin. So far, SMVs have not been used chronically for right heart bypass.

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Dynamic

Cardiomyoplasty

The other method of utilizing skeletal muscle for cardiac augmentation has been termed dynamic cardiomyoplasty. After dissection of the left latissimus dorsi, the muscle is brought into the thorax while the proximal end of the muscle is anchored to the chest wall by suturing the tendon to the third rib. The pedicle graft is wrapped around the heart through a separate sternotomy incision (Figure 3). This muscle flap undergoes electrical conditioning over the following 4 months, at which time it can be made to contract during systole at a stimulation ratio of 1: 1 with the heart, cardiomyostimulator by using a (Medtronic SP- 1005). Carpentier was first to use this technique clinically in a

TCMVol, I. No. 3. 1991

patient after resection of a cardiac tumor (Carpentier and Chachques 1985). To date, over 100 patients have undergone this procedure for various forms of heart failure. Most hospital survivors have had a dramatic improvement in their symptoms of heart failure, yet in many it has been difficult to document improvements in cardiac function clearly. Anderson et al. (1988) performed cardiomyoplasty in dogs as part of a chronic study. Although the muscle grafts contracted during stimulation, as documented by strain gauge, they did not cause noticeable increases in left ventricular pressure

or cardiac

output.

They

used healthy dogs with normal hearts. Chachques et al. (1988), however, using healthy goats, did show augmentation of cardiac function with cardiomyoplasty. We have also studied cardiomyoplasty in goats. Our results to date have been less encouraging than those of Chachques. We have failed to show hemodynamic improvement in goats with normal hearts (Figure 4). We then tested cardiomyoplasty in the ultimate heart

Conclusion

Skeletal muscle is capable of acquiring greater fatigue resistance and thereby being used for cardiac assistance. At present, only cardiomyoplasty has been used clinically. This is not surprising, since it is a relatively safe operation to perform, avoids problems of thrombosis, and is unlikely to do harm. Evidence is beginning to emerge that clinical improvement may be due to enhanced cardiac output and not simply to limiting ventricular distension or to a placebo effect. We consider SMVs to be experimental. However, our work where one dog continues to do well after 1 year demonstrates that long-term function is achievable. Animal studies and limited clinical research suggest that skeletal muscle grafts may improve cardiac function. Although more studies are required, the potential clinical applications of skeletal muscle grafts for cardiac assistance are enormous.

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Acknowlegment

This work was supported by NM grant HLBI-34778. References Acker MA, Hammond RL., Mannion JD. Salmons S, Stephenson LW: 1986a. An autologus biologic pump motor. J Thorac Cardiovasc Surg 92:733-746. Acker MA, Anderson WA, Hammond FU, et al.: 1986b. Skeletal muscle ventricles in

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circulation: one to eleven weeks experience. J Thorac Canliovasc Surg 9 1:534544. Acker MA, Marmion JD, Brown WE, et al.: 1987a. Canine diaphragm muscle after one year of continuous electrical stimulation: its potential as a myocardial substitute. J Appl Physiol62:12641270. Acker MA, Anderson WA, Hammond RL, et al.: 1987b. Oxygen consumption of chronically stimulated skeletal muscle. J Thorac Cardiovasc Surg 94:702-709. Acker MA, Hammond RL, Mannion JD, Salmons S, Stephenson LW 1987c. Skeletal muscle as a potential power source for a cardiovascular pump: assessment in vivo. Science 236~324327. Anderson WA, Anderson JS, Acker MA, et al.: 1988. Skeletal muscle grafts applied to the hearts: a word of caution. Circulation 78(Suppl3):III-180-190. Anderson DR, Pochettino A, Hammond RL, et al.: 1991. Autogenously lined skeletal muscle ventricles in circulation: up to nine months experience. J Thorac Cardiovasc Surg (in press). Bridges CR, Hammond RL, DiMeo F, Anderson WA, Stephenson LW 1989. Functional right-heart replacement with skeletal muscle ventricles. Circulation 8O(Suppl3):III-

Winnina

tance. J Thorac Cardiovasc Surg 91:534544.

183-191. Carpentier A, Chachques JC: 1985. Myocardial substitution with a stimulated skeletal muscle: first successful clinical case. Lancet 1:1267. Chachques JC, Grandjean P, Schwartz K, et al.: 1988. Effect of latissimus dorsi dynamic cardiomyoplasty on ventricular function. Circulation 78(Suppl3):III-203-216. Chiu RC-J, ed: 1986. Biomechanical Cardiac Assist: Cardiomyoplasty and muscle powered devices. New York, Futura. Clark BJ, Acker MA, Subramanian H, et al.: 1988. In vivo 31P-NMR spectroscopy of chronically stimulated canine skeletal muscle. Am J Physiol254:C258-266. Leriche R, Fontaine R: 1933. Essai exp&imental de traitment de certains infarctus du myocarde et de l’aneurisme du coeur par une greffe de muscle stri6. Bull Sot Nat1 Chir 59:229-232.

Mannion JD, Velchik MA, Acker MA, et al.: 1986b. Transmural blood flow of multilayered latissimus dorsi skeletal muscle ventricles during circulatory assistance. Tram Am Sot Artif Intern Organs 32:454-460. Mannion JD, Acker MA, Hammond RL,Stephenson LW: 1986c. Four-hour circulatory assistance with canine skeletal muscle ventricles. Surg Forum 37:2 1 l-2 13. Mannion JD, Velchik M, Hammond RL, et al.: 1989. Effects of collateral blood vessel ligation and electrical conditioning on blood flow in dog latissimus dorsi muscle. J Surg Res 47~332-340. Neilson IR, Brlster SJ, Khalafalla AS, Chiu RCJ: 1985. Left ventricular assistance in dogs using a skeletal muscle powered device for diastolic augmentation. J Heart Transplant 4:343-347. Pette D: 1984. Activity-induced fast to slow transitions in mammalian muscle. Med Sci Sports Exercise 16:517-528.

Mannion JD, Bitto T, Hammond RL, Rubinstein NA, Stephenson LW: 1986. Histochemical and fatigue characteristics of conditioned canine latissimus dorsi muscle. Circ Res 58:298-304.

Pochettino A, Spanta AD, Hammond RL, et al.: 1990. Skeletal muscle ventricles for total heart replacement. Ann Surg 212:112-l 18.

Mannion JD, Hammond RL, Stephenson LW: 1986a. Canine latissimus dorsi hydraulic pouches: potential for left ventricular assis-

Salmons S, Hem-&son J: 198 1. The adaptive response of skeletal muscle to increased use. Muscle Nerve 494105. TCM

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