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Cardiac Assistance From Skeletal Muscle: Should We Be Downhearted?
EDITORIAL
Cardiac Assistance From Skeletal Muscle: Should We Be Downhearted? Stanley Salmons, MS, PhD Department of Human Anatomy and Cell Biology, University of Liverpool, Liverpool, United Kingdom
C
ardiac assistance from skeletal muscle offers an attractive solution to the problem of end-stage heart failure. Unlike transplantation, it does not carry the risks, debilitating side-effects and costs of long-term immunosuppression therapy. A donor patient (or animal) is not needed, and the patient’s own heart is retained under conditions that offer the potential for myocardial recovery. This is an affordable technology that could be considered in parts of the world where other approaches, including mechanical pumps, would be too costly. Currently, there is much interest in injecting stem cells into infarcted or peri-infarcted regions. Although this is part of a fashionable trend, the technique yields only milligrams of contractile tissue that are isolated electrically and mechanically from the rest of the myocardium. Real benefits— beyond an increase in wall compliance and some local angiogenesis-—remain a distant prospect. In contrast, the technology we are referring to here involves the surgical redeployment of hundreds of grams of existing, mature contractile tissue. Early attempts at cardiac assistance were defeated by muscle fatigue. In 1979, Dr L. W. Stephenson and I initiated a fresh approach, incorporating “conditioning”: a marked increase in fatigue resistance that was part of the adaptive response of skeletal muscle to long-term electrical stimulation [1]. The results were impressive and engendered new interest in the field. In several centers, surgical techniques were developed that allowed a nonessential muscle, usually latissimus dorsi (LD), to be transferred into the chest and configured to provide cardiac assistance. Two techniques, dynamic cardiomyoplasty and aortomyoplasty, were tried clinically. There is now a widespread perception that the approach has failed to fulfill its promise. It is time to revise that view.
Harnessing the Power Cardiomyoplasty Wrapping the LD muscle around the failing heart (cardiomyoplasty) is conservative, insofar as it does not place a new, nonendothelial surface in contact with the blood. However, the persuasive notion that activating the wrap generates a more forceful ventricular contraction runs Address reprint requests to Dr Salmons, British Heart Foundation Skeletal Muscle Assist Research Group, Department of Human Anatomy and Cell Biology, University of Liverpool, The Sherrington Buildings, Ashton St, Liverpool L69 3GE, UK; e-mail: [email protected].
© 2005 by The Society of Thoracic Surgeons Published by Elsevier Inc
counter to elementary muscle mechanics. Because the muscle is heavily loaded it contracts isometrically or at best shortens slowly, operating far from the peak of its power curve (see Salmons [2] for a fuller bibliography on this and other topics). Symptomatic benefit comes mainly from a girdling action, rather than a beat-to-beat assist [3]. Reluctance to abandon the concept of a “systolic squeeze” was a disservice to cardiologists and surgeons, who failed to observe much hemodynamic evidence of it and assumed the procedure had not worked.
Aortomyoplasty Wrapping the LD muscle around the ascending or descending aorta (aortomyoplasty) likewise creates no new blood-contacting surfaces, but there are practical difficulties. On the ascending aorta, the LD muscle must be split to accommodate the branching of major vessels; on the descending aorta, only a small stroke volume can be achieved, unless the diameter is enlarged surgically or a greater length is wrapped. The latter sacrifices spinal arteries, which could result in paraplegia.
Skeletal Muscle Ventricles A skeletal muscle ventricle (SMV) is a separate pump configured from LD muscle and connected to the circulation. Stephenson’s group [4] has done much to establish and refine the surgical techniques. In the most successful configuration, the SMV is connected to the descending aorta and operated in counterpulsation. The SMV filling then reduces left ventricular stroke work, and SMV ejection increases diastolic pressure, enhancing coronary perfusion. As the SMV is not constrained by the geometry of existing structures, the muscle can operate close to the peak of its power curve. At Liverpool, we use a preformed homograft lining, which enables the SMV to be constructed, placed inside the thoracic cavity, and connected to the aorta through a single conduit in one procedure. Thrombogenesis need not be a problem provided that strict design criteria are observed to ensure adequate mixing and exchange [5]. Other configurations are being investigated [6].
Hybrid Devices Progress has been made toward using skeletal muscle as the power source for a more conventional mechanical pump [7, 8]. That still presents challenges, including the overall efficiency of energy conversion, cost, hemocompatibility, connective tissue investment, and the risk of infection associated with multiple implanted devices. Ann Thorac Surg 2005;79:1101–3 • 0003-4975/05/$30.00 doi:10.1016/j.athoracsur.2004.10.009
1102
EDITORIAL SALMONS CARDIAC ASSISTANCE FROM SKELETAL MUSCLE
Conditioning and Activation “Conditioning” of a skeletal muscle enables it to perform cardiac work. For cardiomyoplasty, a clinical protocol was adopted that escalated over a series of weeks [9]. This protocol was largely intuitive, rather than scientifically based. It was certainly far from optimal, for it took 8 postoperative weeks, at the end of which the muscle had an undesirable phenotype. For years we have argued that the goal should be a muscle of the “2A” phenotype, which would possess the necessary fatigue resistance allied to fast, not slow, contractile characteristics. In cardiomyoplasty, a fastercontracting wrap would maintain wall reinforcement during early systole, and would relax quickly enough to ensure unrestricted filling. Such a state can be established and maintained by delivering fewer stimuli to the muscle. In practice, this can be achieved in two main ways: heart synchronization ratio, and demand stimulation.
Ann Thorac Surg 2005;79:1101–3
The unfortunate consequence is that a patient undergoes a highly invasive procedure without immediate benefit. There is a better approach. The vascular trees of the thoracodorsal artery and perforating arteries in the LD muscle are connected by arterial anastomoses. If the muscle is stimulated in situ before raising it as a graft (“prestimulation”), these vascular bridges remain patent, and distal parts of the muscle are then supplied from the intact thoracodorsal artery. Direct comparison of prestimulation with true vascular delay (in which perforating vessels are divided about 2 weeks before elevating the graft) shows that both ameliorate the fall in distal blood flow after mobilization, but prestimulation has the greater effect [12]. Prestimulation enhances distal perfusion through existing vascular networks and so obviates the need to wait for neoangiogenesis. It would also initiate conditioning preoperatively, so patients would reap the benefits of surgery more promptly.
Heart Synchronization Ratio Intramuscular pressure is high during a strong contraction and prevents blood from entering the muscle; sufficient time must be allowed for relaxation and reperfusion. If the muscle is stimulated on every cardiac cycle, venous lactate rises, evidence that a 1:1 régime of stimulation produces partially anaerobic—and therefore unsustainable—working conditions. Unfortunately, some clinical centers implemented 1:1 régimes, and the damage they reported was taken as proof that graft survival would always be a problem. Since the benefits of cardiomyoplasty stem mainly from girdling, not beat-to-beat assistance, the muscle can be safely activated on a smaller proportion of cardiac cycles. In Russia, heart synchronization ratios were sensibly set between 1:4 and 1:16, apparently with good results.
Demand Stimulation Stimulation can be restricted to part of the day—for example, waking hours or times of increased demand. Recent clinical studies provide clear evidence of increased contractile speed (and therefore power) of the grafted muscle when stimulation is switched from a conventional to an intermittent régime [10].
Preserving Viability of the Muscle Graft Most cardiomyoplasty patients improved by one to two New York Heart Association classes, but 15% to 20% did not, and survival data were often disappointing. Evidence from both animal and human studies suggests that outcome was adversely affected by deterioration of the wrap, involving fibrofatty replacement of functional muscle. Of the several factors involved, the most important is ischemia [11]. This ischemia results from the unavoidable division of perforating branches of the intercostal arteries during mobilization of the LD muscle. The usual solution is to delay the onset of stimulation, on the assumption that neovascularization will extend the area perfused by the surviving thoracodorsal artery.
New Devices Premature commercial exploitation of cardiomyoplasty, and the drive to meet regulatory requirements, discouraged departures from a fixed protocol, isolating clinical practice from progress in the underlying basic science. The subsequent withdrawal of Medtronic Inc was damaging, as it was interpreted as a vote of no confidence in the technique rather than a purely commercial decision. New devices are now emerging, such as the LD-Pace II from CCC Uruguay, enabling cardiomyoplasty and related research to be revived in several centers. If new protocols incorporate the advances described here, we may look forward to a more positive and consistent outcome.
Conclusion We are now better placed to exploit the potential of cardiac assistance from skeletal muscle. We know more about maintaining the vascular supply and viability of the graft, about optimizing its properties, and about different assist configurations. This knowledge should encourage us to embrace opportunities for advancing the field, both by refining the protocols for existing clinical techniques and by continuing to explore, initially at the experimental level, alternative configurations that are more radical but will harness the pumping power of skeletal muscle more effectively.
The author acknowledges the research contributions of his colleagues in the Liverpool group, and the support of the British Heart Foundation.
References 1. Salmons S, Sréter FA. Significance of impulse activity in the transformation of skeletal muscle type. Nature 1976;263: 30 – 4. 2. Salmons S. Permanent cardiac assistance from skeletal muscle: a prospect for the new millenium. Artif Org 1999;23: 380 –7.
Ann Thorac Surg 2005;79:1101–3
3. Kass DA, Baughman KL, Pak PH, et al. Reverse remodeling from cardiomyoplasty in human heart failure. External constraint versus active assist. Circulation 1995;91:2314 – 8. 4. Thomas GA, Hammond RL, Greer K, et al. Functional assessment of skeletal muscle ventricles after pumping for up to four years in circulation. Ann Thorac Surg 2000;70: 1281–9. 5. Shortland AP, Jarvis JC, Salmons S. Haemodynamic considerations in the design of a skeletal muscle ventricle. Med Biol Eng Comput 2003;41:529 –35. 6. Guldner NW, Klapproth P, Grossherr M, et al. Biomechanical hearts: muscular blood pumps, performed in a 1-step operation, and trained under support of clenbuterol. Circulation 2001;104:717–22. 7. Trumble DR, Magovern JA. Capturing in situ skeletal muscle power for circulatory support: a new approach to device design. ASAIO J 2003;49:480 –5.
EDITORIAL SALMONS CARDIAC ASSISTANCE FROM SKELETAL MUSCLE
1103
8. Reichenbach SH, Gustafson KJ, Egrie GD, et al. Evaluation of a skeletal muscle energy convertor in a chronic animal model. ASAIO J 2000;46:482–5. 9. Grandjean PA, Lori Austin RN, Chan S, Terpestra B, Bourgeois IM. Dynamic cardiomyoplasty: clinical follow-up results. J Card Surg 1991;6:80 – 8. 10. Barbiero M, Carraro U, Riccardi R, et al. Demand dynamic cardiomyoplasty: two-year results. Basic Appl Myol 1999;9: 195–206. 11. El Oakley RM, Jarvis JC, Barman D, et al. Factors affecting the integrity of latissimus dorsi muscle grafts: implications for cardiac assistance from skeletal muscle. J Heart Lung Transpl 1995;14:359 – 65. 12. Woo EB-C, Jarvis JC, Hooper TL, Salmons S. Avoiding ischemia in latissimus dorsi muscle grafts: electrical prestimulation versus vascular delay. Ann Thorac Surg 2002;73: 1927–32.
Cardiac Assistance From Skeletal Muscle: Should We Be Downhearted? Stanley Salmons, MS, PhD Department of Human Anatomy and Cell Biology, University of Liverpool, Liverpool, United Kingdom
C
ardiac assistance from skeletal muscle offers an attractive solution to the problem of end-stage heart failure. Unlike transplantation, it does not carry the risks, debilitating side-effects and costs of long-term immunosuppression therapy. A donor patient (or animal) is not needed, and the patient’s own heart is retained under conditions that offer the potential for myocardial recovery. This is an affordable technology that could be considered in parts of the world where other approaches, including mechanical pumps, would be too costly. Currently, there is much interest in injecting stem cells into infarcted or peri-infarcted regions. Although this is part of a fashionable trend, the technique yields only milligrams of contractile tissue that are isolated electrically and mechanically from the rest of the myocardium. Real benefits— beyond an increase in wall compliance and some local angiogenesis-—remain a distant prospect. In contrast, the technology we are referring to here involves the surgical redeployment of hundreds of grams of existing, mature contractile tissue. Early attempts at cardiac assistance were defeated by muscle fatigue. In 1979, Dr L. W. Stephenson and I initiated a fresh approach, incorporating “conditioning”: a marked increase in fatigue resistance that was part of the adaptive response of skeletal muscle to long-term electrical stimulation [1]. The results were impressive and engendered new interest in the field. In several centers, surgical techniques were developed that allowed a nonessential muscle, usually latissimus dorsi (LD), to be transferred into the chest and configured to provide cardiac assistance. Two techniques, dynamic cardiomyoplasty and aortomyoplasty, were tried clinically. There is now a widespread perception that the approach has failed to fulfill its promise. It is time to revise that view.
Harnessing the Power Cardiomyoplasty Wrapping the LD muscle around the failing heart (cardiomyoplasty) is conservative, insofar as it does not place a new, nonendothelial surface in contact with the blood. However, the persuasive notion that activating the wrap generates a more forceful ventricular contraction runs Address reprint requests to Dr Salmons, British Heart Foundation Skeletal Muscle Assist Research Group, Department of Human Anatomy and Cell Biology, University of Liverpool, The Sherrington Buildings, Ashton St, Liverpool L69 3GE, UK; e-mail: [email protected].
© 2005 by The Society of Thoracic Surgeons Published by Elsevier Inc
counter to elementary muscle mechanics. Because the muscle is heavily loaded it contracts isometrically or at best shortens slowly, operating far from the peak of its power curve (see Salmons [2] for a fuller bibliography on this and other topics). Symptomatic benefit comes mainly from a girdling action, rather than a beat-to-beat assist [3]. Reluctance to abandon the concept of a “systolic squeeze” was a disservice to cardiologists and surgeons, who failed to observe much hemodynamic evidence of it and assumed the procedure had not worked.
Aortomyoplasty Wrapping the LD muscle around the ascending or descending aorta (aortomyoplasty) likewise creates no new blood-contacting surfaces, but there are practical difficulties. On the ascending aorta, the LD muscle must be split to accommodate the branching of major vessels; on the descending aorta, only a small stroke volume can be achieved, unless the diameter is enlarged surgically or a greater length is wrapped. The latter sacrifices spinal arteries, which could result in paraplegia.
Skeletal Muscle Ventricles A skeletal muscle ventricle (SMV) is a separate pump configured from LD muscle and connected to the circulation. Stephenson’s group [4] has done much to establish and refine the surgical techniques. In the most successful configuration, the SMV is connected to the descending aorta and operated in counterpulsation. The SMV filling then reduces left ventricular stroke work, and SMV ejection increases diastolic pressure, enhancing coronary perfusion. As the SMV is not constrained by the geometry of existing structures, the muscle can operate close to the peak of its power curve. At Liverpool, we use a preformed homograft lining, which enables the SMV to be constructed, placed inside the thoracic cavity, and connected to the aorta through a single conduit in one procedure. Thrombogenesis need not be a problem provided that strict design criteria are observed to ensure adequate mixing and exchange [5]. Other configurations are being investigated [6].
Hybrid Devices Progress has been made toward using skeletal muscle as the power source for a more conventional mechanical pump [7, 8]. That still presents challenges, including the overall efficiency of energy conversion, cost, hemocompatibility, connective tissue investment, and the risk of infection associated with multiple implanted devices. Ann Thorac Surg 2005;79:1101–3 • 0003-4975/05/$30.00 doi:10.1016/j.athoracsur.2004.10.009
1102
EDITORIAL SALMONS CARDIAC ASSISTANCE FROM SKELETAL MUSCLE
Conditioning and Activation “Conditioning” of a skeletal muscle enables it to perform cardiac work. For cardiomyoplasty, a clinical protocol was adopted that escalated over a series of weeks [9]. This protocol was largely intuitive, rather than scientifically based. It was certainly far from optimal, for it took 8 postoperative weeks, at the end of which the muscle had an undesirable phenotype. For years we have argued that the goal should be a muscle of the “2A” phenotype, which would possess the necessary fatigue resistance allied to fast, not slow, contractile characteristics. In cardiomyoplasty, a fastercontracting wrap would maintain wall reinforcement during early systole, and would relax quickly enough to ensure unrestricted filling. Such a state can be established and maintained by delivering fewer stimuli to the muscle. In practice, this can be achieved in two main ways: heart synchronization ratio, and demand stimulation.
Ann Thorac Surg 2005;79:1101–3
The unfortunate consequence is that a patient undergoes a highly invasive procedure without immediate benefit. There is a better approach. The vascular trees of the thoracodorsal artery and perforating arteries in the LD muscle are connected by arterial anastomoses. If the muscle is stimulated in situ before raising it as a graft (“prestimulation”), these vascular bridges remain patent, and distal parts of the muscle are then supplied from the intact thoracodorsal artery. Direct comparison of prestimulation with true vascular delay (in which perforating vessels are divided about 2 weeks before elevating the graft) shows that both ameliorate the fall in distal blood flow after mobilization, but prestimulation has the greater effect [12]. Prestimulation enhances distal perfusion through existing vascular networks and so obviates the need to wait for neoangiogenesis. It would also initiate conditioning preoperatively, so patients would reap the benefits of surgery more promptly.
Heart Synchronization Ratio Intramuscular pressure is high during a strong contraction and prevents blood from entering the muscle; sufficient time must be allowed for relaxation and reperfusion. If the muscle is stimulated on every cardiac cycle, venous lactate rises, evidence that a 1:1 régime of stimulation produces partially anaerobic—and therefore unsustainable—working conditions. Unfortunately, some clinical centers implemented 1:1 régimes, and the damage they reported was taken as proof that graft survival would always be a problem. Since the benefits of cardiomyoplasty stem mainly from girdling, not beat-to-beat assistance, the muscle can be safely activated on a smaller proportion of cardiac cycles. In Russia, heart synchronization ratios were sensibly set between 1:4 and 1:16, apparently with good results.
Demand Stimulation Stimulation can be restricted to part of the day—for example, waking hours or times of increased demand. Recent clinical studies provide clear evidence of increased contractile speed (and therefore power) of the grafted muscle when stimulation is switched from a conventional to an intermittent régime [10].
Preserving Viability of the Muscle Graft Most cardiomyoplasty patients improved by one to two New York Heart Association classes, but 15% to 20% did not, and survival data were often disappointing. Evidence from both animal and human studies suggests that outcome was adversely affected by deterioration of the wrap, involving fibrofatty replacement of functional muscle. Of the several factors involved, the most important is ischemia [11]. This ischemia results from the unavoidable division of perforating branches of the intercostal arteries during mobilization of the LD muscle. The usual solution is to delay the onset of stimulation, on the assumption that neovascularization will extend the area perfused by the surviving thoracodorsal artery.
New Devices Premature commercial exploitation of cardiomyoplasty, and the drive to meet regulatory requirements, discouraged departures from a fixed protocol, isolating clinical practice from progress in the underlying basic science. The subsequent withdrawal of Medtronic Inc was damaging, as it was interpreted as a vote of no confidence in the technique rather than a purely commercial decision. New devices are now emerging, such as the LD-Pace II from CCC Uruguay, enabling cardiomyoplasty and related research to be revived in several centers. If new protocols incorporate the advances described here, we may look forward to a more positive and consistent outcome.
Conclusion We are now better placed to exploit the potential of cardiac assistance from skeletal muscle. We know more about maintaining the vascular supply and viability of the graft, about optimizing its properties, and about different assist configurations. This knowledge should encourage us to embrace opportunities for advancing the field, both by refining the protocols for existing clinical techniques and by continuing to explore, initially at the experimental level, alternative configurations that are more radical but will harness the pumping power of skeletal muscle more effectively.
The author acknowledges the research contributions of his colleagues in the Liverpool group, and the support of the British Heart Foundation.
References 1. Salmons S, Sréter FA. Significance of impulse activity in the transformation of skeletal muscle type. Nature 1976;263: 30 – 4. 2. Salmons S. Permanent cardiac assistance from skeletal muscle: a prospect for the new millenium. Artif Org 1999;23: 380 –7.
Ann Thorac Surg 2005;79:1101–3
3. Kass DA, Baughman KL, Pak PH, et al. Reverse remodeling from cardiomyoplasty in human heart failure. External constraint versus active assist. Circulation 1995;91:2314 – 8. 4. Thomas GA, Hammond RL, Greer K, et al. Functional assessment of skeletal muscle ventricles after pumping for up to four years in circulation. Ann Thorac Surg 2000;70: 1281–9. 5. Shortland AP, Jarvis JC, Salmons S. Haemodynamic considerations in the design of a skeletal muscle ventricle. Med Biol Eng Comput 2003;41:529 –35. 6. Guldner NW, Klapproth P, Grossherr M, et al. Biomechanical hearts: muscular blood pumps, performed in a 1-step operation, and trained under support of clenbuterol. Circulation 2001;104:717–22. 7. Trumble DR, Magovern JA. Capturing in situ skeletal muscle power for circulatory support: a new approach to device design. ASAIO J 2003;49:480 –5.
EDITORIAL SALMONS CARDIAC ASSISTANCE FROM SKELETAL MUSCLE
1103
8. Reichenbach SH, Gustafson KJ, Egrie GD, et al. Evaluation of a skeletal muscle energy convertor in a chronic animal model. ASAIO J 2000;46:482–5. 9. Grandjean PA, Lori Austin RN, Chan S, Terpestra B, Bourgeois IM. Dynamic cardiomyoplasty: clinical follow-up results. J Card Surg 1991;6:80 – 8. 10. Barbiero M, Carraro U, Riccardi R, et al. Demand dynamic cardiomyoplasty: two-year results. Basic Appl Myol 1999;9: 195–206. 11. El Oakley RM, Jarvis JC, Barman D, et al. Factors affecting the integrity of latissimus dorsi muscle grafts: implications for cardiac assistance from skeletal muscle. J Heart Lung Transpl 1995;14:359 – 65. 12. Woo EB-C, Jarvis JC, Hooper TL, Salmons S. Avoiding ischemia in latissimus dorsi muscle grafts: electrical prestimulation versus vascular delay. Ann Thorac Surg 2002;73: 1927–32.