The Clinical Usage of Transformed Muscle Flaps in Dynamic Cardiomyoplasty.
The aim of this literature project is to show that even though dynamic cardiomyoplasty is a promising treatment for heart failure, it is by no means without flaws, these must be addressed before it is to be fully trusted clinically. Although chronic low-frequency stimulation of the latissimus dorsi muscle leads to transdifferentiation into cardiac muscle, reports have shown that in the long term the transformed muscle fatigues, deteriorates and becomes infiltrated with fat. Also complications with vascularisation and ischemic damage need attention. Research is still on going to find the optimum conditioning protocol to lead to sufficient vascularisation and complete fatigue resistance. Until this protocol has been established poor long term survival rates prevent this surgical technique from becoming a routine procedure for the treatment of heart failure and cardiomyopathies.
- What is dynamic cardiomyoplasty?
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Dynamic cardiomyoplasty (d-CMP) is a surgical technique that was developed as an alternative to heart transplant and as a treatment for heart failure and cardiomyopathies. Skeletal muscle is wrapped around the ventricles of the heart and is attached to a device called a cardiomyostimulator that delivers an electrical impulse to the muscle flap to assist cardiac pumping. The surgical procedure was developed and successfully used clinically in 1985 by Carpentier and Chachques. The muscle used to aid the failing heart was the latissimus dorsi muscle (LDM). Reports have shown that other skeletal muscles are being considered for use such as the diaphragm and the rectus abdominus but the most frequent choice is the latissimus dorsi (Salmons, 1999).
The procedure involves the redeployment of the patient’s own skeletal muscle. The left LDM is most frequently used but some authors have reported the use of the right LDM, particularly for patients without the left ventricular enlargement usually present in cardiomyopathies (Moreira and Stolf, 2001). Two separate incisions are required (Moreira at al., 2003). Firstly is a lateral approach, with the patient positioned on his or her side, for muscle flap dissection and secondly a median sternotomy for cardiac access (Benicio et al., 2003). A median sternotomy involves a vertical incision made along the sternum after which the sternum is divided allowing access to the heart (Wikipedia, 2006). The LDM is dissected while leaving the neurovascular bundle of the muscle preserved (Kucukaksu et al., 2003). This leaves the nerve and blood supply of the muscle intact at the neurovascular pedicle (Jessup, 2000). The muscle flap is wrapped around the left and right ventricles providing a left posterior cardio-costal wrapping (Benicio et al., 2003). This means that the LDM is wrapped in a clockwise fashion around the ventricles. To provide electrical stimulation two intramuscular pacing electrodes are implanted in the skeletal muscle graft (Shirota et al., 2000). A sensing lead is placed in either the right or left ventricle and the procedure is finalized by the implantation of a cardiomyostimulator (Chachques et al., 1997). Two weeks are allowed for healing and adherence before a stimulation protocol begins (Jessup, 2000).
- Is dynamic cardiomyoplasty a viable means of cardiac assistance?
Due to growing transplant lists there is an increased need to develop new methods to treat people with heart failure and cardiomyopathies (Salmons, 1998). Cardiac assistance from skeletal muscle has been a promising solution but with a few setbacks, it has not come into routine clinical use. Other alternatives including xenografts could reduce transplant lists but this carries the risk of infection by latent animal viruses. D-CMP seems a sensible approach to reaching a solution as it uses the patient’s own muscle so there would be no need for long-term immunosuppression. It also has the advantage of not being limited by donor availability making d-CMP a very attractive choice to aid the situation (Kucukaksu at al., 2003).
The main benefits that are derived from d-CMP are the mechanical assist and the girdling effect of the muscle (Kass et al., 1995). The heart is assisted mechanically during ejection by the squeezing action of the LDM, thereby increasing cardiac output (Kawaguchi et al., 1992). The girdling action of the muscle wrap can help prevent further enlargement of the ventricles and can promote reverse chamber remodelling (Benvenuti et al., 2004).
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There are certain complications in d-CMP that need to be addressed if this procedure is to become commonplace in hospitals to treat heart failure. These include the development of an optimum chronic low frequency stimulation (CLFS) protocol, and the prevention of muscle deterioration and fatigue and muscle ischemia. CLFS causes the transition of skeletal muscle fibres to fatigue resistant cardiac fibres (Froemming et al., 2000).
However, despite this, many patients, after receiving d-CMP, experience improved quality of life. Reports have suggested that d-CMP significantly reduces the degree of limitation for physical activities (Moreira and Stolf, 2001). Patients in New York Heart Association (NYHA) class III and IV often see improvement to NYHA class II and III respectively. Perioperative mortality is low and in some cases there are in-hospital no deaths (Chachques et al., 2003). Survival rates are usually event free in the short term. In a study by Moreira et al. (2003) results for 1-year event-free survival were 81.3 ± 5.9%.
Long-term viability of d-CMP is still in question; Kucukaksu et al. (2003) found that muscle integrity was lost four years after d-CMP. Deaths can also be attributed to muscle ischemia, ventricular failure and arrhythmia (Moreira and Leirner, 2001). Even though this procedure was developed as an alternative to heart transplant maybe it can only act as a bridge to transplant until a donor becomes available.
2. Types of Muscle
There are four types of muscle, two of which are integral to d-CMP, these are skeletal and cardiac muscle. An outline of all four muscle types will be given, with special attention paid to skeletal and cardiac muscle.
2.1 Smooth muscle
Smooth muscle is involuntary muscle and it contracts slowly and takes a long time to fatigue. It is called smooth since its spindle shaped cells lack striations. These cells lack a nucleus and are capable of cell division. Smooth muscle is found in the walls of the digestive tract, urinary bladder, arteries and other internal organs (Campbell and Reece, 2002). The contraction of smooth muscle is under control of the autonomic nervous system, a part of the peripheral nervous system controlling homeostasis. Smooth muscle contraction involves cross-bridge movements between actin and myosin filaments to generate force, while calcium ions control cross-bridge activity (Widmaier et al., 2004). Unlike skeletal muscle, which will be discussed later, cross-bridge activation comes about from the interaction of Ca2+ with calmodulin as opposed to troponin. Smooth muscle action potential is generated by an influx of Ca2+ through voltage-gated channels. This muscle type has a high tension threshold compared to that of skeletal muscle, as it must cope with changes in volume within hollow organs.
2.2 Myoepithelial cells
Myoepithelial cells are a type of epithelial cell that have similarities to smooth muscle, they are located in the glandular epithelium between secretory cells and the basement membrane. They contract and cause the expulsion or movement of secretions from particular glands (Wikipedia, 2007), for example myoepithelial cells are involved in the ejection of milk from the breast during lactation. These cells contain smooth muscle specific cytoskeletal and contractile proteins (Deugnier et al., 2002). In human foetal breast tissue a smooth muscle marker, a-actin, was found in myoepithelial cells present (Anbazhagan et al., 1998), thus indicating its smooth muscle similarities.
2.3 Skeletal muscle
Skeletal muscles are, as the name suggests, attached to bones and they provide the force that allows movement of the body and the maintenance of posture. Skeletal muscle is normally under voluntary control and nerve impulses sent to the muscle initiate its contraction. Unlike smooth muscle cells, skeletal muscle cells cannot undergo cell division after birth, although new fibres can be formed by satellite cells. Skeletal muscle fibres are cylindrical and multinucleated. The muscle is striated, a series of thick and thin filaments, forming myofibrils, causes this characteristic banding pattern. One unit of this repeating pattern is called the sacromere. The thick filaments contain the contractile protein myosin, while the thin filaments contain actin, troponin and tropomyosin, all of which play an important role in contraction (Widmaier, 2004). Cross-bridges, extensions of myosin molecules, are integral to contraction by interacting with actin on thin filaments and shortening the sacromere. ATP and the influx of calcium ions activate contraction. ATP binds to myosin, while calcium ions bind to troponin causing tropomyosin to reveal myosin-binding sites on actin molecules. Other proteins involved in the contraction cycle will be discussed later in Section 3, which discusses chronic low-frequency stimulation.
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There are three separate types of skeletal muscle fibres that differ in their contractile speed and in the metabolic pathway used, either oxidative or glycolytic. Type I fibres are slow contracting fibres with an oxidative metabolism, they are fatigue resistant, red in colour and are similar to cardiac muscle fibres (Cernaianu et al., 1995). Type IIa fibres are fast and oxidative. They contain a large amount of myoglobin so they are red in colour. This fibre type is moderately resistant to fatigue. Finally Type IIb is a fast contracting fibre with a glycolytic metabolism. This is the predominant fibre type in the LDM (Barron et al., 2001). The fibres are white in colour and are non-resistant to fatigue. Skeletal muscle cells are said to have a certain amount of plasticity when subjected to endurance training or when stimulated electrically, this means that they can convert from a fast fibre type to a slow fibre type, and vice versa. This trait is taken advantage of in the conditioning stage of d-CMP. Given time skeletal muscles could adapt their physiological, biochemical and structural characteristics to a more demanding pattern of use (Salmons, 1999).
2.4 Cardiac muscle
Cardiac muscle is found exclusively in the heart. This is an involuntary muscle that has some characteristics of skeletal muscle. Like smooth muscle it is under control of the autonomic nervous system and its fibres contain a single nucleus. However the fibres are striated as in skeletal muscle but unlike skeletal muscle cardiac muscle is fatigue resistant. The cells are striated due to the arrangement of thick myosin and thin actin filaments. Cells are joined end to end by structures known as intercalated disks. These disks enable the rapid transmission of excitatory waves across the tissue (Hale et al., 2005). Calcium ions bind to troponin, as in skeletal muscle, to initiate contraction.
The cardiac cycle is mediated by ventricular contraction, systole, and ventricular relaxation, diastole. D-CMP uses this mechanism to treat heart failure; the LDM is wrapped around the ventricles and assists the pumping cycle by contracting with the hearts own systole. The LDM is usually stimulated to contract in synchronization with every heartbeat or with every other heartbeat. The time course of cardiac muscle contraction is slower to that of fast skeletal muscle but similar to that of slow skeletal muscle. In 1969 Salmons and Vbrova found that stimulating fast skeletal muscle at low frequencies, similar to those found naturally in slow muscle, lengthened “the time course of contraction and relaxation of the stimulated muscle”.
3. Chronic Low-Frequency Stimulation
Chronic low-frequency stimulation (CLFS) is essential to the success of d-CMP. It enables the transition of fast, type IIb, to slow, type I, skeletal muscle fibres that express protein isoforms found in cardiac muscle. The LDM is stimulated over a period of weeks with a gradual increasing frequency to transform the skeletal muscle fibres. This transformation process is called conditioning. Salmons and Vbrova (1969) found that it was possible to make a slow muscle contract faster and a fast muscle contract slowly by subjecting it to frequencies of stimulation similar to that of a contracting fast or slow muscle, respectively. The changes, as a result of CLFS, enable the muscle to support an increase in activity without fatigue by decreasing the energy needed for contraction while increasing the capacity for generating that energy through an aerobic metabolism (Sutherland et al., 2006). CLFS causes the down-regulation of protein isoforms of fast skeletal muscle, and compensatory to this it causes the up-regulation of slow/cardiac muscle protein isoforms.
Expression levels of proteins can be compared by analysis with SDS-PAGE (sodium dodecyl sulphate-polyacrylamide gel electrophoresis) and immunoblotting using primary and secondary mono- or polyclonal antibodies. Research papers have compared slow skeletal muscle, fast skeletal muscle, and cardiac muscle and chronic low-frequency stimulated fast skeletal muscle. Most of these experiments have been carried out on animal models, rabbit being a primary choice for many. In the studies looked at here the rabbit tibialis anterior muscle and the extensor digitorum longus muscle, both fast twitching, were stimulated continuously (24hr) for periods of between four and sixty days to transform them to slow, cardiac-like, twitching muscles.
The proteins examined here are those involved in voltage sensing, Ca2+ release, Ca2+ uptake and Ca2+ binding. These proteins play a part in the excitation-contraction-relaxation cycle.
3.1 Myosin heavy chain expression
Myosin is involved in muscle contraction, it binds to actin thus forming actomyosin. Prior to CLFS the fast isoform of the myosin heavy chain, MHCIId(x) or MHCf, was predominant. Subsequent to the stimulation protocol the level of MHCf decreased, this was compensated for by the up-regulation of the slow isoform MHCI or MHCs. The slow isoform is present in cardiac muscle fibres. Figures 1 and 2 show the decrease in expression of MHCf after electro-stimulation.
3.2 Expression of sacroplasmic reticulum Ca2+-ATPases
SERCA1 and SERCA2 are ion-regulatory membrane proteins involved in calcium ion homeostasis. SERCA1 is expressed in fast twitch muscles while SERCA2 is expressed in slow twitch and cardiac muscles. After CLFS SERCA1 is clearly down-regulated and thus SERCA2 is significantly up-regulated (Harmon et al., 2001). See Figure 2. Figure 3 the progression of increase of SERCA2 and decrease of SERCA1 over a stimulation protocol of sixty days.
3.3 Expression of Ca2+ channel associated proteins
During the fast to slow transition process the expression of the dihydropyridine recptor (DHPR) a-subunit undergoes a switch in isofrom type. The DHPR is a voltage sensing receptor. The process causes the down-regulation of the a1s-subunit and up-regulation of the a1c-subunit; this subunit is the cardiac counter-part (Ohlendieck, 2000). Figure 4 shows the expression pattern of these isoforms in fast and slow skeletal muscle, cardiac muscle and CLFS fast muscle. The a1c-subunit is absent in cardiac muscle and subsequent to thirty day stimulation is absent in the transformed fast muscle. The ryanodine receptor (RyR) is involved in the Ca2+-release channel. The fast muscle isoform is RyR1which is down-regulated during CLFS, interestingly the cardiac RyR2 isoform is not found to be up-regulated to compensate (Ohlendieck et al., 1999).
3.4 Expression of a Ca2+-binding protein
Calsequestrin (CSQ) is a Ca2+-binding protein. During the fast to slow transition process the fast isoform CSQf is significantly reduced while the slow/cardiac isoform is significantly increased in the stimulated skeletal muscle. Figure 2 shows this transformation.
3.5 Evidence of muscle plasticity
In an experiment by Froemming et al. (2000) it was conclusively shown that skeletal muscle is highly adaptable. Fast skeletal muscle was stimulated for fourteen days, followed by a recovery period of thirty days. The stimulation induced the down-regulation of proteins previously mentioned. An immunoblot analysis was carried out after the recovery period. The protein down-regulation was totally or partially reversed in most cases. This confirms the knowledge that muscle is highly adaptable and capable of meeting increased functional demands.
4. The Effectiveness of Dynamic Cardiomyoplasty
4.1 General benefits
It is the general consensus that the main benefits of d-CMP are the ventricular assist provided by synchronized contraction of the LDM and the girdling action of the muscle wrap. This is believed to allow a certain amount of recovery to the enlarged ventricles and damaged myocardium. There is a suggestion by Benvenuti et al. (2004) that left ventricular-assistance results in a reduction in left ventricular diameter and an increase in wall thickness, this is indicative of reverse remodelling. Another benefit is the reduction of myocardial oxygen consumption due to a decrease in ventricular wall stress, (Misawa and Fuse, 2003). Patients with ischemic cardiomyopathy may derive benefit from the cross-revascularisation between the muscle flap and the ventricular epicardium (Moreira and Leirner, 2001).
The objective of d-CMP is to transform the fast twitch and easily fatigable type II fibres of the LDM to slow twitch, fatigue resistant type I fibres by chronic low-frequency stimulation (Chachques et al., 1997). This transformation to fatigue resistance is to obtain optimal benefit from the subsequent cardiac assistance provided by contraction of the wrap; it is critical to the success of the operation (Yilmaz et al., 2003). As a result left-ventricular ejection fraction is often significantly increased compared to preoperative levels (Benicio et al., 2003). Table 1 shows long-term ejection fractions from several clinical trials, from the preoperative period up to five years after d-CMP (modified from Moreira and Stolf, 2001). The fractions become lowered over time due to muscle flap deterioration.
Table 1. Long-term ejection fractions (%) after dynamic cardiomyoplasty: Preoperative to five-year follow-up.
6 mo. %
1 yr. %
2 yr. %
3 yr. %
4 yr. %
5 yr. %
The table shows that there is an increase in the ejection fraction of the left ventricle after dynamic cardiomyoplasty, however this can decrease over time(modified from Moreira and Stolf, 2001).
These are among the main outcomes of d-CMP from which patients derive benefit. This leads to an improvement in the quality of life of many patients, although some patients derive no benefit from the procedure at all (Salmons, 1999).
4.2 Indications and contraindications
The success of d-CMP is dependent upon a strict screening process for patient selection. D-CMP is used to treat heart failure, chronic congestive and congestive heart failure, ischemic, idiopathic and dilated cardiomyopathies, left ventricular tumour and aneurysm. It has been employed to treat Chagas’ disease cardiomyopathy. Patients with persistent symptoms of NYHA class III and IV are often treated by d-CMP (Jessup, 2000).
Patients indicated for the procedure have persistent severe dilated cardiomyopathies despite the optimal use of medical therapy (Moreira et al., 2003), for example, patients who still experience limitations despite the use of ACE (angiotensin converting enzyme) inhibitors. Those with reduced left ventricular function and an ejection fraction of less than 26% are indicated (Benicio, 2003). Recurrent hospitalisation due to impaired ventricular function is also an indication for d-CMP.
Contraindications for d-CMP are patients with enlargement of the left ventricular chamber over 50mm/m2 (Moreira et al., 2003). Other contraindications include poor lung function, unresolved drug or alcohol abuse and any life threatening noncardiac disease (Moreira and Stolf, 2001).
4.3 Survival rates
In the majority of clinical trials survival in the short-term is high, while long-term survival is low with some exceptions. Overall however survival rates have improved since the introduction of d-CMP in 1985. Mortality is usually due to heart failure progression and arrhythmia, along with deterioration of the LDM flap. Patient screening has helped to reduce in-hospital mortality rates; it has declined to less than 10% in the last number of years (Chachques et al., 1997). Late deaths have been reported subsequent to d-CMP despite improvement in left-ventricular performance (Moreira and Leirner, 2001). A study by Moreira et al. (2003) tracked the survival rates of patients after d-CMP, this included patient follow-up for up to seven years. One year event free survival was promising at 81.3 ± 5.9% but after 6 years this was reduced to 23.1 ± 6.7%. Figure 5 graphs the results obtained, it shows a steady decline in patient survival after year one. These results, which are consistent with other reports and clinical trials, have prevented d-CMP from becoming a routine treatment.
Deaths related to arrhythmia may be prevented by the use of an implantable cardiac defibrillator along with the cardiomyostimulator (Salmons, 1999). Also, if required, a heart transplant can be carried out successfully after d-CMP (Kucukaksu et al., 2003). Sections 4.4 to 4.8 discuss complications of d-CMP and how d-CMP can be made more effective and improve survival rates.
4.4 Decrease in skeletal muscle flap power over time
In the long-term the LDM flap begins to deteriorate and is no longer effective. This is due to several factors such as over stimulation and an increased metabolic demand associated with graft conditioning. A less rigorous stimulation protocol could prevent this. Fat and fibrous tissue infiltration has contributed to loss of power in the muscle flap (Salmons, 1999). The thickness of the flap also decreases with time and prevents adequate functioning of the LDM. One of the main culprits leading to deterioration is the impairment of blood flow to the muscle, a vascular delay (a delay between the operation and the stimulation of the flap) has been used to combat this but it is not known whether this is fully effective yet. This delay, usually a duration of 2 weeks, prevents the patient from experiencing the immediate benefit of cardiac assistance.
4.5 The stimulation protocol
The electrostimulation protocol is started two weeks after d-CMP to allow for vascularisation and adhesion between the heart and LDM (Chachques et al., 1997). Stimulation is achieved by a cardiomyostimulator made by the company Medtronic. The stimulation of the LDM is gradually increased over a number of weeks, the frequency and number of pulses are increased. After approximately two months an optimum frequency of stimulation is maintained to contract in synchronization with every cardiac beat (1:1) or with every other cardiac beat (1:2). It has been observed that a 1:2 stimulation protocol preserves the muscle integrity for longer compared to muscle stimulated to contract with every cardiac beat. The more intense protocol increases the likelihood of irreversible damage to the LDM wrap (Salmons, 1999).
Rigatelli et al. (2002) researched the possibility of an activity-rest stimulation protocol. This meant that fewer impulses were delivered to the LDM per day than standard protocols. They believed that it would prevent deterioration of the muscle flap over the long-term and thought it may improve cardiac assistance. The technique was tested in seven patients. The muscle was stimulated during active hours by a synchronization ratio of between 1:2 – 1:4, the muscle was not stimulated during resting hours. They concluded that the ejection fraction of the ventricles was significantly increased following this protocol as the muscle was allowed to rest, see Table 2. These ejection-fractions are much more powerful than those seen in Table 1 giving further evidence that an activity-rest stimulation protocol would be more effective. A more powerful fatigue resistant muscle was created, they believed this to be due to an intermediate level of transformation of the LDM.
Table 2. The ejection-fraction levels: Preoperative and at the follow up.
Preoperative ejection fraction (%)
Follow-up ejection fraction (%)
This table shows that the ejection-fractions were significantly increased in patients following the activity-rest stimulation protocol (modified from Rigatelli et al., 2002).
4.6 Blood flow and perfusion
Muscle ischemia is one of the major causes of deterioration of the LDM as blood flow to the muscle is restricted. It mainly affects the distal part of the muscle flap, it arises as the flap is lifted by perforating arteries that enter the muscle (Salmons, 1999). When the flap is mobilized during the surgical procedure it results in the reduction of blood flow to the distal regions of the LDM, perfusion remains reduced, which has implications on the integrity of the muscle flap (Barron et al., 1997). Adopting a preconditioning protocol of the LDM before mobilization is thought to improve blood flow and muscle performance (Ali et al., 1998).
In 1998 Tang at al. investigated this hypothesis in a study using sheep. They saw that the configuration of the vascular supply could provide a solution and lead to reperfusion of the LDM. Anastomotic channels would enable blood from the thoracodorsal artery to perfuse the distal region of the LDM by its existing vascular network. It was believed that preconditioning the LDM would allow this. They stimulated the muscle with a moderate protocol in situ before raising it as a graft. They subsequently found that this stimulation regime, prior to mobilization, could significantly enhance blood flow from the thoracodorsal artery to the LDM via its existing vascular network.
4.7 Muscle expansion
It can often be the case that the ventricles have become too enlarged for adequate wrapping by the LDM and so d-CMP does not perform as effectively in such patients. A study by Chachques et al. (1996) showed that the surface area of the muscle could be increased with the use of a silicone expander prior to d-CMP surgery. The expander was placed under an in situ LDM and gradually inflated over a period of eight weeks, this was coupled with a preconditioning protocol. The expander enabled entire wrapping of the ventricles and so patients received the same benefits as those without excessive ventricular enlargement. There were added benefits to the use of the expander, as it seemed to prepare the LDM for vascularisation after d-CMP. There were no signs of ischemia. Stretching the muscle also promoted transformation of the muscle fibers from type II to type I. The stretching was anabolic allowing the lengthening of the muscle. It was concluded that the regime induced a favorable and effective performance from the LDM.
Skeletal muscle assist devices such as gracilomyoplasty have become routine hospital procedures, but dynamic cardiomyoplasty remains a promising prospect and not a primary treatment for heart failure. Complications previously described prevent this surgical technique from becoming a routine procedure. Although chronic low-frequency stimulation does transform proteins of the fast skeletal muscle fibers of the latissimus dorsi muscle to slow or cardiac ones, its contractile power decreases over time due to fatigue. A stimulation protocol that produces complete fatigue resistance is required. The lack of perfusion to the distal part of the muscle adds to the deterioration of the graft. Research is on going to tackle such obstacles. An activity-rest stimulation protocol and preconditioning prior to mobilization have produced encouraging results. Muscles treated in this way were more fatigue resistant and vascularisation was improved. Muscle expansion can increase the number of patients indicated for the procedure. Survival rates have risen since the introduction of dynamic cardiomyoplasty in 1985. Long-term survival rates remain low however, but with the introduction of an optimum conditioning protocol patients may enjoy a longer life. At present dynamic cardiomyoplasty can only act as a bridge to heart transplant.
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