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Transmyocardial revascularization (TMR): current status and future directions

  • Keith B. AllenEmail author
  • Amy Mahoney
  • Sanjeev Aggarwal
  • John Russell Davis
  • Eric Thompson
  • Alex F. Pak
  • Jessica Heimes
  • A. Michael Borkon
Review Article
  • 35 Downloads

Abstract

Purpose

Cardiac surgeons are increasingly faced with a more complex patient who has developed a pattern of diffuse coronary artery disease (CAD), which is refractory to medical, percutaneous, and surgical interventions. This paper will review the clinical science surrounding transmyocardial revascularization (TMR) with an emphasis on the results from randomized controlled trials.

Methods

Randomized controlled trials which evaluated TMR used as sole therapy and when combined with coronary artery bypass grafting were reviewed. Pertinent basic science papers exploring TMR’s possible mechanism of action along with future directions, including the synergism between TMR and cell-based therapies were reviewed.

Results

Two laser-based systems have been approved by the United States Food and Drug Administration (FDA) to deliver laser therapy to targeted areas of the left ventricle (LV) that cannot be revascularized using conventional methods: the holmium:yttrium-aluminum-garnet (Ho:YAG) laser system (CryoLife, Inc., Kennesaw, GA) and the carbon dioxide (CO2) Heart Laser System (Novadaq Technologies Inc., (Mississauga, Canada). TMR can be performed either as a stand-alone procedure (sole therapy) or in conjunction with coronary artery bypass graft (CABG) surgery in patients who would be incompletely revascularized by CABG alone. Societal practice guidelines have been established and are supportive of using TMR in the difficult population of patients with diffuse CAD.

Conclusions

Patients with diffuse CAD have increased operative and long-term cardiac risks predicted by incomplete revascularization. The documented operative and long-term benefits associated with sole therapy and adjunctive TMR in randomized trials supports TMR’s increased use in this difficult patient population.

Keywords

Transmyocardial revascularization TMR Laser 

Introduction

CAD is a manifestation of atherosclerosis, which often leads to angina, myocardial infarction, congestive heart failure, and ultimately death. Currently, available options for treating CAD include life style changes in conjunction with drug therapy (medical management), percutaneous coronary intervention (PCI), and CABG. Unfortunately, despite optimal therapy, there remain patients who have medically refractory angina who are not eligible for conventional revascularization [1] or who be incompletely revascularized by CABG alone [2]. The hallmark of this difficult patient population is the presence of diffuse CAD.

It is estimated that 3% of patients presenting with CAD are not candidates for conventional revascularization (Fig. 1a) and that 15–25% of patients undergoing CABG will have one or more major target areas incompletely revascularized due to diffuse CAD (Fig. 1b) [1, 2]. Incomplete revascularization due to diffuse CAD is recognized as an independent predictor of operative mortality [3, 4, 5], particularly in the elderly [6], and is associated with decreased long-term freedom from cardiac death, acute myocardial infarction, and cardiac events [6, 7, 8]. Diffuse CAD, when quantified, is a strong independent predictor of operative mortality [9] and the quality of distal target during CABG has been identified as a strong predictor of vein graft failure [10]. TMR has yielded positive clinical results in these difficult subsets of patients.
Fig. 1

Angiogram in a patient with Canadian Cardiovascular Class IV angina with diffuse coronary artery disease a who would be a candidate for sole therapy TMR. Angiogram in a diabetic patient in whom standard of care would be CABG b but who is likely to be incompletely revascularized by CABG alone and who may benefit from TMR

TMR is an approved surgical procedure in which 1-mm transmural laser channels are created in ischemic myocardium, which cannot be conventionally revascularized. TMR can be performed either as a stand-alone procedure (sole therapy) or in conjunction with CABG in patients, who would be incompletely revascularized by CABG alone [11]. In prospective randomized trials, sole therapy TMR in no-option patients with medical refractory angina has yielded significant improvements in angina, event-free survival, and a reduction in cardiac-related hospitalizations compared to patients randomized to continued maximum medical therapy [12, 13, 14, 15, 16]. Long-term follow-up of TMR as a primary therapy shows an enduring benefit over time [16, 17, 18] and 5-year follow-up of one prospective randomized trial involving the most severe Canadian Cardiovascular Society (CCS) Class IV patients demonstrated improved survival in the TMR-treated patients [17]. This paper will review the clinical science surrounding TMR with an emphasis on the results from randomized controlled trials. In addition, future directions with the potential of combining TMR with biologics, such as stem cells to achieve an enhanced synergistic effect will be discussed.

Devices and procedure descriptions

Two laser-based systems have been approved by the FDA to deliver laser therapy to targeted areas of the left ventricle that cannot be revascularized using conventional methods: the holmium:yttrium-aluminum-garnet (Ho:YAG) laser system (CryoLife, Inc., Kennesaw, GA) and the carbon dioxide (CO2) laser system (PLC Medical Systems, Franklin, MA), although the CO2 laser has been discontinued. The Ho:YAG system (Fig. 2) uses a 20-watt-pulsed laser to deliver 7 W per laser pulse at a rate of 5 pulses per second through a 1-mm flexible fiber optic bundle. The hand piece allows the surgeon to position and stabilize the embedded fiber optic bundle against the epicardial surface. The CO2 laser system is set to deliver 800 W in a single pulse 1 to 99 msec long at energies of 8 to 80 J to create 1-mm diameter channels. Energy is delivered via an articulated arm and hand piece. The CO2 system uses helium-neon laser guidance for proper epicardial positioning of the hand piece, and electrocardiographic (ECG) synchronization to fire on the R-wave of the ECG cycle when the ventricle is maximally distended and electrically quiescent.
Fig. 2

The holmium:yttrium-aluminum-garnet (Ho:YAG) laser system (CardioGenesis Corporation, CryoLife, Inc., Kennesaw, GA) uses a 20 watt pulsed laser to deliver 7 W per laser pulse at a rate of 5 pulses per second through a 1-mm flexible fiber optic bundle. The hand piece allows the surgeon to position and stabilize the embedded fiber optic bundle against the epicardial surface

Regardless of which laser is utilized, sole therapy TMR does not require cardiopulmonary bypass (CPB), anticoagulation, or a sternotomy. Anesthesia includes a short-acting inhalation agent supplemented with low-dose narcotics and propofol. The distal two thirds of the left ventricle is exposed using a limited left anterolateral thoracotomy through the fifth intercostal space; and lung isolation is rarely needed. Laser channels are placed every square centimeter in the distal two thirds of the left ventricle pausing between groups of channels to obtain hemostasis and allow for myocardial recovery. Epicardial ligation of a laser channel for persistent bleeding is rarely required. Laser energy, when absorbed by ventricular blood, produces an acoustic image analogous to steam that is readily visible by transesophageal echocardiography (TEE). When utilizing the Ho:YAGlaser, TEE can be used to confirm penetration of the laser into the left ventricle; however, after several procedures, tactile and auditory feedback enable the surgeon to confirm transmural penetration without TEE. When using the CO2 laser, TEE is mandatory to confirm transmural penetration and to determine the appropriate energy setting for the laser.

TMR, when performed as an adjunct to CABG, can be performed with or without cardiopulmonary bypass. When TMR is performed with the Ho:YAG system during on-pump cases, it is recommended TMR channels be created on an arrested heart. This facilitates the procedure and may reduce bleeding as compared to placing laser channels at the conclusion of the case. For off pump cases, TMR is performed after bypass grafts are completed. Adjunctive TMR using the CO2 system must be performed on a beating heart either before or after bypass grafts have been placed.

Trial designs and results: TMR as sole therapy

The safety and effectiveness of TMR as sole therapy have been evaluated in five prospective, randomized trials [12, 13, 14, 15, 16], summarized in (Table 1). Experimental designs and patient selection criteria were similar across the five trials. Study endpoints included operative (in-hospital/30 days) mortality and 1-year survival, improvement in angina class, myocardial perfusion, exercise tolerance, quality of life, cardiac-related hospitalization, and major adverse events. Aside from a variation in the number of patients enrolled, certain features made some trials unique. Whereas Allen et al. [12] only randomized patients with medically refractory CCS Class IV angina, Schofield and associates [15] enrolled patients with primarily CCS Class III angina, which may have influenced results.
Table 1

Baseline patient characteristics from randomized controlled trials of sole therapy TMR

Characteristic1

Allen [12]

Frazier [13]

Burkhoff [14]

Schofield [15]

Aaberge [16]

Number of centers

18

12

16

1

1

Patients (N)

275

192

182

188

100

Crossover allowed

Yes

Yes

No

No

No

Age2 (years)

60

61

63

60

61

Male gender (%)

74

81

89

88

92

EF (%)

47

50

50

48

49

Class III/IV (%)

0/100

31/69

37/63

73/27

66/34

CHF (%)

17

34

NR

9

NR

Diabetes (%)

46

40

36

19

22

Hyperlipidemia (%)

79

57

77

NR

76

Hypertension (%)

70

65

74

NR

28

Prior MI (%)

64

82

70

73

70

Prior CABG (%)

86

92

90

95

80

Prior PCI (%)

48

47

53

29

38

No. of channels2

39

36

18

30

48

1Demographic characteristics listed for patients randomized to TMR

2Mean or median

CHF congestive heart failure, EF ejection fraction, MI myocardial infarction, NR not reported

Operative mortality and long-term survival

Operative mortality (in-hospital/30-day) for sole therapy TMR patients ranged from 1 to 5%. The lowest rate (1%) which was reported by Burkhoff et al. [14] was attributed to strict study enrollment criteria that excluded patients without at least one region of protected myocardium, left main stenosis > 50%, or a change in angina symptoms or medication usage in the preceding 21 days prior to enrollment. Allen et al. [12] reported a reduced operative mortality rate from 5% overall to 2% in the last 100 consecutively randomized patients, attributable to refinement of surgical technique and improved patient selection.

A more recent, multicenter, nonrandomized post-approval study (PAS) was conducted to further define the disease characteristics of the population being treated and potential risk factors for 30-day postoperative mortality. A total of 358 patients with stable CCS Class IV angina and preoperative ejection fraction of ≥ 25% underwent sole therapy TMR with the Ho:YAG laser system from 18 US centers. The primary endpoint, 30-day all-cause mortality, was significantly lower than the pre-market approval (PMA) study (2.2% vs. 5.3%; p = 0.0033). Univariate analyses identified only number of TMR channels (≥ 40 vs. 40 channels), to be a significant independent predictor of 30-day MACE (18.67% vs. 6.96%, p = 0.0095). Preoperative ejection fraction of ≤ 30% vs. > 30% was the only significant predictor of operative mortality (11.1% vs. 1.5%; p = 0.0167).The observed rates of events in the PAS study were also lower than those previously reported for patients in the original PMA study for: non-Q wave MI (4.5% PMA vs. 0.6% PAS), Q wave MI (0.8% PMA vs. 0.3% PAS), and arrhythmia (30.1% PMA vs. 6.7% PAS).

In a meta-analysis of randomized TMR trials conducted by the International Society of Minimally Invasive Cardiothoracic Surgery (ISMICS), Kaplan-Meier 1-year survival was similar between patients randomized to medical therapy versus TMR [19]. The effect on long-term survival is a key component in establishing the risk/benefit profile of any treatment. In a 5-year follow-up of randomized patients all with class IV angina, Allen [17] reported increased Kaplan-Meier survival in patients randomized to TMR versus maximal medical management (MM) (65% vs. 52%, P = 0.05). The annualized mortality rate after1 year was 13% per year for medically managed patients compared to 8% per year for patients randomized to TMR (P = 0.03).

Angina improvement

Randomized trials have consistently demonstrated significant angina improvement (defined as a reduction of two or more angina classes from baseline) following TMR when compared to continued medical management. In a meta-analysis of randomized controlled TMR trials conducted by ISMICS, forest plots of two class angina improvement depict the superiority of TMR versus maximal medical management at 1 (Fig. 3a) and 3 and 5-year (Fig. 3b) follow-up [19]. Variations between trials with regard to angina relief efficacy may be attributable to patient’s angina class at the time of enrollment (Table 2). Schofield et al. [15] reported only a 25% 2-class angina improvement at 1-year compared to a 76% 2-class improvement reported by Allen et al. [11]. In both studies, 2-class angina relief was significantly better with TMR compared to best medical therapy but the difference may have been that Schofield et al. [15]enrolled primarily Class III patients (73%), while Allen enrolled only Class IV patients.
Fig. 3

a Forest plot demonstrating significant 2-class angina improvement in patients randomized to TMR compared to maximum medical management at 1-year. b Forest plot demonstrating significant 2-class angina improvement in patients randomized to TMR compared to medical management at 3- to 5-years follow-up

Table 2

Operative mortality and 1-year survival in RCTs of sole therapy TMR

Studies

Number randomized

Operative mortality1

1-year Kaplan-Meier survival2

TMR

MM

TMR

TMR

MM

Allen [12]

132

143

5%

84%

89%

Frazier [13]

91

101

3%

85%

79%

Burkhoff [14]

92

90

1%

95%

90%

Schofield [15]

94

94

5%

89%

96%

Aaberge [16]

50

50

4%

88%

92%

1Operative: in-hospital and to day 30

2No statistically significant differences between groups

Additional effectiveness measures

Angina relief remains subjective even when evaluated by third parties thus more objective endpoints are desirable. Burkhoff and colleagues [14] utilized exercise tolerance time (ETT) as their primary FDA endpoint and reported improved median modified Bruce treadmill exercise tolerance times at 12 months (+ 65 s vs. − 46 s, TMR vs. medical management, p < 0.0001) as assessed by a blinded independent core laboratory. Moreover, at 1 year, a significant reduction in chest pain at peak exercise without evidence of silent ischemia was observed when comparing TMR and medically managed patients [20]. In designing this trial, investigators negated possible exercise habituation effects and ensured test reproducibility by requiring a minimum of two tests at baseline with durations varying by less than 15%.

Practice guidelines for sole therapy TMR

The totality of randomized trials involving sole therapy TMR have led to the incorporation of sole therapy TMR into practice guidelines published by the STS, ISMICS, and ACC/AHA [21, 22, 23, 24], which are summarized in (Table 3).
Table 3

Practice guidelines for patients undergoing sole therapy TMR and TMR + CABG

Society

Sole therapy TMR

TMR + CABG

ACC/AHA1 [23]

Class IIa, level of evidence: A

Class IIa, level of evidence: A

ISMICS2 [22]

Class I, level B evidence

Class IIa, level of evidence: B

ACCF/AHA3 [25]

n/a

Class IIb, level of evidence: B

STS4 [21]

Class I, level of evidence: A

Class IIA, level of evidence B

ACCF/AHA/ACP/AATS/PCNA/SCAI/STS5 [24]

Class IIb, level of evidence: B

Class IIb, level of evidence: B

1American College of Cardiology/American Heart Association

2International Society of Minimally Invasive Cardiothoracic Surgery (ISMICS)

3American College of Cardiology Foundation/American Heart Association

4The Society of Thoracic Surgeons

5American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons

Trial designs and results: TMR as an adjunct to CABG

The safety and effectiveness of adjunctive TMR have been more difficult to assess due to the influence of adjacent bypass grafts and lack of randomized control arms in some studies [26, 27, 28]. In addition, since national databases and commonly used models for predicting surgical risk (STS, EuroScore, Parsonnet) do not take into account diffuse CAD, propensity or case-matched comparisons in retrospective or nonrandomized studies are inherently unreliable. Nonetheless, two prospective, multicenter, randomized FDA trials in patients who would be incompletely revascularized by CABG alone have compared CABG plus TMR to CABG alone.

Allen et al. [29] randomized 263 patients who had one or more ischemic areas not amenable to bypass grafting and who would be incompletely revascularized by CABG alone to either CABG plus TMR (N = 132) or CABG alone (N = 131). Operative characteristics were similar between groups and patients were blinded as to whether they received TMR through 1 year. Significantly reduced operative mortality was observed following CABG plus TMR compared to CABG alone (1.5% vs. 7.6%, p = 0.02) even though preoperative STS predicted mortality risk was comparable (6.3%, CABG/TMR vs. 6.6%, CABG alone, p = 0.80). Patients undergoing CABG/TMR required less postoperative inotropic support (30% vs. 55%, p = 0.0001) and had a greater 30-day freedom from major adverse cardiac events (97% vs. 91%, p = 0.04). Compared to CABG alone patients, CABG/TMR patients had a significantly better one-year survival (95% vs. 89%, p = 0.05) and freedom from major adverse cardiac events, prospectively defined as death or myocardial infarction (92% vs. 86%, p < 0.05). The only multivariable predictor of the composite endpoint of death, MI, or recurrent class III/IV Angina at 12 months was being randomized to CABG alone (odds ratio 2.9; CI 1.4–6.2: p = 0.04).

Angina improvement was the primary endpoint in this FDA IDE trail; however, angina relief was similar between CABG/TMR and CABG alone patients at 1-year with a trend toward better angina relief with CABG/TMR (p = 0.2). At 5-year follow-up, however, CABG/TMR patients had significantly lower mean angina scores compared to CABG alone patients (0.4 ± 0.7 vs. 0.7 ± 1.1, p = 0.05) based on blinded, independent (non-surgeon) assessment during follow-up [30]. The clinically relevant manifestation of this difference is in the significant reduction in patients with recurrent, severe angina (class III/IV) at 5 years (0%, CABG/TMR vs. 10% CABG alone, p = 0.009). In addition, there tended to be more CABG/TMR compared to CABG alone patients who were angina-free (78% vs. 63%, p = 0.08). In the subgroup of diabetics who are prone to micro vascular, diffuse disease, significantly more diabetic patients who received CABG/TMR were free from angina at 5 years compared to diabetics who received CABG alone (93% vs. 63%, p = 0.02). In a multivariable analysis, predictors of long-term freedom from angina included diabetes (p = 0.04), no prior CABG (p = 0.002), and a strong trend favoring adjunctive TMR treatment (p = 0.06).

In a smaller prospective, randomized trial conducted at five U.S. Centers, Frazier et al. [31] randomized 49 patients who would be incompletely revascularized by CABG alone due to diffuse CAD to either CABG/TMR (N = 22) or CABG alone (N = 27). Patients were at high operative risk due to depressed ejection fraction (< 0.35 [19%]), unstable angina (16%), preoperative intra- aortic balloon pump (18%), and prior CABG surgery (68%). A strong trend in reduced operative mortality was observed in the adjunctive TMR group compared to the CABG alone group (9% vs. 33%, p = 0.09). At 1 year, the rate of treatment failure (prospectively defined as death, repeat revascularization, or failure to improve by two or more angina classes) was non-significantly reduced in adjunctive TMR versus CABG alone patients (37% vs. 66%, p = 0.3). A 4-year follow-up of these randomized patients demonstrated a significant reduction in recurrent angina requiring percutaneous or repeat surgical revascularization in CABG/TMR versus CABG alone patients (0% vs. 24%, p < 0.05), even though the number of bypass grafts placed at the time of enrollment (3.1 ± 0.7 vs. 3.1 ± 0.8, p = 0.85) were similar between groups. The long-term freedom from treatment failure (freedom from death, repeat revascularization, and recurrent angina) showed a strong trend favoring CABG/TMR patients at a mean of 4-year follow-up (39% vs. 14%, p = 0.06) [32].

The early benefits observed in both of these trials with CABG/TMR must be evaluated in the context of potential study limitations. Concern has been raised regarding potential randomization bias in terms of characterization of bypassable vessels and surgical conduct. Allen and colleagues [28] reported similar operative characteristics between groups with respect to time on cardiopulmonary bypass and the number and distribution of bypass grafts, indicating groups were well matched. In addition, whereas the operative mortality rates observed following CABG alone in both studies (7.6 and 33%) might be viewed as excessive, the evidence in the clinical literature indicates that such incomplete revascularization due to diffuse, distal CAD significantly contributes to this increased risk, which is not accounted for in any risk prediction model. Based on randomized controlled trials involving both sole therapy and adjunctive TMR, evidence-based medicine supports the use of TMR to treat ischemic regions of myocardium supplied by diffusely diseased coronary arteries that are not amenable to conventional percutaneous or surgical revascularization [21, 22, 23, 24, 25], as summarized in (Table 3).

Mechanism of action

The mechanism(s) responsible for the persistent clinical improvement demonstrated in randomized trials involving TMR are the source of ongoing scientific inquiry. Four mechanisms of action for TMR have been postulated and include blood flow via patent channels, sympathetic denervation, angiogenesis, and the placebo effect. While the patent channel theory has been generally dismissed, the mechanism for TMR is likely multifactorial with denervation responsible for the acute benefits and angiogenesis responsible for the long-term benefits.

Placebo effect

Because of the difficulty in blinding surgical trials, the placebo effect from sole therapy TMR remains a difficult issue to put to rest. Two placebo controlled surgical trials were conducted in the 1950’s comparing sham thoracotomy to the Vineberg procedure [33, 34]. In both trials, the placebo effect was real. But, by 9-month follow-up, it had disappeared. While the placebo effect from TMR cannot be discounted, replicated clinical trial results at 1 year and reported long-term 3 to 5-year sustained angina relief help to assuage concerns that the enduring effect from TMR is solely the result of the placebo effect. In addition, patients enrolled in the CABG/TMR trials were blinded to treatment arm through 1-year making those results less suspect for a placebo effect.

Denervation

Laser-induced regional denervation may be responsible for the acute clinical reduction in angina following TMR. Kwong et al. [35] first provided evidence of regional myocardial denervation 2 weeks following TMR. Allen et al. [36] studied regional sympathetic denervation in TMR patients using C-11 hydroxyephedrine-traced positron emission tomography. Significant denervation was demonstrated in lased regions 2 months postoperatively. Beek et al. [37], and later Muxi et al. [38], reported evidence of acute regional sympathetic myocardial denervation using 123I-metaiodobenzylguanide scintigraphy; however, reinnervation progressed through 1 year. Hughes et al. [39], using a chronic ischemic porcine model, demonstrated acute regional sympathetic denervation 3 days following TMR with reinnervation occurring by 6 months, suggesting that denervation may occur acutely; however, mechanisms other than denervation appear to account for long-term clinical outcomes.

If TMR produces regional denervation, the concern that clinically silent ischemia might occur in the postoperative period has been raised. In a blinded core lab analysis of 182 symptom-limited exercise tests following randomization to TMR or continued medical management, Myers et al. [20] reported that TMR did not induce significant silent ischemia. These clinical observations confirm experimental observations that chronic denervation is an unlikely explanation for TMR’s long-term clinical benefit. Acute denervation, however, does provide a reasonable explanation for the immediate angina relief sometimes observed follow sole therapy TMR. Furthermore, regional sympathetic denervation in areas, which cannot be conventionally grafted, may provide an explanation for the operative mortality benefit observed following adjunctive TMR. Tran and colleagues [40] demonstrated improvement in vein graft blood flow when TMR was performed in the vein graft bed suggesting regional denervation improved coronary flow reserve, and therefore graft runoff [38].

Angiogenesis

Angiogenesis resulting from laser revascularization has been reported in both acute and chronic ischemic animal models [41, 42, 43, 44, 45, 46, 47, 48]. Hughes et al. [45] examined the neovascularization response 6 months post-TMR in an ischemic porcine model and reported significant increases in vascular density in lased regions. In addition, these investigators studied different laser systems, and their effects on myocardial blood flow and contractile reserve at 6 months post-TMR using positron emission tomography and stress echocardiography. They reported that laser systems which create an injury (carbon dioxide and Holmium:YAG) improved myocardial blood flow and contractile reserve in lased regions, whereas improvements were not observed following a sham thoracotomy or using a non-injury producing excimer laser [46]. Investigators have also compared TMR to mechanical transmyocardial procedures [47, 48]. Regions treated with mechanical TMR showed no angiogenic response suggesting that a threshold injury was needed to induce angiogenesis. In an evaluation of their cumulative studies, Hughes and Lowe [49] concluded that TMR induced neovascularization in lased regions is likely due to an upregulation of the angiogenic cascade secondary to an inflammatory response after laser treatment.

The angiogenic cascade initiated by TMR can be explained by the “biomechanical trigger” effect initiated by the laser–tissue interaction at both the local (Fig. 4a) and systemic (Fig. 4b) levels [50]. The border zone immediately surrounding the laser channel is created by the thermo-acoustic energy from the laser as it traverses the heart muscle. The localized acute healing response to this laser–tissue interaction includes an upregulation of injured myocytes, platelet activation with growth factor release, as well as the recruitment of intrinsic myocardial stem cells [51]. In addition, TMR has been shown to upregulate vascular endothelial growth factor messenger ribonucleic acid (RNA) and increase expression of other growth factors 1 week following TMR [52]. The systemic injury response from the TMR laser channeling and tissue effect results from the cytokine release and platelet activation, which serve as a homing signal for circulating bone marrow derived stem cells, particularly endothelial progenitor cells. This cascade of activity in the acute phase of the natural wound healing response contributes to the angiogenesis resulting from TMR.
Fig. 4

The angiogenic cascade initiated by TMR demonstrating the “biomechanical trigger” effect initiated by the laser–tissue interaction at both the a. local and b. systemic levels

Multifactorial

While research continues on the underlying mechanism of the clinical effect of TMR, the current prevailing theory combines ablation of afferent sensory pathways, i.e., pain sensation, along with stimulation of angiogenesis. Denervation may be responsible for the immediate relief of angina symptoms, whereas angiogenesis may provide the mechanism for longer term benefits.

TMR: future directions

Researchers continue to pursue cell therapy/delivery strategies to stimulate angiogenesis/myogenesis for the treatment of heart disease. Although the prospect of regeneration of cardiac tissue provided an initial stimulus for cell-based therapies [53] work in animals has put into question the autocrine ability of bone marrow cells to effectively generate cardiomyocytes [54, 55]. The important functional benefit of bone marrow cells may be mediated, not through their autocrine effect, but rather their paracrine effect. The paracrine secretion of growth factors and/or cytokines by bone marrow cells may promote survival of injured cardiomyocytes through the mobilization of progenitor cells and the stimulation of angiogenesis [56]. Since the goal in treating patients with diffuse CAD is to improve perfusion in areas of ischemic myocardium that cannot be conventionally revascularized, cell therapy, which takes advantage of the paracrine rather than autocrine effect, may be a more rational approach.

Although TMR’s superiority over medical therapy has been demonstrated in randomized trials, its effectiveness is not 100%. In up to 25% of patients treated with sole therapy TMR, angina relief is not significantly improved at 1 year [9, 10]. To increase the angiogenic response and the associated clinical efficacy of TMR in treating ischemic heart disease, the potential synergy of combining TMR with a cell-based therapy has been evaluated. Bone marrow laser revascularization (BMLR) describes the delivery of autologous bone marrow concentrate in conjunction with TMR channels into targeted ischemic tissue. It is hypothesized that the delivery of bone marrow derived stem cells to the laser-stimulated border zone surrounding the channels will significantly enhance the angiogenic response compared with TMR alone.

Ischemic animal models have demonstrated enhanced perfusion and improved mechanical function when TMR is combined with biological therapy [57, 58]. In addition, Patel et al. [58] have demonstrated enhanced stem cell retention when stem cells are injected into the border zone of a laser channel, suggesting that the microenvironment created by the laser–tissue interaction may be important for stem cell retention in ischemic tissue. Finally, the small, early clinical experience with TMR combined with stem cell therapy has demonstrated its safety and feasibility and the potential for improving outcomes [59, 60]. Larger clinical trials will be required to validate the clinical benefit of combining TMR with cell therapy.

Conclusion

Cardiac surgeons are increasingly faced with a more complex patient who has developed a pattern of diffuse coronary artery disease that cannot be completely revascularized by CAGB alone. Considering the increased operative and long-term cardiac risks predicted by incomplete revascularization, and the documented operative and long-term benefits associated with sole therapy and adjunctive TMR in randomized trials, increased use of sole therapy and adjunctive TMR therapy is warranted. In parallel, it is imperative that research continues to elucidate the potential of cell-based materials, which when co-administered with TMR, may enhance the clinical effect.

Notes

Compliance with ethical standards

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Conflicts of interest

Dr. Keith Allen has had prior research support from CryoLife, Inc., as national PI for TMR studies (none currently) and currently serves in the speaker’s bureau. Amy Mahoney is employed by CryoLife, Inc. All other authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

Informed consent was not necessary for the review article.

References

  1. 1.
    Muhkerjee D, Bhatt DL, Roe MT, Patel V, Ellis SG. Direct myocardial revascularization and angiogenesis – how many patients might be eligible? Am J Cardiol. 1999;84:598–600.CrossRefGoogle Scholar
  2. 2.
    Weintraub WS, Jones EL, Craver JM, Guyton RA. Frequency of repeat coronary bypass or coronary angiogplasty after coronary artery bypass surgery using saphenous venous grafts. Am J Cardiol. 1994;73:103–12.CrossRefGoogle Scholar
  3. 3.
    Osswald BR, Blackstone EH, Tochtermann U, et al. Does the completeness of revascularization affect early survival after coronary artery bypass grafting in elderly patients? Eur J Cardiothorac Surg. 2001;20:120–6.CrossRefGoogle Scholar
  4. 4.
    Mohr FW, Rastan AJ, Serruys PW, et al. Complex coronary anatomy in coronary artery bypass graft surgery: impact of complex coronary anatomy in modern bypass surgery? Lessons learned from the SYNTAX trial after two years. J Thorac Cardiovasc Surg. 2011;141:130–40.CrossRefGoogle Scholar
  5. 5.
    Allen KB. Holmium:YAG laser system for transmyocardial revascularization. Expert Rev Med Devices. 2006;3:137–46.CrossRefGoogle Scholar
  6. 6.
    Schaff H, Gersh BJ, Pluth J, et al. Survival and functional status after coronary artery bypass grafting: results 10 to 12 years after surgery in 500 patients. Circulation. 1983;68:II200–4.Google Scholar
  7. 7.
    Lawrie GM, Morris GC, Silvers A, et al. The influence of residual disease after coronary bypass on the 5-year survival rate of 1274 men with coronary artery disease. Circulation. 1982;66:717–23.CrossRefGoogle Scholar
  8. 8.
    Bell MR, Gersh BJ, Schaff HV, et al. Effect of completeness of revascularization on long-term outcome of patients with three-vessel disease undergoing coronary artery bypass surgery. A report from the Coronary Artery Surgery (CASS) Registery. Circulation. 1992;86:446–57.CrossRefGoogle Scholar
  9. 9.
    Allen KB, Dowling RD, DelRossi AJ, et al. Transmyocardial laser revascularization combined with coronary artery bypass grafting: a multicenter, blinded, prospective, randomized, controlled trial. J Thorac Cardiovasc Surg. 2000;119:540–9.Google Scholar
  10. 10.
    Lopes RD, Hafley GE, Allen KB, et al. Endoscopic versus open vein-graft harvesting in coronary-artery bypass surgery. N Engl J Med. 2009;361:235–44.Google Scholar
  11. 11.
    Allen KB, Dowling RD, Heimansohn DA, Reitsma E, Didelot G, Shaar CJ. Transmyocardial revascularization utilizing a holmium:YAG laser. Eur J Cardiothorac Surg. 1998;14:S100–4.CrossRefGoogle Scholar
  12. 12.
    Allen KB, Dowling RD, Fudge TL, et al. Comparison of transmyocardial revascularization with medical therapy in patients with refractory angina. N Engl J Med. 1999;341:1029–36.CrossRefGoogle Scholar
  13. 13.
    Frazier OH, March RJ, Horvath KA. Transmyocardial revascularization with a carbon dioxide laser in patients with end-stage coronary artery disease. N Engl J Med. 1999;341:1021–8.CrossRefGoogle Scholar
  14. 14.
    Burkhoff D, Schmidt S, Schulman SP, et al. Transmyocardial laser revascularisation compared with continued medical therapy for treatment of refractory angina pectoris: a prospective randomized trial. Lancet. 1999;354:885–90.CrossRefGoogle Scholar
  15. 15.
    Schofield PM, Sharples LD, Caine N, et al. Transmyocardial laser revascularization in patients with refractory angina: a randomised controlled trial. Lancet. 1999;353:519–24.CrossRefGoogle Scholar
  16. 16.
    Aaberge L, Nordstrand K, Dragsund M, et al. Transmyocardial revascualrization with CO2 laser in patients with refractory angina pectoris: clinical results from the Norwegian randomized trial. J Am Coll Cardiol. 2000;35:1170–7.CrossRefGoogle Scholar
  17. 17.
    Allen KB, Dowling RD, Angell WW, et al. Transmyocardial revascularization: five-year follow-up of a prospective, randomized, multicenter trial. Ann Thorac Surg. 2004;77:1228–34.CrossRefGoogle Scholar
  18. 18.
    Horvath KA, Aranki SF, Cohn LH, et al. Sustained angina relief 5 years after transmyocardial laser revascularization with a CO2 laser. Circulation. 2001;104:I-81–4.CrossRefGoogle Scholar
  19. 19.
    Cheng D, Diegeler A, Allen K, et al. Transmyocardial laser revascularization: a meta-analysis and systematic review of controlled trials. Innovations. 2006;1:295–313.Google Scholar
  20. 20.
    Myers J, Oesterle S, Jones J, Burkhoff D. Do transmyocardial and percutaneous laser revascularization induce silent ischemia? An assessment by exercise testing. Am Heart J. 2002;143:1052–7.CrossRefGoogle Scholar
  21. 21.
    Bridges CR, Horvath KA, Nugent B, Shahian DM, Haan CK, Shemin RJ. Society of Thoracic Surgeons practice guideline: transmyocardial laser revascularization. Ann Thorac Surg. 2004;77:1484–502.CrossRefGoogle Scholar
  22. 22.
    Diegeler A, Cheng D, Allen K, et al. Transmyocardial laser revascularization: a consensus statement of the International Society of Minimally Invasive Cardiothoracic Surgery (ISMICS) 2006. Innovations. 2006;1:314–22.Google Scholar
  23. 23.
    Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/AHA 2002 guideline update for the management of patients with chronic stable angina—summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Chronic Stable Angina). Circulation. 2003;107:149–58.CrossRefGoogle Scholar
  24. 24.
    Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: executive summary: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation. 2012;126:3097–137.CrossRefGoogle Scholar
  25. 25.
    Hillis LD, Smith PK, Anderson JL, et al. 2011 ACCF/AHA guideline for coronary artery bypass graft surgery: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011;124:2610–42.CrossRefGoogle Scholar
  26. 26.
    Wehberg KE, Julian JS, Todd JC, Ogburn N, Klopp E, Buchness M. Improved patient outcomes when transmyocardial revascularization is used as adjunctive revascularization. Heart Surg Forum. 2003;6:328–30.Google Scholar
  27. 27.
    Peterson ED, Kaul P, Kaczmarek RG, et al. From controlled trials to clinical practice: monitoring transmyocardial revascularization use and outcomes. J Am Coll Cardiol. 2003;42:1611–6.CrossRefGoogle Scholar
  28. 28.
    Allen KB, Dowling RD, Richenbacher W. From controlled trial to clinical practice: monitoring transmyocardial revascularization use and outcomes. J Am Coll Cardiol. 2004;43:2364–5.CrossRefGoogle Scholar
  29. 29.
    Allen KB, Dowling RD, DelRossi AJ, et al. Transmyocardial laser revascularization combined with coronary artery bypass grafting: a multicenter, blinded, prospective, randomized, controlled trial. J Thorac Cardiovasc Surg. 2000;119:540–9.Google Scholar
  30. 30.
    Allen KB, Dowling RD, Schuch DR, et al. Adjunctive transmyocardial revascularization: five-year follow-up of a prospective, randomized, trial. Ann Thorac Surg. 2004;78:458–65.CrossRefGoogle Scholar
  31. 31.
    Frazier OH, Boyce SW, Griffith BP, et al. Transmyocardial revascularization using a synchronized CO2 laser as adjunct to coronary artery bypass grafting: results of a prospective, randomized multi-center trial with 12 month follow-up. Circulation. 1999:100:I248.Google Scholar
  32. 32.
    Frazier OH, Tuzun E, Eichstadt A, et al. Transmyocardial laser revascularization as an adjunct to coronary artery bypass grafting: a randomized, multicenter study with 4-year follow-up. Tex Heart J. 2004;31:231–9.Google Scholar
  33. 33.
    Diamond EG, Kittle CF, Crockett JE. Evaluation of internal mammary artery ligation and sham procedure in angina pectoris. Circulation. 1958;18:712–3.Google Scholar
  34. 34.
    Cobb LA, Thomas GI, Dillard DH, Merendino KA, Bruce RA. An evaluation of internal- mammary- artery ligation by a double-blind technic. N Engl J Med. 1959;260:1115–8.CrossRefGoogle Scholar
  35. 35.
    Kwong KF, Kanellopoulos GK, Nickols JC, et al. Transmyocardial laser treatment denervates canine myocardium. J Thorac Cardiovasc Surg. 1997;114:883–90.CrossRefGoogle Scholar
  36. 36.
    Al-Sheikh T, Allen KB, Straka SP, et al. Cardiac sympathetic denervation after transmyocardial laser revascularization. Circulation. 1999;100:135–40.CrossRefGoogle Scholar
  37. 37.
    Beek JF, van der Sloot JA, Huikeshoven M, et al. Cardiac denervation after clinical transmyocardial laser revascularization: short-term and long-term iodine 123-labeled meta-iodobenzylguanide scintigraphic evidence. J Thorac Cardiovasc Surg. 2004;127:517–24.CrossRefGoogle Scholar
  38. 38.
    Muxi A, Magrina J, Martin F, et al. Technetium 99m-labeled tetrofosmin and iodine 123-labeled metaiodobenzylguanide scintigraphy in the assessment of transmyocardial laser revascularization. J Thorac Cardiovasc Surg. 2003;125:1493–8.CrossRefGoogle Scholar
  39. 39.
    Hughes GC, Baklanov DV, Biswas SS, et al. Regional cardiac sympathetic innervation early and late after transmyocardial laser revascularization. J Card Surg. 2004;19:21–7.CrossRefGoogle Scholar
  40. 40.
    Tran R, Brazio PS, Kallam S, Gu J, Poston RS. Transmyocardial laser revascularization enhances blood flow within bypass grafts. Innovations. 2007;2:226–30.Google Scholar
  41. 41.
    Yamamoto N, Kohmoto T, Gu A, DeRosa C, Smith CR, Burkhoff D. Angiogenesis is enhanced in ischemic canine myocardium by transmyocardial laser revascularization.JACC.1998;31:1426–33.Google Scholar
  42. 42.
    Kohmoto T, DeRosa CM, Yamamoto N, et al. Evidence of vascular growth associated with laser treatment of normal canine myocardium. Ann Thorac Surg. 1998;65:1360–7.CrossRefGoogle Scholar
  43. 43.
    Malekan R, Reynolds CF, Narula N, Kelley ST, Suzuki Y, Bridges CR. Angiogenesis in transmyocardial laser revascularization. A nonspecific response to injury. Circulation. 1998;98:II62–5.Google Scholar
  44. 44.
    Huikeshoven M, Belien J, Tukkie R, Beek JF. The vascular response induced by transmyocardial laser revascularization is determined by the size of the channel scar: results of CO2, holmium and excimer lasers. Lasers Surg Med. 2004;35:35–40.CrossRefGoogle Scholar
  45. 45.
    Hughes GC, Lowe JE, Kypson AP, et al. Neovascularization after transmyocardial laser revascularization in a model of chronic ischemia. Ann Thorac Surg. 1998;66:2029–36.CrossRefGoogle Scholar
  46. 46.
    Hughes GC, Kypson AP, Annex BH, et al. Induction of angiogenesis after TMR: a comparison of holmium:YAG, CO2, and excimer lasers. Ann Thorac Surg. 2000;70:504–9.CrossRefGoogle Scholar
  47. 47.
    Hughes GC, Biswas SS, Yin B, et al. A comparison of mechanical and laser transmyocardial revascularization for induction of angiogenesis and arteriogenesis in chronically ischemic myocardium. J Am Coll Cardiol2002;39:1220–28.CrossRefGoogle Scholar
  48. 48.
    Domkowski PW, Biswas SS, Steenbergen C, Lowe JE. Histological evidence of angiogenesis 9 months after transmyocardial laser revascularization. Circulation. 2001;103:469–71.CrossRefGoogle Scholar
  49. 49.
    Hughes GC, Lowe JE. Revascularization versus denervation: what are the mechanisms of symptom relief? In: Abela GS, editor. Myocardial revascularization: novel percutaneous approaches. New York: Wiley-Liss; 2002. p. 63–79.Google Scholar
  50. 50.
    Allen KB, Kelly J, Borkon AM, et al. TMR: from randomized trials to clinical practice. a review of techniques, evidence based outcomes, and future directions. Anesthesiol Clin. 2008;26:501–19.CrossRefGoogle Scholar
  51. 51.
    Atluri P, Suarez EE, Liao GP, et al. Transmyocardial revascularization to enhance myocardial vasculogenesis and hemodynamic function. J Thorac Cardiovasc Surg. 2008;135:283–91.CrossRefGoogle Scholar
  52. 52.
    Horvath KA, Chiu E, Maun D, et al. Up-regulation of vascular endothelial growth factor mRNA and angiogenesis after transmyocardial laser revascularization. Ann Thorac Surg. 1999;68:825–9.CrossRefGoogle Scholar
  53. 53.
    Selke FW, Ruel M. Vascular growth factors and angiogenesis in cardiac surgery. Ann Thorac Surg. 2003;75:S685–90.CrossRefGoogle Scholar
  54. 54.
    Losordo DW, Schatz RA, White CJ, et al. Intramyocardial transplantation of autologous CD34+ stem cells for intractable angina: a phase I/IIa double-blind, randomized controlled trial. Circulation. 2007;115:3165–72.CrossRefGoogle Scholar
  55. 55.
    Pompillo G, Steinhoff G, Liebold A, et al. Direct minimally invasive intramyocardial injection of bone marrow -derived AC133+ stem cells in patients with refractory ischemia: preliminary results. Thorac Cardiovasc Surg. 2008;56:71–6.CrossRefGoogle Scholar
  56. 56.
    Orlic D, Kajstura J, Chimenti S, et al. Bone marrow cells regenerate infarcted myocardium. Nature. 2001;410:701–5.CrossRefGoogle Scholar
  57. 57.
    Abdel-Latif A, Bolli R, Tleyjeh IM, et al. Adult bone marrow-derived cells for cardiac repair: a systematic review and meta-analysis. Arch Intern Med. 2007;167:989–97.CrossRefGoogle Scholar
  58. 58.
    Patel AN, Spadaccio C, Kuzman M, et al. Improved cell survival in infarcted myocardium using a novel combination transmyocardial laser and cell delivery system. Cell Transplant. 2007;16:899–905.CrossRefGoogle Scholar
  59. 59.
    Rosenzweig A. Cardiac cell therapy – mixed results from mixed cells. N Engl J Med. 2006;355:1274–7.CrossRefGoogle Scholar
  60. 60.
    Reyes G, Allen KB, Aguado B, et al. Bone marrow laser revascularisation for treating refractory angina due to diffuse coronary heart disease. Eur J Cardiothorac Surg. 2009;36:192–4.CrossRefGoogle Scholar

Copyright information

© Indian Association of Cardiovascular-Thoracic Surgeons 2018

Authors and Affiliations

  1. 1.Saint Luke’s Mid America Heart InstituteKansas CityUSA
  2. 2.CryoLife, Inc.KennesawUSA

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