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The committee
members were given the task of making recommendations for diagnostic
evaluation and appropriate therapeutic applications of TMR. Our
classification system follows the format established in previous
American College of Cardiology/American Heart Association guidelines
for diagnostic and therapeutic procedures:
Class I:
Conditions for which there is evidence and/or general agreement
that a given procedure or treatment is useful and effective
Class II:
Conditions for which there is conflicting evidence and/or
a divergence of opinion about the usefulness/efficacy of a procedure
or treatment
IIA.
Weight of evidence/opinion is in favor of usefulness/efficacy
IIB. Usefulness/efficacy is less well established by
evidence or opinion
Class III:
Conditions for which there is evidence and/or general agreement
that the procedure/treatment is not useful and in some cases may
be harmful.
The level
of evidence was assigned using the following criteria:
A:
Data derived from multiple randomized clinical trials
B:
Data derived from a single randomized trial or from several nonrandomized
studies
C:
Consensus expert opinion
PROCESS
We reviewed
articles obtained through a search of the MedLine database (1966-present),
the National Center for Biotechnology Information (NCBI), PubMed
database (using keywords including "TMR," "laser," "revascularization,"
"transmyocardial," "TMLR," "PMR," and "DMR" as well as subject
headings to which these terms were mapped and logical combinations
of these sets). Using the same databases, searches were performed
by author for investigators active in the field. Additional references
were obtained through direct communication with investigators.
Selected manuscripts cited in the references were also reviewed.
BACKGROUND
The nature
of the connections between the lumina of the ventricles and the
coronary arteries has been debated at least since the description
by Vieussens in 1706 of "fleshy vessels" thought to represent
direct communications between left ventricular myocardium and
the left cardiac chambers (1). These communications are not to
be confused with the channels described by Thebesius in 1708 (2).
Unlike the fleshy vessels of Vieussens, these "thebesian" veins
connect the heart chambers exclusively with the venous circulation.
Although the existence of the thebesian veins is well accepted,
the debate about the existence and significance of direct "arterio-luminal"
communications was reignited by Wearn and colleagues with their
classic description of myocardial sinusoids in 1933 (3). Yet,
these myocardial "sinusoids" have largely evaded detection using
modern histochemical and electron microscopic techniques (4).
Nonetheless, the concept of functionally significant direct aterio-luminal
connections is galvanized by an extrapolation to more primitive
vertebrate hearts such as the single-chambered hearts of hagfish
and lampreys and reptilian hearts that are supplied, at least
in part, by blood from the ventricular cavity (5,6). Furthermore,
there is a clinical precedent in patients with pulmonary atresia,
intact ventricular septum, and proximal obstruction of the coronary
arteries in whom lumen-dependent myocardial perfusion has been
clearly demonstrated (7). Wearn's classic description of myocardial
microanatomy stimulated several investigators to develop new techniques
for delivering oxygenated blood to the myocardium. Vineberg sought
to increase blood flow to the myocardium by grafting the mammary
artery directly into the myocardium (8). Pifarre et al. modified
Vineberg's concept by implanting autogenous vein grafts anastamosed
to the descending aorta into the canine myocardium (9). Several
investigators attempted to deliver oxygenated blood to the myocardium
by creating a mechanical connection between the left ventricular
myocardium and the left ventricular lumen. Goldman et al. (10)
implanted carotid artery grafts into canine myocardium and ligated
the left anterior descending coronary artery. A similar experimental
approach was taken by Sen et al. (11), White and Hershey (12),
and Pifarre et al. (13) using acupuncture needles, and Massimo
and Boff using T-shaped tubes (14).
More than
two decades ago, Mirhoseini and associates used a 450-watt industrial
carbon dioxide laser in a canine model of acute ischemia to create
transmyocardial channels resulting in a marked decrease in mortality
(15). He was the first to use the technique clinically as an adjunct
to CABG and to demonstrate the safety of the technique (16). The
major limitation of Mirhoseini's approach was that the CO2 laser
available for clinical use had only 80 watts of power and required
at least one complete cardiac cycle to complete creation of a
transmyocardial channel. Therefore, it was required that the heart
be stationary during channel creation. This limitation made it
necessary to perform the procedure under conditions of ischemic
arrest or during ventricular fibrillation (17).
The original
rationale for TMR was the hypothesis that direct channels from
the left ventricular lumen could supply the myocardium with oxygenated
blood. Subsequent observations have lead most to reject this hypothesis
since most experimental and clinical autopsy studies demonstrate
that the channels do not remain patent (18-30). Pifarré et al.
rejected this hypothesis on theoretical grounds. He maintained
that blood flow from the left ventricular lumen to the myocardium
is a physiologic impossibility since intra-cavitary pressure is
always less than intramyocardial pressure (13). Thus, although
the mechanism of action of TMR is unknown, a variety of newer
hypotheses have emerged.
LASERS
USED FOR TMR
Since Mirhoseini's
pioneering efforts, a variety of laser wavelengths have been investigated
for the creation of transmyocardial channels. Robert Rudko, a
laser engineer and co-founder of PLC Systems, Franklin, MA, developed
an 800-1000 watt CO2 laser in 1990. In contrast to the CO2 laser
employed by Mirhoseini, the PLC laser was specifically designed
with sufficient pulse energy to allow for creation of transmyocardial
channels in the left ventricle in approximately 40 milliseconds
- fast enough to successfully create transmural channels in a
beating heart. This important engineering accomplishment heralded
the first clinical trial of TMR. Some of the earliest experimental
studies using a Thulium-Holmium-Chromium (THC): YAG laser were
performed by Jeevanandum, et al. (32) and using a Holmium: YAG
laser by Yano, et al. (33). Using each of these lasers, they demonstrated
an improvement in mortality in dogs that underwent TMR after acute
ligation of the left anterior descending coronary artery. Other
laser systems investigated for use in TMR have included the excimer
(34), argon, Nd: YAG, and pulsed dye lasers.
Currently,
the only FDA-approved lasers for TMR are the CO2 laser (PLC Systems,
Franklin, MA) and the Holmium: YAG laser (Cardiogenesis, Sunnyvale,
CA). The CO2 laser energy (wavelength 10.6 microns) is more efficiently
absorbed by water molecules than the Holmium: YAG laser energy
(wavelength 2.1 microns). The energy per pulse of the CO2 system
is 20 joules to 80 joules, and only one pulse is required to create
a transmural channel. In contrast, the pulse energy of the Holmium:
YAG laser used clinical is typically 2 joules to 5 joules, and
multiple pulses are required to generate a transmural channel.
The Holmium: YAG laser, therefore, requires delivery during several
cardiac cycles to create a single channel and creates a channel
by manually advancing the fiber through myocardium.
CURRENT HYPOTHESES
FOR TMR MECHANISM OF ACTION
Clinical
studies of TMR using a CO2 laser or Holmium: YAG laser have consistently
demonstrated a marked reduction in angina symptoms and, in most
cases, an improvement in exercise tolerance and quality of life
(35-52). These clinical results have lead to a search for the
"true" mechanism of action of TMR. The two leading proposed mechanisms
of TMR effect include laser-induced angiogenesis with improvement
in regional myocardial blood flow and laser-induced denervation
of the myocardium resulting in an improvement in angina symptoms
without the requirement for any improvement in oxygen delivery.
Angiogenesis
In a porcine
chronic ischemia model four weeks after TMR, evidence of TMR-induced
stimulation of angiogenesis within channels was demonstrated by
Zlotnick, et al. (30). In a normal canine model, Kohmoto, et al.
similarly demonstrated that several weeks after laser revascularization
there is immuno-histochemical evidence of new blood vessel formation
within channels and extending to 0.5 cm. from the outer circumference
of the channels (26). In both of these studies, however, all channels
were closed. More recently, however, experimental studies in normal
and ischemic canine, porcine, and ovine models have demonstrated
that myocardial laser injury leads to an increase in the density
of arterial vessels (18,21,23-27,29,31,53-55). Four weeks after
TMR, Malekan, et al. found a similar degree of new arterial blood
vessel formation after creating channels of equal diameter using
a power drill or a CO2 laser in a normal ovine model (21). In
a chronically ischemic porcine model, Chu, et al. demonstrated
that sufficient needle-injury of the myocardium and TMR lead to
similar degrees of stimulation of VEGF expression and angiogenesis
(31). Horvath, et al. showed that TMR leads to an induction of
VEGF gene expression and elevated tissue levels of VEGF mRNA (55).
Thus, the bulk of the available evidence demonstrates that there
is, indeed, a molecular basis for laser-induced TMR angiogenesis.
Thus, if angiogenesis is the proximate mechanism of TMR on angina
relief, then the method of channel creation may not be of critical
importance. Several investigators have used mechanical means other
than laser to create transmural myocardial channels. The techniques
utilized experimentally have included needle puncture (11-13,
55, 56), a mechanical drill (21), a non-energized laser fiber
(53), and ultrasound (56). Although some of these mechanical techniques
may have theoretical merit, the results have been variable and
no mechanical technique is approved by the FDA.
Denervation
Evidence for
and against denervation as the primary mechanism of TMR effect
has been reported. Kwong, et al. studied the effects of Holmium:
YAG TMR on myocardial afferent nerve fibers in a canine model.
Both phenol (known to destroy nerve fibers) and TMR abolished
the hypotensive response to topical application of bradykinin
(a potent analgesic) to the myocardium implying interruption of
subepicardial visceral afferent neural signals. These authors
also demonstrated a loss of the neural-specific enzyme tyrosine
hydroxylase using an immunoblotting technique after TMR treatment
or phenol application but not in sham-operated controls (57).
Hirsch, et al. used a Holmium: YAG laser to create 20 transmural
channels in dogs (58). These authors did not find evidence of
a reduction in ventricular contractile responses to direct electrical
or chemical activation of sympathetic or parasympathetic efferent
neurons after TMR. Al-Sheik, et al in a clinical study of 8 patients
after Holmium: YAG TMR found no increase in resting or stress
myocardial perfusion using PET imaging with [13N ] ammonia but
found that most patients had an increase in sympathetic denervation
as assessed by PET imaging with [11C] hydroxyephedrine. Since
the patients had an average reduction in angina symptoms of 2.4
CCS classes, the authors concluded that the angina relief was
due at least in part to cardiac sympathetic denervation (59).
OUTCOMES
STUDIES: SYMPTOMS. FUNCTION AND
SURVIVAL
Numerous non-randomized
clinical studies using either the Holmium: YAG laser or the CO2
laser consistently demonstrated a significant improvement in angina
class using the Canadian Cardiovascular Society (CCS) scoring
system. Many of these studies also demonstrated an increase in
exercise capacity after TMR (34-43, 49-51)).
Randomized
Clinical Trials of TMR as Sole Therapy
These encouraging
results stimulated the design and completion of five recently
published randomized trials comparing TMR to medical therapy (36,
44-48). In each randomized trial, TMR patients demonstrated a
statistically significant improvement in angina as compared to
patients treated with medical therapy alone, although none of
the trials demonstrated a significant survival benefit. A summary
of the several key results of these trials is presented in Table
1.
The multicenter
trial published by Frazier, et al. included patients from 12 U.S.
centers (48). Ninety-one patients were prospectively randomized
to CO2 laser TMR and 101 patients to medical therapy. Sixty of
the medically- treated patients who developed unstable angina
crossed over to TMR therapy. Sixty-nine percent of the patients
assigned to TMR and 63 percent of the patients assigned to medical
therapy had CCS class IV angina. These authors found that 72 percent
of the patients in the TMR group but only 13 percent of patients
in the medical therapy arm had a reduction in angina of two or
more CCS classes. Using thallium 201 SPECT imaging, the percentage
of myocardial segments with fixed and/or reversible perfusion
defects decreased by an average of 20 percent in the TMR group
at 12 months. This is the only trial to demonstrate improved myocardial
perfusion. In contrast, in the medically treated group, the percentage
of segments with defects increased by 27 percent during the same
time period. There was a reduction in admissions for unstable
angina from 69 percent in the medical group to 2 percent in the
TMR group as well as an improvement in quality of life. Each of
these differences was highly significant.
Schofield,
et al. reported a single center prospective randomized trial (36)
in which 188 patients were randomly assigned to CO2 laser TMR
or medical therapy. In contrast to the study by Frazier, et al.
only 27 percent of the patients enrolled had CCS Class IV angina.
These authors also found a significant decrease in angina symptoms
in the TMR group. Twenty- five percent of the TMR group but only
twelve percent of the medical group had a reduction of two or
more CCS classes (P<0.001). The reduction in angina symptoms was
less dramatic than in the study by Frazier, et al. (48), although
this finding may be a result of the less severe baseline angina
symptoms in the patients enrolled. There were no significant improvements
in exercise capacity, and the mortality at 12 months was 11 percent
in the TMR group and 4 percent in the medically treated group,
although the difference in mortality was not statistically significant.
There was a significant reduction in the number of myocardial
segments with reversible perfusion defects in both groups compared
to baseline but no significant difference between groups (TMR
vs. medical therapy) at 12 months of follow up. There was a disproportionate
increase in the number of fixed defects in the medical therapy
group, prompting Frazier et al (48) to speculate that the decrease
in reversible defects in the TMR group represented improved perfusion
while in the medical group it was likely due to the progression
some previously ischemic regions to complete infarction. Despite
the better control of angina experienced by TMR patients in this
study compared with medically treated patients, the authors concluded
that TMR "cannot be advocated".
Aaberge,
et al. presented the results of the Norwegian randomized single
center study comparing medical therapy with CO2 laser TMR in patients
with refractory angina. One hundred patients were randomized 1:1,
and angina symptoms, exercise capacity, and maximal oxygen consumption
were evaluated at one year (44). Myocardial perfusion was not
assessed post-operatively. Angina severity was assessed using
the New York Heart Association (NYHA) functional classification
rather than the CCS class used by other investigators. Of the
patients randomized to TMR, 24 percent were in NYHA Class IV and
76 percent in NYHA Class III. Of the medically treated patients,
34 percent were NYHA Class IV and 66 percent NYHA Class III. These
authors found no improvement in total exercise time and no improvement
in maximal oxygen consumption (MVO2) in the patients who underwent
TMR. At one year 39 percent of the TMR patients experienced an
improvement of two or more NYHA functional classes compared to
0 percent of the medically treated group. In a more recent study,
Aaberge and associates (45) reported 32 to 60 month follow-up
on the same group of patients. At a mean follow up of 43 months,
60 percent of the TMR patients were in NYHA Class I or II while
16 percent of the medically treated patients were in Class II
and none were in Class I, and 24 percent of patients in the TMR
group had > 2 NYHA functional class improvement compared with
3 percent of the medically treated patients. Although there was
a statistically significant (55 percent) reduction in hospitalizations
for unstable angina, there also was a significant increase in
the use of angiotensin converting enzyme inhibitors (ACE-I) and
the use of diuretics at 43 months mean follow-up in the TMR group
compared to the medically treated group. The authors interpreted
these findings to indicate an increase in the incidence of clinical
heart failure in the TMR group, although no significant difference
in LVEF was observed.
Allen, et
al. reported the results of a prospective, randomized trial comparing
Holmium:YAG laser TMR with medical therapy (46). In this multicenter
report, 275 patients, all with medically refractory CCS Class
IV angina, were randomly assigned to TMR or medical therapy. After
12 months of follow-up, 76 percent of the patients in the TMR
group and only 32 percent of the patients treated medically had
a reduction in angina of two or more CCS classes. Cardiac-related
rehospitalization was more common in the medically treated group
(61 percent) than in the TMR group (33 percent). Both of these
differences were highly significant. However, there was no significant
difference in myocardial perfusion as assessed using dipyridamole-thallium
stress testing at 12 months.
Burkhoff,
et al. presented the results of a prospective, multicenter, randomized
trial also comparing Holmium:YAG laser TMR with medical therapy
(47). One hundred eighty-two patients from 16 centers in the United
States were randomly assigned to undergo TMR (n=92) or medical
management (n=90). Thirty-eight percent of the randomized patients
were in CCS Class III and 62 percent in CCS Class IV. At 12 months,
48 percent of the TMR patients and 14 percent of the medically
treated patients were in CCS Class I or II (p<0.01). TMR significantly
increased exercise tolerance and afforded improvement in quality
of life as compared to medical therapy. As in the study by Allen,
et al. (46), there was no difference in myocardial perfusion assessed
using dipyridamole-thallium stress testing in the two groups at
12 months.
Studies
of TMR Combined with CABG
Allen, et
al. reported the results of a prospective, randomized, multicenter
trial of holmium: YAG TMR combined with CABG versus CABG alone
for 263 patients with ungraftable myocardial segments (60). In
this study, the ungraftable areas were treated with TMR in the
TMR-plus-CABG arm and were left ungrafted in the CABG-alone arm.
These authors reported a significant reduction in the perioperative
mortality rate (1.5 percent versus 7.6 percent) in the patients
treated with TMR. It should be noted that the mortality rate in
the TMR-plus-CABG group was substantially lower than the predicted
mortality rate for these same patients (8.8 percent) for CABG
alone (60). . At one year, the survival for patients in the TMR
plus CABG group was 95 percent but only 89 percent in the CABG
only group (p=. 05).
In an analysis
of results obtained from the STS National Cardiac Database (NCD)
for procedures performed between January 1998 and December 2001,
Peterson et al (61) reported the results of 2,475 patients underwent
TMR (Holmium:YAG and CO2 laser combined) with concomitant CABG
with a perioperative mortality of 4.2 percent. These authors also
compared CABG/TMR patients with triple vessel disease but only
one or two bypass grafts against similar patients in the STS NCD
who underwent CABG alone and found no significant difference in
risk-adjusted mortality. In a retrospective study, Stamou, et
al. reviewed the results of CO2 laser TMR plus CABG in 169 patients
at the Washington Hospital Center. There were significant improvements
in angina class during the follow-up period. After 12 months,
only 4 percent of the patients were in CCS Class III or Class
IV versus 90 percent of the patients preoperatively (p<0.001)
(52). However, the operative mortality rate of 8.4 percent was
not significantly different than the predicted mortality based
on the STS NCD multi-variable model for CABG alone (8.9 percent).
Thus, this study (52) and the study by Peterson et al (61) both
failed to substantiate the results of Allen, et al. (60). Taken
together, these studies do not support the hypothesis that TMR
confers a survival benefit to patients who undergo CABG when added
as an adjunctive procedure for the treatment of ischemic but ungraftable
regions.
Intermediate Term Results: Retrospective Studies
Since TMR
is a relatively new form of therapy, there is little intermediate-term
or long-term data. Horvath, et al. presented the results of CO2
laser TMR in 78 patients followed for up to seven years (49).
After an average of five years, the average CCS angina class had
improved from 3.7 +/-0.4 to 1.6+/-1.0 and was unchanged at five
years from the value at one year (1.5+/-1.0). DeCarlo, et al.
reported the intermediate-term results of Holmium:YAG laser TMR
on 34 patients. The mean preoperative CCS angina class was 3.6+/-0.5,
which decreased to 1.8+/-0.8 at one year. However, there was a
statistically significant increase in angina at a mean follow-up
of 35 months to a mean CCS class of 2.2+/-0.7 (p=0.005, compared
to the value at one year) (51). In another study by Schneider,
et al. of 41 patients who underwent Holmium:YAG laser TMR, mean
CCS angina class was improved at 18 months, but there was progressive
increase in angina symptoms over the ensuing 18 months in patients
who underwent TMR alone. In contrast, patients who underwent TMR
plus CABG had sustained angina relief (62) at 36 months follow-up.
OUTCOMES ANALYSIS:
PROCEDURAL MORBIDITY AND MORTALITY
Mortality
The largest
retrospective study of TMR available is derived from the STS NCD
(61). In an analysis of results obtained from the STS NCD for
procedures performed between January 1998 and December 2001, 661
patients underwent TMR alone (Holmium:YAG and CO2 laser combined)
with a perioperative mortality of 6.4 percent. As discussed above,
for 2,475 patients who underwent TMR with concomitant CABG, the
mortality was 4.2 percent. In the prospective randomized trials
of CO2 laser TMR, procedural mortality ranged from 3 percent to
5 percent with one-year survival of 85 percent to 89 percent (36,44,45,48).
In the two prospective, randomized trials of Holmium:YAG TMR,
the procedural mortality ranged from 1 percent to 5 percent with
one-year survival of 89 percent to 96 percent (46,47).
In each of
the randomized studies, patients with ejection fractions less
than 20 percent to 30 percent were excluded (36,44-48), in part
accounting for the lower perioperative mortality rate observed
when compared to several retrospective studies (35, 37, 39-42).
In the study by Peterson et al, mortality was significantly higher
in patients with unstable angina or MI within 21 days. Furthermore,
in the 661 patients in the TMR-only group, the 143 patients without
unstable angina and with EF >50% had an operative mortality of
only 2.1%. These authors concluded that appropriate patient selection
is the most important factor influencing acute mortality after
TMR (61).
Morbidity
Morbidity
from TMR may include myocardial infarction, arrhythmias, left
ventricular dysfunction and cerebral microembolization (35-37,39,40,63-66).
In a study of normal pigs, Holmium:YAG but not CO2 laser TMR resulted
in an acute decrease in left ventricular systolic function as
assessed by preload recruitable stroke work area (PRWA) (67).
Both types of laser TMR resulted in significant increases in myocardial
water content and impaired diastolic relaxation (67). Kadipasaoglu,
et al. compared the results of CO2 laser TMR, Holmium:YAG laser
TMR and excimer laser TMR in normal pigs (64). In their study,
70 percent of the animals who underwent TMR using the excimer
laser and 60 percent of those with Holmium:YAG TMR had ventricular
tachycardia compared to only 3 percent of the animals that underwent
CO2 laser TMR. In the study by Peterson, et al (61), using data
derived from the STS NCD for patients who underwent TMR as sole
therapy, the incidence of major morbidity included: reoperation
for any reason (2.7 %), stroke(0.76 %), renal failure ( 4.8 %),
and prolonged ventilation (7.7 %). In the four randomized trials
of TMR as sole therapy published 1999, the incidence of CHF ranged
from 12 percent to 32 percent; MI varied from 7 percent to 18
percent, and arrhythmias occurred in 8 percent to 22 percent (36,46-48).
In an analysis of 49 patients who underwent CO2 laser TMR enrolled
in the Norwegian randomized trial, Tjomsland, et al. found a transient
but significant decrease in cardiac index that was maximal immediately
after the procedure (63). Four patients (8 percent) suffered a
myocardial infarction, seven patients (14 percent) developed atrial
fibrillation, and two patients (4 percent) had ventricular arrhythmias
(63). In a study of 21 patients who underwent CO2 laser TMR by
Hughes, et al., all patients had elevations in CPK and CPK-MB
levels, and 54 percent of patients had ischemic changes on EKG
in the first 48 hours after TMR (66).
RISK FACTORS
FOR MORBIDITY AND MORTALITY FOLLOWING TMR
Unstable
Angina
In the randomized
trial by Frazier, et al., more than 70 percent of the patients
who crossed over to TMR from the medical treatment arm had unstable
angina, and these patients had the highest perioperative mortality
rate (9 percent) (48). In the study by Hughes, et al., the presence
of unstable angina was also a significant predictor of postoperative
morbidity and mortality (65). Similarly, in a multicenter study
by Hattler, et al., perioperative mortality was 16 percent in
patients with unstable angina compared with 3 percent in patients
with chronic angina (68).
Global
Myocardial Ischemia
Burkhoff,
et al. investigated the effects of age, gender, ejection fraction,
prior CABG, unstable angina, and an index described as the anatomic
myocardial perfusion index (AMP) as possible predictors of mortality
after CO2 laser TMR as sole therapy in 132 patients. They graded
each vascular territory as AMP=1 if there was unobstructed blood
flow through a major artery to that territory and AMP=0 if there
was not. Patients with at least one territory with AMP=1 had a
mortality of 5 percent while those with AMP=0 in all territories
had a mortality of 25 percent, (p=0.002) (69). Only AMP was a
significant risk factor for operative mortality in the multivariate
analysis. Kraatz, et al. found that mortality was highest in patients
who underwent TMR alone or TMR plus CABG in whom, after the procedure,
there was neither a patent bypass graft nor a native coronary
artery perfusing at least one of the three major perfusion zones
(70).
Diminished
Left Ventricular Function
Lutter, et
al. found that higher mortality after TMR has also been observed
in patients with impaired left ventricular function or hemodynamic
instability and limited reserve (71). In seven patients with unstable
angina and reduced ejection fraction (< 35 percent), the combination
of CO2 laser TMR with the use of a preoperative IABP resulted
in survival of all seven patients associated with significant
improvements in both CCS angina class and NYHA classification
(71).
It seems quite
important to note that patients with unstable angina, acute ischemia,
and low ejection fraction have the highest risk of perioperative
complications from sole therapy TMR. However, when TMR is combined
with CABG, the literature provides little information regarding
specific risks and benefits of adjunctive TMR.
RECOMMENDATIONS
FOR TMR AS SOLE THERAPY
Class
I:
1. Patients
with an ejection fraction greater than 30% and Canadian Cardiovascular
Class III or IV angina that is refractory to maximal medical
therapy. These patients should have reversible ischemia of the
left ventricular free wall and coronary artery disease corresponding
to the region of myocardial ischemia. In all regions of the
myocardium, the coronary disease must not be amenable to CABG
or PTCA, either due to a) severe diffuse disease, b) lack of
suitable targets for complete revascularization, c) lack of
suitable conduits for complete revascularization. (Level
of Evidence: A)
Class
IIB:
1. Patients
who otherwise have Class I indications for TMR but who have
either:
a. Ejection
fraction less than 30 percent with or without insertion of
an intraaortic balloon pump. (Level of Evidence: C)
b. Unstable angina / acute ischemia necessitating intravenous
antianginal therapy. (Level of Evidence: B)
c. Patients with Class II angina. (Level of Evidence:
C)
Class
III:
1. Patients
without angina or with Class I angina. (Level of Evidence:
C)
2. Acute evolving myocardial infarction or recent transmural
or nontransmural myocardial infarction. (Level of Evidence:
C)
3. Cardiogenic shock defined as a systolic blood pressure less
than 80 mm/Hg. or a cardiac index of less than 1.8L/min/m2.
(Level of Evidence: C)
4. Uncontrolled ventricular or supraventricular tachyarrythmias.
(Level of Evidence: C)
5. Decompensated congestive heart failure. (Level of Evidence:
C)
RECOMMENDATIONS
FOR TMR AS AN ADJUNCT TO CABG
Class
IIa:
1. Patients
with angina (Class I - IV) in whom CABG is the standard
of care who also have at least one accessible and viable ischemic
region with demonstrable coronary artery disease which cannot
be bypassed, either due to a) severe diffuse disease, b) lack
of suitable targets for complete revascularization, or c) lack
of suitable conduits for complete revascularization. (Level
of Evidence: B)
Class
IIb:
1. Patients
without angina in whom CABG is the standard of care who
also have at least one accessible and viable ischemic region
with demonstrable coronary artery disease which cannot be bypassed,
either due to a) severe diffuse disease, b) lack of suitable
targets for complete revascularization, or c) lack of suitable
conduits for complete revascularization. (Level of Evidence:
C)
Class
III:
Patients
in whom CABG is not the standard of care. (Level of Evidence:
C)
FUTURE
APPLICATIONS OF TMR
Additional
clinical applications have been suggested for TMR including the
treatment of graft vasculopathy after cardiac transplantation,
although the benefits of such an approach have not yet been established
(72). There have also been new approaches proposed for the delivery
of TMR. In most surgical studies of TMR, the left ventricular
free wall has been approached via a left thoracotomy. There have
been several reports of the performance of TMR using thoracoscopy.
These early reports suggest that the technique can be performed
safely and adequately via this approach (73). In contrast, the
early results of randomized trials of percutaneous laser myocardial
revascularization (PMR), also referred to as direct myocardial
revascularization (DMR), using a Holmium: YAG laser catheter-based
approach has been less promising (74,75). The degree of angina
reduction has been less significant than that achieved with TMR,
most likely due to the fact that only a minority of the myocardial
wall is traversed with PMR, and the placement of the channels
may be less precisely correlated with the location of areas of
inadequate myocardial perfusion. Finally, careful investigation
of alternative means for channel creation should continue including
the use of ultrasound (56) and radio frequency ablation techniques
(76).
The mechanism
of TMR's clinical effects has not been clearly established, although
the improvements in angina symptoms have been consistent for all
laser wavelengths tested clinically. TMR appears to stimulate
angiogenesis but this effect may represent a nonspecific result
of myocardial injury. Experimental studies demonstrate that the
Holmium: YAG laser results in a greater degree of myocardial tissue
damage than the CO2 laser (27). A positive correlation between
myocardial tissue injury and reduction in contractility after
TMR has been demonstrated (77). The inflammatory response to TMR-induced
myocardial injury is the most cogent hypothesis for TMR-induced
angiogenesis. Investigation of alternative laser wavelengths may
allow for further reduction in the ratio of potentially deleterious
laser-induced myocardial tissue injury to the degree of angiogenic
stimulus achieved. Ideally, maximum induction of new vessel growth
can be achieved with minimal tissue injury. Experimental studies
suggest that the combination of TMR with the co-administration
of growth factors such as VEGF and ßFGF or genes encoding these
and other growth factors may allow for even greater induction
of new vessel growth (78,79).
CONCLUSION
TMR offers
consistent amelioration of severe angina in patients having no
conventional therapeutic alternative. Surgeons should recognize
that the procedure is intended only for the purpose of reducing
angina symptoms. There is no statistically conclusive evidence
for increased longevity or enhanced myocardial function. Careful
patient screening is particularly important because of the unacceptably
high operative mortality in patients with acute ischemic syndromes
and / or significant myocardial dysfunction. With proper patient
selection and observance of appropriate surgical technique, TMR
provides very gratifying symptomatic improvement to desperately
ill patients who otherwise would be crippled by unrelenting angina
pectoris.
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