See you… Laser
Rami Khouzam, M.D.
2/04/05
Index Case
71 y o WM with hx. Of CAD, HTN, CHF,
CABG x 2 (78’, 89’), PCI x 2
• Clinic visit @ the VA c/o recurrent angina
Last cath (96’): - Severe native 3 vs. CAD
- One graft patent
- 2 grafts down
MUGA (98’): EF: 35%
Dipsesta (00’):
Lateral, anterior & inferior wall scars
Negative for ischemia
Meds:
Metoprolol, ASA, Lisinopril, ISDN,
Simvastatin, Felodipine and Lasix
Evolving revascularization
approaches for myocardial ischemia
• Recent advances in PTCA have attempted to
address restenosis (stents/drug-eluting).
• Developments in CABG have focused on
reducing the invasiveness of the procedure.
Transmyocardial Laser
Revascularization
1. What is transmyocardial laser revascularization?
2. In whom should this technique be employed?
3. How does transmyocardial laser revascularization
work/ Pathophysiology?
4. What are the details of operative techniques?
5. What is the potential morbidity of this procedure?
6. What are the long term results?
7. Can any laser system be used?
1.
What is transmyocardial laser
revascularization?
TMR: Relatively new technique that attempts to
improve the blood supply to ischemic
myocardium by using a high-powered CO2 laser
to create multiple transmyocardial channels.
These new channels bring blood from the
ventricular cavity directly into the myocardium.
The result is a heart that functions more like a
reptilian heart, in which approximately half of
the myocardial blood supply comes from
sinusoidal perfusion by the left ventricular
cavity.
TMR employs a high powered CO2 laser that
puts a high energy pulse into the myocardium
and completely vaporizes a channel with a
diameter of 1 mm transmurally.
These channels are placed in the ischemic
myocardium approximately 1 cm apart, so that
there is multiple channel perfusion of ischemic
areas.
The CO2 laser is triggered to the ECG to
prevent onset of ventricular arrhythmias,
including ventricular tachycardia.
(For the procedure, the patient is off of the
heart lung machine and heparin is not
administered).
This procedure can be used to revascularize
the free left ventricular wall, but not the
septum.
LASER HISTORY (1917-1996)
• Einstein can be considered as the father of
the laser.
• ~ 80-90 years ago he postulated photons
and stimulated emission and won the Nobel
prize for related research on the
photoelectric effect.
"A splendid light has dawned on me..."
- Albert Einstein
• Although Einstein did not invent laser, his work
laid the foundation. It was Einstein who pointed
out that stimulated emission of radiation could
occur.
• He used his photon mathematics to examine the
case of a large collection of atoms full of excess
energy and ready to emit a photon at some
random time in a random direction. If a stray
photon passes by, then the atoms are stimulated
by its presence to emit their photons early.
• Remarkably, the emitted
photons go in the same
direction and have exactly
the same frequency as the
original photon ! Later, as
the small crowd of identical
photons moves through the
rest of the atoms, more and
more photons will leave
their atoms early to join in
the subatomic parade.
• All it took to invent the laser was for
someone to find the right kind of atoms and
to add reflecting mirrors & lenses to help
the stimulated emission along.
• LASER: Light Amplification by (using
Einstein's ideas about) Stimulated Emission
of Radiation.
LASER history
* 1917 : Einstein postulates photons and stimulated
emission
* 1954 : First microwave laser
* 1960 : First optical laser
* 1965 : Discovery of cosmic background radiation
using microwave laser
* 1970 : First postulate of laser action in stars
* 1979 : Near Infrared laser star found in Orion nebula
LASER history
* 1981 : Carbon dioxide laser discovered in
atmosphere of mars and venus
* 1984 : First x-ray laser
* 1994 : Artificial laser guide stars
* 1995 : Far infrared laser star discovered
* 1996 : Ultraviolet laser star discovered
* 2003 : Knowledge base of the world’s most
powerful research and military lasers
The Procedure… History &
Technique
• TMR is a derivative of older procedures developed
before CABG surgery to augment coronary blood flow.
• Arthur Vineberg 1903-1988
(Canadian Cardiac Surgeon)
in 1946 attempted to improve
myocardial blood flow by
tunneling the left internal
mammary artery directly into the
left ventricular myocardium.
• He found, using early angiographic techniques, that
with this procedure a communication was created
between the left mammary artery and the coronary
circulation that remained patent for at least 4 months
after the procedure was performed.
• How this communication forms and persists was
unanswered.
• His procedure fell out of favor with the advent of the
more physiologic CABG surgery in the 1960s.
Vineberg AM. CMAJ. 1946;55:117–119
2. In whom should this technique
be employed? Indications..
 Previous CABG/PTCA (high risk candidates for redo).
 Genetic metabolic disease which has produced
extensive peripheral coronary disease.
• ... Poor runoff and no place to perform a
conventional revascularization ...
• “End-stage coronary vascular disease (diffuse)"
and can not be reconstructed by the usual means.
Indications (continued)
• Evidence of reversible ischemia on a
radioactive perfusion scan.
• Reasonable ventricular function (EF > 20%).
• Very severe disabling angina, class III or IV,
on maximal anti-anginal therapy.
3. How does TMR work?
Mechanism of action/ Pathophysiology
• Exact mechanism: considerable controversy.
• Several mechanisms have been proposed:
-  direct blood flow to the myocardium
(Open Channel Hypothesis)
- Sympathetic denervation of the myocardium
- Angiogenesis
- Placebo ??
Open Channel Hypothesis
• Theoretically, the new channels should allow blood
supply from the LV cavity up the channels to form
buds off of the main channels.
• It has been difficult to demonstrate that
revascularization has occurred consistently in all
patients.
• Does not  blood flow acutely.
•  blood flow after 2-6 months.
Open Channel Hypothesis
Is there objective evidence of
increased myocardial
perfusion?
Open Channel Hypothesis (Pros)
• Some autopsy specimens have shown open
channels (investigators in Hilemberg,
Germany, using special angulated color
doppler echo on human beings, have seen
patent channels 30 days after the creation of
these channels).
• Animal studies have also been conflicting, but,
angioneogensis has definitely been shown to
be a factor in both experimental and clinical
Open Channel Hypothesis (Pros)
• Frazier et al, using PET demonstrated
improved subendocardial flow in 11 patients
treated with TMR.
Frazier OH, et al. N Engl J Med. 1999;341:1021–1028
• Burkhoff et al found no difference in
myocardial perfusion assessed by
dipyridamole thallium scintigraphy, although
there was significantly increased exercise
tolerance in the treatment group.
Burkhoff D, et al. Lancet. 1999;354:885–890
• Horvath et al evaluated 200 patients in 8
hospitals who were treated with TMR.
• Technetium 99m sestamibi or thallium 201 at
baseline, and at 3, 6, and 12 months after TMR.
• A  number of reversible defects in the left
ventricular free wall was found in the TMR
group at 6 and 12 months, suggesting an
improvement in myocardial ischemia in treated
areas.
• No significant change in the number of fixed
defects after TMR arguing against procedureinduced myocardial scarring.
Horvath KA, et al. J Thorac Cardiovasc Surg. 1997;113:645–654
• Furthermore, the mechanism of action of
TMR remains undefined. Additional studies
need to be done with TMR to assess whether
it is a useful treatment or an addition to the
list of placebo therapies initially thought to
have been of benefit in the therapy for angina
pectoris.
Goldberg, et al. Cardiology in Review. 2005;13(1):52-55
Open Channel Hypothesis (Cons)
• Kohmoto et al, using a canine model:
demonstrated very little blood flow through the
anatomic channels created by TMR, even as
early as 2 weeks.
• Not protective if an acute occlusion of epicardial
coronary vessels occurred.
• Fisher et al also found no substantial blood flow
through these channels.
Kohmoto T, Fisher PE, et al., Ann Thorac Surg. 1996;61:861–868
Open Channel Hypothesis (Cons)
• Schofield et al could not demonstrate 
myocardial perfusion in CO2 laser treated
patients using thallium imaging.
Schofield PM, et al. Lancet. 1999;353:519–524
Myocardial denervation (Pros)
• Sympathetic denervation of the myocardium:
laser energy  damage to the epicardial
sympathetic fibers  blunting of ischemic
symptoms.
• In a canine model, Kwong et al demonstrated
 in tyrosine hydroxylase, a sympathetic
nerve-specific enzyme, as well as a loss of
sympathetic cardiac nerve function due to
TMR.
• Another study found that TMR causes left
ventricular cardiac sympathetic denervation
without affecting myocardial blood flow at rest
or during stress.
Do TMR & PMR induce silent ischemia?
An assessment by exercise testing.
• Exercise tolerance improved after TMR and
after PTMR. Relative to PTMR, TMR more
effectively suppressed pain during exercise
and ischemic ST depression.
• However, neither TMR nor PTMR induced
significant silent ischemia.
• These results suggest that denervation may
not be a significant factor contributing to angina
relief after these procedures. (Contribution of
placebo effect not determined)
Myers J - Am Heart J - 01-JUN-2002; 143(6): 1052-7
Angiogenesis (Pros)
• Creation of a controlled injury to the myocardium
 natural wound-healing response.
• In a porcine model: neovascularization
prominent at the periphery of channel remnants
in ischemic, but viable parts, of the myocardium.
Pelletier MP, et al. Ann Thorac Surg. 1998;66:12–18
Angiogenesis (Pros)
•  angiogenic factors (e.g. VEGF) :
One study showed a 2-fold  VEGF mRNA in the
ischemic zones of the CO2 laser–TMR group when
compared with a control group & a 3-fold  number
of new blood vessels in the ischemic zone of the
TMR patients.
• Histology: muscular arterioles found within channel
remnants after a short period, followed by
proliferating capillaries that were characteristic of
granulation tissue.
Angiogenesis (Cons)
• In contrast, Whittaker et al found no evidence
of angiogenesis 2 months after performing
TMR.
One-year outcome after combined CABG
and TMR for refractory angina pectoris.
• Results of 30-day and 3-, 6-, and 12-month
clinical follow-up after CABG plus TMR in a
consecutive series of patients with refractory
angina pectoris and > or = 1 myocardial
ischemic area not amenable to CABG (n =
169).
• Procedural success at 30 day & overall
actuarial survival & event-free survival at 1
year were 85 % & 81 %, respectively.
• CABG plus TMR is a safe revascularization
option for patients with intractable angina
pectoris.
Stamou SC, et al Am J Cardiol 2002; 89(12): 1365-8
Rationale for TMR
• Epicardial approach
(surgery)
• Endocardial approach
(percutaneous)
• Holmium:yttrium –
argon – garnet
(Ho:YAG) & CO2
lasers approved by US
Food and Drug Admin
• Ho:YAG beam
transmitted by optical
fiber
• CO2 laser beam
transmitted by mirrors
and lenses
• Different lasers have
not been compared in
clinical trials
4. Details of operative techniques?
• Left anterior thoracotomy usually through the
fifth intercostal space. (Europe : thoracoscopic
approach has been used).
• The pericardium is opened, a cradle is made,
and the dissection of the pericardium is
carefully carried off of the heart.
(No heparin is administered, nor is the patient
cannulated for cardiopulmonary bypass).
Technique of TMR vs PMR
TMR
• L anterior
thoracotomy or
median sternotomy
• Cannulation and
heparin needed ONLY
if concurrent CABG
• 25-50 channels made
with 1 cm separation
in L ventricle
•
•
•
•
•
PMR
3 catheter based
Ho:YAG devices
Lack FDA approval
Introduced into LV via
femoral artery
Laser against
endocardium
Multiple pulses to create
up to 20 channels
• A transesophageal echo (TEE) is necessary
to document the transmural nature of the laser
pulse by preservation of laser "steam" in the
left ventricle.
• Once the heart is in its pericardial cradle, the
probes are placed directly on the myocardium.
The laser beam is synchronized with the ECG
and then a foot switch allows for production of
the laser pulse and vaporization of the
transmural myocardial channels.
• The channels are made one cm apart in all of
the ischemic areas and the borders in and
around the ischemic areas noted from the
thallium sestamibi scans.
• After 25 to 40 channels are drilled, the
pericardium is loosely re-approximated and
the patient is closed in the usual fashion for a
small thoracotomy and returned to the ICU.
5. What is the potential morbidity of
this procedure?
• Complications:
- atrial arrhythmias (atrial fibrillation)
- hypotension
- ventricular arrhythmias
- ventricular dysfunction
- myocardial infarctions
- pleural effusion
Adverse outcomes
• Perioperative mortality rates : 1% - 9% .
• Complications:
- atrial arrhythmias (atrial fibrillation)
- hypotension
- ventricular arrhythmias
- ventricular dysfunction
- myocardial infarctions
- pleural effusion
Maintaining perfusion pressures is key...
Hypotension to be avoided, & IABP prohylactic
for mechanical support.
 BP  AMI (the most lethal complication)
Perioperative mortality: 1-9 %
Mortality also correlated with EF, with highest
early and late mortality in patients with worse
left ventricular function.
6. What are the long term results?
• In one study, 77 patients randomized to TMR
and 83 randomized to medical therapy.
• Results at 6 months demonstrated:
- a marked  in mortality
- a marked improvement in angina
- a  in post-procedure hospitalizations
• Randomization discontinued by the FDA on
September 6, 1996.
• ~ 75% of patients experienced meaningful
relief of angina by one year.
• Concomitant  in anti-anginal medications
and cardiac-related hospitalization.
• Myocardial perfusion ( by spect scanning with
computerized sestamibi left ventricular
maps): significantly improved.
ATLANTIC
• The Angina Treatments – Lasers and Normal
Therapies in Comparison (ATLANTIC) study was a
prospective randomized study comparing TMR via
Ho:YAG laser with maximum medical therapy.
• This study assessed angina class, exercise
tolerance, quality of life, and patients’ stress test
results at 3, 6, and 12 months after the procedure.
Results from clinical trials of TMR
•
•
•
•
6 studies
86-275 patients
Ho:YAG and CO2
All show symptom
improvement
• No study shows
survival benefit
1.Allen NEJM 1999
2.Frazier NEJM 1999
3.Schofield Lancet 1999
4.Burkhoff Lancet 1999
5.Aaberge JACC 2000
6.Jones Ann Thorac Surg 1999
% of patients with decrease
of =2 CCS angina classes
80
70
60
50
TMR
40
Con
30
20
10
0
1 2 3 4 5
7. Can any laser system be used?
• Unknown ??.
• The most commonly used lasers for this
procedure have been the holmium:yttriumaluminum garner laser (Ho:YAG) and the
carbon dioxide CO2 laser (more commonly
used… less thermal injury to surrounding
tissues, more efficient tissue penetration).
How does it compare to other
treatments?
• Transmyocardial revascularization has
received FDA approval for use in patients with
severe angina who have no other treatment
options. It has also produced early promising
results in three large multi-center clinical trials.
The angina of 80-90 percent of patients
who've had this procedure has significantly
improved (at least 50 percent) through one
year after surgery. There's still limited followup data as to how long this procedure might
last, however.
Cost
• Mean year cost x TMR: $ 11,470
vs. $ 2586 x Medical management alone
Campbell et al Eur J Cardothorac Surg 2001;20:312-8
Summary & Conclusion
TMR
• Low-powered lasers: first used in the 1980s as an
adjunct to CABG.
• High-powered lasers: introduced in the 1990s:
transmyocardial channels with minimal damage
to surrounding tissues.
• Patients with inoperable CAD and angina pectoris
refractory to medical therapy.
• FDA granted approval of TMR as a sole therapy.
• TMR + CABG and 2 types of laser systems:
currently available.
• Contrasting findings regarding benefit, and
potential morbidity and mortality risk associated
with the procedure.
TMR
• Encouraging initial clinical results
• Considerable controversy.
• Discordance between relief of anginal
symptoms, which has been significant, and
objective evidence of improved myocardial
blood flow, which has been inconsistent,
raising legitimate concerns about the role of a
placebo effect in the procedure’s effects.
More than just a Placebo?!
• Placebo effect notwithstanding, should
patients be offered TMR as a therapeutic
option?
• In my judgement, this is a decision to be made
by the physician and the patient after risks and
limitations are fully reviewed.
• Maybe, when additional clinical experience
accumulates, the ultimate role of TMR will be
more clearly defined.