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 LaserRevascularization

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 re-do).

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 studies.

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 procedure-induced 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) & CO2lasers approved by USFood and Drug Admin

• Ho:YAG beamtransmitted by opticalfiber

• CO2 laser beamtransmitted by mirrorsand lenses

• Different lasers havenot been compared inclinical 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 ormedian sternotomy

• Cannulation andheparin needed ONLYif concurrent CABG

• 25-50 channels madewith 1 cm separationin L ventricle

PMR• 3 catheter based

Ho:YAG devices

• Lack FDA approval

• Introduced into LV viafemoral artery

• Laser againstendocardium

• Multiple pulses to createup 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 symptomimprovement

• No study showssurvival benefit

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TMRCon

7. Can any laser system be used?

• Unknown ??.

• The most commonly used lasers for this procedure have been the holmium:yttrium-aluminum 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 follow-up 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.