Course Authors

Ran Kornowski, M.D. and Martin B. Leon, M.D.

Drs. Kornowski and Leon are from the Cardiology Research Foundation, Washington Hospital Center, Washington, DC, USA.

Drs. Kornowski and Leon report no commercial conflict of interest.

Estimated course time: 1 hour(s).

Albert Einstein College of Medicine – Montefiore Medical Center designates this enduring material activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

In support of improving patient care, this activity has been planned and implemented by Albert Einstein College of Medicine-Montefiore Medical Center and InterMDnet. Albert Einstein College of Medicine – Montefiore Medical Center is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

 

Learning Objectives

Upon completion of this Cyberounds^®, you should be able to:

• Understand the theoretical basis for the benefit achieved by creating laser cut channels in ischemic myocardium

• Discuss both the surgical approaches and percutaneous approaches to TMR

• Understand the criteria for determining potential patient candidates for TMR trials.

 

One of the most perplexing problems facing cardiologists is those patients who have had several coronary revascularization procedures and now present with refractory angina. Many times these patients have no approachable lesions for either percutaneous interventions or repeat bypass surgery. They might also not have any residual conduits for making bypasses. A new technique under consideration for possibly stimulating auxiliary capillary growth into these ischemic regions is called transmyocardial laser revascularization. Please welcome our colleagues from the Washington Hospital Center, Drs. Kornowski and Leon who are leading authorities in this area and will review this exciting, new and potentially revolutionary technique.

-- Richard W. Smalling, M.D., Ph.D., Cardiovascular Moderator

Introduction

Direct myocardial revascularization (DMR) is an investigational therapeutic strategy designed to enhance myocardial perfusion by applying a laser energy source or pharmacologic agents directly into the ischemic myocardium. Also known as trans-myocardial revascularization (TMR), trans-myocardial laser revascularization (TMLR), or percutaneous myocardial revascularization (PMR), DMR can be performed using either surgical or catheter-based approaches. In surgical DMR, myocardial access is from the epicardial surface via a thoracotomy, whereas for catheter-based DMR an endocardial approach is achieved via percutaneous techniques. Surgical and catheter-based DMR could also deliver pharmacotherapy directly into the myocardium utilizing injector technologies.

Preliminary surgical DMR clinical trials have indicated a significant reduction in angina severity, improved quality of life and some evidence of improved myocardial perfusion in refractory coronary ischemic syndromes. The catheter-based DMR procedure may provide equivalent benefit to surgical DMR without the need for a surgical procedure.

Patient Candidates for DMR Procedures

Patients are considered candidates for investigational clinical DMR protocols if they meet the following criteria:

1. severe (functional class III or IV) angina despite maximal anti-ischemic drug therapy;
2. poor candidates for catheter-based angioplasty procedures due to no acceptable target sites or high procedural risk;
3. poor candidates for surgical revascularization due to a lack of acceptable target vessels, no remaining surgical conduits, or prohibitive risk.

Currently, the major categories for clinical DMR investigations involve patients with degenerated saphenous vein graft disease (especially in patients with a patent internal mammary artery conduit), diffuse coronary disease or small target vessels (e.g., diabetics), incessant post-angioplasty restenosis or recurrent diffuse in-stent restenosis, and chronic total occlusions with either non-visualized or poor distal vessels. For the latter category, it remains to be determined whether collateral supply to the treated area would enhance the therapeutic response to DMR.

Another potential indication for DMR is its "hybrid" use in combination with non-revascularizable territories during either coronary angioplasty or coronary artery bypass graft surgery. Ultimately, this latter indication may constitute the largest patient cohort for DMR procedures. At present, patients with overt heart failure or very low left-ventricular ejection fractions (<30%) are excluded from most study protocols.

Clinical Results with Surgical DMR

In 1982, Mirhoseini et al. proposed using laser energy to create myocardial channels to elicit direct communications between the left ventricular cavity and the ischemic myocardium.(1),(2) In 1983, Mirhoseini et al. applied surgical DMR technique using a CO₂ laser as an adjunct to CABG in a patient who could not be completely revascularized by conventional techniques.(3) Post-operative nuclear studies showed improved regional wall motion in the DMR treated zone. Subsequently, they have continued using surgical DMR as an adjunct to CABG with CO₂ laser and reported improved angina and improved nuclear perfusion studies in DMR treated regions.(4),(5)

More recently, Frazier and Cooley have used a similar surgical DMR approach with CO₂ lasers as "sole therapy" in 21 patients.(6),(7) Overall, the results showed improved angina, increased exercise capacity, and enhanced sub-endocardial perfusion by PET scans for at least 12 months. Similar favorable results applying surgical CO₂ laser DMR techniques were also reported by Horvath and Cohn.(8) They have studied 20 patients with angina refractory to medical therapy with evidence of reversible ischemia by 99mTc sestamibi, who were not candidates for angioplasty, CABG or cardiac transplantation. A significant improvement in angina was observed (angina class decreased from 3.7 to 1.0 at 12 months, p<0.01).

Also, improved perfusion by sestamibi was found in the area of reversible ischemia treated by DMR. Results of a multicenter trial with CO₂ laser surgical DMR as sole therapy for end-stage coronary artery disease in 200 registry patients have recently confirmed the beneficial preliminary results.(9) The peri-operative mortality was 9%. Angina class decreased significantly from pre-operative status and there was a significant decrease in the number of admissions for angina in the year after the procedure (2.5 versus 0.5 admissions per patient year). Using the definition that a decrease of two angina classes after the operation is considered a success, the procedure had a 75% success rate for patients at three, six and 12 months. The results of the radionuclide perfusion scans showed significant decrease in number of segments with reversible perfusion defects in treated zones without a change in the number of segments with fixed defects in DMR treated areas.

A randomized study comparing "best" medical therapy versus surgical CO₂ laser DMR in patients not amenable to conventional revascularization addressed the question of whether DMR is superior to medical therapy. The preliminary analysis supports the registry experience -- there was an improvement in symptoms and quality of life assessment and some evidence of improved myocardial perfusion in the treated areas.(10),(11) Sixty-seven percent of patients randomized to surgical DMR had a reduction of two or more angina classes compared with 6% in the medical therapy group and hospitalization for unstable angina was markedly reduced (13% post-DMR versus 72% with medical therapy).

Interestingly, there was persistence of the clinical efficacy (reduction in angina threshold) for as long as two years after DMR, suggesting more of a permanent beneficial effect on myocardial perfusion rather than transient placebo effect from the surgical procedure. Nuclear studies, with analysis limited to the first three months thus far, showed a less impressive 15% reduction in reversible defects in the DMR group versus a 7% increase in reversible defects in the control group.

In a sub-study of this trial, Donovan et al.(11) studied 12 patients treated with surgical CO₂ laser DMR by dobutamine stress echocardiography and found a significant improvement in regional contractility in the treated segments (47% versus 23%). Recently, in a prospective randomized trial of surgical DMR using a Ho:yttrium-aluminum-garnet (YAG) laser versus "best" medical therapy, Allen et al.(12) reported significant improvement in angina class (85% versus 18%) and decreased hospitalizations for angina compared to the medical group at six months; clinical benefit was sustained for up to 12 months.

Surgical DMR Studies in Perspective

Despite the preliminary promising results of surgical DMR, there are important caveats that need to be considered when evaluating the surgical DMR experiences.

First, most surgical DMR reports have been non-randomized studies, with a relatively small number of patients.

Second, most clinical reports lacked rigorous outcome end-points to enable accurate objective assessment of DMR clinical effects. Although other studies were conducted as randomized clinical trials, the validity of comparing surgical intervention with "best" medical therapy remains problematic since an exaggerated placebo effect of the surgical group cannot be excluded. Moreover, there seems to be a disparity between clinical responses and objective end-points, especially the lack of consistent improvement in myocardial perfusion studies in patients with subjective clinical improvement. Importantly, the underlying mechanism to explain the beneficial clinical results remains to be established.

Finally, it is unknown whether the laser-induced myocardial damage and fibrosis can lead to cardiac arrhythmias and increased late mortality among DMR treated patients.

Catheter-Based Approaches for DMR

The catheter-based approach for DMR may provide equal effect to surgical DMR without the need for a thoracotomy or general anesthesia.(13) In addition, it enables access to areas not approachable using surgical DMR (e.g., the ventricular septum and the posterior wall) and provides opportunities for multiple treatment sessions using a "lesser invasive" approach.

System requirements for "optimal" catheter-based DMR include the integration of catheter guidance with an ablative laser system utilizing the "most appropriate" laser parameters. Most importantly, the percutaneous approach must ensure penetrating energy delivery to pre-specified viable treatment zones without

1. perforation or other undesirable tissue effects (thrombosis, particulate debris, infarction, etc.)
2. ventricular arrhythmias
3. effects of endocardial motion, and
4. multiple laser application into the same location.

The catheter should include a laser fiber and should permit access to all endocardial zones. This requires adequate torque response, tip deflection, and endocardial contact stability as well as a tip configuration that minimizes surface trauma.

Catheter Navigation During DMR

Navigational control of the distal tip of the laser catheter may be necessary to achieve optimal laser-tissue contact at treatment zones. In addition, navigational control may be helpful to prevent repetitive same-site laser firing that may increase the risk of perforation. Conventional catheter navigational modalities, such as bi-plane fluouroscopy and echocardiography, are limited by their two dimensional endocardial representation, non-optimal echocardiographic resolution at the catheter tip-endocardial interface, inability to identify target viable treatment zones on-line, and inability to identify in advance "channel-on-channel" laser firing which may contribute to myocardial perforation.

A novel navigational platform for catheter-based DMR has been derived from a new diagnostic and guidance-navigational system (Biosense^TM). This device utilizes electromagnetic field energy in order to create electro-mechanical maps for catheter guidance in three-dimensional space without the use of fluouroscopy. The electro-mechanical maps are used to identify viable target zones for DMR based on intra-cardiac electrical and mechanical signals. This catheter system is integrated with a laser to perform the DMR procedure at precise locations within the left ventricle. The exact channel location is indicated in real-time on the electro-mechanical map. It remains to be determined whether such precise localized treatment directed to viable myocardial zones would enhance therapeutic benefit and improve procedural safety of the catheter-based DMR procedure.

Current Status of Catheter-Based DMR Clinical Trials

Three commercially available catheter-based laser DMR systems (CardioGenesis^TM, Sunnyvale, CA, USA; Eclipse^TM, Sunnyvale, CA, USA; and Biosense^TM/Johnson & Johnson^TM, Tirat-Hacarmel, Israel) are currently undergoing evaluation in clinical trials. The energy source for all three systems is a Ho:YAG laser with differing energy parameters, fiber diameters, and catheter design. Phase I registries were designed to prove the safety and feasibility of pecutaneous DMR and are followed by randomized controlled clinical trials. Initially, patient cohorts will include those with chronic refractory ischemia, but probably this will be followed by "hybrid" procedures combined with routine coronary angioplasty procedures. The clinical end points in all trials are symptomatic angina improvement and assessments of exercise capacity and radionuclide myocardial perfusion.

Conclusions

DMR, both surgical and catheter-based, are potential treatment modalities for chronic refractory ischemic syndromes in patients who are "poor" candidates for conventional revascularization procedures. Although the clinical data seem promising for surgical DMR, more rigorous assessment of objective endpoints is still required to render definitive conclusions. Catheter-based DMR is in its infancy. Hurdles which still confront clinical investigators include further catheter development, improved guidance systems, predictable energy delivery, and acute complications. There are serious gaps in our understanding of the optimal channel size and channel density as well as the ideal energy source to produce desired tissue responses. The underlying mechanisms to explain observed beneficial clinical results must be explored further and the dichotomy between clinical responses and objective endpoint assessments must be resolved before DMR is accepted as a viable therapeutic alternative in patients with severe ischemic heart disease.

Corresponding Authors

Martin B. Leon, MD and Ran Kornowski, MD
Cardiology Research Foundation
Washington Hospital Center
110 Irving St. NW, 4B-1
Washington, DC 20010 USA

(202) 877-5975 (TEL)
(202) 877-2715 (FAX)

E-mail: mbl1@mhg.edu (M.B.L.) or rxk3@mhg.edu (R.K.)