Ran Kornowski and Shmuel Fuchs

KEY POINTS

■ A growing population of patients suffer severe cardiac disease that cannot be treated effectively using conventional modalities such as pharmacotherapy, coronary angioplasty, and/or coronary bypass surgery. This is the "target" population for transmyocardial therapeutic approaches.

■ The effect of surgical laser transmyocardial revascularization (TMR) on vascular and myocardial functions was studied and growing clinical experiences were derived from surgical TMR procedures indicating symptomatic benefit among treated patients.

■ The results of pivotal randomized efficacy studies comparing percutaneous TMR to best medical treatment or sham controls were reported. Altogether these studies dictated the doubtful fate of this technique as an alterna tive mode of myocardial revascularization that is no longer in routine clinical use.

■ Currently, it is unknown whether dissimilarities among TMR devices may account for the differences in clinical outcomes observed among the clinical trials.

■ The delivery of biologic compounds (e.g., genetic or progenitor cell experimental compounds) has been considered as an alternative and more "natural" approach for restoration of myocardial perfusion and/or mechanical function in the diseased ischemic heart.

■ It remains to be seen to what extent transmyocardial delivery of biologic agents can diminish myocardial damage and/or restore blood flow in ischemic cardiomy-opathy syndromes.

Despite the great achievements in preventing and treating coronary artery disease and cardiovascular disorders over the last decade, there is still a wide-scale population of patients who suffer severe cardiac disease that cannot be treated effectively using conventional treatment modalities such as pharmaco-therapy, coronary angioplasty, and/or coronary artery bypass grafting (CABG). This population, which has been estimated as 3% to 15% of patients referred for invasive cardiac evaluation, may suffer from significant morbidity and mortality throughout the years after diagnosis.1,2

In recent years, alternative therapeutic options (e.g., enhanced external counterpulsation, spinal cord stimulation, and novel antiangina pectoris medications) have been used to alleviate angina symptoms and improve quality of life in patients with refractory myocardial ischemia. Moreover, a variety of mechanical devices and energy sources have been investigated, aiming at improving angina pectoris symptoms and enhancing myocardial perfusion by creating intramyocardial penetrating channels.3-5 Most mechanical strategies for transmyocardial revascularization (TMR) have employed a laser energy source via either surgical (transepicardial) or catheter-based (transendocardial) techniques. However, none of these techniques has become the "gold standard" of medical care in this challenging clinical scenario. Experimental strategies such as gene transfer and progenitor cell transplantation approaches have been explored to enrich collateral perfusion and improve contractility in the severely ischemic myocardium; these procedures are still considered purely investigational. This chapter describes these various therapeutic strategies and discusses the evolution of the field defined as "transmyocardial therapeutics"

using either laser energy or biologic compounds delivered into the ischemic or infarcted myocardium.

The patients under discussion are those who continue to suffer severe refractory angina pectoris despite maximal medical (i.e., pharmacologic) treatment, and in whom most invasive treatments such as coronary angioplasty or CABG have been used multiple times with temporary or only limited success. In addition, there is a population of patients with cardiac insufficiency and a combination of symptoms such as chest pain and shortness of breath. These patients are also frequently hospitalized, and the treatments presently suggested can only slightly improve the suffering bound to their disease.6

We propose herein clinical criteria for defining those patients who are candidates for "alternative" revascularization procedures7:

1. Patients with symptomatic coronary artery disease that cannot be treated effectively using percutaneous and/or surgical approaches, agreed by both the cardiologist and the surgeon

2. Patients with symptomatic chronic myocardial ischemia (either moderate to severe angina pectoris of Canadian Cardiovascular Society [CCS] class II, III, or IV or angina equivalent symptoms) while on best attempted medical treatment, defined as the administration of antiangina medications (e.g., P-blockers, nitrates, calcium channel blockers, angiotensin blockers, antiplatelet agents, and statin medications), other risk factors modifiers, and heart failure management if indicated

3. Patients with limited exercise capacity due to typical effort-related symptoms (e.g., <8 minutes on modified Bruce or equivalent exercise protocol) or, if exercise treadmill testing (ETT) is the only objective test for assessing myocardial ischemia, then transient ST-segment depression >1 mm at 80 msec after the J point present during and/or immediately after the test

4. Unequivocal reversible perfusion defects (either partial or complete) on single-photon emission computed tomography (SPECT) nuclear imaging study (either single- or dual-isotope study), positron emission tomography (PET), or magnetic resonance imaging (MRI) and/or with stress-induced functional impairment findings using dobutamine echocardiography

5. A target region for experimental intervention that is defined upfront and regional left ventricular dysfunctional myocardium that is categorized as a viable or nonviable territory. For the viable myocardium, the main endeavor is to restore perfusion and, in case of impaired contractility, to improve function. For the nonviable myocardium, restoration of function (i.e., myocardial "regeneration") is the primary end point, and enhancing perfusion may be necessary to allow survival support of the implanted compound (e.g., cells, grafted tissue). For transmyocardial interventions, identification of potential sources of collateral vessels is imperative, because the absence of any collateral source (i.e., no vascular conduit without a significant narrowing) compromises the ability to achieve a meaningful clinical response. Data have indeed suggested that patients with good blood flow to at least one region of the heart through a native artery or a patent vascular graft have a markedly better clinical outcome after TMR treatment.8

A typical profile of patients with chronic refractory myocardial ischemia includes the following characteristics: (1) age between 55 and 70 years and relatively early initial clinical onset of coronary artery disease, (2) long-standing history (e.g., >10 years) of coronary artery disease, (3) multivessel coronary artery disease, (4) previous CABG and/or multiple angioplasty procedures, (5) previous myocardial infarction, (6) at least one viable myocardial territory that is supplied by an occluded vessel and has a compromised collateral-dependent perfusion, (7) relatively preserved left ventricular function (e.g., left ventricular ejection fraction [LVEF] >40%), (8) high prevalence of diabetes mellitus (~40%) along with other multiple cardiovascular risk factors, and (9) predominantly male patients.

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