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Ann Thorac Surg 1999;67:1596-1601
© 1999 The Society of Thoracic Surgeons

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Original Articles

Holmium: YAG laser transmyocardial revascularization relieves angina and improves functional status

^a Department of Surgery, Baylor College of Medicine and Veterans Affairs Medical Center, Houston, Texas, USA

Address reprint requests to Dr Jones, Department of Surgery, University of Missouri, M580 Health Sciences Center, Columbia, MO 65212
e-mail: jonesjw{at}health.missouri.edu

Presented at the Forty-fifth Annual Meeting of the Southern Thoracic Surgical Association, Orlando, FL, Nov 12–14, 1998.

	Abstract

Top Footnotes Abstract Introduction Patients and methods Results Comment References

 
Background. Transmyocardial revascularization (TMR) surgery uses laser channeling of diseased myocardium to treat ischemia and angina. Rigorous prospective randomized studies have been previously unavailable.

Methods. Forty-three patients were randomized to a medication group and 43 to a group scheduled for TMR surgery and medication. All had advanced cardiac ischemia with CCSA class 3 or 4 angina, took at least 2 cardiac medications at maximum doses, and were ineligible for angioplasty or bypass.

Results. Forty-two of 43 TMR group patients received surgery and were discharged after hospitalizations averaging 3.2 days. Two suffered perioperative MIs, with one death. Four others died within 12 months of surgery, 3 from cardiac events and 1 from pneumonia. Five medical group patients died from cardiac events within 12 months. Three, 6, and 12 month exams showed angina class improvement in TMR patients compared to preoperative values (3.86 ± 0.05 vs 1.71 ± 0.2 P < 0.0001), and to controls at 12 months (3.77 ± 0.07 vs 1.71 ± 0.2, P < 0.0001). Exercise tolerance improved in TMR patients over preoperative values, and was better than medication group scores after 12 months (490 ± 17 sec. vs 294 ± 12 sec., p = 0.0002).

Conclusions. Holmium:YAG laser channeling of the myocardium improves function and reduces angina in advanced cardiac patients who lack alternative therapeutic options.

	Introduction

Top Footnotes Abstract Introduction Patients and methods Results Comment References

 
Transmyocardial revascularization (TMR) effectively relieves angina pectoris in patients for whom conventional treatment is not indicated or has proven insufficient [1–3]. Initial reports encouraged further large trials which indicated that myocardial perfusion was improved [4]. While these longitudinal trials using the carbon-dioxide laser yielded promising results, randomized trials, which provide greater scientific certainly, are needed to confirm the extent and duration of benefits. In addition, data from published studies of other laser technology, including the Holmium:YAG laser, are beginning to show favorable clinical results [5, 6]. To assess these results, particularly those reporting quantitative functional improvement, a rigorous randomized clinical trial utilizing the CardioGenesis Holmium:YAG laser was initiated in our institution in October of 1996.

	Patients and methods

Top Footnotes Abstract Introduction Patients and methods Results Comment References

 
Procedures
After obtaining Institutional Review Board approval and written informed consent from each candidate, 86 patients from 168 candidates at our primary single institution were randomized to 2 study groups by an independent data management group. Strict entrance criteria specified that those randomized must have disabling angina pectoris (Canadian Cardiovascular Society Angina [CCSA] class 3 or 4), not be candidates for conventional therapy, be maintained on maximal tolerated doses of at least two cardiac medications, and have areas of viable ischemic myocardium by dipyridamole-thallium testing. Additional entry criteria required that coronary angiograms (Medrad, Indianola, PA) performed within 3 months of randomization show 1 area of adequate perfusion in the region of 1 of the major coronary arteries. All angiograms were reviewed for appropriateness by an independent cardiologist from another institution. Criteria required that entry exercise testing by Modified Bruce Protocol be reproduced within 15% on consecutive tests, and to have resulted in angina as an endpoint on at least 1 test. A total of 3 tests were permitted before disqualification. Those monitoring the exercise tests were blinded to the group assignment of patients. Results, including ETTs, echocardiograms, and thallium scans, were sent to a core laboratory, blind toindividual group assignments, for final interpretation. Patients were experiencing chronic angina at the time of randomization. Waiting periods of 21 days after any acute ischemic syndrome requiring hospitalization, and 3 months following interventions or myocardial infarctions, were observed before initiation of the study protocol. The ejection fractions of all participants were 30% or greater. Patients with left main coronary artery lesions of greater than 70% without open bypasses to the anterior descending or circumflex arteries, and those with congestive heart failure, were excluded. Obstructive pulmonary disease was an exclusion criterion when, in the opinion of the principal investigator, it would affect exercise testing.

An operative protocol similar to that described by Horvath and Cohn [3] was followed. Procedures were done through a muscle-sparing 4-inch anterior thoracotomy. This allowed an approach which avoided the most severe scarring in patients, 40 (95%) of whom had prior coronary bypass procedures; 2 had previous sternectomies to treat infections. A univent endotracheal tube was used to improve exposure, but was typically released once the pericardial suspension sutures were in place. Measures to limit postoperative pain included placement of an epidural catheter, avoidance of rib damage, pre-incision injection of lidocaine in the site of the incision, intercostal nerve block with a marcaine-depomedrol solution at the end of the procedure, and full analgesic coverage. All patients were extubated within 2 hours of arrival in the intensive care unit (ICU). Nursing staff were briefed on the procedure and specifically on the need for strict pain control. A nitroglycerin drip was titrated to a maximal tolerated dose (blood pressure of 100 to 110 mm Hg systolic) in the ICU and a nitroglycerin patch was used for 2 weeks postoperatively. Analgesics were administered every 3 waking hours.

Statistical methods
Univariate analyses of continuous variables between groups were conducted using unpaired Student’s t tests. Univariate analyses of continuous variables within groups were performed using repeated measures analysis of variance. Univariate categorical data were compared using contingency table methods. Multivariate comparisons between groups were conducted using two-way analysis of variance. The relationship between change in anginal class and change in treadmill time was estimated using both ANOVA and multiple linear regression models. F statistics were used to assess overall correlation and partial t statistics computed using type II sums of squares to investigate independent variable effects in the regression models. Univariate correlations were computed using Pearson product-moment and Spearman rank correlations. Analysis of covariance was used to account for differences between groups with respect to risk factors at baseline. The null hypothesis was rejected at p < 0.05. Data were maintained in a Paradox database (Corel Corp, Ottawa, Onatario, Canada). All analyses were conducted using SAS software version 6.12 (SAS Institute, Cary, NC) running under Windows NT 4.0 (Microsoft Corp, Seattle, WA).

	Results

Top Footnotes Abstract Introduction Patients and methods Results Comment References

 
Forty-three patients were randomly assigned to continued medical therapy and 43 patients were randomized to TMR surgery. One surgery group patient was excluded after he elected to delay surgery and suffered a myocardial infarction, resulting in a total of 42 operative patients. All but 2 living patients were followed for 12 full months. All patients were males and averaged 62 years of age. Preoperative variables, such as age, prior operations, average ejection fraction, diabetes, and pattern of disease, were similar in the 2 groups (Table 1). Significantly more patients in the surgical group had hypertension; this was examined by multivariate analysis and had no effect on endpoints.

All patients were extubated within 2 hours of arrival in the ICU; 1 patient required reintubation after instability from a perioperative myocardial infarction. Two patients who had sleep apnea developed severe hypercarbia, which resolved with close observation. The average time to extubation in the ICU was 0.12 days. This included the patient who died. Patients remained in the intensive care unit overnight, for an average of 0.86 days, and had an average length of hospital stay of 3.2 days. Forty percent were discharged during the second postoperative day.

Two patients had postoperative evidence of a myocardial infarction; 1 died and 1 recovered with minimal heart damage (maximal CPK-MB was 90 units). No patient had postoperative bleeding requiring surgical exploration. The only 2 patients who were transfused with bank blood were anemic before surgery. Four patients suffered phrenic nerve paralysis diagnosed from an elevated left hemi-diaphragm; 3 had recovered completely at the time of the 3 month follow-up examination, and 1 continued to experience severe symptoms at 1 year. No wound infections occurred. One patient had chest wall pain requiring analgesia for 3 months before spontaneous resolution.

Angina pectoris was dramatically improved immediately following surgery, with only 2 patients reporting any angina-like symptoms before discharge; both were experiencing perioperative myocardial infarcts. At every interval tested, average CCSA angina class was significantly better in the TMR group (Fig 1). Average baseline angina class trended lower among medication controls than among TMR patients. At 3 month follow-up, average angina class among controls was unchanged, but was improved by an average of 2 classes among TMR patients. At 6 month follow-up, controls slightly increased their angina class, but some TMR patients showed additional improvement. At the 12 month conclusion of the scheduled follow-up period, the medication group showed little change from baseline, but TMR patients retained improvement of more than 2 angina classes (3.77 ± 0.07 vs 1.71 ± 0.2, p < 0.0001).

View larger version (46K): [in this window] [in a new window]   Fig 1. Average Canadian Cardiovascular Society angina class and standard deviation of the two groups at 3, 6, and 12 months.

View larger version (40K): [in this window] [in a new window]   Fig 2. Comparison of average modified Bruce Treadmill times at baseline, 3, 6, and 12 months.

View larger version (26K): [in this window] [in a new window]   Fig 3. Anginal class changes in TMR patients at follow-up.

View larger version (27K): [in this window] [in a new window]   Fig 4. Correlation between the changes in angina class and changes in treadmill time at 3, 6, and 12 month follow-up visits.

View larger version (26K): [in this window] [in a new window]   Fig 5. Correlation between changes in angina class and changes in treadmill time at 6 months.

View larger version (26K): [in this window] [in a new window]   Fig 6. Correlation between changes in angina class and changes in treadmill time at 12 months.

	Comment

Top Footnotes Abstract Introduction Patients and methods Results Comment References

TMR is a return to direct treatment of the microcirculation. The approach has several theoretical advantages for treating all patients with ischemic heart disease, because suitable target arteries needed for bypass or balloon angioplasty procedures are not required. This will become more important in coming years, because the number of patients who have exhausted their eligibility for conventional procedures is substantial and is increasing. In addition, TMR-produced microcirculatory angiogenesis or new arterio-venous connections may not be subject to the degenerative processes that presently limit the benefits of coronary artery bypass grafts.

Patients eligible for these no option studies are generally quite ill and, accordingly, have significant mortality rates during follow-up. They are maintained on multiple cardiac medications with inadequate symptomatic relief [3]. Although not mentioned in other large studies, non-cardiac comorbidity was common in our population. Frazier, the first to publish TMR as a sole therapy [2], reports a high incidence of cardiovascular comorbidity, including hypertension and peripheral vascular disease. Similar to our experience, he probably saw comorbidity that extended beyond the cardiovascular system to other organ systems. The majority of our patients had advanced ischemic heart disease and had exhausted their therapeutic options with multiple surgical and endovascular procedures, rather than having unsuitable target vessels from the onset. Special caution should be exercised in performing the procedure in patients with comorbidity which may limit anginal relief; a patient with leukemia and severe anemia did not improve, nor did another with Lupus Erythmatosis and coronary vasculitis.

Most of the previously published data on TMR uses the carbon dioxide laser, with only a few reports of small patient populations treated with the Holmium:YAG laser [5, 6]. Early studies had operative mortality rates in the range of 0% to 10%, with fairly high attrition in the first 3 months. Although TMR is not technically demanding for the surgeon, there is a learning curve. Krabatsch and associates [10] reported a mortality rate of 8% in their first 40 patients, which fell to 2.5% in their latest 40 patients. Recent TMR study experience, including our own, has shown minimal mortality and morbidity with consistently excellent symptomatic relief.

In each of the studies reported to date, TMR effectively reduces angina regardless of which type of laser is used. This clinical benefit is maintained through the 12 month follow-up period in this and other studies [1, 3, 4]. Horvath, a pioneer of this procedure, followed patients for an average of 24 months and found that angina class improvements were maintained [11]. In addition to symptomatic relief, objective corroboration by functional improvement in exercise tolerance testing is significant. The exercise tolerance test times of our study patients were significantly better than those of both the control group and the study patients’ own baseline values, consistent with symptomatic improvement. Frazier [2] and others [5], likewise, reported a significant improvement in ETT times in patients 6 months after TMR when compared to preoperative performance.

The mechanism of angina relief from TMR is assumed to result from improving blood flow to the ischemic tissues, but uncertainties have arisen as data accumulate. The original postulate, whereby laser channels immediately redirected oxygenated blood from the ventricular chamber to ischemic tissue, is now controversial. Several papers show increased perfusion by thallium scan [3, 4, 12], and others report no significant change [2, 10]. Thallium scans in our study did not show improvement in the TMR group when compared to the medication control group. Exploring this apparent inconsistency, Frazier used PET scanning, the most sensitive test for myocardial perfusion, and reported that patients showed an increase in the relative perfusion of the subendocardial to epicardial areas after TMR [2]. Most important, these findings were seen in patients who had no significant improvement in thallium scans. If these conflicting reports are accepted as fact, it is conceivable that the thallium scan lacks the necessary sensitivity, or that flow redistributes from areas of adequate perfusion to underperfused myocardium, such as epicardium and subendocardium, through new microvascular connections or denervation. A computer-generated three-dimensional reconstruction of an area previously channeled showed that, although open channels were not found, there were capillary networks along a linear scar [13]. This is consistent with histopathological examinations [14, 15].

As an alternative explanation, laser energy delivered to the myocardium denervates the exposed area in dogs, both acutely and for up to 2 weeks after operation [16]. Angina pectoris was conspicuously absent in almost all of our surgical patients (40 of 42), beginning immediately postoperatively. Others have also noted the immediacy of relief [2, 3]. Denervation is thus consistent with what is observed clinically. Postmortem examination in humans shows that most laser channels have closed, suggesting that actual revascularization through these channels is not the main mechanism of action for relief of angina [17]. Similarly, analgesia without treatment of ischemia in inoperable situations by thoracic epidural blocks [18] or neurostimulation [19] has proven effective in providing clinical relief. Neurostimulation reduces angina, allows a decrease in consumption of short-acting nitrates, and increases exercise capacity [19]. Furthermore, thoracic epidural block reduced the size of acute infarctions by 46% in anesthetized dogs and redistributed blood flow to the endocardium as measured by microspheres [20].

TMR by Holmium:YAG laser in a carefully controlled single-site randomized trial is better than continued medical treatment in providing symptomatic improvement and enhancing functional status, but has not thus far been shown to improve survival; more lengthy experience will be necessary to reach a determination on this critical point. The procedure can be done with acceptably low mortality and morbidity. It remains an effective but empirical therapy for end-stage ischemic heart disease patients and awaits elucidation of its mechanism of therapetic action.

	Footnotes

Top Footnotes Abstract Introduction Patients and methods Results Comment References

 
Funding for this project was provided by the Cardiogenesis Corporation.

	References

Top Footnotes Abstract Introduction Patients and methods Results Comment References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): James W. Jones Daniel Burkhoff John C. Baldwin Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jones, J. W. Articles by Baldwin, J. C. Search for Related Content PubMed PubMed Citation Articles by Jones, J. W. Articles by Baldwin, J. C.