Allen, Keith B

Dowling, Robert D

Richenbacher, Wayne

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However, an animal model would provide results that may help to
understand pathophysiological mechanisms in AF.
In our study (3), we did not assert to use the immunological
analysis for quantification. After finding clear histological differ-
ences (by visualization) between patients in sinus rhythm (SR) and
AF, we quantified the expression of AT1 and AT2 by Western blot
techniques. We could detect a significant increase in AF compared
to SR in the AT1 expression, but not in the AT2 expression (Fig.
3A [3]). As shown in Figure 2, there was a higher level of AT1 in
patients with both lone AF and MVD  AF compared to a lower
level in patients with SR. In contrast to the claim of Goette et al.,
there was no lack of expression of AT1 in SR; however, a low level
(Fig. 2 [3]).
We cannot exclude that other substrates or pathways may
influence the expression of AT1/AT2 in patients with AF. How-
ever, a time-dependent expression of AT1 has not yet been
analyzed and is difficult to investigate in humans. In fact, differ-
ences exist in the expression of angiotensin II receptor subtypes
between human left and right atrium. Furthermore, because AF
depends from the left atrium (5), it is important to consider both
atria to draw possible conclusions about pathophysiological influ-
ences of signaling pathways. Owing to our results, AF is associated
with an upregulation of AT1 in the left atrium, but not in the right
atrium. This suggests a pathophysiological role of AT1 in AF
(3,6,7).
Andreas Boldt, MSc
Jens Garbade, MD
Jan Fritz Gummert, MD
Stefan Dhein, MD
University of Leipzig
Heart Center
Cardiovascular Surgery
Stru¨mpellstrasse 19
D-04289 Leipzig
Germany
E-mail: AndreasBoldt@web.de
doi:10.1016/j.jacc.2004.03.027
REFERENCES
1. Allessie M, Ausma J, Schotten U. Electrical, contractile and structural
remodeling during atrial fibrillation. Cardivasc Res 2002;54:230–46.
2. Nakashima H, Kumagai K, Urata H, Gondo N, Ideishi M, Arakawa K.
Angiotensin II antagonist prevents electrical remodeling in atrial
fibrillation. Circulation 2000;101:2612–7.
3. Boldt A, Wetzel U, Weigl J, et al. Expression of angiotensin II
receptors in human left and right atrial tissue in atrial fibrillation with
and without underlying mitral valve disease. J Am Coll Cardiol
2003;42:1785–92.
4. Goette A, Arndt M, Ro¨cken C, et al. Regulation of angiotensin II
receptor subtypes during atrial fibrillation in humans. Circulation
2000;101:2678–81.
5. Allessie MA, Boyden PA, Camm AJ, et al. Pathophysiology and
prevention of atrial fibrillation. Circulation 2001;103:769–77.
6. Kumagai K, Nakashima H, Urata H, Gondo N, Arakawa K, Saku K.
Effects of angiotensin II type-1 receptor antagonist on electrical and
structural remodeling in atrial fibrillation. J Am Coll Cardiol 2003;41:
2197–204.
7. Madrid AH, Bueno MG, Rebollo JM, et al. Use of irbesartan to
maintain sinus rhythm in patients with long-lasting persistent atrial
fibrillation: a prospective and randomized study. Circulation 2002;106:
331–6.
From Controlled Trials to Clinical
Practice: Monitoring Transmyocardial
Revascularization Use and Outcomes
Considering the significant clinical experience with transmyocar-
dial revascularization (TMR) in both the controlled trial and
“real-world” setting, we felt compelled to comment on the recent
retrospective registry report by Peterson et al. (1) culled from the
Society of Thoracic Surgeons national cardiac database. Regarding
sole-therapy TMR, the investigators confirm findings observed in
five prospective randomized trials comparing TMR to medical
therapy in “no option” class III/IV angina patients: like most new
technologies, there is a learning curve, and surgical risk is increased
in sicker patients (2–6). Their commentary, similarly, is not new.
Allen et al. (2) reported reduced operative mortality rate from 5%
overall to 2% in the last 100 randomized patients, attributable to
surgical technique refinement and patient selection; Frazier et al.
(3) reported unstable angina as a significant predictor of operative
mortality. Others with clinical experience in treating unstable
patients (2,7,8) confirm that such patients without conventional
options represent a higher risk group for TMR.
Although not the intent of their retrospective study, Peterson et
al. (1) fail to summarize adequately the clinical benefits of
sole-therapy TMR. In prospective randomized trials at one year,
TMR provided superior angina relief, decreased rehospitalizations,
and improved exercise times compared to patients managed
medically. A recent five-year follow-up of randomized patients
demonstrated significantly increased Kaplan-Meier survival rates
and sustained, significantly superior angina relief in patients
randomized to TMR compared to medical therapy (9).
As reported by the investigators (1), TMR is increasingly being
utilized adjunctively with coronary artery bypass grafting (CABG)
in patients with diffuse coronary artery disease (CAD) who would
be incompletely revascularized by CABG alone. In a prospective,
randomized trial involving 263 such patients, CABG/TMR pro-
vided operative and one-year mortality benefits with a trend
toward superior angina relief compared to CABG alone (10). The
retrospective report by Peterson et al. (1) compares patients in the
STS database who received CABG/TMR with a concocted
control group consisting of CABG-only patients with triple-vessel
disease who received 3 grafts. The appropriateness of this
comparison is questionable, because it assumes that incomplete
revascularization in the control group occurred in an area of
ischemic viable myocardium supplied by a diffusely diseased,
ungraftable coronary artery and that all participating centers
accurately and consistently defined three-vessel disease. It is not
possible to verify this by simply querying the STS database. It is
important also to note that surgeons are increasingly operating on
patients with diffuse-CAD, which has been shown to be a
powerful independent predictor of operative mortality (11,12).
Unfortunately, the presence of diffuse-CAD is not factored into
the STS database or other national databases. Thus, such case-
matched comparisons against CABG/TMR-treated patients with
diffuse-CAD can be unreliable because control database sources
fail to account for diffuse-CAD and therefore underestimate pre-
dicted operative mortality in this select patient group.
We applaud the investigators in supporting continued physician
training and education regarding the judicious application of
sole-therapy TMR or adjunctively in patients who would be
incompletely revascularized by CABG alone. Long-term
2364 Letters to the Editor JACC Vol. 43, No. 12, 2004
June 16, 2004:2363–6
follow-up of the latter group will further define the role of TMR
in the treatment of an increasingly complex cardiac surgical
patient.
Keith B. Allen, MD
Indiana Heart Institute
10590 North Meridian Street
Indianapolis, IN 46260
E-mail: kallen2340@aol.com
Robert D. Dowling, MD
Wayne Richenbacher, MD
doi:10.1016/j.jacc.2004.03.028
REFERENCES
1. Peterson ED, Kaul P, Kaczmarek RG, et al. From controlled trials to
clinical practice: monitoring transmyocardial revascularization use and
outcomes. J Am Coll Cardiol 2003;42:1611–6.
2. Allen KB, Dowling RD, Fudge TL, et al. Comparison of transmyo-
cardial revascularization with medical therapy in patients with refrac-
tory angina. N Engl J Med 1999;341:1029–36.
3. Frazier OH, March RJ, Horvath KA. Transmyocardial revasculariza-
tion with a carbon dioxide laser in patients with end-stage coronary
disease. N Engl J Med 1999;341:1021–8.
4. Burkhoff D, Schmidt S, Schulman SP, et al. Transmyocardial revas-
cularization compared with continued medical therapy for treatment of
refractory angina pectoris. Lancet 1999;354:885–90.
5. Schofield PM, Sharples LD, Caine N, et al. Transmyocardial laser
revascularization in patients with refractory angina: a randomized
controlled trial. Lancet 1999;353:519–24.
6. Aaberge L, Nordstrand K, Dragsund M, et al. Transmyocardial
revascularization with CO2 laser in patients with refractory angina
pectoris. J Am Coll Cardiol 2000;35:1170–7.
7. Hattler B, Griffith B, Zenati M, et al. Transmyocardial laser revascu-
larization in the patient with unmanageable unstable angina. Ann
Thorac Surg 1999;68:1203–9.
8. Dowling RD, Petracek MR, Selinger SL, Allen KB. Transmyocardial
revascularization in patients with refractory, unstable angina. Circula-
tion 1998;98 Suppl II:73–6.
9. Allen KB, Dowling R, Angell W, Gangahar D, et al. Transmyocardial
revascularization versus medical therapy: five-year follow-up of a
prospective, randomized, multicenter clinical trial. Circulation 2003;
108 Suppl IV:326–7.
10. Allen KB, Dowling RD, DelRossi A, et al. Transmyocardial laser
revascularization combined with coronary artery bypass grafting: a
multicenter, blinded, prospective, randomized, controlled trial. J Tho-
rac Cardiovasc Surg 2000;119:540–9.
11. Graham MM, Chambers RJ, Davies RF. Angiographic quantification
of diffuse coronary artery disease: reliability and prognostic value for
bypass operations. J Thorac Cardiovasc Surg 1999;118:618–27.
12. Osswald B, Blackstone E, Tochtermann U, et al. Does the complete-
ness of revascularization affect early survival after coronary artery
bypass grafting in elderly patients? Eur J Cardiothorac Surg 2001;20:
120–6.
REPLY
The letter by Dr. Allen and colleagues raises a number of
important issues. First, they point out that the operative risk
factors for transmyocardial revascularization (TMR) identified in
our study (1) were similar to those noted in earlier randomized
studies. Although we agree that the preoperative risk factors
identified were not unique, our study provided confirmatory
evidence as to their generalizability in a broader clinical practice
setting. More significantly, our national study demonstrated there
is still a need to optimize appropriate patient selection for the
procedure in contemporary care. Specifically, our study and others
clearly demonstrate the risks of TMR in patients with unstable
symptoms or recent myocardial infarction (MI). Despite this, we
found more than half of TMR cases done in community practice
were performed under these conditions. Thus, we believe it
valuable to re-emphasize to clinicians these potentially modifiable
operative risk factors as a means of encouraging safer use of TMR
in community practice in the future.
Dr. Allen and colleague’s second point was that we failed to
acknowledge the efficacy data for TMR-only. In this regard, we
would argue that our study did reference the six randomized
clinical trials that support the effectiveness of TMR-only to reduce
patient symptoms. The recent abstract on five-year results sited by
Allen was not available before our study’s publication, and we look
forward to seeing this work in press soon.
The third point raised by Dr. Allen and colleagues concerns the
role of TMR when used in conjunction with coronary artery bypass
graft (TMR  CABG). Our study confirms that this combined
procedure has become the dominant role for TMR in contempo-
rary practice. There is less compelling evidence for the efficacy of
TMR in this setting, however, than is found in TMR-only. The
sole randomized trial of TMR  CABG failed to identify a
significant reduction in angina symptoms, but it did report an
unexpected reduction in perioperative event rates (2). Our obser-
vational study could not confirm these promising findings when
comparing operative outcomes among patients with three-vessel
disease who got TMR CABG versus those receiving incomplete
revascularization with CABG-only (i.e., one or two grafts only).
We agree with Dr. Allen and colleagues that observational
treatment comparisons, even when risk-adjusted, may still be
challenged by unmeasured patient selection biases (a point we
included in our report).
In conclusion, our study emphasized the importance and utility
of clinical registry information in providing evidence to further
refine the optimal application of technology after its introduction
into clinical care. Its main goals were to describe contemporary
practice patterns; to improve the safety of the procedure through
appropriate patient selection; and to stimulate future research in
areas requiring further clarification. We hope we have accom-
plished these goals and that Dr. Allen and colleagues continue to
refine the optimal role for this procedure.
Eric D. Peterson, MD, MPH, FACC
Duke University Medical Center
Box 3236
Durham, NC 27710
E-mail: peter016@mc.duke.edu
T. Bruce Ferguson, Jr, MD
doi:10.1016/j.jacc.2004.03.029
REFERENCES
1. Peterson ED, Kaul P, Kaczmarek RG, et al. From controlled trials to
clinical practice: monitoring transmyocardial revascularization use and
outcomes. J Am Coll Cardiol 2003;42:1611–6.
2. Allen KB, Dowling RD, DelRossi AJ, et al. Transmyocardial laser
revascularization combined with coronary artery bypass grafting: a
2365JACC Vol. 43, No. 12, 2004 Letters to the Editor
June 16, 2004:2363–6


From controlled trials to clinical practice: monitoring transmyocardial revascularization use and outcomes 

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