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Off-pump, minimally invasive and robotic coronary revascularization yield

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Article  in  International Journal of Medical Robotics and Computer Assisted Surgery · March 2009
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THE INTERNATIONAL JOURNAL OF MEDICAL ROBOTICS AND COMPUTER ASSISTED SURGERY
Int J Med Robotics Comput Assist Surg 2009; 5: 1–12.
Published online 30 December 2008 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/rcs.230
Off-pump, minimally invasive and robotic coronary
revascularization yield improved outcomes over
traditional on-pump CABG
Pavan Atluri
Elliott D. Kozin
William Hiesinger
Y. Joseph Woo*
Division of Cardiovascular Surgery,
Department of Surgery, University of
Pennsylvania School of Medicine,
Philadelphia, PA, USA
*Correspondence to: Y. Joseph Woo,
Division of Cardiovascular Surgery,
Department of Surgery, University
of Pennsylvania, Silverstein 6, 3400
Spruce Street, Philadelphia, PA
19104, USA.
E-mail: wooy@uphs.upenn.edu
Accepted: 12 November 2008
Copyright  2008 John Wiley & Sons, Ltd.
REVIEW ARTICLE
Abstract
Coronary artery disease is a global health concern, with increasing
morbidity and mortality. Surgical coronary artery bypass grafting has been
performed on cardiopulmonary bypass for nearly four decades, with excellent
long-term durability. Beating-heart coronary surgery has been increasing
in frequency in an attempt to decrease cardiopulmonary bypass-related
morbidity. Furthermore, with increasing expertise and technology, minimally
invasive and robotic techniques have been developed to enhance post-
operative recovery, patient satisfaction and cosmesis. Several clinical trials
have demonstrated decreased morbidity and more rapid recovery following
off-pump, minimally invasive and robotic procedures when compared to
on-pump coronary artery bypass grafts (CABGs). An equivalent extent
of revascularization and medium-term anastomotic patency has been
demonstrated among all approaches. Furthermore, for a large number
of patients who do not have anatomy amenable to traditional coronary
revascularization, adjunctive molecular therapies may provide alternative
myocardial micro-revascularization. Copyright  2008 John Wiley & Sons,
Ltd.
Keywords robotic surgery; coronary artery bypass grafting; minimally invasive;
off-pump; OPCAB; MIDCAB
Introduction
The American Heart Association estimates that 16 million Americans have
significant coronary artery disease (CAD), making this the leading cause
of mortality in the USA (1). With an increase in obesity, diabetes
and physical inactivity, the incidence of CAD is expected to rise
dramatically, necessitating a growing number of coronary revascularization
procedures. An estimated 664 000 percutaneous coronary interventions
(PCIs) and 427 000 coronary artery bypass graft (CABG) procedures
were performed in 2004 (2). Traditionally, coronary bypass has been
performed on cardiopulmonary bypass (CPB). Unfortunately, CPB is
associated with significant systemic consequences, including haemodilution,
systemic inflammation, coagulopathy, embolization, aortic injury and global
myocardial ischaemia (3–7). A renewed interest in beating-heart surgery has
developed as a means to minimize CPB-associated complications.
At present, 20% of all coronary artery bypass grafts are performed on
a beating heart in the USA (8). With advancing expertise, techniques
in performing coronary artery bypass grafts utilizing minimally invasive
and robotic methods have been developed. The present data suggest
2 P. Atluri et al.

improved morbidity and more rapid recovery following
these procedures when compared to traditional on-pump
CABG. However, advocates of on-pump coronary surgery
question the patency and durability of the anastomosis
performed on the beating heart.
In this paper, we attempt to elucidate the advantages
and short-comings of off-pump, minimally invasive
and robotic coronary artery grafting as compared to
conventional CABG. Our experience in these procedures
is presented to provide further insight into the morbidity
and mortality following these techniques. Additionally,
adjunctive and experimental therapies available to
revascularize ischaemic myocardium lacking anatomically
correctable coronary vasculature is discussed.
Coronary artery bypass grafting on
cardiopulmonary bypass or
off-pump – which is the better
alternative?
For the past four decades, coronary artery bypass grafting
on cardiopulmonary bypass (CABG) has been the widely
accepted approach to surgically bypass coronary artery
stenosis. Unfortunately, CPB is associated with significant
systemic complications. CPB activates the complement
cascade, incites the release of pro-inflammatory cytokines,
upregulates inflammatory mediators (IL-1, TNFα, IL-6,
IL-8, IL-10), initiates the systemic inflammatory response
syndrome (SIRS), stimulates oxygen-free radical gener-
ation, and increases oxidative stress (3–7). Moreover,
CPB exposes the circulating blood to haemodilution, arti-
ficial surfaces and mechanical trauma, thereby activating
coagulation, fibrinolysis and platelet destruction. These
systemic manifestations result in increased blood loss,
end-organ dysfunction and increased overall morbidity
(9–12). Additionally, aortic cross-clamping during CPB
is associated with calcific embolization, aortic dissec-
tion and global, obligate, mild, myocardial ischaemia.
The negative consequences have prompted the investiga-
tion of alternative strategies of coronary grafting without
using CPB. The most common alternative to CABG has
been off-pump, beating-heart coronary artery bypass graft
(OPCAB) (Figure 1).
The first beating heart coronary bypass was performed
in 1962 by Sabiston, utilizing the saphenous vein to
the right coronary artery (13). Subsequently, Kolesov
performed the first internal mammary artery–coronary
artery anastomosis on a beating heart in 1964 (14).
With the widespread utilization of the cardiopulmonary
bypass machine, there was a marked decrease in OPCAB
procedures until the early 1990s, when a significant
number of reports describing coronary artery anastomoses
without utilizing CPB appeared (15–18). Since the 1990s
there has been a rapid increase in OPCAB worldwide.
Critics of OPCAB remain sceptical of the true advantages
of OPCAB over CABG and cite incomplete and inferior
revascularization as shortcomings of this procedure.
Since the re-emergence of OPCAB, there have been
several retrospective and observational studies that have
demonstrated better gas exchange, shorter post-operative
time to extubation (19), decreased ICU stays, and

Figure 1. Intra-operative photograph of myocardial positioning and utilization of stabilization devices to perform coronary
arterial anastomosis to the: (A) left anterior descending coronary (LAD); (B) diagonal coronary; (C) obtuse marginal (OM); and
(D) posterior descending coronary (PDA) arteries during off-pump, beating-heart coronary artery bypass grafting (OPCAB)

Copyright  2008 John Wiley & Sons, Ltd. Int J Med Robotics Comput Assist Surg 2009; 5: 1–12.
DOI: 10.1002/rcs
Improved outcomes over traditional on-pump CABG
more rapid discharge from the hospital. These studies
have demonstrated a statistically significant decrease in
mortality with OPCAB. Moreover, a dramatic decrease in
post-operative atrial fibrillation has been demonstrated
with OPCAB as compared to CABG (20). Additionally,
a smaller fraction of OPCAB patients require inotropic
or intra-aortic balloon pump support when compared to
their propensity-matched CABG counterparts. A marked
decrease in the need for transfusion of blood, platelets
and fresh frozen plasma has also been noted (21–34).
With core temperature thermoregulation, utilizing an
active heating jacket, we have demonstrated further
improvements in outcomes following OPCAB (i.e. reduc-
tions in transfusions, time to extubation, ICU stay and
length of hospitalization) (35). A retrospective analysis
of 118 140 patients in the Society of Thoracic Surgeons
(STS) National Adult Cardiac Surgery Database demon-
strated a statistically significant decrease in risk-adjusted
mortality (2.31% vs. 2.93%; p < 0.0001) and major com-
plication rate (stroke, renal failure, post-operative cardiac
arrest, prolonged ventilation, re-exploration for bleeding;
10.62% vs. 14.15%; p < 0.0001) for OPCAB as compared
to CABG (36).
Decreased myocardial injury and decreased rates
of cerebrovascular accidents (CVA) further enhance
improvements in morbidity following OPCAB. Measure-
ment of markers of myocardial damage (troponin-I,
troponin-T and CK-MB), demonstrate significantly less
myocardial damage. This is important in that ele-
vated post-operative myocardial damage has been asso-
ciated with prolonged mechanical ventilation, as well as
increased short- and long-term mortality (37–41). Ran-
domized clinical trials have demonstrated a more rapid
recovery of myocardial oxidative metabolism, function,
and decreased inotropic function following OPCAB, which
may relate to the regional as opposed to global myocardial
ischaemia with CABG (42).
CPB is associated with a significant increase in stroke
risk. Observational studies have demonstrated a signif-
icant increase in both retinal and cerebral microemboli
following CPB (43–45). CPB has also been associated
with increased cerebral emboli, inflammation and water
content (43,46–48). Functionally, this correlates with
cognitive dysfunction, decreased regional cerebral perfu-
sion and a greater frequency of CVAs as compared to
OPCAB (49–54).
Prospective, randomized studies have demonstrated
clear benefits of OPCAB when compared to CABG.
Puskas and colleagues investigated 200 patients who
were randomized to either OPCAB or CABG (55).
Statistical analysis demonstrated equivalent Index of
Completeness of Revascularization (ICOR; number of
grafts performed/number of intended grafts, 1.00 ± 0.18
vs. 1.01 ± 0.09) and number of grafts (3.39 ± 1.04
vs. 3.40 ± 1.08) between OPCAB and CABG. The
OPCAB subset manifested significantly less myocardial
injury and coagulopathy, as well as improved platelet
counts, fibrinogen levels and international normalized
ratios (INR), resulting in decreased transfusions. On
Copyright  2008 John Wiley & Sons, Ltd.
3
average, OPCAB patients were extubated more rapidly
and discharged from the hospital nearly 1 day earlier.
Prior prospective, randomized data have demonstrated
significantly lower in-hospital morbidity, including atrial
fibrillation, sternal infections, post-operative inotrope
requirement, bleeding and transfusion associated with
OPCAB (56–59). Moreover, OPCAB is more cost-effective,
with $1839 in direct cost savings per patient (60).
OPCAB demonstrates equivalent graft
patency
In order for OPCAB to replace the ‘gold standard’
procedure (CABG), equivalent revascularization and long-
term graft patency must be demonstrated. Several studies
have demonstrated a considerable learning curve with
OPCAB, especially with regard to lateral wall vasculature
and low ejection fraction hearts. During this period,
careful supervision and guidance by an experienced
senior surgeon is required to ensure superior results.
However, once expertise is gained, several studies
have demonstrated equivalent revascularization and graft
patency between these techniques.
A randomized prospective trial comparing the results
of OPCAB and CABG performed by a single, highly
experienced surgeon demonstrated equivalent graft
patency by coronary angiography at both initial discharge
and 1 year following revascularization (34). Similarly,
Nathoe and colleagues demonstrated equivalent graft
patency between CABG and OPCAB 1 year following
revascularization (60). Furthermore, complete, multi-
vessel revascularization has demonstrated 96.6% patency
1 month following OPCAB (61). One year following
OPCAB, patency for saphenous vein grafts has been 87%,
and IMA grafts have demonstrated nearly 96% patency
(62). Overall 1- and 5-year patency following OPCAB
have been very good, at 91.9% and 88.3%, respectively
(63). Moreover, OPCAB grafts demonstrate equivalent
flow, pulsatility and flow reserve when compared to
CABG further demonstrating equivalent, highly patent
anastomoses (64). Pharmacological stress 201 thallium
single-photon emission computed tomography confirm
similar perfusion characteristics post-bypass for the
OPCAB and CABG groups (65). These patency results
have provided for equivalent midterm outcomes following
OPCAB and CABG, as measured by freedom from re-
operation (98.1% vs. 99.0%) or need for PCI (94.3% vs.
95.5%) (66).
There are divergent data regarding graft patency
following OPCAB. Studies have been published that
demonstrate inferior graft patency following OPCAB.
Retrospective analysis in these studies have demonstrated
higher rates of repeat revascularization following OPCAB
(29,30,67). A randomized prospective study comparing
OPCAB and CABG noted decreased graft patency
(combination saphenous vein and internal mammary
artery) at 3 months following OPCAB (68). It is difficult
to compare these studies objectively, given divergent
Int J Med Robotics Comput Assist Surg 2009; 5: 1–12.
DOI: 10.1002/rcs
4 P. Atluri et al.
variables between the studies. It appears that the trials
with inferior graft patency had a fraction of cases
performed by surgeons with variable expertise in off-pump
techniques. As previously indicated, there is a significant
learning curve associated with OPCAB. It is possible that,
until expertise is gained, anastomotic patency following
OPCAB will be inferior. Therefore, adequate supervision
by a senior surgeon with extensive experience in OPCAB
until a trainee has gained technical skill is mandatory.
Initially, straightforward cases should be selected, with a
gradual progression to allow the trainee to perform larger
portions of a case as well as more complex cases (69).
OPCAB indications
Initially, OPCAB was reserved for healthy young individu-
als with one- or two-vessel disease and good distal targets.
Indications were then relaxed to incorporate the elderly
population, in order to reduce cardiopulmonary bypass-
related complications, i.e. stroke. Originally, haemody-
namic instability, severe left ventricular dysfunction, car-
diomyopathy, frequent arrhythmias and emergent oper-
ations were considered contraindications to OPCAB, but
with increasing experience in beating heart surgery by
individual practitioners, these once-absolute contraindi-
cations are now relative contraindications, depending on
the expertise of the surgeon. Several reports have demon-
strated OPCAB to be a safe procedure in high-risk patients
and those with low ejection fractions (22,70–73).
Based upon a meta-analysis of currently available data,
the International Society for Minimally Invasive Car-
diothoracic Surgery (ISMICS) has released a consensus
statement on OPCAB vs. CABG. The following recommen-
dations have been published (74):
• OPCAB should be considered a safe alternative to
conventional coronary artery bypass surgery (CCAB)
with respect to risk of mortality.
• With appropriate use of modern stabilizers, heart-
positioning devices and adequate surgeon experience,
similar completeness of revascularization and graft
patency can be achieved.
• OPCAB is recommended to reduce perioperative
morbidity.
• OPCAB may be recommended to minimize mid-term
cognitive dysfunction.
• OPCAB should be considered as an equivalent alterna-
tive to CCAB in regard to quality of life.
• OPCAB is recommended to reduce the duration
of ventilation, ICU and hospital stay and resource
utilization.
• OPCAB should be considered in high-risk patients to
reduce perioperative mortality, morbidity and resource
utilization.
Furthermore, based upon the present clinical data,
a scientific consensus statement was published by the
American Heart Association Council on Cardiovascular
Surgery and Anesthesia. The council notes that few
Copyright  2008 John Wiley & Sons, Ltd.
conclusions can be obtained based upon present data, but
reported that excellent results can be achieved with both
CABG and OPCAB procedures. Furthermore, they noted
trends including decreased blood loss and transfusion,
myocardial enzyme release, neurocognitive dysfunction
and renal insufficiency following OPCAB. The Council
notes a higher morbidity following conversion of OPCAB
to emergent CABG, thereby mandating careful selection of
patients for OPCAB, based upon surgical and anaesthetic
expertise (75).
Minimally Invasive and Robotic
Coronary Revascularization
Minimally invasive coronary artery
bypass grafting
The rapid onset in minimally invasive approaches to
general surgical, gynaecological, urological and vascu-
lar surgery has prompted techniques to revascularize
myocardium utilizing smaller incisions, and less anatom-
ical and physiological manipulation. The most logi-
cal progression for coronary revascularizations was to
perform beating-heart revascularization through either
partial sternotomies or left anterolateral thoracotomies
(Figure 2), originally termed ‘minimally invasive direct
coronary artery bypass’ (MIDCAB). Often these incisions
can be limited to 8–10 cm and yield excellent cosmetic
results. Srivastava and colleagues have reported a 5–6 cm
left lateral thoracotomy as a means for LAD harvest
and complete myocardial revascularization, with a mean
2.9 ± 1.08 grafts performed via this incision (76). In
women, MIDCAB scars can easily be hidden in the infra-
mammary crease. Patient satisfaction has been excellent
and recovery rapid following MIDCAB (77). The advent
of peripheral cannulation techniques and endoluminal
aortic occlusion balloons has allowed MIDCAB to be
performed either on- or off-pump. Clinical studies have
demonstrated that this procedure can be performed safely,
with limited morbidity and mortality, under both native
and re-operative situations (78–81). Preliminary studies
suggest excellent long-term patency of grafts following
MIDCAB.
Robotic coronary revascularization
The emergence of robotic technology in medicine
has greatly advanced minimally invasive techniques in
thoracic surgery and further advanced minimally invasive
CABG. Currently available robotic platforms provide
three-dimensional (3D) vision, magnification, miniature
instruments, and mobility through multiple degrees of
movement, thereby allowing very precise and controlled
motion (82). Moreover, these systems computer-correct
and eliminate even the slightest of tremors.
Initially, robotic cardiac surgery was focused only
on harvesting the left internal mammary artery (IMA).
Int J Med Robotics Comput Assist Surg 2009; 5: 1–12.
DOI: 10.1002/rcs
Improved outcomes over traditional on-pump CABG 5

Figure 2. MIDCAB incision. (A) Left anterior thoracotomy incision utilized for minimally invasive coronary artery anastomosis.
(B) Exposure of the left anterior descending coronary artery (black arrow), utilizing a myocardial stabilization device performed
through a left anterior thoracotomy MIDCAB incision

Figure 3. Intraoperative images of total endoscopic coronary artery bypass grafting (TECAB). (A) Surgeon operating at da Vinci
robotic console remote from the patient. (B) Operative robot positioning, with arms within the patient’s chest. (C) Illustration of
robotic arms within the chest. (D) Harvest of the LAD from the chest wall, utilizing the robot. (E) Schematic of coronary anastomosis
performed with robotic assistance

Robotic-assisted IMA takedown was then followed by a
small (5–9 cm) anterior thoracotomy to perform the arte-
rial anastomosis (83–85). Following a significant learning
curve, robotic IMA takedown has been demonstrated to
be a safe procedure (86,87).
Eventually, as expertise was gained, robotic cardiac
surgery was advanced to perform not only IMA
harvests but also a LIMA to the LAD anastomosis
(Figure 3). An initial prospective multicentre clinical
trial of robotic-assisted LIMA to LAD anastomosis in
32 patients demonstrated that the procedure could be
performed safely, with good graft flow (88). A subsequent
prospective multicentre trial of robotic-assisted totally
endoscopic coronary artery bypass grafting (TECAB)
on cardiopulmonary bypass performed in 85 patients
demonstrated TECAB to be a safe procedure, with
angiographic patency, mortality and morbidity equivalent
to standard CABG procedures (89). A recent clinical
study of 41 patients who underwent TECAB for isolated
LAD lesions found a 92.7% 5 year survival and 87.2%
freedom from re-intervention (90). Immediate and mid-
term angiographic patencies have been equivalent to
standard CABG, but with unparalleled patient satisfaction
(91–93), further advocating increased focus on advancing
techniques of TECAB.
Expertise in robotic cardiac surgery follows a recog-
nized learning curve. Several groups have attempted to
optimize this learning curve while improving outcomes.
The main points to minimizing the learning process have
included: appropriate patient selection with straightfor-
ward cases initially; a consistent and regular anaesthesia
and nursing team; and a modular approach to the learning
curve. In the case of TECAB, the modules include inter-
nal mammary artery takedown, pericardial fat lipectomy,

Copyright  2008 John Wiley & Sons, Ltd. Int J Med Robotics Comput Assist Surg 2009; 5: 1–12.
DOI: 10.1002/rcs
6 P. Atluri et al.
pericardial opening and, finally, anastomotic suturing
(94–96).
Coronary Revascularization
Experience
We have analysed our coronary revascularization
database in order to provide additional specific outcomes
data: 478 consecutive, isolated coronary artery bypass
procedures performed by a single surgeon at the Univer-
sity of Pennsylvania between February 2002–April 2008
were analysed – no patients were excluded; 349 patients
underwent OPCAB, 113 patients underwent CABG and
16 patients had CABG performed by minimally invasive
means (MIDCAB/robotic).
Methods
CABG was performed through a standard median
sternotomy while on cardiopulmonary bypass. OPCAB
was also performed via a median sternotomy. A
combination of the Medtronic (Minneapolis, MN, USA)
Octopus and Starfish stabilizers was utilized to secure
the myocardium of the desired distal target vessels.
Robotic IMA take-down was performed utilizing a DaVinci
roboticplatform (Intuitive Surgical, Sunnyvale, CA, USA).
In the case of MIDCAB, left anterior thoracotomy incisions
were made (4–8 cm) through the fourth interspace. Post-
operatively patients were recovered in the cardiothoracic
surgical intensive care unit. Patients were extubated
as soon as deemed haemodynamically stable and that
anaesthesia had been reversed. Following resolution of
critical care issues, patients were transferred to the
cardiothoracic step-down unit for physical rehabilitation
and recovery.
Statistical significance
Statistical significance for mortality and morbidity
between groups was computed utilizing Fisher’s exact
test. Student’s t-test was utilized to compute the statistical
significance of differences in length of stay and total
conduits. A difference was considered significant at p <
0.05. Data are presented as mean ± standard deviation
(SD), or median values.
Table 1. Operative and post-operative variables for CABG, OPCAB and minimally invasive groups
Mean age Mean length of
(years) hospitalization (days) hospitalization (days)
CABG (n = 113) 63.1 ± 9.8 8.7 ± 7.9
OPCAB (n = 349) 66.7 ± 8.5 7.4 ± 7.4
Minimally invasive (n = 16) 62.6 ± 12.2 4.5 ± 1.3
Total (n = 478) 65.5 ± 10.3 7.5 ± 7.5
Copyright  2008 John Wiley & Sons, Ltd.
Results
We noted excellent results in all groups that were
investigated – CABG, OPCAB and minimally invasive
(Table 1). Nineteen of the OPCAB patients and three
patients in the CABG group underwent emergent
revascularization. Eight patients in the OPCAB group
and two patients in the CABG group had carotid
endarterectomy performed at the time of coronary bypass.
Two of the OPCAB patients had adjunctive Anginera patch
(Theregen Inc, San Francisco, CA, USA), described later,
placed on non-revascularizable, ischaemic myocardium.
OPCAB
The 30 day mortality rates for the OPCAB and CABG
groups were equivalent (1.4% vs. 0.9%; p = NS), even
with OPCAB patients being significantly older than
CABG patients (p = 0.0008). This operative mortality
for OPCAB is markedly better than the 2.72% risk-
adjusted predicted mortality rate for the patients in this
group. It should be noted that the overall mortality of
1.3% is also better than the 2.1% operative mortality
for coronary artery bypass grafting noted in the 2007
Society for Thoracic Surgery Database. There was no
statistical difference in morbidity between the OPCAB
and CABG groups. In the OPCAB group, two patients
had prolonged ventilatory requirements, two patients
had cerebrovascular accidents, one patient had heparin-
induced thrombotic thrombocytopenia, and one patient
had a post-operative bowel obstruction. One patient in
the CABG group had prolonged ventilatory requirements.
Length of stay was significantly shorter for the OPCAB
group as compared to the CABG group (p = 0.03). The
mean number of grafts was slightly higher in the CABG
group (0.2 grafts/patient; p = 0.001).
Minimally invasive CABG
There was no mortality noted in the first 30-days
following minimally invasive coronary revascularization.
Additionally, there was no in-hospital morbidity in the
minimally invasive group. Length of stay (LOS) was
significantly shorter for minimally invasive CABG as
compared to CABG (p = 0.02) and approached statistical
significance when compared to OPCAB groups (p = 0.06).
As expected, a significantly larger number of grafts were
performed in the CABG (p = 0.000004) and OPCAB
(p = 0.00005) groups when compared to the minimally
invasive group, since this group received primarily LIMA
to LAD anastomoses.
Median length of Total 30-day Post-operative
grafts survival (%) complications (%)
7 3.1 ± 0.8 99.1 6.2
6 2.9 ± 0.6 98.6 3.4
4.5 1.6 ± 0.9 100.0 0.0
6 2.9 ± 0.8 98.7 4.0
Int J Med Robotics Comput Assist Surg 2009; 5: 1–12.
DOI: 10.1002/rcs
Improved outcomes over traditional on-pump CABG 7

Conclusions perfusion and increased myocardial viability have been

With appropriate indications, OPCAB and minimally
invasive CABG can be performed with excellent results
and shorter length of stay when compared to CABG.
Overall outcomes for coronary revascularization were
excellent, with 30 day mortality nearly half that of the
national benchmark.
Adjunctive and Experimental
Revascularization Strategies
Complete revascularization with either CABG or PCI is
not possible in 20–27% of patients with symptomatic
coronary artery disease (97). Enhancing perfusion to
the remaining ischaemic myocardium remains a clinical
challenge. Several experimental and adjunctive thera-
pies, including transmyocardial laser revascularization,
endothelial progenitor cell (EPC)-mediated vasculogen-
esis and tissue engineering, are potential therapies to
enhance myocardial perfusion.
Transmyocardial laser
revascularization
Transmyocardial laser revascularization (TMR) was
developed in an attempt to replicate reptilian myocar-
dial perfusion, in which sinusoids provide blood directly
from the ventricular chamber to the myocardial tis-
sue. Modern TMR utilizes a high-energy laser to create
channels through the myocardium to the endocardium.
Randomized, prospective clinical studies have demon-
strated improvements in perfusion, angina, morbidity
and function following therapy with TMR (98–102).
But, histologically, these channels appear to be occluded
shortly after TMR, thereby raising the question as to the
molecular mechanism underlying therapy. Experimen-
tally enhanced EPC-mediated vasculogenesis, enhanced
demonstrated following TMR (103–108). In a porcine
model of ischaemic cardiomyopathy, we have demon-
strated an increase in microvascular perfusion following
TMR (Figure 4) (104).
Clinically, TMR can be performed at the time of
coronary revascularization as an adjunctive therapy with
limited morbidity or mortality. Alternatively, TMR can be
utilized as an isolated therapy for ischaemic myocardium
by robotic or thoracoscopic means (109,110). Although
still experimental, in the future more robust angiogenesis
may be generated by combining TMR with either
progenitor cell or angiogenic cytokine administration via
the TMR handpiece (111).
Angiogenic cytokine administration
Angiogenic cytokines are ligands capable of attracting and
initiating EPC-mediated vasculogenesis. In experimental
models of myocardial ischaemia, cytokine administration
has demonstrated the ability to increase collateral vessel
formation, augment perfusion, limit infarct progression
and enhance cardiac function. The most notable cytokines
include fibroblast growth factor (FGF), vascular endothe-
lial growth factor (VEGF), placental growth factor (PlGF),
hepatocyte growth factor (HGF) and stromal cell derived
factor-1α (SDF) (112–120). Utilizing HGF, PlGF and
SDF, our group has demonstrated significant increases
in myocardial perfusion, viability and haemodynamic
function when compared to controls (118,121–124)
(Figure 5).
Both FGF and VEGF have been investigated in
clinical trials. Administration of FGF has resulted in
anginal relief and a trend toward increased myocardial
perfusion. VEGF has demonstrated enhanced perfusion to
ischaemic limbs but, as yet, has failed to demonstrate
therapeutic benefits to the myocardium. Although
further investigation remains to be performed, adjunctive
cytokine administration either via open sternotomy
or minimally invasive approaches at the time of

Figure 4. Three-dimensional microvascular lectin angiogram demonstrating enhanced myocardial perfusion following therapy with
TMR. Representative angiograms from remote myocardium and ischaemic myocardium from Sham thoracotomy and TMR animals
are presented (z-series, ×25 oil magnification, Zeiss LSM-510 meta-confocal microscope). There was no difference in remote
myocardial perfusion between the Sham and TMR groups. Perfusion of the ischaemic myocardium was significantly increased
following TMR therapy. Orientation is presented in the lower left corners (red, y axis; green, x axis; blue, z axis). Reproduced with
permission from: Atluri P, Panlilio CM, Liao GP et al. Transmyocardial revascularization to enhance myocardial vasculogenesis and
haemodynamic function. J Thorac Cardiovasc Surg 2008; 135(2): 283–291. With permission from Elsevier

Copyright  2008 John Wiley & Sons, Ltd. Int J Med Robotics Comput Assist Surg 2009; 5: 1–12.
DOI: 10.1002/rcs
8 P. Atluri et al.

Figure 5. (A) Representative haematoxylin and eosin-stained cross-sections of saline control and SDF/GM-CSF-treated hearts.
Large arrows indicate where left ventricular diameter was measured, and small arrows indicate where border-zone thickness was
measured. (B) Graph of the mean ventricular diameter and wall thickness for each group. Reproduced with permission from: Woo
YJ, Grand TJ, Berry MF et al. Stromal cell-derived factor and granulocyte–monocyte colony-stimulating factor form a combined
neovasculogenic therapy for ischemic cardiomyopathy. J Thorac Cardiovasc Surg 2005; 130(2): 321–329. With permission from
Elsevier

revascularization may prove beneficial in enhancing
perfusion via vasculogenesis.
Tissue engineering
An alternative means of stimulating robust angiogenesis
is to provide a continuous, high concentration of locally
secreted cytokines. One such tissue is the Anginera
patch (Theregen). This is a 3D dermal fibroblast
mesh that is created by culturing neonatal dermal
fibroblasts onto a knitted vicryl mesh. Experimentally,
the mesh has been shown to synthesize and secrete
a number of angiogenic factors, including VEGF,
basic FGF and HGF (125). In a laboratory model
of myocardial ischaemia, Anginera patch placement
has resulted in enhanced myocardial preservation and
function (126,127). Furthermore, clinically, utilization
of the Anginera patch on diabetic and venous stasis
ulcers has significantly increased local tissue perfusion
(128,129).
Based upon these preliminary data, we have begun
clinical trials to investigate the angiogenic potential of
this patch in the setting of myocardial ischaemia. As
such, we have placed this patch on regions of ischaemic
myocardium without revascularizable coronary anatomy
(Figure 6). This therapy has promise as an adjunctive
therapy to CABG to revascularize territories without
coronary targets.

Figure 6. Intraoperative photograph taken during placement
of the Anginera patch on non-revascularizable, ischaemic
myocardium
Conclusion
Excellent results have been demonstrated following on-
pump, off-pump and minimally invasive and robotic
coronary artery bypass grafting. Elimination of the
cardiopulmonary bypass circuit eliminates the negative
systemic manifestations and associated morbidity of the
bypass circuit. OPCAB appears to demonstrate similar
anastomotic patency and graft flow when compared to
CABG bypass grafts. Use of minimally invasive and robotic
techniques further enhances post-operative physical
recovery while preserving excellent anastomotic integrity.
With surgical expertise, off-pump, robotic and minimally

Copyright  2008 John Wiley & Sons, Ltd. Int J Med Robotics Comput Assist Surg 2009; 5: 1–12.
DOI: 10.1002/rcs
Improved outcomes over traditional on-pump CABG
invasive techniques should be employed to revascularize
coronary arteries in order to minimize morbidity and
facilitate rapid post-operative recovery. Novel molecular
therapies, including TMR, angiogenic cytokines and
tissue engineering, allow revascularization of ischaemic
myocardium lacking revascularizable coronary anatomy
by enhancing microvascular perfusion.
Acknowledgements
This work was supported in part by the National Institutes
of Health, National Heart Lung and Blood Institute/Thoracic
Surgery Foundation for Research and Education (Grant No. KO8
HL072812 to Y.J.W.) and the National Institutes of Health,
National Heart Lung and Blood Institute (Grant Nos RO1
HL089315 to Y.J.W. and F32 HL 79769 and T32 HL07843
to P.A.).
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