The
potential role of growth factors and direct myocardial revascularization
in patients with refractory myocardial ischemia following coronary
artery bypass surgery with a patent internal mammary artery
graft
Jonathan Hill1, Adam Timmis2
1 St Bartholomew’s Hospital, London, UK
1, 2 London Chest Hospital, London, UK
Correspondence: Dr Jonathan Hill, St Bartholomew’s Hospital,
London, UK.
We report a case of a 52-year-old man presenting
with incapacitating angina who is not amenable to further percutaneous
or surgical intervention. Obstructive airways disease now increases
the operative risk of a limited thoracotomy for laser transmyocardial
revascularization (TMR). The patient is on maximal medical management
and is desperate for any relief from his angina.
The risk factors for coronary artery disease include hypertension,
hypercholesterolemia, and a very strong family history. A recent
angiogram shows severe left main stem disease with severe proximal
disease of the left anterior descending/diagonal territory. The
circumflex system is diffusely diseased and the previous saphenous
vein graft to the lateral circumflex branch is now occluded at
its origin after a previously unsuccessful attempt at disobliteration.
The right coronary territory was previously ungrafted but is now
occluded in the proximal third with some minor collateral formation
supplying the posterior descending artery territory. The previous
vein graft to the diagonal system is also occluded at its origin
and again does not appear amenable to percutaneous intervention.
On injection of the left internal mammary artery the graft is
found to be widely patent with major collateral formation to the
diagonal territory and to a lesser extent the circumflex and distal
right coronary artery territories. Despite this, the left ventricular
function remains good overall with an inferobasal hypokinetic
segment.
Figure 1. Biosense™ guidance allows accurate
placing of DMR channels
A thallium perfusion scan revealed a large reversible defect in
the inferolateral wall suggesting that the collateral formation
fed from the left internal mammary artery graft is insufficient.
A dilemma is therefore presented with a relatively young patient
in whom further surgery would be difficult because of obstructive
airways disease. It would also jeopardize the widely patent internal
mammary artery graft. In any case the distal native vessels are
poor and probably now impossible to graft or regraft.
  Figure 2. BiosenseTM magnetic voltage and
shortening map.
Discussion
There are a number of options available to this patient involving
a direct myocardial revascularization (DMR) strategy. Several
methods have shown considerable promise in pilot studies involving
either the creation of small channels in the myocardium, the administration
of a growth factor, or gene transfection. The intention is to
promote the formation of new blood vessels, ie, to stimulate angiogenesis.
Several of these studies are at an early stage in their evaluation
and have only just begun phase-II clinical trials.
Surgical TMR
A variety of surgical approaches have been used with a combination
of different laser types. The holes are created from the epicardial
through to the endocardial surface. These channels quickly become
occluded[1] with the fibrotic process, causing
release of angiogenic cytokines and hence promotion of angiogenesis.
There is now widespread use of this method and an accumulating
body of evidence. A recent trial from the UK,[2]
whilst showing an improvement in two angina classes in 25% of
patients, showed there was no significant improvement in exercise
time in the laser-treated group compared with those on maximal
medical management. The authors concluded that overall the procedure
could not be recommended. One reason for this could be the significant
mortality associated with the procedure. Other investigators would
contend that the patient group in this study does not compare
with that of other trials.
Horvath et al [3] advocate surgical TMR as an
efficacious treatment strategy in patients with refractory CCS
class 3 or 4 angina. They randomized 192 patients to laser TMR
plus maximal medication, or to maximal medical management alone,
and found a significant improvement by at least two angina classes
in the TMR group (72% vs. 13%, P < 0.001). Quality of life
parameters also improved. At 1 year there was 15% mortality in
the TMR group, with no significant difference from the medically
treated arm.
Catheter-based DMR/percutaneous TMR/PMR
A percutaneous approach to DMR obviates the need for surgery and
general anesthesia, thus avoiding the significant perioperative
mortality reported in some surgical DMR series.[3]
More recently, the development of a novel electromechanical mapping
system has removed the need for prolonged fluoroscopic screening.[4]
Recently reported randomized clinical trials have shown encouraging
results. The 6-month results of the EclipseTM study using a holmium:YAG
laser would suggest significant benefit in the laser-treated group.
A group of 335 patients not amenable to other forms of intervention
were randomized to receive optimal medical treatment alone, or
percutaneous DMR plus maximal medication. There was only one death
during the procedure and a risk of tamponade of around 3%. At
6 months, the mean exercise time had significantly increased in
the DMR group (381 vs. 529 s, P = 0.0002). A significant symptomatic
benefit was seen at 3 months. In the PACIFIC trial,[6]
70% of DMR-treated patients were CCS class 0, 1, or 2. Forty-six
percent of DMR patients had improvement by at least two angina
classes whilst only 6% of nonDMR patients had a similar improvement.
Neither of these trials were blinded, let alone double-blinded,
and it must be borne in mind that the placebo effect in this group
of patients can be considerable. The Direct trial [7]
using the BiosenseTM 3D magnetic guidance system enabled the procedure
to be blinded (with mapping alone or mapping plus DMR). In a trial
of 77 patients treated with percutaneous DMR using a holmium:YAG
laser there was a significant improvement in exercise duration
at 1 and 6 months, with 74% of patients experiencing symptomatic
improvement for at least 3 months. There was a 2.6% incidence
of major inhospital events although there were no deaths.
 
Figure 3. 3D generated pictures of map left
ventricle using the BiosenseTM system.
Angiogenic growth factors
Isner’s group in Boston [8,9]
reported the successful transfection of peripheral arteries with
cDNA encoding for vascular endothelial growth factor (VEGF)-165
using a hydrogel-coated balloon. This experiment was proof of
concept and stimulated a rapidly growing body of research, although
the original experiments have been criticized for lacking a control
group.
Schumacher et al [10] subsequently reported
the first clinical experience of direct intramyocardial injection
of fibroblast growth factor (FGF)-I to stimulate the angiogenic
response as an adjunct to conventional bypass surgery. They injected
0.01 mg/kg FGF-I close to the LAD after completion of an internal
mammary artery anastomosis. Angiographically detectable vessels
were found in the treatment group, but not in controls, with collateral
growth around the injection site. Losordo et al [11]
injected naked plasmid DNA encoding phVEGF165 directly into ischemic
myocardium, and only a transient decrease into ischemic myocardium
of five patients using a minithoracotomy approach. There was a
transient decrease in cardiac output initially, but all patients
had a significant reduction in ischemia. Perfusion and angiographic
data were also positive.
The use of growth factors in this context remains the subject
of much scrutiny until the precise mechanism of angiogenesis is
elucidated. There are several notes of caution regarding their
use. Atherectomy specimens have been shown to demonstrate plaque
neovascularization, which has been associated with a higher prevalence
of plaque rupture, mural hemorrhage, or unstable angina.[12]
Moulton [13] has shown that prolonged treatment
with angiogenesis inhibitors reduces plaque growth and intimal
neovascularization in apolipoprotein E-/- mice. Although the mechanism
is not clear, it would suggest that angiogenesis may actually
promote atherogenesis
Combined DMR and growth factor treatment
Using the BiosenseTM system it would be possible to precisely
target both the laser channels and growth factor injection via
a catheter-based route. Clinical studies are underway to test
the feasibility and safety of such an approach. Data from animal
studies have been encouraging.[13,14]
Conclusions
The development of new transcatheter technologies coupled with
a rapid growth in knowledge of angiogenic mechanisms has offered
new hope to patients with refractory myocardial ischemia who are
not candidates for further conventional intervention. The encouraging
6-month results from the percutaneous trials of DMR suggest the
need for larger blinded, randomized trials. Perhaps the addition
of growth factor administration at the same time as the laser
procedure would give even greater clinical benefit.
REFERENCES
1. Reference 168-170 from Serruys paper
- Erratum in:
 |
Lancet 1999 May 15;353(9165):1714 |
Comment in:
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Lancet. 1999 Feb 13;353(9152):512-3
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|
Lancet. 1999 May 15;353(9165):1704-5;
discussion 1706-7 |
|
Lancet. 1999 May 15;353(9165):1704;
discussion 1706-7 |
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Lancet. 1999 May 15;353(9165):1705-6;
discussion 1706-7 |
|
Lancet. 1999 May 15;353(9165):1705;
discussion 1706-7 |
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Lancet. 1999 May 15;353(9165):1706-7 |
Transmyocardial laser revascularisation in patients with
refractory angina: a randomised controlled trial.
Schofield PM, Sharples LD, Caine N, Burns S, Tait S, Wistow
T, Buxton M, Wallwork J.
Papworth Hospital NHS Trust, Papworth Everard, Cambridge,
UK.
BACKGROUND: Transmyocardial laser revascularisation (TMLR)
is used to treat patients with refractory angina due to severe
coronary artery disease, not suitable for conventional revascularisation.
We aimed in a randomised controlled trial to assess the effectiveness
of TMLR compared with medical management. METHODS: 188 patients
with refractory angina were randomly assigned TMLR plus normal
medication or medical management alone. At 3 months, 6 months,
and 12 months after surgery (TMLR) or initial assessment (medical
management) we assessed exercise capacity with the treadmill
test and the 12 min walk. FINDINGS: Mean treadmill exercise
time, adjusted for baseline values, was 40 s (95% CI -15 to
94) longer in the TMLR group than in the medical-management
group at 12 months (p=0.152). Mean 12 min walk distance was
33 m (-7 to 74) further in TMLR patients than medical-management
patients (p=0.108) at 12 months. The differences were not
significant or clinically important. Perioperative mortality
was 5%. Survival at 12 months was 89% (83-96) in the TMLR
group and 96% (92-100) in the medical-management group (p=0.14).
Canadian Cardiovascular Society score for angina had decreased
by at least two classes in 25% of TMLR and 4% of medical-management
patients at 12 months (p<0.001). INTERPRETATION: Our findings
show that the adoption of TMLR cannot be advocated. Further
research may be appropriate to assess any potential benefit
for sicker patients.
Publication Types:
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Clinical trial |
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Randomized controlled trial |
PMID: 10028979 [PubMed - indexed for MEDLINE]
-
-
Transmyocardial laser revascularization: results of a multicenter
trial with transmyocardial laser revascularization used as sole
therapy for end-stage coronary artery disease.
Horvath KA, Cohn LH, Cooley DA, Crew JR, Frazier OH, Griffith
BP, Kadipasaoglu K, Lansing A, Mannting F, March R, Mirhoseini
MR, Smith C.
Brigham and Women's Hospital, Boston, Mass. 02115, USA.
BACKGROUND: Transmyocardial laser revascularization was used
as the sole therapy for patients with ischemic heart disease
not amenable to percutaneous transluminal coronary angioplasty
or coronary artery bypass grafting. This technique uses a carbon
dioxide laser to create transmyocardial channels for direct
perfusion of the ischemic heart. METHODS: Since 1992, 200 patients,
at eight hospitals in the United States, have undergone transmyocardial
laser revascularization. The patients have a combined 1560 months
of follow-up for an average of 10 +/- 3 months per patient.
Their age was 63 +/- 10 years and their ejection fraction was
47% +/- 12%. Eighty-two percent had at least one previous bypass
graft operation and 38% had a prior angioplasty. Preoperatively,
the patients underwent nuclear single photon emission computed
tomography perfusion scans to identify the extent and severity
of their ischemia. These scans were repeated at 3, 6, and 12
months. Angina class, admissions for angina, and medications
were recorded. RESULTS: The perioperative mortality was 9%.
Angina class decreased significantly from before treatment to
3, 6, and 12 months (p < 0.001). Likewise, there was a significant
decrease in the number of perfusion defects in the treated left
ventricular free wall. Concomitantly, there was a significant
decrease in the number of admissions for angina in the year
after the procedure when compared with the year before treatment
(2.5 vs 0.5 admissions per patient-year). CONCLUSION: These
combined results indicate that transmyocardial laser revascularization
provides angina relief, decreases hospital admissions, and improves
perfusion in patients with severe coronary artery disease.
Publication Types:
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Clinical trial |
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Controlled clinical trial
|
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Multicenter study |
PMID: 9104973 [PubMed - indexed for MEDLINE]
-
Nonfluoroscopic, in vivo navigation and mapping technology.
Ben-Haim SA, Osadchy D, Schuster I, Gepstein L, Hayam G,
Josephson ME.
Cardiovascular Research Laboratory, Bruce Rappaport Faculty
of Medicine, Technion-Israel Institute of Technology, Haifa,
Israel.
PMID: 8946843 [PubMed - indexed for MEDLINE]
5. Whitlow PL. Percutaneous transmyocardial
revascularization versus medical therapy in patients with refractory
angina. American College of Cardiology ACCIS Meeting, March 1999.
6. Oesterle SN. Initial clinical results of
the cardiogenesis PACIFIC trial (Potential Angina Class Improvement
From Intramyocardial Channels). American College of Cardiology
ACCIS Meeting, March 1999.
7. Kornowski R, Leon MB. Biosense guided direct
myocardial revascularisation. Angiogenesis and DMR 2nd Annual
Symposium, June 1999.
-
Arterial gene therapy for therapeutic angiogenesis in patients
with peripheral artery disease.
Isner JM, Walsh K, Symes J, Pieczek A, Takeshita S, Lowry
J, Rossow S, Rosenfield K, Weir L, Brogi E, et al.
Publication Types:
|
News |
PMID: 7538919 [PubMed - indexed for MEDLINE]
-
-
Comment in:
|
Lancet. 1996 Nov 16;348(9038):1380-1;
discussion 1381-2 |
|
Lancet. 1996 Nov 16;348(9038):1381;
discussion 1381-2 |
Clinical evidence of angiogenesis after arterial gene transfer
of phVEGF165 in patient with ischaemic limb.
Isner JM, Pieczek A, Schainfeld R, Blair R, Haley L, Asahara
T, Rosenfield K, Razvi S, Walsh K, Symes JF.
Department of Medicine, St Elizabeth's Medical Center, Tufts
University School of Medicine, Boston, MA 02135, USA.
BACKGROUND: Preclinical findings suggest that intra-arterial
gene transfer of a plasmid which encodes for vascular endothelial
growth factor (VEGF) can improve blood supply to the ischaemic
limb. We have used the method in a patient. METHODS: Our patient
was the eighth in a dose-ranging series. She was aged 71 with
an ischaemic right leg. We administered 2,000 micrograms human
plasmid phVEGF165 that was applied to the hydrogel polymer coating
of an angioplasty balloon. By inflating the balloon, plasmid
DNA was transferred to the distal popliteal artery. FINDINGS:
Digital subtraction angiography 4 weeks after gene therapy showed
an increase in collateral vessels at the knee, mid-tibial, and
ankle levels, which persisted at a 12-week view. Intra-arterial
doppler-flow studies showed increased resting and maximum flows
(by 82% and 72%, respectively). Three spider angiomas developed
on the right foot/ankle about a week after gene transfer; one
lesion was excised and revealed proliferative endothelium, the
other two regressed. The patient developed oedema in her right
leg, which was treated successfully. INTERPRETATION: Administration
of endothelial cell mitogens promotes angiogenesis in patients
with limb ischaemia.
PMID: 8709735 [PubMed - indexed for MEDLINE]
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-
Comment in:
|
Circulation. 1998 Feb 24;97(7):628-9 |
Induction of neoangiogenesis in ischemic myocardium by human
growth factors: first clinical results of a new treatment of
coronary heart disease.
Schumacher B, Pecher P, von Specht BU, Stegmann T.
Klinik fur Thorax-, Herz und Gefasschirurgie, Klinikum Fulda,
Germany.
BACKGROUND: The present article is a report of our animal experiments
and also of the first clinical results of a new treatment for
coronary heart disease using the human growth factor FGF-I (basic
fibroblast growth factor) to induce neoangiogenesis in the ischemic
myocardium. METHODS AND RESULTS: FGF-I was obtained from strains
of Escherichia coli by genetic engineering, then isolated and
highly purified. Several series of animal experiments demonstrated
the apathogenic action and neoangiogenic potency of this factor.
After successful conclusion of the animal experiments, it was
used clinically for the first time. FGF-I (0.01 mg/kg body weight)
was injected close to the vessels after the completion of internal
mammary artery (IMA)/left anterior descending coronary artery
(LAD) anastomosis in 20 patients with three-vessel coronary
disease. All the patients had additional peripheral stenoses
of the LAD or one of its diagonal branches. Twelve weeks later,
the IMA bypasses were selectively imaged by intra-arterial digital
subtraction angiography and quantitatively evaluated. In all
the animal experiments, the development of new vessels in the
ischemic myocardium could be demonstrated angiographically.
The formation of capillaries could also be demonstrated in humans
and was found in all cases around the site of injection. A capillary
network sprouting from the proximal part of the coronary artery
could be shown to have bypassed the stenoses and rejoined the
distal parts of the vessel. CONCLUSIONS: We believe that the
use of FGF-I for myocardial revascularization is in principle
a new concept and that it may be particularly suitable for patients
with additional peripheral stenoses that cannot be revascularized
surgically.
Publication Types:
|
Clinical trial |
|
Randomized controlled trial |
PMID: 9495299 [PubMed - indexed for MEDLINE]
-
-
Gene therapy for myocardial angiogenesis: initial clinical
results with direct myocardial injection of phVEGF165 as sole
therapy for myocardial ischemia.
Losordo DW, Vale PR, Symes JF, Dunnington CH, Esakof DD,
Maysky M, Ashare AB, Lathi K, Isner JM.
Departments of Medicine, Biomedical Research, Surgery, and
Anesthesiology, St. Elizabeth's Medical Center, Tufts University
School of Medicine, Boston, Mass 02135, USA.
BACKGROUND: We initiated a phase 1 clinical study to determine
the safety and bioactivity of direct myocardial gene transfer
of vascular endothelial growth factor (VEGF) as sole therapy
for patients with symptomatic myocardial ischemia. METHODS
AND RESULTS: VEGF gene transfer (GTx) was performed in 5 patients
(all male, ages 53 to 71) who had failed conventional therapy;
these men had angina (determined by angiographically documented
coronary artery disease). Naked plasmid DNA encoding VEGF
(phVEGF165) was injected directly into the ischemic myocardium
via a mini left anterior thoracotomy. Injections caused no
changes in heart rate (pre-GTx=75+/-15/min versus post-GTx=80+/-16/min,
P=NS), systolic BP (114+/-7 versus 118+/-7 mm Hg, P=NS), or
diastolic BP (57+/-2 versus 59+/-2 mm Hg, P=NS). Ventricular
arrhythmias were limited to single unifocal premature beats
at the moment of injection. Serial ECGs showed no evidence
of new myocardial infarction in any patient. Intraoperative
blood loss was 0 to 50 cm3, and total chest tube drainage
was 110 to 395 cm3. Postoperative cardiac output fell transiently
but increased within 24 hours (preanesthesia=4.8+/-0.4 versus
postanesthesia=4.1+/-0.3 versus 24 hours postoperative=6.
3+/-0.8, P=0.02). Time to extubation after closure was 18.4+/-1.4
minutes; average postoperative hospital stay was 3.8 days.
All patients had significant reduction in angina (nitroglycerin
[NTG] use=53.9+/-10.0/wk pre-GTx versus 9.8+/-6.9/wk post-GTx,
P<0.03). Postoperative left ventricular ejection fraction
(LVEF) was either unchanged (n=3) or improved (n=2, mean increase
in LVEF=5%). Objective evidence of reduced ischemia was documented
using dobutamine single photon emission computed tomography
(SPECT)-sestamibi imaging in all patients. Coronary angiography
showed improved Rentrop score in 5 of 5 patients. CONCLUSIONS:
This initial experience with naked gene transfer as sole therapy
for myocardial ischemia suggests that direct myocardial injection
of naked plasmid DNA, via a minimally invasive chest wall
incision, is safe and may lead to reduced symptoms and improved
myocardial perfusion in selected patients with chronic myocardial
ischemia.
Publication Types:
|
Clinical trial |
|
Clinical trial, phase i |
PMID: 9860779 [PubMed - indexed for MEDLINE]
-
Neovascularization in atherectomy specimens from patients
with unstable angina: implications for pathogenesis of unstable
angina.
Tenaglia AN, Peters KG, Sketch MH Jr, Annex BH.
Tulane University Medical Center, New Orleans, La 70112, USA.
atenagl@tmc.tulane.edu
Although neovascularization has been noted in atherosclerotic
plaque, the presence of neovascularization has not been correlated
with clinical syndromes. This study examined the relation between
neovascularization in atherosclerotic plaque removed during
directional coronary atherectomy and clinical status in 28 patients.
Neovascularization was determined by immunohistochemistry with
endothelial cell-specific monoclonal antibodies and was found
in nine (50%) of 18 specimens from patients with unstable angina
and in only one (10%) of 10 specimens from patients with stable
angina (p < 0.05). There was no significant relation between
neovascularization and other clinical factors (age, sex, race,
hypertension, diabetes, tobacco use, hypercholesterolemia, positive
family history of coronary artery disease, history of myocardial
infarction, or stenosis severity). These results suggest that
neovoscularization may play a role in the pathogenesis of unstable
angina.
PMID: 9453515 [PubMed - indexed for MEDLINE]-
-
Plaque angiogenesis and atherosclerosis.
Moulton KS.
Cardiovascular Division, Brigham and Women's Hospital, and Surgical
Research, Children's Hospital, 300 Longwood Avenue, Enders 10,
Boston, MA 02115, USA. Moulton@HUB.TCH.Harvard.edu
Therapeutic angiogenesis trials refer to the stimulation of
collateral arterioles and new vascular conduits to perfuse ischemic
myocardium and limbs. Atherosclerotic lesions responsible for
vascular occlusions themselves are associated with angiogenesis
within the vessel wall. Plaque neovascularization is comprised
of a network of capillaries that arise from the adventitial
vasa vasorum and extend into the intimal layer of atherosclerotic
lesions and other types of vascular injury. The functions of
these plaque capillaries are proposed to be important regulators
of plaque growth and lesion instability. The development of
agents that are positive and negative regulators of angiogenesis
may have potential therapeutic implications in the progression
and acute manifestations of atherosclerosis. This review focuses
on the role of plaque angiogenesis in atherosclerosis and discusses
the potential therapeutic applications of angiogenesis inhibitors
in this disease.
Publication Types:
|
Review |
|
Review, tutorial |
PMID: 11286644 [PubMed - indexed for MEDLINE]
14. Fuchs, et al. JACC, Abstract
813-5, March 1999.
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