(Circulation. 2000;102:965.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Left Ventricular Electromechanical Mapping to Assess Efficacy of phVEGF165 Gene Transfer for Therapeutic Angiogenesis in Chronic Myocardial Ischemia
Presented as an entry in the finals for the Samuel A. Levine Young Investigator Award at the 72nd Scientific Sessions of the American Heart Association, Atlanta, Ga, November 7–10, 1999, and published in abstract form (Circulation. 1999;100[suppl I]:I-24. Abstract 122).
From the Divisions of Cardiology and Vascular Medicine (P.R.V., D.W.L., M.M., D.D.E., J.M.I.), Cardiovascular Research (C.E.M.), and Cardiothoracic Surgery (J.F.S.), St. Elizabeth’s Medical Center and Tufts University School of Medicine, Boston, Mass.
Correspondence to Douglas Losordo, MD, or Jeffrey M. Isner, MD, St. Elizabeth’s Medical Center, 736 Cambridge St, Boston, MA 02135. E-mail jisner{at}opal.tufts.com
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Abstract |
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Background—NOGA left ventricular (LV) electromechanical mapping (EMM) can be used to distinguish among infarcted, ischemic, and normal myocardium. We investigated the use of percutaneous LV EMM to assess the efficacy of myocardial gene transfer (GTx) of naked plasmid DNA encoding for vascular endothelial growth factor (phVEGF165), administered during surgery by direct myocardial injection in patients with chronic myocardial ischemia.
Methods and Results—A total of 13 consecutive patients (8 men,
mean age 60.1±2.3 years) with chronic stable angina due to
angiographically documented coronary artery disease, all of
whom had failed conventional therapy (drugs, PTCA, and/or CABG), were
treated with direct myocardial injection of phVEGF165 via a
minithoracotomy. Foci of ischemic myocardium were
identified on LV EMM by preserved viability associated with an
impairment in linear local shortening. Myocardial viability, defined by
mean unipolar and bipolar voltage recordings 
5 and 2 mV,
respectively, did not change significantly after GTx. Analysis
of linear local shortening in areas of myocardial ischemia,
however, disclosed significant improvement after (15.26±0.98%) versus
before (9.94±1.53%, P=0.004) phVEGF165
GTx. The area of ischemic myocardium was
consequently reduced from 6.45±1.37 cm2 before GTx to
0.95±0.41 cm2 after GTx (P=0.001). These
findings corresponded to improved perfusion scores calculated from
single-photon emission CT–sestamibi myocardial perfusion scans
recorded at rest (7.4±2.1 before GTx versus 4.5±1.4 after GTx,
P=0.009) and after pharmacological stress (12.8±2.7
before GTx versus 8.5±1.7 after GTx, P=0.047).
Conclusions—The results of EMM constitute objective evidence that phVEGF165 GTx augments perfusion of ischemic myocardium. These findings, together with reduction in the size of the defects documented at rest by serial single-photon emission CT–sestamibi imaging, suggest that phVEGF165 GTx may successfully rescue foci of hibernating myocardium.
Key Words: mapping • coronary disease • angiogenesis • ischemia
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Introduction |
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Preclinical studies performed in animal models of limb and myocardial ischemia1 2 3 4 5 have documented that certain cytokines, including vascular endothelial growth factor (VEGF) and fibroblast growth factor-1 and -2, administered as recombinant protein or cDNA, may promote neovascularization of ischemic tissues. More recently, preliminary clinical trials have established that the results of these animal studies may extend to human subjects with limb6 7 8 and myocardial9 10 11 12 ischemia.
Earlier studies performed in our laboratory documented that symptomatic improvement in patients with myocardial ischemia was associated with improvement in the outcome of single-photon emission CT (SPECT)-sestamibi myocardial perfusion imaging10 ; not only was there a reduction in the perfusion deficits associated with pharmacological stress, but large defects detected at rest were often resolved as well. These findings constituted objective evidence of improved myocardial perfusion after therapeutic neovascularization, including the possibility that foci of hibernating myocardium might be successfully rescued.
To determine whether the implications of SPECT imaging could be confirmed by an independent diagnostic technique, we used a novel strategy of catheter-based electromechanical assessment of myocardial perfusion (NOGA system, Biosense-Webster, Johnson & Johnson). This system uses electromagnetic field sensors to combine and integrate real-time information from percutaneous intracardiac electrograms acquired at multiple endocardial locations. The resulting interrogations can be used to distinguish between infarcted and normal myocardium13 and thus permit online assessment of myocardial function and viability.14
In the present study, NOGA electromechanical mapping (EMM) was prospectively performed in 13 consecutive patients with chronic myocardial ischemia before and 60 days after gene transfer (GTx) of naked DNA encoding for the 165–amino acid isoform of VEGF-1 (phVEGF165), administered during surgery by direct myocardial injection. The results of the present study constitute additional objective evidence that phVEGF165 GTx augments perfusion of ischemic myocardium, and the results also support the notion that phVEGF165 GTx may successfully rescue foci of hibernating myocardium.
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Methods |
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Patient Selection
All patients described in the present report participated in a phase-1 clinical trial of direct myocardial phVEGF165 GTx initiated in February 1998. Eligibility and exclusion criteria have been previously published.10 Contraindications to EMM included aortic valve prosthesis, recent myocardial infarction with significant wall thinning, or evidence of left ventricular (LV) aneurysm and/or thrombus.
NOGA EMM was initiated at St. Elizabeth’s Medical Center in July 1998. Since that time, all patients entered into this protocol have undergone prospective EMM before and after GTx with one exception: one patient was excluded from EMM (but not intraoperative GTx) on the basis of a mechanical aortic valve prosthesis.
LV Electromechanical (NOGA) Mapping
Subjects underwent LV EMM in conjunction with cardiac
catheterization and coronary angiography <1
month before and 60 days after GTx. The NOGA system produces 3D
electromechanical maps of the heart by analyzing parameters
generated from intracardiac electrograms acquired at multiple
endocardial locations that characterize mechanical, dynamic, and
electrical LV functions. The mapping and navigation system comprises a
locator pad, a reference catheter, a mapping catheter, and a processing
unit with a graphics computer (Silicon Graphics) and has been
previously described in detail.15
To construct an electromechanical map, the mapping catheter (Biosense-Webster), a 7F fused-tip catheter with a miniature passive magnetic field sensor embedded within its distal tip that determines the position and rotation of the distal catheter segment, is introduced via a femoral arterial puncture and advanced to the LV. Three points (high septum, high lateral wall, and apex) are obtained with fluoroscopic guidance to generate the initial 3D image of the LV. An icon of the mapping catheter is displayed superimposed on the 3D map, thus enabling catheter manipulation in relation to the map. At each point, 3 electrophysiological parameters are monitored to determine the stability of endocardial contact with the catheter tip: location, cycle length, and local activation time. The reconstruction was updated in real time with the acquisition of each new point.
Local functional analysis (wall motion) is based on linear
local shortening (LLS), a parameter that calculates the
fractional shortening of regional endocardial surfaces at end systole.
Unipolar (UpV) and bipolar (BpV) endocardial potentials are
recorded from the tip electrode, and measurements that are based on
these local intracardiac signal amplitudes formulate a guide to
myocardial viability. The combination of these 2 data sets permits
assessment of electromechanical function that identifies foci of
myocardial ischemia. For example, for a given region of
interest, UpV 5 mV (suggesting viable myocardium) and
normal (12%) LLS (suggesting normal contraction) would indicate
normal myocardium. In contrast, UpV <5 mV and abnormal
(<4%) LLS (signifying severe regional hypokinesis or akinesis) would
indicate a site of LV infarction. Alternatively, UpV 5 mV and
abnormal LLS of 4% to 12% (indicating mild to moderate impairment of
contractility) would suggest a site of ischemic
hibernating myocardium.13 16
To quantify the degree of myocardial perfusion demonstrated visually by the mapping images, the long axis of the heart was divided into 4 regions: anterior, inferoposterior, septal, and lateral. Mean values for LLS, UpV, and BpV were calculated for ischemic myocardium (area of electromechanical uncoupling on NOGA mapping). In addition, for comparative analysis with nuclear imaging, LLS and voltage values from ischemic regions were compared with the corresponding perfusion score on the resting SPECT-sestamibi perfusion study. To quantify the area of ischemia, a 2D algorithm was used to calculate both the area of ischemia and the total surface area in the view depicting maximal ischemia.
SPECT Myocardial Perfusion Study
Subjects underwent a Persantine SPECT-sestamibi study. The
acquisition of the poststress SPECT image began 10 minutes after the
end of the stress period. Redistribution images were recorded
either before or at least 4 hours after stress with the subject at
rest. Redistribution and reinjection data were reconstructed in
short-axis, vertical, and longitudinal long-axis views. Perfusion
scores were calculated for each patient on the basis of the
Cedars-Sinai 20-segment short-axis system.17 On day 60,
subjects underwent repeat nuclear perfusion testing; stress protocol
and isotope were identical to those used at baseline.
Plasmid DNA (phVEGF165)
The VEGF plasmid administered to all patients in the present
study is a eukaryotic expression vector encoding the
165–amino acid isoform of the human VEGF gene18
transcriptionally regulated by the cytomegalovirus promoter/enhancer
(phVEGF165).6 7
Direct Myocardial phVEGF165 GTx
A left lateral minithoracotomy was used to expose the heart,
after which direct myocardial GTx was performed with a 25-gauge needle
under continuous transesophageal
echocardiographic monitoring.19 A total
dose of 250 µg (n=5) or 500 µg (n=8) was divided into 4 aliquots,
each delivered in 2.0 mL of normal saline to the lateral, anterior, or
septal LV wall. Injection sites were selected according to the areas of
ischemia identified by prior NOGA and sestamibi imaging.
Evaluation of Gene Expression
Evidence of successful GTx was documented by ELISA (R&D Systems)
performed on serial samples of plasma obtained from each patient at
predetermined time points as previously described.7
Statistical Analysis
Data are reported as mean±SEM. Comparisons between paired
variables were performed by Student t test with a
significance level of P<0.05. For comparison between
variables, the Pearson correlation coefficient was used. Post hoc
testing was performed by using Fisher r to z
analysis (for probability value). A value of P<0.05
was required for assumption of statistical significance.
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Results |
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Patients
Clinical data regarding the 13 patients (mean age 60.1±2.3 years) treated with direct myocardial injection of phVEGF165 and studied by EMM are listed in Table 1
. All patients had 2
cardiovascular risk factors. Antianginal therapy
included nitrates, calcium channel antagonists, and
ß-blockers. All patients had had previous bypass surgery, and all had
a history of at least one prior myocardial infarction. Angioplasty was
performed in 12 patients an average of 1.5 times. All patients were
Canadian Cardiovascular Society functional class 3 or
4.
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Perioperative Course
All patients underwent successful myocardial GTx. Serial ECGs
showed no evidence of acute myocardial infarction in any patient. No
patient had an increase in creatine phosphokinase-MB above normal
limits. There were no major perioperative
complications.
Gene Expression
Gene expression was documented by ELISA, which disclosed a
rise in plasma levels of VEGF from 43.0±12.7 pg/mL at baseline to a
peak of 150.9±30.3 pg/mL (P=0.004) at a mean of 12 days
after GTx. Peak levels were not significantly different between
patients who received 250 µg (97.2±27.7 pg/mL) and those who
received 500 µg (167.0±45.6 pg/mL).
LV Electromechanical (NOGA) Mapping
Electromechanical maps of the LV recorded during sinus rhythm
were successfully generated in all patients before and 60 days after
GTx. During the mapping procedure, there were no significant changes in
mean heart rate or blood pressure. EMM was associated with transient
ventricular ectopic activity, but neither sustained
ventricular arrhythmias nor other
arrhythmias were observed. In all patients, NOGA maps were
reliably reproduced after GTx in terms of the number of points,
end-diastolic volume, end-systolic volume, and
average loop stability (data not shown). The LV ejection fraction,
calculated on the basis of algorithms incorporated in the NOGA system,
increased from 31.3±2.7% before GTx to 36.9±2.3% after GTx
(P=0.023).
Foci of ischemic myocardium, identified by
preserved viability associated with impaired LLS, ie, electromechanical
uncoupling, were demonstrated in all patients before GTx. Foci of
ischemia involved the anterior (n=1), anteroseptal (n=1),
lateral (n=1), inferolateral (n=2), posterior (n=3), posterolateral
(n=2), septal (n=2), and inferoseptal (n=1) walls. Mean UpV and BpV
recordings 5 mV and 2 mV, respectively, defining myocardial
viability in the ischemic zone, did not change significantly
after GTx (Table 2). Mean LLS in areas of
myocardial ischemia, however, improved significantly from
9.94±1.53% before phVEGF165 GTx to
15.26±0.98% after phVEGF165 GTx
(P=0.004). The area of ischemic
myocardium was consequently reduced from 6.45±1.37
cm2 before phVEGF165 GTx to
0.95±0.41 cm2 after GTx (P=0.001,
Table 2). Examples of NOGA maps showing septal, lateral,
anterior, and inferior ischemic zones before GTx
with improvement after GTx are shown in panel A of Figures 1 through 5.
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Clinical Outcome
Clinically, these 13 patients reported significant reduction in
anginal episodes per week (48.1±4.9 versus 2.0±0.8,
P<0.0001) and in weekly consumption of
nitroglycerin tablets (55.0±7.1 versus 1.9±0.8,
P<0.0001). Standard Bruce protocol exercise tolerance
testing was performed in all patients at days 90 and 180 after GTx
(Table 3). The mean duration of
exercise increased from 272 to 453 seconds (P=0.001) up to
180 days after GTx. LV ejection fraction remained the same (n=5) or
increased (n=8, mean increase 5%) up to day 180 after GTx (mean
ejection fraction 53.5±3.7% before GTx versus 58.1±3.8% after GTx,
P=0.004).
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SPECT Myocardial Perfusion Study
The results of EMM corresponded to improved perfusion scores
calculated from SPECT-sestamibi myocardial perfusion scans recorded
at rest (7.4±2.1 before GTx versus 4.5±1.4 after GTx,
P=0.009) and after pharmacological stress (12.8±2.7 before
GTx versus 8.5±1.7 after GTx, P=0.047; Table 2
). A
positive correlation existed between the change in rest perfusion score
for ischemic myocardium and the reduction in
ischemic area as measured by NOGA mapping (P=0.042,
r=0.567). Shown in panel B of Figures 1 through 5 are
selected perfusion images showing improvement after GTx, corresponding
to the NOGA maps shown in panel A of Figures 1 through 5.
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Discussion |
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The patients in the present study comprise a consecutive series of 13 patients treated with direct myocardial GTx of phVEGF165 as part of a phase-1, dose-escalating, open-label clinical study for symptomatic myocardial ischemia.
The collated electrical and mechanical results of
percutaneous EMM provide both an assessment of
myocardial viability (ie, the presence of normal versus reduced
voltage) and wall motion (presence of normal versus reduced fractional
shortening). Validation of intracardiac signal recording and
location accuracy has been previously established, both in vitro and in
vivo.20 Clinical investigations have demonstrated that the
mapping capabilities of the NOGA system may be used to distinguish
between infarcted and normal myocardium. Gepstein et
al13 found significantly lower LLS (<4%) and bipolar
voltages (<2 mV) in infarcted versus noninfarcted
myocardium. Furthermore, comparison with pathological
specimens confirmed that the location and extent of infarction could be
accurately defined by EMM. These earlier findings were confirmed by
Kornowski and colleagues,16 21 who showed that patients
with prior myocardial infarction had reduced UpV (7.2±2.7 mV) and BpV
(1.4±0.7 mV) recordings compared with patients without prior
infarction (19.7±4.4 and 5.8±1.0 mV for UpV and BpV, respectively)
and that these patients had reduced local endocardial shortening
compared with patients without prior infarction. Moreover, Kornowski et
al14 demonstrated that mean voltage and LLS values are
highest when measured in myocardial segments with normal perfusion and
lowest when measured from segments with fixed perfusion defects;
intermediate LLS (4% to 12%) and voltage (5 mV) recordings
were documented for myocardial segments with reversible perfusion
defects.
In the present clinical study, LV EMM was used in a serial fashion
to provide an independent objective analysis of the impact of
phVEGF165 GTx on myocardial perfusion. Foci of
ischemic myocardium were identified by preserved
viability associated with impaired LLS. Myocardial viability, defined
by both mean UpV and BpV recordings of 5 and 2 mV,
respectively, did not change significantly after GTx. Analysis
of LLS in areas of myocardial ischemia, however, documented
marked improvement after GTx. Consequently, the area of
ischemic myocardium was reduced to a statistically
significant extent.
These findings corresponded with improved perfusion scores calculated from SPECT-sestamibi myocardial perfusion scans recorded at rest and after pharmacological stress. Perfusion defects on the resting SPECT images were associated with ischemic characteristics on EMM. Sequential SPECT scans recorded before and after GTx demonstrated partial or complete resolution of fixed defects in 4 (33%) and 5 (43%) patients, respectively, in whom defects were present on the rest images.
Resolution of rest defects observed in these SPECT scans after GTx is particularly intriguing. In this population of severely disabled, so-called no-option, patients, the rest defects were presumed to represent sites of myocardial scar associated with the clinical history of myocardial infarction in 13 of 13 patients. Partial or complete resolution of these rest defects after GTx is consistent with the notion that these preexisting defects constitute foci of hibernating myocardium22 23 24 and may have been successfully resuscitated as the result of therapeutic neovascularization.
The corresponding NOGA maps likewise showed reduced evidence of ischemia after GTx. EMM provides separate assessments of viability (endocardial voltage recording) and function (LLS). Thus, those areas of the NOGA map that showed viable myocardium with impaired function before GTx versus viable myocardium with improved function after GTx support the notion that the defects that resolved on the SPECT scans constitute sites of hibernating myocardium22 23 24 that have been resuscitated as a result of myocardial neovascularization. These findings further confirm that LV EMM may represent an independent diagnostic tool that may be useful for defining the myocardial consequences of improved perfusion. In the present series of patients, EMM was used in all cases to identify the extent of myocardial ischemia before and after GTx administered via thoracotomy. Preliminary studies performed in swine with myocardial ischemia25 and more recently in patients26 suggest that mapping the extent of ischemia may also be used online to direct percutaneous myocardial GTx. Such an adjunct may be particularly advantageous for optimizing low-efficiency strategies, such as naked DNA GTx, in which EMM may direct the injection of naked DNA to ischemic muscle, which has been shown previously to yield higher levels of gene expression.27
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Acknowledgments |
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This study was supported in part by a grant from the E.L. Weigand Foundation, Reno, Nev; and the Peter Lewis Educational Foundation. Dr Vale is the recipient of a fellowship from Bracco Diagnostics Inc/Society for Cardiac Angiography and Interventions.
Received January 10, 2000; revision received March 24, 2000; accepted March 29, 2000.
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