Preconditioning during coronary angioplasty: no influence of collateral perfusion or the size of the area at risk
Laurent Argauda,b,
G. Rioufolc,
M. Lièvred,
L. Bontempse,
P. Legaleryc,
M. Stumpfc,
G. Finetc,
R. Ittie,
X. André-Fouëtc and
M. Ovizeb,c,*
a Urgence-Réanimation Médicale, Hôpital E. Herriot, 5 Place d'Arsonval, 69437 Lyon, France
b INSERM E 0226, 8 Avenue Rockefeller, 69373 Lyon cedex 08, France
c Hémodynamique, Hôpital L.Pradel, 59 Bd Pinel, 69394 Lyon cedex 03, France
d Pharmacologie Clinique, Hôpital L.Pradel, 59, Bd Pinel, 69394 Lyon cedex 03, France
e Médecine Nucléaire, Hôpital L.Pradel, 59 Bd Pinel, 69394 Lyon cedex 03, France
Received May 7, 2004;
revised July 8, 2004;
accepted July 29, 2004
* Corresponding author. Tel.: +33 4 72 35 75 90; fax: +33 4 72 35 73 76 (E-mail: ovize{at}rockefeller.univ-lyon1.fr).
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Abstract
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AIMS: It is unclear whether the protection observed in human heart following repetition of brief episodes of ischaemia is due to opening of coronary collaterals or to ischaemic preconditioning. We investigated whether the improvement in ST segment change following repeated episodes of brief ischaemia during coronary angioplasty is due to preconditioning when the size of the area at risk and the collateral flow are taken into account.
METHODS AND RESULTS: Thirty-six patients underwent percutaneous transluminal coronary angioplasty. Intracoronary ST segment changes were measured throughout the procedure and used as an endpoint. The size of the area at risk and the collateral perfusion within the ischaemic bed were measured using single photon emission computerized tomography (SPECT).
Mean ST segment shift observed in all patients significantly decreased from 11.0±2.6 mm during the first balloon inflation to 8.5±2.3 mm during the second inflation. This protective effect occurred in the absence of any change in the size of the area at risk (mean: 46±5% of LV) and of the collateral perfusion to the ischaemic zone (mean: 23±4% of flow in the non-ischaemic zone).
CONCLUSION: These results suggest that ischaemic preconditioning does occur during repeated brief coronary artery occlusion in the human heart.
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Introduction
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Preconditioning renders the heart more resistant to a sustained ischaemic insult.1 The mechanism of this endogenous protection is currently unknown, although recent investigations suggest a major role of mitochondria.26 Preconditioning has been observed in all animal species in which it has been studied.79 Evidence that preconditioning protects the human heart remains indirect. Ikonomidis et al.,10demonstrated that cultured human cardiomyocytes that underwent previous brief simulated hypoxia better tolerate a subsequent prolonged hypoxic insult. Walker et al.,11using human atrial trabeculae exposed to rapid pacing plus hypoxia reported improved contractile function in preconditioned samples. Retrospective clinical studies have been performed in patients with acute myocardial infarction, e.g., Kloner et al.,12 using the TIMI 4 trial database, reported that patients who experienced angina within 48 h of an acute myocardial infarction developed less severe irreversible injury, as estimated by creatinine kinase release. In order to try to demonstrate the existence of preconditioning in vivo, several investigators used CABG, exercise stress testing or PTCA as experimental models.13 Deutsch et al.,14 first reported that patients who underwent a 90-s occlusion of the left anterior descending artery during coronary angioplasty developed less chest pain, less ST segment deviation and produced less lactate during a second coronary artery occlusion. These authors concluded that the first angioplasty balloon inflation hadpreconditioned these patients' hearts.
Myocardial tolerance to ischaemia depends on three independent determinants: the duration of occlusion, coronary collateral perfusion during the ischaemic episode and the size of the risk region.15,16 When trying to demonstrate the protective effect of preconditioning during coronary angioplasty, one is dealing with: (i) an observed effect (ST segment change during successive episodes of ischaemia), (ii) a presumed cause for the effect: preconditioning, but also, (iii) two confounding variables for the causal relationship: collateral blood flow and the size of the area at risk. Opening of coronary collateral vessels may be triggered by the first episode of ischaemia, and explain, at least partly, ST segment decrease.17,18 In addition, the size of the area at risk may vary widely among patients. These confounding factors have been poorly addressed in previous human studies.
The objective of the present study was to determine whether a 2.5-min balloon inflation during coronary angioplasty may precondition the human myocardium, under controlled conditions without anti-anginal treatment, using intracoronary ECG as an endpoint while evaluating both the size of the area at risk and collateral myocardial blood flow.
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Methods
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The study was performed according to the declaration of Helsinki (revised version of Somerset West, Republic of South Africa, 1996) and according to the European Guidelines of Good Clinical practice (version 11 July 1990) and French Laws. The study protocol was approved by the Ethics Committee of our Institution. All subjects gave a written informed consent prior to inclusion into the study.
Study population
Male and female patients, aged 1880 years, with stable angina and a significant, but not occlusive, coronary artery disease had been prospectively planned to undergo a single vessel angioplasty of a major coronary artery. Patients that displayed one of the following criteria were not included in the study: history of myocardial infarction or abnormal Q wave in more than 2 adjacent leads in the same territory as PTCA, history of coronary artery bypass grafting, established atrial fibrillation, left or right bundle branch block, severe or poorly controlled hypertension, history of sustained ventricular tachycardia or of ventricular fibrillation. Anti-ischaemic and anti-anginal treatments, including beta-blockers, Ca2+ antagonists, nitrates, nicorandil and sulfonylureas had been stopped at least five half-lives before PTCA.
Experimental design
This was a monocentric, centrally randomized, double-blind, placebo-controlled, parallel groups study. Because it was impossible to measure myocardial perfusion during each balloon inflation in the same patient, the measurement was performed in one group during the first inflation, and during the second inflation in the other group. If the collateral perfusion was statistically equivalent in both groups, it was considered that no meaningful change in myocardial perfusion occurred between the first and second inflations in each group. The main objective of the study was therefore both to demonstrate the equivalence between the groups in terms of collateral perfusion and to demonstrate intra-group differences in ST-segment change between two successive balloon inflations.
Randomization procedure
When notified by the Cardiology Department of the eligibility of a patient, the Clinical Pharmacology Department determined the order of the hot or cold (vehicle) 99Technetium Sestamibi injections allocated to the patient according to the randomization list, and notified the order by fax to the Nuclear Medicine Department (NMD), who prepared two syringes, labeled A (first) and B (second injection). The cardiologist performing the PTCA procedure was unaware of the hot or cold nature of the syringe content. The NMD investigator who performed the SPECT imaging was later unaware of the treatment group of the patient (see Fig. 1).

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Fig. 1 Experimental protocol. All patients underwent two 2.5-min balloon inflation separated by 5 min of reperfusion. Hot 99Technetium-sestamibi was injected as an IV bolus during the first (group 1) or the second (group 2) inflation. Two to three hours after the end of the angioplasty procedure, SPECT imaging was performed to measure collateral perfusion and the size of the area at risk. Intracoronary ECG was recorded throughout the procedure. Nitroglycerin was continuously infused from 15 min before the angioplasty to 5 min after the 2nd balloon inflation.
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Coronary angioplasty
All patients were premedicated with hydroxyzine (Atarax®, UCB Pharma, France) (50 mg per os, given 15 min before catheterization). A continuous IV infusion of nitroglycerin (1mg/h) was started 15 min before catheterization and ended after completion of the angioplasty to induce a comparable degree of coronary vasodilation in all patients. Aspirin (250 mg) and heparin (100 IU/kg) were administered intravenously just before positioning the angioplasty guide wire. Sodium and meglumine ioxaglate (Hexabrix®, Guerbet, France) was used as contrast agent for coronary angiography.
Coronary angioplasty of the stenosed coronary artery was performed by a standard Seldinger technique, and a 0.014-in guide wire was positioned across the coronary artery stenosis. Using a sterile clip, the proximal end of the guide wire was connected to the V5 lead of a standard ECG. All recordings were performed with the distal end of the guide wire positioned 34 cm downstream of the coronary stenosis. Two balloon inflations of 2.5 min separated by approximately 5 min were performed. When needed, a third balloon inflation was performed.
SPECT imaging for assessment of risk region and myocardial perfusion
The size of the risk region and the regional myocardial blood flow were assessed using SPECT (Single Photon Emission Computerized Tomography) imaging. One minute into the first and second balloon inflation, 500 MBq of hot or cold 99Technetium-sestamibi, were administered intravenously as a bolus in a double blind manner. Within two to three hours after the end of the angioplasty, patients were referred for SPECT Imaging. This was performed on a single-head Sophycamera DS7, using 32 projections of 30 s each, from the 45° left posterior oblique to the 45° right anterior oblique projection. Tomographic reconstruction was carried out by filtered (HammingHann) back projection and the myocardial volume was displayed as reoriented slices in three planes: horizontal long axis, vertical long axis and short axis, as well as a standard (with angular sampling) polar-map (bull's-eye) for synthetic analysis.
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Analysis
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Intracoronary ECG
Intracoronary ECG was recorded at baseline, every 30 s during each balloon inflation, one minute before the second, and 5 min after the last balloon inflation. Measurements of ST segment changes were performed by a cardiologist unaware of the study protocol. At all time points, ST segment shift was measured 80 ms after the J point. For each time point, the mean of the absolute value of ST segment shift of three consecutive beats was calculated.
Assessment of risk region size and collateral myocardial perfusion
Using 99Technetium-sestamibi, the area at risk appears as a perfusion defect on SPECT images19 (Fig. 2). After 3D reconstruction of the myocardial volume, tracer uptake was quantified using a dedicated software.20 This method is based on the analysis of a special type of polar map (different from the standard bull's-eye mentioned above) constructed from a series of long-axis radial slices turning around the myocardium (pie-slices). By comparison with a normal database, assuming 2.5 standard deviations as the confidence interval, both the size (i.e., area of abnormal uptake, as a percentage of the total myocardium) and the severity (maximal and mean decrease in tracer uptake as a percentage of the background-corrected normal myocardial activity: 100% defect=background activity) of the scintigraphic defect were calculated. This software takes into account the deformation of the original bullet-shaped volume of the left ventricle when it is compressed as a polar map, so that the numbers are as close as possible to the actual abnormal fraction of the myocardium. The size of the area at risk was expressed as percentage of the LV size, and risk region myocardial blood flow as percentage of flow in the remote non-ischaemic myocardium.

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Fig. 2 Typical 99Tc-MIBI scintigraphy during LAD coronary angioplasty. Colour encoding depicts normal perfusion as red or white. Area at risk encompasses yellow, green and blue zones.
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Statistical analysis
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Comparison of qualitative variables at baseline and during the study was performed using the two-sided Fisher's exact test or
2 test. Continuous variables were compared at baseline by means of a two-sided Student's t-test or non-parametric tests. Equivalence of collateral flow (derived from 99Tc-sestamibi) between group 1 (1st inflation) and group 2 (2nd inflation) was accepted if the 95% confidence interval of the inter-group difference in mean collateral flow excluded the values 15% and +15%.12,13 The target variables were the difference between the maximum and mean ST changes at the end of the 2nd inflation and the maximum and mean ST changes at the end of the 1st inflation in the pooled preconditioning and control groups. The difference in ST changes was assessed by an analysis of variance and was further adjusted on collateral blood flow and ST segment change during the first inflation using a general linear model procedure. From the previous experience of the NMD, it was determined that the standard deviation of the mean collateral blood flow was 15%, and this value was chosen as the equivalence limit, resulting in a sample size of 36 patients to determine equivalence at an alpha-risk of 0.05 and a 80% power. This sample size allowed the detection of a 4.0-mm difference in ST segment change between two successive inflations with a 90% power. Because any conclusion regarding the changes in ST-segment was conditional on the demonstration of equivalence between groups regarding collateral blood flow, no adjustment was made for multiple comparisons.
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Results
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Coronary angioplasty
Thirty-six patients (10 F and 26 M) aged 61±12 years, were included into the study. Table 1 summarizes the anatomic and haemodynamic features of the study population. PTCA was successfully performed in all 36 patients. There was no statistically significant difference between groups with respect to the location or the severity of the coronary artery disease.
Haemodynamics
Heart rate, systolic and diastolic blood pressures were comparable between the two groups and did not significantly vary throughout the angioplasty procedure (Table 2).
Assessment of area at risk and collateral myocardial perfusion
The size of the area at risk averaged 48±5% of the myocardium area in group 1 versus 44±5% in group 2 (Fig. 3). Myocardial perfusion in the centre of the area at risk averaged 20±5% of uptake in non-ischaemic myocardial in group 1 versus 26±3% in group 2. Mean myocardial perfusion in the whole risk region averaged 56.5±2.5% of uptake in non-ischaemic myocardium in group 1 versus 57.7±2.7% in group 2. The difference between the groups was 1.2%, 95% confidence interval [6.3; +8.6], and formal equivalence between the groups was demonstrated. In other words, the two groups displayed similar collateral myocardial perfusion in the ischaemic region during the first and second balloon inflations.

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Fig. 3 Area at risk and collateral perfusion. Area at risk was comparable in the two groups (G1 and G2). Collateral perfusion, averaged over the whole area at risk (whole AR) or in its centre (centre AR), was comparable between the two groups.
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Intra-coronary ECG during balloon inflations
During the first balloon inflation, all patients displayed significant mean and maximal ST segment shifts that were similar in both groups (Table 3). The delay to maximum ST change averaged 1.72±0.20 min in group 1 versus 2.17±0.16 min in group 2 (p=0.09).
During the second balloon inflation, a ST segment elevation was observed in all patients. Both groups confounded, maximal and mean ST segment elevation were lower during the second inflation than the first inflation by 4.0±1.5 mm (p=0.013) and 2.7±1.3 mm (p=0.04) (Fig. 4). After adjustment on change in collateral blood flow and ST segment elevation at first inflation, decreases in maximal and mean ST segment elevation at second inflation were respectively 3.9±1.3 (p=0.005) and 2.6±1.1 (p=0.02).

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Fig. 4 ST segment shift. Maximum and mean ST segment shift were significantly reduced during the second balloon inflation (I2) in pooled groups 1 and 2. *p<0.05 versus I1 (inflation 1).
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In the subgroup of 19 patients (9 in group 1 and 10 in group 2) that underwent 3 balloon inflations, ST segment shift averaged 11.1±1.8, 9.3±1.9* and 7.4±1.8
mm during the first, second and third inflation, respectively (*p=0.19 vs. inflation 1,
p=0.05 vs. inflation 2,
p=0.02 vs. inflation 1).
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Discussion
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In this randomized, blinded, controlled study, we demonstrated a significant decrease in ST segment shift following repetitive episodes of ischaemia and the equivalence of collateral perfusion measured at first and second episodes of ischaemia in two different randomized groups.
Ischaemic preconditioning is a protective phenomenon whose primary effect is to reduce infarct size.1 Reimer et al.,16 demonstrated that the extent of infarct size is determined by three major determinants including myocardial collateral flow, the size of the risk region and the rate-pressure product. Similarly, the surrogate endpoint ST segment shift is significantly influenced by the size of the ischaemic bed, presence of collateral circulation and the metabolic demand of the ischaemic myocardium.2123 Therefore, demonstration of the existence of preconditioning in humans need to take these three factors into account.
Unlike animal preparations, the major difficulty in any human model of repetitive ischaemia is the feasibility to measure the two major determinants of ischaemic injury, i.e., area at risk and collateral flow twice in the same patient, at brief time intervals. Several previous studies of preconditioning during coronary angioplasty have attempted to assess collateral perfusion using unsatisfactory methods such as coronary angiography, pressure or flow velocity-derived collateral flow index, or contrast echocardiography.2427 In the present study, we used SPECT to assess simultaneously collateral perfusion at the myocardial level and the size of the risk region during balloon inflation.28,29 Another key methodological feature of our study is that we constituted two comparable groups of patients by randomization. Collateral flow was assumed to be similar in both groups during the first balloon inflation. We postulated that if this parameter did not change between the two inflations, then the value measured in one group during the first inflation would be similar to the value measured in the other group during the second inflation. Our results demonstrate formal statistical equivalence in collateral flow between the two study groups. Consequently, the difference in ST segment change between the two ischaemic episodes can be considered to be due to preconditioning only. The validity of this conclusion is further strengthened by: (i) the double blind nature of the isotope injection, (ii) the discontinuation of all anti-anginal treatments before entry into the protocol, (iii) a systematic nitroglycerin infusion that provided a stable coronary vasodilatation in all patients throughout the protocol and minimized variation in opening of coronary collaterals as a consequence of ischaemia.
In agreement with previous studies, we showed that ST segment shift was reduced during the second balloon inflation when compared to the first one.14,30,31 When a third ischaemia occurred, ST changes further decreased suggesting a doseresponse effect as reported by others.3133 This latter result, however must be interpreted with caution, because a third inflation was only used in a subgroup of patients in which a change in collateral blood flow between the second and third inflations cannot be ruled out.
SPECT has been recognized as a valid tool to measure the size of the risk region, including during coronary angioplasty.3438 In our study, both groups displayed comparable area at risk that averaged 48±5% and 44±5%, respectively. Previous studies have demonstrated a close correlation between SPECT and microspheres evaluation of collateral perfusion in animal models.29 Our data are in agreement with those of Sand et al.,18 who found an estimated mean collateral flow of 63±9% during balloon inflation versus 66±3% in the present study. In the centre of the risk region, mean myocardial blood flow averaged 20 and 26% in the two groups. As expected with SPECT, myocardial perfusion was expressed as a percentage of flow in the non-ischaemic area. It might be argued that flow in a territory remote from the area at risk might not be comparable between the two groups of patients. Yet, since patients were randomly assigned into the two groups, since a haemodynamics were similar in both groups and because we checked that the supposed non-ischaemic myocardium was perfused by a coronary artery devoid of any significant stenosis, we can admit that there was likely no difference in myocardial perfusion in the non-ischaemic territories between the two groups of patients. An advantage of SPECT is the ability to simultaneously measure collateral perfusion and the size of the area at risk. However, due to the limited spatial resolution, SPECT can only detect collateral perfusion at the myocardial level, averaging out transmural differences. On the other hand, contrast echocardiography or flow or pressure-derived coronary flow index lack sensitivity to detect subtle variations at low perfusion pressure or flow, or in the presence of ischaemia.38
In conclusion, the present study demonstrated that, when collateral perfusion and the size of the risk region are taken into account, there persists a decrease in ST segment shift following a first brief episode of ischaemia; this protective effect is likely to be due to ischaemic preconditioning.
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References
|
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- Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium Circulation 1986;5:1124-1136.
- Hausenloy DJ, Maddock HL, Baxter GF, et al. Inhibiting mitochondrial permeability transition pore opening: a new paradigm for myocardial preconditioning? Cardiovasc Res 2002;55:534-543.[CrossRef][ISI][Medline]
- Javadov SA, Clarke S, Das M, et al. Ischaemic preconditioning inhibits opening of mitochondrial permeability transition pores in the reperfused rat heart J Physiol 2003;549:513-524.[Abstract/Free Full Text]
- Akao M, O'Rourke B, Kusuoka H, et al. Differential actions of cardioprotective agents on the mitochondrial death pathway Circ Res 2003;92:195-202.[Abstract/Free Full Text]
- Korge P, Honda HM, Weiss JN. Protection of cardiac mitochondria by diazoxide and protein kinase C: implication for ischemic preconditioning Proc Natl Acad Sci USA 2002;99:3312-3317.[Abstract/Free Full Text]
- Argaud L, Gateau-Roesch O, Chalabreysse L, et al. Preconditioning delays Ca2+-induced mitochondrial permeability transition Cardiovasc Res 2004;61:115-122.[CrossRef][ISI][Medline]
- Li Y, Whittaker P, Kloner RA. The transient nature of the effect of ischemic preconditioning on myocardial infarct size and ventricular arrythmia Am Heart J 1992;123:346-353.[ISI][Medline]
- Liu GS, Thornton J, Van Winkle DM, et al. Protection against infarction afforded by preconditioning is mediated by A1 adenosine receptors in rabbit heart Circulation 1991;84:350-356.[Abstract]
- Ovize M, Kloner RA, Hale SH, et al. Coronary cyclic flow variations precondition the ischemic myocardium Circulation 1992;85:779-789.[Abstract]
- Ikonomidis JS, Tumiati LC, Weisel RD, et al. Preconditioning human ventricular cardiomyocytes with brief periods of simulated ischaemia Cardiovasc Res 1994;28:1285-1291.[ISI][Medline]
- Walker DM, Walker JM, Pugsley WB, et al. Preconditioning in isolated superfused human muscle J Mol Cell Cardiol 1995;27:1349-1357.[ISI][Medline]
- Kloner RA, Shook T, Przyklenk K, et al. Previous angina alters in hospital outcome in TIMI 4. A clinical correlate to preconditioning? Circulation 1995;91:37-47.[Abstract/Free Full Text]
- Yellon DM, Baxter GF, Marber MS. Angina reassessed: pain or protector? Lancet 1996;347:1059-1062.[Medline]
- Deutsch E, Berger M, Kussmaul WG, et al. Adaptation to ischemia during percutaneous transluminal angioplasty: clinical, hemodynamic, and metabolic features Circulation 1990;82:2044-2051.[Abstract]
- Reimer KA, Jennings RB. The "Wavefront Phenomenon" of myocardial ischemic cell death. II. Transmural progression of necrosis within the framework of ischemic bed size (myocardium at risk) and collateral flow Lab Invest 1979;6:633-644.
- Reimer KA, Jennings RB, Cobb FR, et al. Animal models for protecting ischemic myocardium : Results of the NHLBI Cooperative Study. Comparison of unconscious and conscious dog models Circ Res 1985;56:651-665.[Abstract]
- Piek JJ, Koolen JJ, Hoedemaker G, et al. Severity of single-vessel coronary arterial stenosis and duration of angina as determinants of recruitable collateral vessels during balloon angioplasty occlusion Am J cardiol 1991;67:13-17.[ISI][Medline]
- Sand NP, Rehling M, Bagger JP, et al. Functional significance of recruitable collaterals during temporary coronary occlusion evaluated by 99mTc-sestamibi single-photon emission computerized tomography J Am Coll Cardiol 2000;35:624-632.[CrossRef][ISI][Medline]
- Bontemps L, Gabain M, Doudouh A, et al. Severity and extent of perfusion defects provoked by transient coronary occlusion compared with myocardial damage observed after infarction Nucl Med Commun 2000;21:147-154.[CrossRef][ISI][Medline]
- Benoit T, Vivegnis D, Foulon J, et al. Quantitative evaluation of myocardial signle-photon emission tomographic imaging: application to the measurement of perfusion defect size and severity Eur J Nucl Med 1996;23:1603-1612.[ISI][Medline]
- Holland RP, Arnsdorf MF. Solid angle theory and the electrocardiogram: physiologic and quantitative interpratation Prog Cardiovasc Dis 1977;19:431-457.[ISI][Medline]
- Tomai F, Crea F, Gaspardone A, et al. Determinants of myocardial ischemia during percutaneous transluminal coronary angioplasty with significant narrowing of a single coronary artery and stable or unstable angina pectoris Am J Cardiol 1994;74:1089-1094.[CrossRef][ISI][Medline]
- Ross Jr. J. Electrocardiographic ST segment analysis in the characterization of myocardial ischemia and infarction Circulation 1976;53:I73-I81.[Medline]
- Sakata Y, Kodama K, Kitakaze M, et al. Different mechanisms of ischemic adaptation to repeated coronary occlusion in patients with and without recruitable collateral circulation J Am Coll Cardiol 1997;30:1679-1686.[CrossRef][ISI][Medline]
- Piek JJ, van Liebergen RAM, Koch KT, et al. Comparison of collateral vascular responses in the donor and the recipient coronary artery during transient coronary occlusion assessed by intracoronary blood flow velocity analysis in patients J Am Coll Cardiol 1997;29:1528-1535.[CrossRef][ISI][Medline]
- Doucette JW, Corl PD, Payne HM, et al. Validation of a Doppler guide wire for intravascular measurement of coronary artery velocity Circulation 1992;85:1899-1911.[Abstract]
- van Liebergen RAM, Piek JJ, Koch KT, et al. Quantification of collateral flow in humans: a comparison of angiographic, electrocardiographic and hemodynamic variables J Am Coll Cardiol 1999;33:670-677.[CrossRef][ISI][Medline]
- Sinusas AJ, Shi Q, Saltzberg MT, et al. Technetium-99m-tetrofosmin to assess myocardial blood flow: experimental validation in an intact canine model of ischemia J Nucl Med 1994;35:664-671.[Abstract]
- Christian TF, O'Connor MK, Schwartz RS, et al. Technetium-99m MIBI to assess coronary collateral flow during acute myocardial infarction in two closed-chest animal models J Nucl Med 1997;38:1840-1846.[Abstract]
- Tomai F, Crea F, Gaspardone A, et al. Effects of naloxone on myocardial ischemic preconditioning in humans J Am Coll Cardiol 1999;33:1863-1869.[CrossRef][ISI][Medline]
- Leesar MA, Stoddard MF, Ahmed M, et al. Preconditioning of human myocardium with adenosine during coronary angioplasty Circulation 1997;95:2500-2507.[Abstract/Free Full Text]
- Eltchaninoff H, Cribier A, Tron C, et al. Adaptation to myocardial ischemia during coronary angioplasty demonstrated by clinical, electrocardiographic, echocardiographic, and metabolic parameters Am Heart J 1997;133:490-496.[ISI][Medline]
- Billinger M, Fleisch M, Eberli FR, et al. Is the development of myocardial tolerance to repeated ischemia due to preconditioning or to collateral recruitment? J Am Coll Cardiol 1999;33:1027-1035.[CrossRef][ISI][Medline]
- Gallik DM, Obermueller SD, Swarna US, et al. Simultaneous assessment of myocardial perfusion and left ventricular function during transient coronary occlusion J Am Coll Cardiol 1995;25:1529-1538.[CrossRef][ISI][Medline]
- Borges-Neto S, Puma J, Jones RH, et al. Myocardial perfusion and ventricular function measurements during total coronary artery occlusion in humans. A comparison with rest and exercise radionuclide studies Circulation 1994;89:278-284.[Abstract]
- Sinusas AJ, Trautman KA, Bergin JD, et al. Quantification of area at risk during coronary occlusion and degree of myocardial salvage after reperfusion with technetium-99m methoxyisobutyl isonitrile Circulation 1990;82:1424-1437.[Abstract]
- Braat SH, de Swart H, Rigo P, et al. Value of technetium MIBI to detect short lasting episodes of severe myocardial ischaemia and to estimate the area at risk during coronary angioplasty Eur Heart J 1991;12:30-33.[Abstract]
- Seiler C, Fleisch M, Garachemani A, et al. Coronary collateral quantitation in patients with coronary artery disease using intravascular flow velocity or pressure measurements J Am Coll Cardiol 1998;32:1272-1279.[CrossRef][ISI][Medline]