Circulation. 2003;108:2979-2986
Published online before print December 8, 2003,
doi: 10.1161/01.CIR.0000103682.19844.10
(Circulation. 2003;108:2979.)
© 2003 American Heart Association, Inc.
Clinical Investigation and Reports |
Impact of Infarct-Related Artery Flow on QT Dynamicity in Patients Undergoing Direct Percutaneous Coronary Intervention for Acute Myocardial Infarction
Hendrik Bonnemeier, MD;
Uwe K.H. Wiegand, MD;
Frank Bode, MD;
Franz Hartmann, MD;
Volkhard Kurowski, MD;
Hugo A. Katus, MD, FESC;
Gert Richardt, MD
From the Universität zu Lübeck (H.B., U.K.H.W., F.B., F.H., V.K.), Medizinische Klinik II, Lübeck, Germany; Ruprecht-Karls-Universität-Heidelberg (H.A.K.), Innere Medizin III, Heidelberg, Germany; and Herzzentrum Segeberger Kliniken (G.R.), Kardiologie, Bad Segeberg, Germany.
Correspondence to Hendrik Bonnemeier, MD, Medizinische Klinik II, Universität zu Lübeck, Ratzeburger Allee 160, D-23538 Lübeck, Germany. E-mail Bonnemei{at}medinf.mu-luebeck.de
Received February 18, 2003; de novo received August 15, 2003; revision received September 11, 2003; accepted September 12, 2003.
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Abstract
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Background— Complete coronary artery reperfusion in acute
myocardial infarction (AMI) has been shown to significantly
improve survival. Electrical stability may be the decisive mechanism
for this beneficial effect. Because electrical stability is
largely dependent on ventricular repolarization, we sought to
determine the impact of a modern reperfusion strategy (ie, direct
percutaneous coronary intervention [PCI]) on QT dynamicity in
AMI and examined its association with infarct-related artery
flow.
Methods and Results— We prospectively investigated QT dynamicity in 128 patients undergoing direct PCI for a first AMI. Slopes and correlation coefficients of the linear QT/RR regression were determined in the time interval before reperfusion, within the initial hour after reperfusion, and within the remaining recording period from Holter ECG recordings, which were initiated on admission. Subgroup analysis based on TIMI 3 (n=100) and TIMI 2 (n=28) flow after PCI revealed no significant differences in QT/RR slope before PCI (0.145±0.12 versus 0.160±0.19,P=NS). After PCI, QT/RR slopes increased only in the TIMI 2 subgroup (P<0.05). In TIMI 2 patients, QT/RR slopes were significantly steeper in the hour after PCI and in the remaining recording period, respectively (0.155±0.12 versus 0.192±0.15,P<0.05, and 0.159±0.10 versus 0.210±0.17,P<0.01).
Conclusions— Alterations of QT dynamicity in patients with incomplete reperfusion may suggest an altered electrical restitution, potentially providing a substrate for serious ventricular arrhythmias. Thus, our findings offer new insights into mechanisms by which complete reperfusion may affect electrical stability.
Key Words: myocardial infarction • dynamics • angioplasty • reperfusion
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Introduction
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Despite angiographic evidence of an open infarct-related coronary
artery, a delayed or sluggish antegrade flow (ie, Thrombolysis
In Myocardial Infarction [TIMI] 2 flow)
1 is associated with
an increased risk for cardiac mortality in patients with acute
myocardial infarction (AMI).
2,3 A substantial number of these
patients are prone to develop life-threatening arrhythmias,
obviously facilitated by the interaction of cardiac autonomic
imbalance and an abnormal arrhythmic substrate. There is growing
evidence that ventricular repolarization, which has been implicated
in the development of ventricular arrhythmias, is altered in
the acute phase of AMI. It appears likely that more extensive
tissue injury with persistent microvascular dysfunction may
alter the electrophysiological characteristics of ventricular
myocardial cells in the border zone,
4–6 leading to local
differences of ventricular recovery durations. Ventricular repolarization
is a complex process that occurs nonuniformly in space and time
and is closely coupled with the underlying RR interval. This
QT/RR relationship, a major property of ventricular repolarization,
is known to be dynamic. QT rate dependence may be altered in
the setting of AMI and especially after incomplete reperfusion
of the infarct-related artery, which may be associated with
an increased susceptibility for malignant ventricular arrhythmias.
Recent data strongly suggest an association of abnormal QT rate
dependence and ventricular arrhythmogenesis.
7–9
Therefore, we hypothesized that incomplete coronary artery reperfusion in AMI, in contrast to complete reperfusion, leads to an abnormal QT/RR relationship due to a sustained transmural "electrical injury." Using QT dynamicity, we evaluated the impact of a modern reperfusion strategy (ie, direct percutaneous coronary intervention [PCI]) on QT rate dependence in the acute phase of AMI and examined its association with the epicardial infarct-related artery flow.
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Methods
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Patient Population
A total of 194 consecutive patients with ST-segment elevation
AMI, in whom primary PCI for an occluded infarct artery was
performed at our institution, were prospectively screened for
this study. Inclusion criteria were presence of ischemic chest
pain for >30 minutes but <24 hours associated with ST-segment
elevation
0.1 mV in
2 leads of the
surface ECG. Exclusion criteria were cardiogenic shock, blood
pressure <90 mm Hg and clinical signs of heart failure, left
bundle-branch block, pacemaker rhythm and rhythm other than
sinus, chronotropic incompetence, class I and III antiarrhythmic
medication before admission, age >75 years, prior MI or CABG,
coronary occlusions unsuitable for PCI, and invalid Holter ECG
recordings. ß-Blockers and nitrates were given according
to current guidelines. All patients gave informed consent for
the research protocol, which was by the local ethics committee.
Catheterization
Coronary angioplasty was performed by the percutaneous femoral approach. Calculation of left ventricular ejection fraction (LVEF) was performed offline with a computerized algorithm (QLVA, Medis Medical). Antegrade perfusion of the infarct-related artery was graded according to the classification of the TIMI trial.1 When the study was performed, the primary objective of angioplasty was to achieve an optimal angiographic result by coronary angioplasty alone. Stent implantation was performed if TIMI flow was <2, residual stenosis was >30%, or extensive intimal dissection was present. Arterial plasma concentrations of norepinephrine were investigated before PCI, 60 minutes after PCI, and 6 hours after PCI by the high-performance liquid chromatography method.10
Clinical Follow-Up
All patients were seen in our arrhythmia outpatient department at 3, 6, and 12 months after AMI. Major arrhythmic events (MAEs) were assessed after the first 48 hours after AMI and were defined as sudden cardiac death, ventricular fibrillation with consecutive resuscitation, and sustained ventricular tachycardias.
Measurement of QT Dynamicity
The QT interval was analyzed on aPathfinder 700 analysis system (Reynolds Medical) from 2-lead, 24-hour Holter monitoring (Tracker II, Reynolds Medical), which was started at hospital admission. Immediately after the PCI procedure, a marker was set on the Holter recording (Figure 1). All tapes were edited manually for exclusion of artifacts and premature beats. Beats with a heart rate <30 bpm, >160 bpm, or with a prevailing RR interval <66% or >180%, respectively, were automatically excluded from the analysis. Recordings with longer intervals of severe artifacts or imperceptibility of the T wave were also not suitable for analysis. A minimum of 18 hours of recording time and a minimum of 90% successive QT intervals were required for a tape to be accepted as valid. Twenty-four-hour files of RR and QT intervals were then processed on a personal computer with a special software package (QT/RR Research Tools version 0.02, Reynolds Medical). Slopes and correlation coefficients of the linear QT/RR regression were computed for the time interval from admission to PCI, the first hour after PCI, and the remaining hours (Figures 1 and 2
). Recordings were excluded from further analysis if the pooled QT/RR correlation was <0.5.
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Figure 1. Tachograms of RR intervals and corresponding QT intervals in 55-year-old male patient with anterior AMI. Time of PCI is shown by arrow. Intervals for QT dynamicity analyses are depicted as I, interval before PCI; II, 60-minute interval after PCI; and III, interval from hour 2 to hour 24 after PCI.
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Figure 2. Individual plots of QT dynamicity obtained in representative patients with TIMI 3 flow (A) and TIMI 2 flow (B) after PCI for acute MI. RR intervals are plotted on horizontal axis and QT intervals on vertical axis.
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Statistical Analysis
Statistical analyses were conducted with a commercially available software package (SPSS version 11.0; SPSS Inc). Continuous variables were tested for normal distribution with the Kolmogorov-Smirnov goodness-of-fit test. Discrete variables were compared by 
2 analysis. Multiple comparisons between groups were done by Bonferroni-corrected ANOVA for repeated measures. Consecutively, an 
-corrected paired Student t test was performed for interval-to-interval comparisons. Pearson’s coefficient of correlation was used to assess the association between QT/RR slopes and clinical variables. Stepwise linear multivariate regression analysis was performed with QT/RR slope as a dependent variable to determine the most important predictors of differences in QT/RR slope. QT and RR data are presented as mean±SD. QT and RR data in figures are presented as mean±SEM. A 2-tailed significance level of 0.05 was used for the analyses.
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Results
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Patient Characteristics
Among the 194 screened patients with a first AMI, a total of
128 fulfilled the clinical and technical inclusion criteria,
had valid Holter ECG recordings (median duration 23 hours),
and had recanalization of the infarct-related coronary artery.
Of the 66 withdrawn patients, a total of 44 had insufficient
Holter ECG recordings for analysis of QT dynamicity. Subgroup
analysis based on TIMI flow of the target vessel after direct
PCI revealed no significant differences in baseline and clinical
characteristics between patients with TIMI 3 (n=100) and TIMI
2 (n=28) flow (
Table 1), except the more frequent use of glycoprotein
IIb/IIIa antagonists (
P=0.003) in the TIMI 2 subgroup. In the
acute phase of MI, almost 40% of patients in both groups received
intravenous ß-blockade. There were no statistically
significant differences in LVEF, left ventricular end-diastolic
pressure, peak creatine kinase, or lactate dehydrogenase levels,
but there was a trend toward more depressed left ventricular
function and higher cardiac enzyme release in patients with
TIMI 2 perfusion grade. Serum potassium levels were not significantly
different between groups. During the 12-month follow-up, a total
of 16 MAEs were documented in 13 patients. The majority of MAEs
occurred during the hospitalization period (62.5%). Patients
with TIMI 2 flow tended to have a higher incidence of MAEs (TIMI
2 17.8%, n=5; TIMI 3 8.0%, n=8;
P=NS).
Time Course of QT Dynamicity
QT/RR slopes of the entire population averaged 0.156±0.13 before PCI and tended to increase to 0.166±0.13 in the hour after PCI and to 0.173±0.12 in the remaining recording period (P=NS). Subgroup analysis based on TIMI flow after PCI revealed no significant differences of QT/RR slope before PCI (0.145±0.12 versus 0.160±1.19,P=NS). However, in the TIMI 2 subgroup, QT/RR slopes were significantly steeper in the hour after PCI and in the remaining recording period (0.155±0.12 versus 0.192±0.15,P<0.05 and 0.159±0.10 versus 0.210±0.17,P<0.01, respectively). There was a significant increase in QT/RR slope from baseline levels only in the TIMI 2 subgroup within the observation period (Figure 3). There were no significant differences between TIMI groups regarding QT/RR correlation coefficient and mean RR interval (Figure 3). In both subgroups, mean RR interval remained constant in the hour after PCI (TIMI 2 719.6±103 to 736.4±109 ms,P=NS; TIMI 3 739.4±108 to 740.7±100 ms,P=NS) and significantly increased within the subsequent recording period (TIMI 2 793.1±150 ms,P<0.05; TIMI 3 819.5±138 ms,P<0.05). Mean QT interval was stable in patients with TIMI 3 flow and only slightly increased in patients with TIMI 2 flow (P=NS) within the observation period (Figure 3). Patients with TIMI 2 flow exhibited higher mean QT intervals after PCI (before PCI 380.4±51.9 versus 378.5±41.7 ms,P=NS; 60 minutes after PCI 386.8±42.9 versus 378.1±41.9 ms,P<0.05; remaining recording period 387.4±59.0 versus 377.4±47.2 ms,P<0.05).
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Figure 3. QT/RR slope, QT/RR correlation coefficient, RR interval, and QT interval before PCI, in first hour after PCI, and in interval from hours 2 to 24 after PCI in patients with TIMI 2 and 3 flow.
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QT Dynamicity and Clinical Parameters
There were no significant correlations between QT/RR slopes measured before PCI and clinical parameters. In the time period after PCI, QT/RR slopes were moderately related to age (Table 2). Furthermore, there was a moderate inverse correlation with LVEF and a weak correlation with left ventricular end-diastolic pressure in the time interval from hour 2 to hour 24 after PCI. No relation was found between QT/RR slopes and either peak enzyme release levels or time of ischemia (Table 2). As previously reported,11 female patients exhibited steeper slopes (0.185±0.14 versus 0.169±0.11,P<0.05). Anterior infarct localization was also associated with a steeper QT/RR slope after PCI (0.181±0.13 versus 0.162±0.12,P<0.05). QT/RR slopes were not significantly different in patients with single-vessel versus multivessel coronary artery disease, current smokers and nonsmokers, and patients with or without diabetes mellitus. Furthermore, there were no significant differences of QT dynamicity in patients with or without ß-blockade. Patients with MAEs in the follow-up period exhibited significantly steeper QT/RR slopes after PCI than patients without MAEs (MAEs 0.242±0.09; no MAEs 0.162±0.12; P=0.018; Figure 5). There were no significant differences in patients with and without MAEs regarding measures of ventricular repolarization on the discharge surface ECG (QT interval: MAE 381±25 ms, no MAE 385±31 ms [P=NS]; QTc interval: MAE 409±39 ms, no MAE 401±31 ms [P=NS]; QT dispersion: MAE 59.8±24 ms; no MAE 61.9±25 ms [P=NS]). Norepinephrine concentrations tended to be higher in the TIMI 2 subgroup within the observation period but only reached statistical significance in the hour after PCI (TIMI 2 806.6±608 pg/mL, TIMI 3 621.5±411 pg/mL; P=0.07; Figure 4). In TIMI 2 patients, there was a slight increase of serum norepinephrine after PCI (P=NS). Norepinephrine concentrations before PCI, 60 minutes after PCI, and 6 hours after PCI revealed no significant relation to the corresponding QT/RR slopes (respectively,r=0.066,P=NS; r=0.13,P=NS; andr=0.13,P=NS). Stepwise multivariate linear regression analysis with QT/RR slope as the dependent variable revealed that after correction for the covariates, only TIMI flow (P=0.035) and LVEF (P=0.013) were significantly associated with QT/RR slopes, whereas age, gender, infarct site, serum norepinephrine levels, diabetes mellitus, Killip class, and presence of troponin T on hospital admission were not significantly associated with QT/RR slopes.
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Figure 5. Group differences in QT/RR slopes after PCI of patients with (n=13) and without (n=115) MAEs in 12-month follow-up. In these box plots, central line represents distribution median, box spans from 25 to 75 percentile points, and error bars extend from 10 to 90 percentile points.
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Figure 4. QT/RR slopes and corresponding norepinephrine concentrations in patients with TIMI 2 and 3 flow after direct PCI for AMI.
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Discussion
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Patency of the infarct-related artery in AMI reduces subsequent
mortality, and both an improvement of left ventricular function
and an increased myocardial electrical stability may contribute
to this favorable effect.
12,13 Because patency is not perfusion,
the optimal outcome after AMI further depends on complete and
sustained perfusion of the infarct-related artery.
13 Despite
angiographic evidence of an open infarct vessel, a number of
patients have a mismatch between patency and myocardial perfusion.
14,15 Incomplete reperfusion may affect ventricular repolarization,
either directly by influencing the electrophysiological milieu
or indirectly by interference with cardiac autonomic nervous
tone. The data of the present study indicate that, largely independent
of left ventricular function, incomplete reperfusion is associated
with significant alterations of QT dynamicity in the early postinfarction
period, which potentially provides a substrate for serious ventricular
arrhythmias. Therefore, the present results suggest that reperfusion
of myocardial tissue rather than patency of the infarct-related
artery per se is beneficial by improving electrical stability.
Ventricular repolarization is a dynamic process, influenced by changeable variables such as the underlying heart rate, interference with cardiac autonomic nervous tone,16 and the local ventricular electrophysiological milieu. Therefore, only a dynamic assessment of QT intervals allows an accurate characterization of ventricular repolarization. An abnormal dynamic behavior of ventricular repolarization in relation to heart rate changes has been linked to susceptibility to ventricular arrhythmias8,9; however, QT rate dependence has so far not been studied in the acute phase of AMI.
There are only a few previous studies investigating the QT/RR relationship in post-AMI patients. Savelieva et al17 observed significantly steeper QT/RR slopes in patients in the chronic phase of AMI than in normal subjects. In the Groupe d’Etude du Prognostic de l’Infarctus du Myocarde (GREPI) trial, diurnal QT/RR slopes independently predicted sudden cardiac death among patients with recent AMI.18 Extramiana et al,9 who also investigated patients with a history of AMI, found significantly steeper QT/RR slopes in patients with life-threatening ventricular tachyarrhythmias. Furthermore, their data showed that analysis of heart rate variability and QT rate dependence do not reflect the same components, which suggests that autonomic nervous tone is not the major determinant of the QT/RR relationship. We found that the QT/RR slope significantly increased after PCI in patients with incomplete reperfusion, whereas it remained constant in patients with complete reperfusion. These findings may suggest an ongoing process of microcirculatory malperfusion in TIMI 2 patients, leading to altered electrophysiological properties of the myocytes.
The mechanism by which incomplete reperfusion alters the effects of heart rate changes on ventricular refractory periods remains speculative. It is well recognized that there is a physiological delay in the adaptation of repolarization durations to changing heart rates.19 It has been shown that the properties and balance of the repolarizing inward sodium and outward potassium channels of ventricular myocardial cell membranes and the metabolic processes surrounding them play an important role in this process.20 Acute ischemia results in an acidosis- and anoxia-induced depression of membrane excitability and delayed recovery of excitability.21 There is strong evidence that ischemia-induced delayed conduction is reversible by thrombolytic therapy.22 In incomplete reperfusion, the ischemia-induced intrinsic myocardial properties may be maintained, resulting in an altered electrical restitution or a loosening of the physiological coupling between repolarization duration and the diastolic interval of the preceding beat.23 Electrical restitution dynamics have been shown to be altered significantly in the infarction border zone.24 Abrupt changes in the diastolic interval may significantly increase regional dispersion of repolarization because of regional differences in conduction velocity combined with regional differences in electrical recovery. Steeper QT/RR slopes in patients with incomplete reperfusion may therefore indicate an inadequate coupling between the QT interval and the preceding diastolic interval, which is strongly associated with susceptibility to the development of malignant ventricular arrhythmias by facilitating reentry. Using QT-interval variability, we25 were previously able to demonstrate an abnormal coupling between ventricular repolarization and heart rate in patients with malignant ventricular arrhythmias after AMI. However, QT-interval variability did not discriminate between TIMI 2 and 3 flow. In contrast to the present study, there was a only a trend toward longer QT intervals in TIMI 2 patients, which did not reach statistical significance, probably because of the smaller patient population.
Lecocq et al26 described that sympathetic stimulation resulted in significant alterations of the QT/RR relationship in healthy subjects. In the present study, serum norepinephrine levels, which reflect efferent sympathetic nervous tone,27 were slightly higher in patients with TIMI 2 flow. However, the fact that there was almost no relation between norepinephrine concentrations and QT/RR slopes indicates that QT rate dependence is not determined mainly by sympathetic stimulation. Because there were also no significant differences in the underlying mean RR intervals between different perfusion grades, it is likely that steeper QT/RR slopes in patients with incomplete reperfusion are induced mainly by an abnormal cellular repolarization due to a persistent electrical injury rather than due to cardiac autonomic nervous interference with or without corresponding heart rate changes. This effect of incomplete reperfusion on the QT/RR slope appears to be largely independent of left ventricular function, time of ischemia, and size and site of the AMI. Therefore, an increase in the QT/RR slope after reperfusion therapy for AMI may provide independent prognostic information and may reflect an "electrical stunning" of the incompletely perfused ventricular myocardium.
Study Limitations
There are important factors to be considered in interpreting the results of the present study. First, it has been suggested that the QT/RR relationship in younger healthy subjects exhibits a high intrasubject stability, whereas it has a substantial intersubject variability.28 However, in a sample of 12 healthy subjects (aged 57±18 years) with 5 consecutive 24-hour Holter recordings from our QT-interval database,29 we were able to show that QT/RR slopes in healthy subjects are intraindividually (coefficient of variance 8.6%) and interindividually (coefficient of variance 12.4%) very reproducible. In the acute phase of AMI, in addition to poor recording quality and artifacts, flat, abnormally shaped, and imperceptible T waves may lead to inaccurate QT-interval measurement, even after manual editing. Almost 26% of the Holter recordings were not suitable for analysis of QT dynamicity in the present study.
Second, we cannot definitely rule out that the changes observed are due to the PCI procedure itself. One would have expected a correlation between time of ischemia and QT/RR slopes, because complete reperfusion was able to stop the process of increasing QT/RR slopes. However, there was no relation between QT/RR slopes and time interval from pain onset to reperfusion in the present study. One explanation may be that the accuracy of this parameter is known to be limited by different thresholds of pain perception, episodes of spontaneous reflow, and ischemic preconditioning.
Finally, it is premature to regard the QT/RR slope as an indicator of complete or incomplete reperfusion or even as a risk stratifier in the acute phase of AMI, even though patients with MAEs exhibited significantly steeper QT/RR slopes. The previously unreported alterations of the QT/RR relationship in patients with incomplete reperfusion need further investigation to determine the underlying cellular mechanisms.
Conclusions
Steeper QT/RR slopes in patients with incomplete reperfusion after direct PCI for AMI, which reflect an inadequate shortening of repolarization with increasing heart rate, suggest a distorted electrical restitution that may potentially provide a substrate for serious ventricular arrhythmias by facilitating reentry. Thus, our findings offer new insights into mechanisms by which early complete reperfusion may affect cardiac electrical stability and might explain in part the lower mortality rate in patients with TIMI 3 flow after PCI for AMI.
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Acknowledgments
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Supported by a grant from the Deutsches Forschungsgemeinschaft
(DFG, Ri 423/4-2). The authors are indebted to all the patients
who participated in this study.
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References
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Abstract
Introduction