Exercise-Induced Repolarization Changes in Patients with Isolated Myocardial Bridging

Background

Myocardial bridging (MB) is a congenital coronary anomaly that is defined when a segment of a major epicardial coronary artery is “tunneled” in the myocardium. It extends intramurally through the myocardium beneath a muscular bridge [1,2]. The incidence of myocardial bridging is elaborated as 1.5–16% in angiographic studies and may rise up to 80% at autopsy [3,4]. MB is most commonly located in the middle left anterior descending artery (LAD) [5] and the prominent angiographic finding is systolic compression of the involved epicardial coronary artery [6].

Although MB is a phenomenon with a benign course, it has also been reported to cause myocardial ischemia [7], acute coronary syndrome [8], coronary vasospasm [9], atrioventricular block [10], transient ventricular dysfunction [11], ventricular septal rupture [12], ventricular tachycardia [13], and sudden cardiac death [14]. These reports suggest that at least some of the patients with MB may have a predisposition for major cardiac events. It has been postulated that the adverse events in the reported cases are related to the effect of MB on the coronary blood flow. On the other hand, the electrophysiological effects and arrhythmogenic potential of these effects on the coronary flow are not well-described.

Previous research has shown the importance of detecting myocardial repolarization abnormalities in the prediction of arrhythmogenic potential. QT dispersion (QTd) is defined as the minimum QT interval subtracted from the maximum and cQTd is defined as the QTd corrected for the rate. These parameters have been associated with adverse outcomes [15,16]. On the other hand, the recently defined parameters of Tp-e interval (defined as the difference between the QT interval and the QT-peak time period) and Tp-e/QT index were reported to indicate myocardial repolarization abnormalities better than QTd and cQTd parameters [17,18]. Increased Tp-e interval has been associated with cardiovascular mortality and ventricular tachyarrhythmias [19,20]. In this study, we analyzed the effects of exercise on myocardial repolarization parameters in patients with and without myocardial bridging.

Material and Methods

STUDY POPULATION:

Patients enrolled in this prospective study were consecutive patients who underwent diagnostic coronary angiography for suspected coronary artery disease (CAD) at Ondokuz Mayıs University Hospital between January 2011 and April 2014. Fifty patients who were diagnosed as having isolated MB at coronary angiography (Group I) and 48 patients with normal coronary angiograms (Group II) were included in this study. Patients with coronary atherosclerosis, those with acute coronary syndromes, left ventricular systolic dysfunction (LVEF <50%), significant valvular heart disease, renal failure (creatinine-based estimated GFR <90 mL/min/1.73 m² calculated by the Cockcroft-Gault formula), bundle branch block and atrioventricular conduction abnormalities on the electrocardiography (ECG), thyroid dysfunction, pulmonary disease, chronic infections or inflammatory diseases, electrolyte imbalance, and those with ECG’s without clearly analyzable QT and Tp-e intervals were excluded from the study. All the patients were in sinus rhythm, and none of them were taking antiarrhythmic medications, tricyclic antidepressants, antihistamines, or antipsychotics.

BIOCHEMICAL MEASUREMENTS:

Biochemical parameters were measured with an Abbott ARCHITECT c8000 (Abbott Laboratories, Abbott Park, IL, USA) autoanalyzer using commercial kits. Hematologic parameters were measured with an Abbott CellDyn 3700 (Abbott Laboratories, Abbott Park, IL, USA) device with laser and impedance method. High sensitive C-reactive protein (hs-CRP) (CardioPhase, hs-CRP) was measured quantitatively in BN II System Nephelometer (Dade Behring, Marburg, Germany) by immunonephelometric method from patient serum and results were reported in mg/L.

CORONARY ANGIOGRAPHY:

All patients underwent coronary angiography with Judkins technique and femoral approach. Images were recorded at a digital angiographic system (ACOM.PC; Siemens AG, Germany) at a speed of 15 frames/second during the procedure. Iopromide (Ultravist 370, Schering AG, Berlin, Germany) was used as contrast material. The cine-angiograms were evaluated by two independent cardiologists and MB was identified as 50% or more systolic narrowing by visual estimation. Quantitative measurements of the coronary arteries were performed on the digital angiographic system (ACOM.PC; Siemens AG, Germany). The length of MB and percentage of diameter reduction in the bridged segments were calculated by quantitative coronary angiography (QCA).

ELECTROCARDIOGRAPHY AND CALCULATION OF VENTRICULAR REPOLARIZATION PARAMETERS:

The 12-lead ECG recording was performed after 10 minute of rest at supine position at 50 mm/s speed and 20 mm/mV amplitude (Nihon Kohden, Tokyo, Japan). ECG measurements of QT and Tp-e intervals were performed by two cardiologists who were blinded to the patient data. In order to lessen errors in QT and Tp-e interval analyses, each interval was measured manually with calipers and magnifying glass. In order to improve accuracy, average value of three readings were calculated and used as data. We measured the QT interval from the beginning of the QRS complex to the end of the T wave. The QT maximum (QTmax) and QT minimum (QTmin) were calculated in all leads of a 12-lead ECG. QTd was defined as the maximum minus minimum QT interval and corrected QTd (cQTd) was calculated according to Bazett’s Formula adjusted according to heart rate [21]. QT peak interval was defined as the time from QRS complex onset to the peak of the T wave, whereas Tp-e interval was defined as the time from the peak to the end of the T wave. The measurements of Tp-e interval were performed from precordial leads and were corrected according to heart rate [19]. The Tp-e/QT ratios were subsequently calculated (Figure 1).

The reproducibility of ECG repolarization indices was assessed by coefficients of variation (standard deviation of differences between the repeated measurements divided by the mean value and expressed as a percentage) between measurements. The intra-observer variability was calculated in 34 randomly selected study participants (18 patients with myocardial bridging and 16 control subjects) by repeating the measurements under the same basal conditions. Intra-observer and inter-observer variation was found to be <5%.

STRESS ELECTROCARDIOGRAPHY:

Treadmill exercise stress test was applied to subjects according to the Bruce protocol (Customed Cardio 100, Germany). The reproducibility of ECG repolarization indexes was assessed by coefficients of variation (standard deviation of differences between the repeated measurements divided by the mean value and expressed as a percentage) between measurements. Intra-observer and inter-observer variation were <5%. The abnormal response (positive test) to exercise testing included a horizontal or downsloping ST-segment depression equal to or greater than 1 mm (0.1 mV) at 60–80 ms after J-point [22]. Functional capacity was assessed by the peak metabolic equivalent (METs peak), indirectly obtained by formulas, according to the maximum slope and speed achieved in an incremental exercise treadmill test, with the ramp protocol adjusted to the individual [23].

STANDARD ECHOCARDIOGRAPHY:

Transthoracic echocardiography was performed in all patients at left lateral decubitus position with a GE Vingmed Vivid 7 (GE Vingmed Ultrasound, Horten, Norway) echocardiography device. Images at the parasternal longitudinal axis, short axis, apical four chambers and two chambers were obtained and evaluated by M-mode, 2-D, continuous wave Doppler, pulsed wave Doppler methods based on American Echocardiography Association criteria [24]. Values were measured on three separate beats and then the average was calculated for all parameters. Left ventricular mass (LVM) was calculated by Devereux et al. using the equation previously described [25]. LVM was indexed to body surface area to obtain the LV mass index (LVMI). Relative wall thickness (RWth) was measured at end-diastole as the ratio of [2× posterior wall thickness (PWth)/left ventricular end-diastolic diameter (LVEDD)].

STATISTICAL ANALYSIS:

All data were loaded to the SPSS 15 program. Subsequently, the normal distribution of the data was tested using the Kolmogorov–Smirnov test. The t-test was used to compare two groups of variables demonstrating normal distribution, while groups of variables without normal distribution were compared using the Mann-Whitney U test. Comparison of categorical variables was carried out by the chi-square test. Wilcoxon signed-rank test or paired sample t test were used to analyze the change (in individual subjects) of measurements between baseline and peak exercise according to the variables distribution. Any correlation between data was tested with the Spearman and Pearson correlation analysis. While the continuous data were expressed as “mean ±SD” (standard deviation), the categorical data were expressed as percentage values and a p value of <0.05 was accepted as statistically significant. Multivariate stepwise logistic analysis was performed to assess the parameters that are associated with prolonged cTp-e interval and age, LVMI, length of MB and percentage of diameter reduction were included as the covariates in the multivariate regression model.

Results

A total of 50 patients with MB (Group I, 21 males; mean age 48.2±9.8 years) and age and sex-matched 48 healthy subjects (Group II, 22 males; mean age 49.1±8.4 years) were included in this study. The baseline clinical and laboratory characteristics of the patients are presented in Table 1. There were no significant differences between the groups in terms of baseline laboratory and clinical characteristics. In addition, no significant difference was found between the patient groups in terms of drug usage. The length of MB was found to be 15.3±4.5 mm in the MB patient group and the percentage of diameter reduction in the bridged segments was found to be 65.1±9.7%. Also, no significant differences were observed between the conventional echocardiographic measurements of the groups (p>0.05) (Table 2).

The results of exercise testing are shown in Table 3. No significant differences were observed between the result of exercise testing of the groups (p>0.05). No rhythm abnormalities or hemodynamic deteriorations were detected in the two groups during exercise testing. Additionally, the exercise testing yielded a positive result in 9 patients (18%) in the MB group, while it was negative in 41 patients (82%).

The changes in the ventricular repolarization parameters of the patients during exercise are shown in Table 4. QT max and QT min intervals during peak exercise showed a significant decrease in comparison with the baseline values in the two groups (372.3±12.1 vs. 327.8±10.7 ms, p<0.001; 335.8±14.1 vs. 285.1±10.5 ms, p<0.001; 368.3±11.5 vs. 304.5±15.1 ms, p<0.001; 344.9±13.2 vs. 275.4±14.9 ms, p<0.001, respectively). However, QTd and cQTd at peak exercise increased significantly in comparison to baseline values in the MB patient group (36.4±10.3 vs. 42.6±14.1 ms, p=0.003 and 39.3±10.1 vs. 65.4±16.7 ms, p<0.001 respectively). Additionally, significant increases were detected in Tp-e, cTp-e intervals and Tp-e/QT ratio during peak exercise in comparison to baseline values in patients with MB (69±5.7 vs. 81.1±8.4 ms, p<0.001; 75.2±6.6 vs. 94.5±7.4 ms, p<0.001; 0.18±0.01 vs. 0.20±0.02, p<0.001, respectively) (Figure 2).

On the other hand, significant differences in QTd, cQTd, Tp-e, cTp-e intervals and Tp-e/QT ratio during peak exercise in comparison with baseline values were not detected in the control group (p=0.178, p=0.071, p=0.065, p=0.182, p=0.07, respectively) (Table 4).

Multivariate analysis demonstrated that the length of MB (standardized β coefficient=0.446, p<0.001) and percentage of diameter reduction (standardized β coefficient=0.510, p<0.001) were independent predictors of a prolonged cTp-e interval in the multivariate stepwise logistic regression model (Table 5). Standardized β coefficient and P values were 0.125 and 0.110 for age, −0.109 and 0.128 for LVMI, respectively.

Discussion

STUDY LIMITATIONS:

We were not able to interpret the potential prognostic role of the exercise-induced changes of the repolarization indexes in correlation to future adverse events. To determine the predictive value of prolonged Tp-e interval and increased Tp-e/QT ratio, longer follow-up and large-scale prospective studies in patients with myocardial bridging are needed.

Conclusions

A significant increase in QTd, cQTd, Tp-e, and cTp-e intervals and Tp-e/QT ratio during exercise testing was detected in patients with myocardial bridges. The observed increase in ventricular repolarization dispersion indexes may possibly develop on an ischemic background induced by exercise in the MB artery area.