- Email: [email protected]
Effects of epinephrine over P wave duration and ventricular repolarization in subjects without structural heart disease
International Journal of Cardiology 204 (2016) 142–146
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Effects of epinephrine over P wave duration and ventricular repolarization in subjects without structural heart disease Abdel J. Fuenmayor A ⁎,1, Luisangelli Gómez R 1, Moisés I. Solórzano 1 Cardiovascular Research Institute “Abdel M. Fuenmayor P”, University Hospital of the Andes, Mérida, Venezuela
a r t i c l e
i n f o
Article history: Received 28 October 2015 Received in revised form 23 November 2015 Accepted 27 November 2015 Available online 2 December 2015 Keywords: Epinephrine Repolarization Inter-atrial conduction QRS QT Corrected QT Variability Peak-to-end of T wave Dispersion
a b s t r a c t Background: Little is known about the effects of epinephrine over atrial electrical function, AV conduction and ventricular repolarization in normal subjects. We intended to study the effects of intravenous epinephrine on the duration of P wave, inter-atrial conduction time, PR, QRS, QT, corrected QT (QTc), QTc dispersion (QTc max–min), the peak-to-end interval of T wave (Tp-e), the Tp-e/QT index, and the middle portion of ventricular repolarization length (QT − (QRS + Tp-e)) in healthy subjects. Methods: Forty-three, 37.20 ± 17.05 year-old, 25 (58%) female patients without structural heart disease took part in the study. They underwent an electrophysiological study. An epinephrine infusion (50 to 100 ng/kg/min) was administered for 5 min until an increase of at least 10% of the initial heart rate (HR) was achieved. Results: No complication arose from epinephrine infusion, and the drug facilitated arrhythmia induction. A significant increase in heart rate, systolic blood pressure, QRS, QTc, Tp-e, Tp-e/QT index, and QTc max–min interval duration was documented. No significant effect on diastolic blood pressure, P wave duration, inter-atrial conduction time, and PR, QT and QT − (Tp-e + QRS interval) was observed. Conclusions: In this group of patients without structural heart disease, epinephrine infusion did not produce any complication and it facilitated arrhythmia induction. It did not modify P wave duration, PR interval or inter-atrial conduction time. Moreover, it significantly increased the duration of depolarization, the final portion of repolarization, transmural dispersion of repolarization, and regional dispersion of repolarization without inducing significant changes in the middle portion of repolarization. © 2015 Published by Elsevier Ireland Ltd.
1. Introduction Epinephrine has been used for a long time in medicine but several adverse effects have been reported in the literature. For example, between 1991 and 2002, Japanese cardiologists described patients who suffered precordial pain after being submitted to emotional stress or catecholamine injection. The majority of the patients were women; their ECG displayed ST segment elevation and/or inverted T waves in precordial leads and QT prolongation. The left ventricular angiogram showed apical aneurysms resembling the traps used in Japan to catch octopuses (Takotsubo) [1–3]. The entity was named Takotsubu cardiomyopathy. Similar changes have been described in patients suffering from acute medical conditions, such as hemorrhagic strokes, surgery, sepsis, pheochromocytoma, cocaine abuse, or catecholamine administration [3–6]. The Abbreviations: QTc, corrected QT interval; QTc max–min, regional QTc dispersion; Tpe, peak-to-end of T wave interval; QT − (QRS + Tp-e), middle portion of ventricular repolarization length. ⁎ Corresponding author at: Urbanización Los Cortijos, calle 3, N° 42, La Pedregosa Norte, Mérida 5101, Venezuela. E-mail address: [email protected] (A.J. Fuenmayor A). 1 This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
http://dx.doi.org/10.1016/j.ijcard.2015.11.182 0167-5273/© 2015 Published by Elsevier Ireland Ltd.
electrophysiological effects of epinephrine have been studied in a few subjects only, and most reports have been conducted in patients with structural cardiomyopathy. Stratton et al. studied 10 normal subjects and reported that an epinephrine infusion of 25 to 100 ng/kg/min produced a significant rise of plasma epinephrine concentration that was equivalent to the levels attained performing isotonic exercise in a cycle-ergometer [7]. The subjects also showed significant increases in stroke volume, ejection fraction, heart rate and systolic arterial pressure accompanied by a decrease of systemic vascular resistance [7]. Morady et al. investigated some of the electrophysiological effects of epinephrine in humans [8]. They found a decrease in the atrial and AV node refractory period and an acceleration of the AV nodal conduction, and reported that the epinephrine infusion facilitated arrhythmia induction [8]. Cheema et al. reported a significant prolongation of the signal averaged P wave in normal subjects who received an epinephrine infusion (50 ng/kg/min) [9]. Magnano et al. described prolongation of the QT interval in normal subjects who were administered epinephrine infusion in a dose of up to 300 ng/kg/min [10]. The duration of the QT interval in the ECG approximately reflects the duration of the ventricular action potential [11,12]. QT interval
A.J. Fuenmayor A et al. / International Journal of Cardiology 204 (2016) 142–146
143
prolongation and increased QT interval dispersion have been considered markers of risk for the appearance of polymorphic ventricular tachycardia [13]. Regional QT interval dispersion has been assessed by measuring the differences in QT interval duration in the different ECG leads [13]. Repolarization has been measured in the different portions of the ventricular wall, and it has been found that midmyocardial cell repolarization last longer than the repolarization of the epicardial and endocardial cells. The intramural dispersion of repolarization reflects the differences in repolarization length between the mid-myocardial cells and those of the epicardial and endocardial layers [14]. Epicardial cell repolarization ends when the peak of the T wave occurs, and the mid-myocardial repolarization process finishes at the end of the T wave. Intramural dispersion of repolarization has been assessed by measuring the interval between the peak and the end of the T wave (Tp-e). Tp-e prolongation has been advocated as a marker of risk for lethal ventricular arrhythmias and sudden death [14–16]. Gupta et al. reported that Tp-e is influenced by body size and heart rate and advocated the relation Tp-e/QT as a more independent and reliable index of transmural dispersion of repolarization [17]. The duration of the middle portion of ventricular repolarization could be measured by subtracting the initial (QRS) and final (TP-E) portions from the QT interval {QT − (QRS + Tp-e)}, but this interval has not been investigated. Isoproterenol is not available in Venezuela. This is why, in our electrophysiological studies, we have been using epinephrine infusions to facilitate arrhythmia induction. Since little is known about epinephrine effects in subjects without structural heart disease, we decided to study the effects of an epinephrine infusion over P wave duration, inter-atrial conduction time, PR interval, QRS, QT, corrected QT, QT interval dispersion, and Tp-e, Tp-e/QT and QT − (QRS + Tp-e). Our hypothesis was that epinephrine infusion (50–100 ng/kg/min) does not produce significant collateral effects and that it can modify the above-mentioned electrophysiological parameters.
The cardiologists responsible for measuring the variables under study were trained in the Electrophysiology Section until an inter-observer variability b6 ms was achieved. When the beginning or the end of the waves was not well defined, the gain and speed of recordings were modified for obtaining precise measurements. Electrocardiographic intervals were measured according to standard recommendations [18]. Depolarization and repolarization measurements were performed in simultaneously acquired 12 lead ECG. The result obtained in each ECG lead was recorded, and the 12 measures were averaged. The variability and dispersion of the measures were computed in an Excel(R) sheet where the values were stored. Tp-e was measured from the maximal voltage of the T wave to its intersection with the basal line. Tp-e/QT was calculated with the Excel sheet were the values were stored. The middle portion of depolarization duration was computed adding the Tp-e to QRS duration and subtracting the result from the QT interval. Interatrial conduction time was measured from the beginning of the A wave recorded with the high right atrial catheter to the beginning of the A recorded with the distal pair of electrodes of the catheter placed in the coronary sinus.
2. Methods
3.1. Population
We certify that we complied with the Principles of Ethical Publishing of the International Journal of Cardiology. The study protocol conforms to the ethical guidelines of the 2013 Declaration of Helsinki as reflected in an a priori approval by our Institution's Human Research Committee.
Forty-three patients (25–58% — female) took part in the study. The mean age was 37.2 + 17.02 years. All the patients had normal hearts and preserved cardiovascular function. The left ventricular ejection fraction was 0.61 ± 0.05. No complication arose.
2.1. Population
3.2. Heart rate and arterial pressure
Written informed consent was obtained from all the patients. Patients were included if they did not have any structural heart disease or conduction disturbances and if they had been admitted to our electrophysiology laboratory to undergo electrophysiological study. A clinical cardiologist evaluated all the patients, and an X-ray, ECG, and a transthoracic echocardiogram were obtained before performing the ablation. Antiarrhythmic drugs were discontinued for at least 5 half-lives. No patient was receiving amiodarone.
Heart rate increased 14% after the epinephrine infusion and reached a mean of 85 beats per minute (see Table 1). Only one patient did not achieve a significant heart rate increase. Epinephrine infusion produced a significant systolic and mean blood pressure increase without significant changes in diastolic blood pressure (see Table 1). In 13 patients, supraventricular arrhythmia was induced only with the epinephrine infusion (p b 0.05).
2.4. Statistical analyses Statistical analyses were performed with Excel(R) and SPSS20(R) statistical packages. Data distribution was assessed with Shapiro–Wilk test. Normally distributed data were compared with paired T-test and Variance analysis. Data that did not fit in a normal distribution were compared with the Wilcoxon Signed Rank and Kruskall–Wallis test. In order to detect differences of 20 ms between the means with 95% confidence intervals and a statistical power of 80%, a sample size (adjusted to 15% missing data) of 42 observations was calculated. 3. Results
3.3. Electrocardiographic and electrophysiological parameters 2.2. Epinephrine infusion 1 mg of epinephrine was diluted in 250 cm3 of 0.9% saline solution. Infusion rate begun at 50 ng/kg/min for 5 min, and heart rate was continuously monitored to check whether an increase of at least 10% on the heart rate had occurred. If the heart rate had not increased, the infusion rate was then adjusted to a maximum of 100 ng/kg/min in order to achieve the 10% heart rate increase. If the heart rate did not increase after adjusting the infusion rate, the measurements were then performed at the maximal infusion rate. 2.3. Measurements The ECG and intracavitary recordings were obtained with a digital polygraph and stored to measure the electrophysiological parameters.
In the control situation, the QRS interval was shorter in women than in men (77 ± 8 vs 84 ± 10 ms; p = 0.018). The QTc interval difference
Table 1 Arterial pressure and heart rate changes after epinephrine infusion. Control
SAP (mm Hg) DAP (mm Hg) MAP (mm Hg) R-R (mseg)
Epinephrine
Mean
SD
Mean
SD
123.61 76.28 92.09 818
25.89 16.01 21.29 179
137.18 78.34 99.51 700
27.19 14.11 17.98 157
p value
b0.0001 0.1200 b0.0001 b0.0001
SD = standard deviation. SAP: Systolic arterial pressure. DAP: Diastolic arterial pressure. MAP: Mean arterial pressure. R-R = Electrocardiographic R-R interval.
144
A.J. Fuenmayor A et al. / International Journal of Cardiology 204 (2016) 142–146
between women and men did not reach statistical significance (443 ± 49 vs 417 ± 39 ms; p = 0.076). P wave, interatrial conduction time, PR interval, and QT interval did not significantly change (see Table 2). We found a significant prolongation of the QRS interval and the corrected QT interval (both for Bazett and Fridericia formulas). The QTc interval regional dispersion, Tp-e and Tp-e/QT also increased significantly with the epinephrine infusion (see Table 2). The middle portion of repolarization [QT − (QRS + Tp-e)] did not display any significant change.
4. Discussion One of the main findings of the present research is that the administration of an epinephrine intravenous infusion at 25 to 50 ng/kg/min is safe for the patient in the electrophysiology laboratory. Indeed, we did not observe any unwanted or collateral effect of the drug. Additionally, the epinephrine infusion facilitated the induction of supraventricular arrhythmias in 30% of the patients who were not inducible in the control state. We did not measure the plasma catecholamine concentration, but the heart rate increase observed in our patients was similar to the one reported by Stratton and Morady [7,8]. Another indicator of the action of epinephrine is that the systolic arterial pressure increased without significant changes in diastolic pressure. These modifications of heart rate and arterial pressure reflect a sympathetic stimulation that is equivalent to the one induced by moderate isotonic exercise [7] and is the type of sympathetic drive that could be useful in the electrophysiology laboratory. In developing countries like Venezuela, the cost of isoproterenol is prohibitive for the public health service. Indeed, in 2014, the year when the data of the present study were collected, in Venezuela one ampoule of epinephrine cost 11 Bolivars, and one ampoule of isuprel cost 4.500 Bolivars. (The official rate of exchange from USD to Bolívares was 1 USD = 6.30 Bs. at that time). The Heart Rhythm Society posted a special note regarding the price of isoproterenol because of the dramatic increases in its cost (http://www.hrsonline. org/iceractice-Guidance/Coding-Reimbursement/Reimbursement/ Additional-Reimbursement-Issues/Special-Notice-Regarding-Pricingof-Isoproterenol-Isuprel#axzz3gfdoGSdN). Our findings showed that epinephrine could be used as a valid alternative to isoproterenol and at a much lower price (several thousands times lower). Cheema et al. studied normal volunteers and reported a P wave shortening induced by epinephrine infusion [9]. In our group of patients the P wave, interatrial conduction time and PR interval did not significantly change. It is worthwhile mentioning that our group of patients was larger (N = 43) than the one studied by Cheema (N = 14) [9]. Table 2 Electrophysiological parameters changes after epinephrine infusion. Control
P PR IACT QRS QT QTc-B QTc-F QTc-B max–min Tp-e Tp-e/QT QT − (QRS + Tp-e)
Epinephrine
Mean
SD
Mean
SD
0.090 0.143 0.068 0.080 0.390 0.433 0.417 0.064 0.078 0.203 0.239
0.013 0.024 0.017 0.010 0.066 0.046 0.050 0.024 0.010 0.030 0.061
0.089 0.139 0.066 0.085 0.393 0.472 0.440 0.077 0.083 0.214 0.232
0.009 0.023 0.017 0.010 0.062 0.053 0.060 0.029 0.014 0.038 0.062
p value
0.498 0.163 0.084 0.000 0.571 0.000 0.000 0.002 0.003 0.010 0.109
P = P wave. PR = PR interval. IACT = Inter-atrial conduction time. QRS = Electrocardiographic QRS complex duration. QT = QT interval duration. QTc-B = Corrected QT interval by means of Bazett formula. QTc-F = Corrected QT interval by means of Fridericia formula. SD = Standard deviation. Max = maximum. Min = minimum. Tp-e = Peak-end of T wave. Measures in seconds.
The QT interval includes both the ventricular depolarization and the repolarization processes. The QRS reflects the ventricular depolarization and the J-T interval the repolarization [19]. The T wave is produced by repolarization of the different layers of the myocardium that, as was previously stated, is slower in mid-myocardial cells [16]. Previous investigations have reported that epinephrine shortens repolarization and, in consequence, the QT interval. This repolarization shortening was attributed to phosphorylation of the KCNQ1 potassium channel that drives IKs. The phosphorylation increases the probability of channel opening and an outward potassium current that accelerates repolarization. Epinephrine also increases L type Ca++ channel current that augments contractility and can induce a plateau (phase 2) prolongation. The IKs current effect predominates over the L type Ca++ channel current, and the net effect should be a QT interval shortening [10,20]. Epinephrine also increases the rate of depolarization in phase 0 of the action potential and improves conduction in Purkinje fibers [21]. Taking into account the above-mentioned actions of epinephrine, we expected a shortening of the QRS and of the middle portion of repolarization that should have become evident as a QT interval shortening. However, the opposite was observed, i.e. a small but significant increase in QRS duration. As has been reported elsewhere [22], we too found that the QRS interval was shorter in women than in men, but there was no significant gender difference in that increase. Nakagawa et al. studied the effect of supine bicycle exercise over QRS duration and autonomic tone in eleven normal subjects [23]. They reported a QRS shortening that was abolished by autonomic blockade (propranolol + atropine). This apparent contradiction with our result should be examined by taking into account the fact that, on the one hand, the two sample sizes were different (11 vs 43) and, on the other, that it is very difficult to compare the effect of an epinephrine infusion with the multiple physiological changes (cardiovascular, autonomic, metabolic, muscular, etc.) that are induced by isotonic exercise. No significant modification of the middle portion of repolarization [QT − (QRS + Tp-e)] or of the QT interval was observed (see Table 2). Here again, we were expecting a QT − (QRS + Tp-e) and a QT shortening, but neither occurred. Our finding contradicts the above-described effect of epinephrine over QT. It should be borne in mind that there are important differences in the method we used to measure QT and QRS and the method used by Ackerman and Vyas who reported a QT abbreviation [20,25,26]. Indeed, Ackerman and Vyas measured the QT interval averaging 4 consecutive beats in lead DII or V5, whereas we measured the interval in the same beat in all 12 leads, and we averaged these 12 values. We believe that measuring and averaging the same complex in the 12 ECG leads provide more and better information about the repolarization process and avoid the beat-to-beat variation that could be induced by autonomic, respiratory and hemodynamic changes that occur in the cardiovascular system from one beat to the next. A significant QTc interval increase was observed. It is our contention that this increase was the result of the R-R interval shortening produced by epinephrine as is reflected by the fact that a significant correlation (p = 0.018) was found between the R-R interval variation and the QTc interval prolongation. It should be remembered that, for the QT interval correction, we used the Bazett and Fredericia formulae in which the squared or the cubic root of the R-R interval are the denominators. As the QTc interval prolongation can be the expression of heart rate increase induced by epinephrine, when the drug is used to perform QT stress testing for long QT syndrome, both the non-corrected and the QTc interval should be analyzed to assess the response. The regional (QTc max–min) and transmural dispersion of repolarization (Tp-e and Tp-e/QT) significantly increased (see Table 2). The regional dispersion of repolarization has long been (and still is) a subject of debate. Some authors argue that a value above 100 ms or an increase over 100% could be an index of cardiovascular risk. Other investigators contend that neither QT nor QTc regional dispersion is a reliable prognostic marker [19]. Our group of patients without structural heart
A.J. Fuenmayor A et al. / International Journal of Cardiology 204 (2016) 142–146
disease had a QTc max–min averaging 64 ms which significantly increased to 77 ms under the epinephrine infusion. This increment can be interpreted as an increase in the differences in repolarization between different segments of the heart, but the increase did not reach the 100 ms value that has been established as a risk marker by previous research [19]. This regional heterogeneity induced by epinephrine could be invoked as one of the factors that make arrhythmias more easily inducible under sympathetic stimulation. Transmural dispersion of repolarization as measured by the Tp-e and Tp-e/QT also increased with epinephrine infusion in this group of patients without structural heart disease who had never experienced either ventricular arrhythmias or long QT syndrome. Several investigators reported increases in transmural dispersion of repolarization induced by epinephrine in patients with long QT syndrome [15–17]. Topilski et al. retrospectively studied 30 patients who had suffered from torsades de pointes associated with bradycardia. They found that Tp-e over 117 ms was the best single discriminator for identifying the patients who suffered from torsade de pointe [27]. The significant epinephrine prolongation of Tp-e observed in our group reached 83 ± 14 ms and was below the values predicting risk. In consequence, epinephrine infusion can be considered safe when administered in the electrophysiology laboratory. Besides, according to our data, Tp-e and Tp-e/QT slight prolongations are generally observed in normal patients submitted to epinephrine infusion. Gupta et al. introduced the Tp-e/QT index advocating that it is more appropriate for the evaluation or transmural dispersion of repolarization because it was neither heart rate nor body mass dependent [17]. The mean Tp-e and Tp-e/QT value in our patients were similar to the ones reported by Gupta, but the dispersion, as estimated by the standard deviation, is significantly greater in our study. Here again, there is an important methodological difference since we averaged the values obtained in the 12 leads of the ECG, whereas Gupta measured the value in V6 only. We decided to perform the Tp-e and Tp-e/QT measures in V6 only (Tp-eV6, Tp-e/QTV6) and, when comparing the measures without intervention, we found that Tp-eV6 was 4 ms shorter than Tp-e (0.074 ± 0.013 vs 0.078 ± 0.010; p = 0.007) and Tp-e/QTV6 was 10 ms shorter than Tp-e/QT (0.193 ± 0.034 vs 0.203 ± 0.030; p = 0.001). Taking these differences into account, and in view of the fact that our goal is to select patients at risk of ventricular arrhythmias, we posit that it is better to average the repolarization values in the 12 ECG leads. No gender differences were recorded in Tp-e values, but we found that Tp-e/QT was significantly shorter in female patients (0.192 ± 0.029 vs 0.220 ± 0.020; p = 0.002). Moreover, we found a significantly negative correlation between Tp-e/QT and RR interval that differs from the results obtained by Gupta et al. This deserves further analysis. 4.1. Study limitations The study group size is modest however it is larger than the previous study groups. Besides, the number of patients included in the study satisfied the sample size estimated to be adequate for the study. Not a single patient in our sample suffered from ventricular arrhythmias, but none had any structural heart disease. In all likelihood, the results would have been different had epinephrine been administered to patients with cardiac disease, long QT syndrome, or patients susceptible to develop stress-related cardiomyopathy syndromes [3, 20,24–26]. 5. Conclusion In this group of patients without structural heart disease, the epinephrine intravenous infusion of 50–100 ng/kg/min: 1. is safe and efficacious to facilitate arrhythmia induction in the electrophysiology laboratory;
145
2. is considerably cheaper than isoproterenol infusion; 3. does not produce any significant changes in the P wave, PR interval or interatrial conduction time; 4. produces a small but significant increase in heart rate and systolic pressure within physiological limits; 5. induces a small but significant prolongation in the duration of the QRS, QTc, QT max–min, Tp-e, Tp-e/QT without significant changes in the middle portion of repolarization (QT − (QRS + Tp-e)); 6. produces a prolongation in the repolarization process and in the transmural and regional repolarization dispersion. These prolongations do not reach values that indicate a risk of suffering from ventricular arrhythmias in these subjects without structural heart disease. Conflict of interest None. Acknowledgments We are thankful to Françoise Salager Meyer for her review of the manuscript. References [1] K. Dote, H. Sato, H. Tateishi, et al., Myocardial stunning due to simultaneous multivessel coronary spasm: a review of 5 cases, J Cardiol 21 (1991) 203–214. [2] S. Kurisu, H. Sato, T. Kawagoe, M. Ishihara, Y. Shimatani, K. Nishioka, et al., Takotsubo-like left ventricular dysfunction with ST-segment elevation: a novel cardiac syndrome mimicking acute myocardial infarction, Am Heart J 143 (2002) 448–455. [3] K.A. Bybee, A. Prasad, Stress-related cardiomyopathy syndromes, Circulation 118 (2008) 397–409. [4] N. Budhwani, K.L. Bonaparte, A.B. Cuyjet, M. Sarik, Severe reversible left ventricular systolic and diastolic dysfunction due to accidental iatrogenic epinephrine overdose, Rev Cardiovasc Med 5 (2004) 130–133. [5] J. Abraham, J.O. Mudd, N. Kapur, K. Klein, H.C. Champion, I.S. Wittstein, Stress cardiomyopathy after intravenous administration of catecholamines and beta-receptor agonists, J Am Coll Cardiol 53 (2009) 1320–1325. [6] I.S. Wittstein, D.R. Thiermann, J.A.C. Lima, K.L. Baughman, S.P. Schulman, G. Gertenblith, et al., Neurohumural features of myocardial stunning due to sudden emotional stress, N Engl J Med 352 (2005) 539–548. [7] J.R. Stratton, M.A. Pfeifer, J.L. Ritchie, J.B. Halter, Hemodynamic effects of epinephrine: concentration-effect study in humans, J Appl Physiol 58 (1985) 1199–1206. [8] F. Morady, S.D. Nelson, W.H. Kou, R. Pratley, S. Schmaltz, M.D. Buttleir, et al., Electrophysiologic effects of epinephrine in humans, J Am Coll Cardiol 11 (1988) 1235–1244. [9] A. Cheema, M. Ahmed, A. Kadish, J. Golderberg, Effects of autonomic stimulation and blockade on signal-averaged P wave duration, J Am Coll Cardiol 26 (1995) 497–502. [10] A.R. Magnano, N. Talathoti, R. Hallur, D.M. Bloomfield, H. Garan, Sympathomimetic infusion and cardiac repolarization: the normative effects of epinephrine and isoproterenol in healthy subjects, J Cardiovasc Electrophysiol 17 (2006) 983–989. [11] R. Shah, The significance of QT interval in drug development, J Clin Pharmacol 54 (2002) 188–202. [12] L. Belardinelli, Assessing predictors of drug-induced torsade de pointes, Trends Pharmacol Sci 24 (2003) 619–624. [13] R. Shah, Drug-induced QT dispersion: does it predict the risk of torsade de pointes? J Electrocardiol 38 (2005) 10–18. [14] M. Yamaguchi, M. Shimisu, T wave peak-to-end interval and QT dispersion in acquired long QT syndrome: a new index for arrhythmogenicity, Clin. Sci. 105 (2003) 671–676. [15] C. Antzelevitch, Role of transmural dispersion of repolarization in the genesis of drug-induced torsades de pointes, Heart Rhythm 2 (2005) S9–15. [16] C. Antzelevitch, Transmural dispersion of repolarization and the T wave, Cardiovasc Res 50 (2001) 426–431. [17] P. Gupta, C.H. Patel, H. Patel, S. Narayanaswamy, B. Malhotra, J.T. Green, et al., Tp-e/QT ratio as an index of arrhythmogenesis, J Electrocardiol 41 (2008) 567–574. [18] L.E. Gering, B. Surawicz, T.K. Knilans, M.E. Tavel, Normal electrocardiogram: origin and description, Chous' Electrocardiography in Clinical Practice, sixth ed.Saunders. Elsevier, Philadelphia 2008, pp. 1–28. [19] M. Bednar, E. Harrigan, R. Anziano, A. Camm, J. Ruskin, The QT interval, Prog Cardiovasc Dis 43 (2001) 1–45. [20] H. Vyas, J. Hejlik, M. Ackerman, Epinephrine QT stress testing in congenital long QT syndrome, J Electrocardiol 39 (2006) S107–S113. [21] T.C. Westfall, D.P. Westfall, Adrenergic agonists and antagonists, in: L.L. Brunton (Ed.), Goodman & Gillman's The Pharmacological Basis of Therapeutics, 12 ed.MacGraw Hill, New York 2011, pp. 279–325. [22] L.E. Gering, T.K. Knilans, B. Surawicz, M.E. Tavel, Normal electrocardiogram: origin and description, Chou's Electrocardiography in Clinical Practice, 6a ed.Saunders ELSEVIER, Philadelphia 2008, pp. 2–27.
146
A.J. Fuenmayor A et al. / International Journal of Cardiology 204 (2016) 142–146
[23] M. Nakagawa, T. Iwao, H. Abe, S. Ishida, N. Takahashi, T. Fujimo, et al., Influence of autonomic tone on the filtered QRS duration from signal averaged electrocardiograms in healthy volunteers, J Electrocardiol 33 (2000) 17–22. [24] W. Shimizu, T. Noda, H. Takaki, et al., Epinephrine unmasks latent mutation carriers with LQT1 form of congenital long-QT syndrome, J Am Coll Cardiol 41 (2003) 633–642. [25] M.J. Ackerman, A. Khositseth, D.J. Tester, J.B. Hejlik, W.K. Shen, C.J. Porter, Epinephrine-induced QT interval prolongation: a gene-specific paradoxical response in congenital long QT syndrome, Mayo Clin Proc 77 (2002) 413–421.
[26] H. Vyas, J. Hejlik, M.J. Ackerman, Epinprhine QT stress testing in the evaluation of congenital long QT syndrome. Diagnostic accuracy of the paradoxical response, Circulation 113 (2006) 1385–1392. [27] I. Topilski, O. Rogowski, R. Rosso, D. Justo, Y. Copperman, M. Glikson, et al., The morphology of the QT interval predicts torsade de pointes during acquired bradyarrhythmias, J. Am. Coll. Cardiol. 49 (2007) 320–328.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Effects of epinephrine over P wave duration and ventricular repolarization in subjects without structural heart disease Abdel J. Fuenmayor A ⁎,1, Luisangelli Gómez R 1, Moisés I. Solórzano 1 Cardiovascular Research Institute “Abdel M. Fuenmayor P”, University Hospital of the Andes, Mérida, Venezuela
a r t i c l e
i n f o
Article history: Received 28 October 2015 Received in revised form 23 November 2015 Accepted 27 November 2015 Available online 2 December 2015 Keywords: Epinephrine Repolarization Inter-atrial conduction QRS QT Corrected QT Variability Peak-to-end of T wave Dispersion
a b s t r a c t Background: Little is known about the effects of epinephrine over atrial electrical function, AV conduction and ventricular repolarization in normal subjects. We intended to study the effects of intravenous epinephrine on the duration of P wave, inter-atrial conduction time, PR, QRS, QT, corrected QT (QTc), QTc dispersion (QTc max–min), the peak-to-end interval of T wave (Tp-e), the Tp-e/QT index, and the middle portion of ventricular repolarization length (QT − (QRS + Tp-e)) in healthy subjects. Methods: Forty-three, 37.20 ± 17.05 year-old, 25 (58%) female patients without structural heart disease took part in the study. They underwent an electrophysiological study. An epinephrine infusion (50 to 100 ng/kg/min) was administered for 5 min until an increase of at least 10% of the initial heart rate (HR) was achieved. Results: No complication arose from epinephrine infusion, and the drug facilitated arrhythmia induction. A significant increase in heart rate, systolic blood pressure, QRS, QTc, Tp-e, Tp-e/QT index, and QTc max–min interval duration was documented. No significant effect on diastolic blood pressure, P wave duration, inter-atrial conduction time, and PR, QT and QT − (Tp-e + QRS interval) was observed. Conclusions: In this group of patients without structural heart disease, epinephrine infusion did not produce any complication and it facilitated arrhythmia induction. It did not modify P wave duration, PR interval or inter-atrial conduction time. Moreover, it significantly increased the duration of depolarization, the final portion of repolarization, transmural dispersion of repolarization, and regional dispersion of repolarization without inducing significant changes in the middle portion of repolarization. © 2015 Published by Elsevier Ireland Ltd.
1. Introduction Epinephrine has been used for a long time in medicine but several adverse effects have been reported in the literature. For example, between 1991 and 2002, Japanese cardiologists described patients who suffered precordial pain after being submitted to emotional stress or catecholamine injection. The majority of the patients were women; their ECG displayed ST segment elevation and/or inverted T waves in precordial leads and QT prolongation. The left ventricular angiogram showed apical aneurysms resembling the traps used in Japan to catch octopuses (Takotsubo) [1–3]. The entity was named Takotsubu cardiomyopathy. Similar changes have been described in patients suffering from acute medical conditions, such as hemorrhagic strokes, surgery, sepsis, pheochromocytoma, cocaine abuse, or catecholamine administration [3–6]. The Abbreviations: QTc, corrected QT interval; QTc max–min, regional QTc dispersion; Tpe, peak-to-end of T wave interval; QT − (QRS + Tp-e), middle portion of ventricular repolarization length. ⁎ Corresponding author at: Urbanización Los Cortijos, calle 3, N° 42, La Pedregosa Norte, Mérida 5101, Venezuela. E-mail address: [email protected] (A.J. Fuenmayor A). 1 This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
http://dx.doi.org/10.1016/j.ijcard.2015.11.182 0167-5273/© 2015 Published by Elsevier Ireland Ltd.
electrophysiological effects of epinephrine have been studied in a few subjects only, and most reports have been conducted in patients with structural cardiomyopathy. Stratton et al. studied 10 normal subjects and reported that an epinephrine infusion of 25 to 100 ng/kg/min produced a significant rise of plasma epinephrine concentration that was equivalent to the levels attained performing isotonic exercise in a cycle-ergometer [7]. The subjects also showed significant increases in stroke volume, ejection fraction, heart rate and systolic arterial pressure accompanied by a decrease of systemic vascular resistance [7]. Morady et al. investigated some of the electrophysiological effects of epinephrine in humans [8]. They found a decrease in the atrial and AV node refractory period and an acceleration of the AV nodal conduction, and reported that the epinephrine infusion facilitated arrhythmia induction [8]. Cheema et al. reported a significant prolongation of the signal averaged P wave in normal subjects who received an epinephrine infusion (50 ng/kg/min) [9]. Magnano et al. described prolongation of the QT interval in normal subjects who were administered epinephrine infusion in a dose of up to 300 ng/kg/min [10]. The duration of the QT interval in the ECG approximately reflects the duration of the ventricular action potential [11,12]. QT interval
A.J. Fuenmayor A et al. / International Journal of Cardiology 204 (2016) 142–146
143
prolongation and increased QT interval dispersion have been considered markers of risk for the appearance of polymorphic ventricular tachycardia [13]. Regional QT interval dispersion has been assessed by measuring the differences in QT interval duration in the different ECG leads [13]. Repolarization has been measured in the different portions of the ventricular wall, and it has been found that midmyocardial cell repolarization last longer than the repolarization of the epicardial and endocardial cells. The intramural dispersion of repolarization reflects the differences in repolarization length between the mid-myocardial cells and those of the epicardial and endocardial layers [14]. Epicardial cell repolarization ends when the peak of the T wave occurs, and the mid-myocardial repolarization process finishes at the end of the T wave. Intramural dispersion of repolarization has been assessed by measuring the interval between the peak and the end of the T wave (Tp-e). Tp-e prolongation has been advocated as a marker of risk for lethal ventricular arrhythmias and sudden death [14–16]. Gupta et al. reported that Tp-e is influenced by body size and heart rate and advocated the relation Tp-e/QT as a more independent and reliable index of transmural dispersion of repolarization [17]. The duration of the middle portion of ventricular repolarization could be measured by subtracting the initial (QRS) and final (TP-E) portions from the QT interval {QT − (QRS + Tp-e)}, but this interval has not been investigated. Isoproterenol is not available in Venezuela. This is why, in our electrophysiological studies, we have been using epinephrine infusions to facilitate arrhythmia induction. Since little is known about epinephrine effects in subjects without structural heart disease, we decided to study the effects of an epinephrine infusion over P wave duration, inter-atrial conduction time, PR interval, QRS, QT, corrected QT, QT interval dispersion, and Tp-e, Tp-e/QT and QT − (QRS + Tp-e). Our hypothesis was that epinephrine infusion (50–100 ng/kg/min) does not produce significant collateral effects and that it can modify the above-mentioned electrophysiological parameters.
The cardiologists responsible for measuring the variables under study were trained in the Electrophysiology Section until an inter-observer variability b6 ms was achieved. When the beginning or the end of the waves was not well defined, the gain and speed of recordings were modified for obtaining precise measurements. Electrocardiographic intervals were measured according to standard recommendations [18]. Depolarization and repolarization measurements were performed in simultaneously acquired 12 lead ECG. The result obtained in each ECG lead was recorded, and the 12 measures were averaged. The variability and dispersion of the measures were computed in an Excel(R) sheet where the values were stored. Tp-e was measured from the maximal voltage of the T wave to its intersection with the basal line. Tp-e/QT was calculated with the Excel sheet were the values were stored. The middle portion of depolarization duration was computed adding the Tp-e to QRS duration and subtracting the result from the QT interval. Interatrial conduction time was measured from the beginning of the A wave recorded with the high right atrial catheter to the beginning of the A recorded with the distal pair of electrodes of the catheter placed in the coronary sinus.
2. Methods
3.1. Population
We certify that we complied with the Principles of Ethical Publishing of the International Journal of Cardiology. The study protocol conforms to the ethical guidelines of the 2013 Declaration of Helsinki as reflected in an a priori approval by our Institution's Human Research Committee.
Forty-three patients (25–58% — female) took part in the study. The mean age was 37.2 + 17.02 years. All the patients had normal hearts and preserved cardiovascular function. The left ventricular ejection fraction was 0.61 ± 0.05. No complication arose.
2.1. Population
3.2. Heart rate and arterial pressure
Written informed consent was obtained from all the patients. Patients were included if they did not have any structural heart disease or conduction disturbances and if they had been admitted to our electrophysiology laboratory to undergo electrophysiological study. A clinical cardiologist evaluated all the patients, and an X-ray, ECG, and a transthoracic echocardiogram were obtained before performing the ablation. Antiarrhythmic drugs were discontinued for at least 5 half-lives. No patient was receiving amiodarone.
Heart rate increased 14% after the epinephrine infusion and reached a mean of 85 beats per minute (see Table 1). Only one patient did not achieve a significant heart rate increase. Epinephrine infusion produced a significant systolic and mean blood pressure increase without significant changes in diastolic blood pressure (see Table 1). In 13 patients, supraventricular arrhythmia was induced only with the epinephrine infusion (p b 0.05).
2.4. Statistical analyses Statistical analyses were performed with Excel(R) and SPSS20(R) statistical packages. Data distribution was assessed with Shapiro–Wilk test. Normally distributed data were compared with paired T-test and Variance analysis. Data that did not fit in a normal distribution were compared with the Wilcoxon Signed Rank and Kruskall–Wallis test. In order to detect differences of 20 ms between the means with 95% confidence intervals and a statistical power of 80%, a sample size (adjusted to 15% missing data) of 42 observations was calculated. 3. Results
3.3. Electrocardiographic and electrophysiological parameters 2.2. Epinephrine infusion 1 mg of epinephrine was diluted in 250 cm3 of 0.9% saline solution. Infusion rate begun at 50 ng/kg/min for 5 min, and heart rate was continuously monitored to check whether an increase of at least 10% on the heart rate had occurred. If the heart rate had not increased, the infusion rate was then adjusted to a maximum of 100 ng/kg/min in order to achieve the 10% heart rate increase. If the heart rate did not increase after adjusting the infusion rate, the measurements were then performed at the maximal infusion rate. 2.3. Measurements The ECG and intracavitary recordings were obtained with a digital polygraph and stored to measure the electrophysiological parameters.
In the control situation, the QRS interval was shorter in women than in men (77 ± 8 vs 84 ± 10 ms; p = 0.018). The QTc interval difference
Table 1 Arterial pressure and heart rate changes after epinephrine infusion. Control
SAP (mm Hg) DAP (mm Hg) MAP (mm Hg) R-R (mseg)
Epinephrine
Mean
SD
Mean
SD
123.61 76.28 92.09 818
25.89 16.01 21.29 179
137.18 78.34 99.51 700
27.19 14.11 17.98 157
p value
b0.0001 0.1200 b0.0001 b0.0001
SD = standard deviation. SAP: Systolic arterial pressure. DAP: Diastolic arterial pressure. MAP: Mean arterial pressure. R-R = Electrocardiographic R-R interval.
144
A.J. Fuenmayor A et al. / International Journal of Cardiology 204 (2016) 142–146
between women and men did not reach statistical significance (443 ± 49 vs 417 ± 39 ms; p = 0.076). P wave, interatrial conduction time, PR interval, and QT interval did not significantly change (see Table 2). We found a significant prolongation of the QRS interval and the corrected QT interval (both for Bazett and Fridericia formulas). The QTc interval regional dispersion, Tp-e and Tp-e/QT also increased significantly with the epinephrine infusion (see Table 2). The middle portion of repolarization [QT − (QRS + Tp-e)] did not display any significant change.
4. Discussion One of the main findings of the present research is that the administration of an epinephrine intravenous infusion at 25 to 50 ng/kg/min is safe for the patient in the electrophysiology laboratory. Indeed, we did not observe any unwanted or collateral effect of the drug. Additionally, the epinephrine infusion facilitated the induction of supraventricular arrhythmias in 30% of the patients who were not inducible in the control state. We did not measure the plasma catecholamine concentration, but the heart rate increase observed in our patients was similar to the one reported by Stratton and Morady [7,8]. Another indicator of the action of epinephrine is that the systolic arterial pressure increased without significant changes in diastolic pressure. These modifications of heart rate and arterial pressure reflect a sympathetic stimulation that is equivalent to the one induced by moderate isotonic exercise [7] and is the type of sympathetic drive that could be useful in the electrophysiology laboratory. In developing countries like Venezuela, the cost of isoproterenol is prohibitive for the public health service. Indeed, in 2014, the year when the data of the present study were collected, in Venezuela one ampoule of epinephrine cost 11 Bolivars, and one ampoule of isuprel cost 4.500 Bolivars. (The official rate of exchange from USD to Bolívares was 1 USD = 6.30 Bs. at that time). The Heart Rhythm Society posted a special note regarding the price of isoproterenol because of the dramatic increases in its cost (http://www.hrsonline. org/iceractice-Guidance/Coding-Reimbursement/Reimbursement/ Additional-Reimbursement-Issues/Special-Notice-Regarding-Pricingof-Isoproterenol-Isuprel#axzz3gfdoGSdN). Our findings showed that epinephrine could be used as a valid alternative to isoproterenol and at a much lower price (several thousands times lower). Cheema et al. studied normal volunteers and reported a P wave shortening induced by epinephrine infusion [9]. In our group of patients the P wave, interatrial conduction time and PR interval did not significantly change. It is worthwhile mentioning that our group of patients was larger (N = 43) than the one studied by Cheema (N = 14) [9]. Table 2 Electrophysiological parameters changes after epinephrine infusion. Control
P PR IACT QRS QT QTc-B QTc-F QTc-B max–min Tp-e Tp-e/QT QT − (QRS + Tp-e)
Epinephrine
Mean
SD
Mean
SD
0.090 0.143 0.068 0.080 0.390 0.433 0.417 0.064 0.078 0.203 0.239
0.013 0.024 0.017 0.010 0.066 0.046 0.050 0.024 0.010 0.030 0.061
0.089 0.139 0.066 0.085 0.393 0.472 0.440 0.077 0.083 0.214 0.232
0.009 0.023 0.017 0.010 0.062 0.053 0.060 0.029 0.014 0.038 0.062
p value
0.498 0.163 0.084 0.000 0.571 0.000 0.000 0.002 0.003 0.010 0.109
P = P wave. PR = PR interval. IACT = Inter-atrial conduction time. QRS = Electrocardiographic QRS complex duration. QT = QT interval duration. QTc-B = Corrected QT interval by means of Bazett formula. QTc-F = Corrected QT interval by means of Fridericia formula. SD = Standard deviation. Max = maximum. Min = minimum. Tp-e = Peak-end of T wave. Measures in seconds.
The QT interval includes both the ventricular depolarization and the repolarization processes. The QRS reflects the ventricular depolarization and the J-T interval the repolarization [19]. The T wave is produced by repolarization of the different layers of the myocardium that, as was previously stated, is slower in mid-myocardial cells [16]. Previous investigations have reported that epinephrine shortens repolarization and, in consequence, the QT interval. This repolarization shortening was attributed to phosphorylation of the KCNQ1 potassium channel that drives IKs. The phosphorylation increases the probability of channel opening and an outward potassium current that accelerates repolarization. Epinephrine also increases L type Ca++ channel current that augments contractility and can induce a plateau (phase 2) prolongation. The IKs current effect predominates over the L type Ca++ channel current, and the net effect should be a QT interval shortening [10,20]. Epinephrine also increases the rate of depolarization in phase 0 of the action potential and improves conduction in Purkinje fibers [21]. Taking into account the above-mentioned actions of epinephrine, we expected a shortening of the QRS and of the middle portion of repolarization that should have become evident as a QT interval shortening. However, the opposite was observed, i.e. a small but significant increase in QRS duration. As has been reported elsewhere [22], we too found that the QRS interval was shorter in women than in men, but there was no significant gender difference in that increase. Nakagawa et al. studied the effect of supine bicycle exercise over QRS duration and autonomic tone in eleven normal subjects [23]. They reported a QRS shortening that was abolished by autonomic blockade (propranolol + atropine). This apparent contradiction with our result should be examined by taking into account the fact that, on the one hand, the two sample sizes were different (11 vs 43) and, on the other, that it is very difficult to compare the effect of an epinephrine infusion with the multiple physiological changes (cardiovascular, autonomic, metabolic, muscular, etc.) that are induced by isotonic exercise. No significant modification of the middle portion of repolarization [QT − (QRS + Tp-e)] or of the QT interval was observed (see Table 2). Here again, we were expecting a QT − (QRS + Tp-e) and a QT shortening, but neither occurred. Our finding contradicts the above-described effect of epinephrine over QT. It should be borne in mind that there are important differences in the method we used to measure QT and QRS and the method used by Ackerman and Vyas who reported a QT abbreviation [20,25,26]. Indeed, Ackerman and Vyas measured the QT interval averaging 4 consecutive beats in lead DII or V5, whereas we measured the interval in the same beat in all 12 leads, and we averaged these 12 values. We believe that measuring and averaging the same complex in the 12 ECG leads provide more and better information about the repolarization process and avoid the beat-to-beat variation that could be induced by autonomic, respiratory and hemodynamic changes that occur in the cardiovascular system from one beat to the next. A significant QTc interval increase was observed. It is our contention that this increase was the result of the R-R interval shortening produced by epinephrine as is reflected by the fact that a significant correlation (p = 0.018) was found between the R-R interval variation and the QTc interval prolongation. It should be remembered that, for the QT interval correction, we used the Bazett and Fredericia formulae in which the squared or the cubic root of the R-R interval are the denominators. As the QTc interval prolongation can be the expression of heart rate increase induced by epinephrine, when the drug is used to perform QT stress testing for long QT syndrome, both the non-corrected and the QTc interval should be analyzed to assess the response. The regional (QTc max–min) and transmural dispersion of repolarization (Tp-e and Tp-e/QT) significantly increased (see Table 2). The regional dispersion of repolarization has long been (and still is) a subject of debate. Some authors argue that a value above 100 ms or an increase over 100% could be an index of cardiovascular risk. Other investigators contend that neither QT nor QTc regional dispersion is a reliable prognostic marker [19]. Our group of patients without structural heart
A.J. Fuenmayor A et al. / International Journal of Cardiology 204 (2016) 142–146
disease had a QTc max–min averaging 64 ms which significantly increased to 77 ms under the epinephrine infusion. This increment can be interpreted as an increase in the differences in repolarization between different segments of the heart, but the increase did not reach the 100 ms value that has been established as a risk marker by previous research [19]. This regional heterogeneity induced by epinephrine could be invoked as one of the factors that make arrhythmias more easily inducible under sympathetic stimulation. Transmural dispersion of repolarization as measured by the Tp-e and Tp-e/QT also increased with epinephrine infusion in this group of patients without structural heart disease who had never experienced either ventricular arrhythmias or long QT syndrome. Several investigators reported increases in transmural dispersion of repolarization induced by epinephrine in patients with long QT syndrome [15–17]. Topilski et al. retrospectively studied 30 patients who had suffered from torsades de pointes associated with bradycardia. They found that Tp-e over 117 ms was the best single discriminator for identifying the patients who suffered from torsade de pointe [27]. The significant epinephrine prolongation of Tp-e observed in our group reached 83 ± 14 ms and was below the values predicting risk. In consequence, epinephrine infusion can be considered safe when administered in the electrophysiology laboratory. Besides, according to our data, Tp-e and Tp-e/QT slight prolongations are generally observed in normal patients submitted to epinephrine infusion. Gupta et al. introduced the Tp-e/QT index advocating that it is more appropriate for the evaluation or transmural dispersion of repolarization because it was neither heart rate nor body mass dependent [17]. The mean Tp-e and Tp-e/QT value in our patients were similar to the ones reported by Gupta, but the dispersion, as estimated by the standard deviation, is significantly greater in our study. Here again, there is an important methodological difference since we averaged the values obtained in the 12 leads of the ECG, whereas Gupta measured the value in V6 only. We decided to perform the Tp-e and Tp-e/QT measures in V6 only (Tp-eV6, Tp-e/QTV6) and, when comparing the measures without intervention, we found that Tp-eV6 was 4 ms shorter than Tp-e (0.074 ± 0.013 vs 0.078 ± 0.010; p = 0.007) and Tp-e/QTV6 was 10 ms shorter than Tp-e/QT (0.193 ± 0.034 vs 0.203 ± 0.030; p = 0.001). Taking these differences into account, and in view of the fact that our goal is to select patients at risk of ventricular arrhythmias, we posit that it is better to average the repolarization values in the 12 ECG leads. No gender differences were recorded in Tp-e values, but we found that Tp-e/QT was significantly shorter in female patients (0.192 ± 0.029 vs 0.220 ± 0.020; p = 0.002). Moreover, we found a significantly negative correlation between Tp-e/QT and RR interval that differs from the results obtained by Gupta et al. This deserves further analysis. 4.1. Study limitations The study group size is modest however it is larger than the previous study groups. Besides, the number of patients included in the study satisfied the sample size estimated to be adequate for the study. Not a single patient in our sample suffered from ventricular arrhythmias, but none had any structural heart disease. In all likelihood, the results would have been different had epinephrine been administered to patients with cardiac disease, long QT syndrome, or patients susceptible to develop stress-related cardiomyopathy syndromes [3, 20,24–26]. 5. Conclusion In this group of patients without structural heart disease, the epinephrine intravenous infusion of 50–100 ng/kg/min: 1. is safe and efficacious to facilitate arrhythmia induction in the electrophysiology laboratory;
145
2. is considerably cheaper than isoproterenol infusion; 3. does not produce any significant changes in the P wave, PR interval or interatrial conduction time; 4. produces a small but significant increase in heart rate and systolic pressure within physiological limits; 5. induces a small but significant prolongation in the duration of the QRS, QTc, QT max–min, Tp-e, Tp-e/QT without significant changes in the middle portion of repolarization (QT − (QRS + Tp-e)); 6. produces a prolongation in the repolarization process and in the transmural and regional repolarization dispersion. These prolongations do not reach values that indicate a risk of suffering from ventricular arrhythmias in these subjects without structural heart disease. Conflict of interest None. Acknowledgments We are thankful to Françoise Salager Meyer for her review of the manuscript. References [1] K. Dote, H. Sato, H. Tateishi, et al., Myocardial stunning due to simultaneous multivessel coronary spasm: a review of 5 cases, J Cardiol 21 (1991) 203–214. [2] S. Kurisu, H. Sato, T. Kawagoe, M. Ishihara, Y. Shimatani, K. Nishioka, et al., Takotsubo-like left ventricular dysfunction with ST-segment elevation: a novel cardiac syndrome mimicking acute myocardial infarction, Am Heart J 143 (2002) 448–455. [3] K.A. Bybee, A. Prasad, Stress-related cardiomyopathy syndromes, Circulation 118 (2008) 397–409. [4] N. Budhwani, K.L. Bonaparte, A.B. Cuyjet, M. Sarik, Severe reversible left ventricular systolic and diastolic dysfunction due to accidental iatrogenic epinephrine overdose, Rev Cardiovasc Med 5 (2004) 130–133. [5] J. Abraham, J.O. Mudd, N. Kapur, K. Klein, H.C. Champion, I.S. Wittstein, Stress cardiomyopathy after intravenous administration of catecholamines and beta-receptor agonists, J Am Coll Cardiol 53 (2009) 1320–1325. [6] I.S. Wittstein, D.R. Thiermann, J.A.C. Lima, K.L. Baughman, S.P. Schulman, G. Gertenblith, et al., Neurohumural features of myocardial stunning due to sudden emotional stress, N Engl J Med 352 (2005) 539–548. [7] J.R. Stratton, M.A. Pfeifer, J.L. Ritchie, J.B. Halter, Hemodynamic effects of epinephrine: concentration-effect study in humans, J Appl Physiol 58 (1985) 1199–1206. [8] F. Morady, S.D. Nelson, W.H. Kou, R. Pratley, S. Schmaltz, M.D. Buttleir, et al., Electrophysiologic effects of epinephrine in humans, J Am Coll Cardiol 11 (1988) 1235–1244. [9] A. Cheema, M. Ahmed, A. Kadish, J. Golderberg, Effects of autonomic stimulation and blockade on signal-averaged P wave duration, J Am Coll Cardiol 26 (1995) 497–502. [10] A.R. Magnano, N. Talathoti, R. Hallur, D.M. Bloomfield, H. Garan, Sympathomimetic infusion and cardiac repolarization: the normative effects of epinephrine and isoproterenol in healthy subjects, J Cardiovasc Electrophysiol 17 (2006) 983–989. [11] R. Shah, The significance of QT interval in drug development, J Clin Pharmacol 54 (2002) 188–202. [12] L. Belardinelli, Assessing predictors of drug-induced torsade de pointes, Trends Pharmacol Sci 24 (2003) 619–624. [13] R. Shah, Drug-induced QT dispersion: does it predict the risk of torsade de pointes? J Electrocardiol 38 (2005) 10–18. [14] M. Yamaguchi, M. Shimisu, T wave peak-to-end interval and QT dispersion in acquired long QT syndrome: a new index for arrhythmogenicity, Clin. Sci. 105 (2003) 671–676. [15] C. Antzelevitch, Role of transmural dispersion of repolarization in the genesis of drug-induced torsades de pointes, Heart Rhythm 2 (2005) S9–15. [16] C. Antzelevitch, Transmural dispersion of repolarization and the T wave, Cardiovasc Res 50 (2001) 426–431. [17] P. Gupta, C.H. Patel, H. Patel, S. Narayanaswamy, B. Malhotra, J.T. Green, et al., Tp-e/QT ratio as an index of arrhythmogenesis, J Electrocardiol 41 (2008) 567–574. [18] L.E. Gering, B. Surawicz, T.K. Knilans, M.E. Tavel, Normal electrocardiogram: origin and description, Chous' Electrocardiography in Clinical Practice, sixth ed.Saunders. Elsevier, Philadelphia 2008, pp. 1–28. [19] M. Bednar, E. Harrigan, R. Anziano, A. Camm, J. Ruskin, The QT interval, Prog Cardiovasc Dis 43 (2001) 1–45. [20] H. Vyas, J. Hejlik, M. Ackerman, Epinephrine QT stress testing in congenital long QT syndrome, J Electrocardiol 39 (2006) S107–S113. [21] T.C. Westfall, D.P. Westfall, Adrenergic agonists and antagonists, in: L.L. Brunton (Ed.), Goodman & Gillman's The Pharmacological Basis of Therapeutics, 12 ed.MacGraw Hill, New York 2011, pp. 279–325. [22] L.E. Gering, T.K. Knilans, B. Surawicz, M.E. Tavel, Normal electrocardiogram: origin and description, Chou's Electrocardiography in Clinical Practice, 6a ed.Saunders ELSEVIER, Philadelphia 2008, pp. 2–27.
146
A.J. Fuenmayor A et al. / International Journal of Cardiology 204 (2016) 142–146
[23] M. Nakagawa, T. Iwao, H. Abe, S. Ishida, N. Takahashi, T. Fujimo, et al., Influence of autonomic tone on the filtered QRS duration from signal averaged electrocardiograms in healthy volunteers, J Electrocardiol 33 (2000) 17–22. [24] W. Shimizu, T. Noda, H. Takaki, et al., Epinephrine unmasks latent mutation carriers with LQT1 form of congenital long-QT syndrome, J Am Coll Cardiol 41 (2003) 633–642. [25] M.J. Ackerman, A. Khositseth, D.J. Tester, J.B. Hejlik, W.K. Shen, C.J. Porter, Epinephrine-induced QT interval prolongation: a gene-specific paradoxical response in congenital long QT syndrome, Mayo Clin Proc 77 (2002) 413–421.
[26] H. Vyas, J. Hejlik, M.J. Ackerman, Epinprhine QT stress testing in the evaluation of congenital long QT syndrome. Diagnostic accuracy of the paradoxical response, Circulation 113 (2006) 1385–1392. [27] I. Topilski, O. Rogowski, R. Rosso, D. Justo, Y. Copperman, M. Glikson, et al., The morphology of the QT interval predicts torsade de pointes during acquired bradyarrhythmias, J. Am. Coll. Cardiol. 49 (2007) 320–328.