IJCA-17989; No of Pages 3 International Journal of Cardiology xxx (2014) xxx–xxx

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Letter to the Editor

Influence of exercise training on T-wave alternans assessed during exercise test in heart failure patients Ewa Piotrowicz a,⁎, Michael Pencina b, Walerian Piotrowski c, Maciej Banach d, Ryszard Piotrowicz e a

Telecardiology Center, Institute of Cardiology, Warsaw, Poland Duke Clinical Research Institute, Duke University School of Medicine, USA Statistic Laboratory, Institute of Cardiology, Warsaw, Poland d Medical University, Lodz, Poland e Department of Cardiac Rehabilitation and Noninvasive Electrocardiology, Institute of Cardiology, Warsaw, Poland b c

a r t i c l e

i n f o

Article history: Received 29 March 2014 Accepted 4 April 2014 Available online xxxx Keywords: Exercise training T-wave alternans Heart failure

The microvolt T-wave alternans (TWA) is an electrophysiological phenomenon that is evident in the electrocardiogram (ECG) as an alternating pattern of ST segment and/or T-wave morphologies on successive beats. TWA reflects spatiotemporal heterogeneity of repolarization, secondary to perturbations in intracellular Ca2+ handling, which is predisposed to malignant arrhythmias and sudden cardiac death (SCD) [1]. In heart failure (HF) the derangement in intracellular Ca2+ handling was observed [2]. Experimental work based on animal models has suggested that exercise training may ameliorate cardiac deterioration during the development of HF in part via normalization of myocardial Ca2+ handling protein expression and/or function and can reduce the predisposition to malignant arrhythmias [3–5]. There are premises that support the theory that exercise training influences Ca2+ handling abnormalities and, in consequence, TWA as well. Therefore, the aim of this study was to evaluate the influence of exercise training on TWA assessed during exercise test in HF patients. The present study formed part of a randomized trial which evaluated the home-based telerehabilitation in HF patients, who were randomized (2:1) to the training (TG) or the control group (CG) and who met the criteria for TWA testing. The study was approved by the local Ethics Committee. Each patient gave written informed consent. We included: patients of either sex with any etiology of left ventricular systolic HF

⁎ Corresponding author at: Telecardiology Center, Institute of Cardiology, Alpejska 42, 04-628 Warsaw, Poland. Tel.: +48 223434664; fax: +48 223434519. E-mail address: [email protected] (E. Piotrowicz).

as defined in the ESC guidelines [6] diagnosed at least for 3 months; with a left ventricular ejection fraction b 40% on echocardiography; in NYHA class II or III; who were clinically stable and receiving an optimal and stable medication regimen for at least 4 weeks before enrolment; who had no contraindications to exercise training. The exclusion criteria were: unstable angina; a history of an acute coronary syndrome within the last month, coronary artery bypass grafting within the last 2 months, or initiation of cardiac resynchronization therapy within the last 6 months, or implantation of a pacemaker and/or ICD within the last 6 weeks; symptomatic and/or exercise-induced cardiac arrhythmia or conduction disturbances; valvular or congenital heart disease requiring surgical treatment; hypertrophic cardiomyopathy; severe pulmonary hypertension or other severe pulmonary disease; uncontrolled hypertension; anemia; acute and/or decompensated non-cardiac disease; physical disability related to severe musculoskeletal or neurological problems; patient's refusal to participate. TWA tests were conducted in the eligible patients in both groups. The exclusion criteria were: atrial fibrillation or flutter, ventricular pacing, QRS duration ≥ 130 ms, N 10 ventricular ectopic beats per minute (bpm), bradycardia b 40 bpm. The TWA qualified patients underwent the following assessments at entry and after completing the 8-week program: clinical examination, TWA test, and cardiopulmonary exercise treadmill test (CPET). The TWA tests were performed on treadmill with the HearTwave system II (Cambridge Heart Inc., Bedford, MA, USA) using the spectral analysis method. The TWA tests were automatically interpreted within the HearTwave system and were reviewed by two physicians. Each TWA report was classified as positive, indeterminate, or negative using accepted criteria [7]. The test was considered positive if the TWA voltage was ≥1.9 mV and the alternans ratio was ≥3 for a period of above N1 min with an onset HR b 110 bpm or at rest in any of three orthogonal leads (X, Y, or Z), or in two adjacent precordial leads. If the recording did not meet the positive criteria and the HR was ≥ 105 bpm at least for 1 min, the TWA test was defined negative. If the result did not meet the positive or negative criteria, it was considered indeterminate. Exercise training was planned in line with the published guidelines for HF patients [8]. Patients underwent an 8-week home-based telerehabilitation based on Nordic walking training (five times a week), methodology of which was described previously [9,10].

http://dx.doi.org/10.1016/j.ijcard.2014.04.088 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.

Please cite this article as: Piotrowicz E, et al, Influence of exercise training on T-wave alternans assessed during exercise test in heart failure patients, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.088

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E. Piotrowicz et al. / International Journal of Cardiology xxx (2014) xxx–xxx

Table 1 Baseline characteristics.

Males, n (%) Females, n (%) Age (years), mean ± SD LVEF (%), mean ± SD Etiology of heart failure, n (%) Ischemic Non-ischemic Functional status NYHA II, n (%) NYHA III, n (%) Past medical history, n (%) Myocardial infarction Angioplasty Coronary artery bypass grafting Diabetes Hyperlipidemia Cardiopulmonary exercise test, mean ± SD Peak VO2 (ml/kg/min) Treatment, n (%) Beta-blocker Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Loop diuretics Spironolactone + eplerenon Aspirin Anticoagulants Statins Implantable cardioverter-defibrillator

Training group (n = 32)

Control group (n = 13)

p value

28 (87.5) 4 (12.5) 54.9 ± 10.4 31.0 ± 7.1

13 (100.0) 0 (0.0) 61.7 ± 11.0 33.4 ± 5.5

ns ns ns ns

24 (75.0) 8 (25.0)

11 (84.62) 2 (15.38)

ns ns

27 (84.38) 5 (15.62)

9 (69.23) 4 (30.77)

ns ns

23 (71.88) 19 (59.38) 7 (21.88) 8 (25.0) 15 (46.88)

11 (84.62) 9 (69.23) 3 (23.08) 6 (46,15) 8 (61.54)

ns ns ns ns ns

17.68 ± 3.5

18.09 ± 3.8

ns

32 (100) 29 (90.63) 3 (9.37) 19 (59.38) 26 (81.25) 25 (78.13) 7 (21.88) 28 (90.32) 22 (68.75)

13 (100) 12 (92.31) 1 (7.69) 7 (53.85) 9 (69.23) 11 (84.62) 3 (23.08) 11 (84.62) 7 (53.85)

ns ns ns ns ns ns ns ns ns

Standard deviation; ns, non-significant; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association class; peak VO2, peak oxygen consumption.

The effectiveness of exercise training was assessed by changes — delta (Δ) in NYHA class and pVO2 in CPET as a result of comparing NYHA and pVO2 from program beginning and from its end. Of the 111 patients randomized, 77 were assigned to the TG and 34 to the CG. Eligible for TWA analysis were 32 patients in TG and 13 patients in CG (57% in TG and 64% in CG were ineligible for TWA assessment due to: atrial fibrillation, pacemaker dependency, physical inability to undertake the exercise test). The groups were comparable in terms of demographic data, baseline clinical parameters and pharmacotherapy — all patients were treated with beta-blockers (Table 1). Within-group analysis of the outcome of the two TWA tests in TG and CG is described in Tables 2 and 3 respectively. Of the 32 pts in TG, 23 had determinate (positive or negative) TWA test results, both before and after exercise training. Among these 23 patients, the test results of 18 (78.3%) were concordant and 5 (21.7%) were discordant (Fig. 1). Of the 13 patients in CG, 10 had determinate TWA test results both before and after the 8-week observation

(Fig. 2). All the determinate test results in the CG were concordant. Between-group analysis showed a greater TWA result variability in TG. In TG we observed lower weighted kappa value [k = 0.4839, 95% CI (0.2164–0.7513)] than in CG [k = 0.8354, 95% CI (0.6181–1)]. These changes achieve statistical difference — test for overall kappa coefficients: χ2 = 3.999, 95% CI (0.5270–0.8643), p = 0.0455. Exercise training resulted in a significant improvement in NYHA class (p = 0.0015) and pVO2 (p = 0.0001). In CG we did not observe significant changes in these parameters. Between-group analysis showed that the differences between TG and CG were statistically significant: in ΔpVO2 (p = 0.006) and ΔNYHA class (p = 0.0364). There are premises that pleiotropic influence of exercise training has significant impact on the

Table 2 Microvolt T-wave alternans results in training group. TWA results before the exercise training

TWA results after an 8-week exercise training

Negative Indeterminate Positive

Negative

Indeterminate

Positive

8 2 2

3 3 0

3 1 10

Table 3 Microvolt T-wave alternans results in control group. TWA results before observation

TWA results after an 8-week observation

Negative Indeterminate Positive

Negative

Indeterminate

Positive

6 0 0

2 1 0

0 0 4

Fig. 1. Agreement of TWA results before and after the training in the training group.

Please cite this article as: Piotrowicz E, et al, Influence of exercise training on T-wave alternans assessed during exercise test in heart failure patients, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.088

E. Piotrowicz et al. / International Journal of Cardiology xxx (2014) xxx–xxx

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the exercise training qualification procedure and its performance in HF patients. Further studies on larger groups of patients are necessary. The study was supported by the National Science Centre, Polandgrant number NN404 107936. References

Fig. 2. Agreement of TWA results before and after observation in the control group.

heterogeneity of repolarization and consequently on the variability and dynamics of TWA. Our results showed that effective exercise training may influence TWA tests in HF patients, yet the results may vary from favorable to unfavorable. For this reason, the problem at hand is how to individualize

[1] Verrier RL, Klingenheben T, Malik M, et al. Microvolt T-wave alternans physiological basis, methods of measurement, and clinical utility-consensus guideline by International Society for Holter and Noninvasive Electrocardiology. J Am Coll Cardiol 2011;58(13):1309–24. [2] Hasenfuss G, Pieske B. Calcium cycling in congestive heart failure. J Mol Cell Cardiol 2002;34(8):951–69. [3] Lu L, Mei DF, Gu AG, et al. Exercise training normalizes altered calcium-handling proteins during development of heart failure. J Appl Physiol 2002;92(4):1524–30. [4] Kemi OJ, MacQuaide N, Hoydal MA, Ellingsen O, Smith GL, Wisloff U. Exercise training corrects control of spontaneous calcium waves in hearts from myocardial infarction heart failure rats. J Cell Physiol 2012;227(1):20–6. [5] Medeiros A, Rolim NPL, Oliveira RSF, et al. Exercise training delays cardiac dysfunction and prevents calcium handling abnormalities in sympathetic hyperactivity-induced heart failure mice. J Appl Physiol 2008;104(1):103–9. [6] McMurray JJ, Adamopoulos S, Anker SD, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. Eur Heart J 2012;33(14):1787–869. [7] Bloomfield DM, Hohnloser SH, Cohen RJ. Interpretation and classification of microvolt T wave alternans tests. J Cardiovasc Electrophysiol 2002;13(5):502–12. [8] Piepoli MF, Conraads V, Corra U, et al. Exercise training in heart failure: from theory to practice. A consensus document of the Heart Failure Association and the European Association for Cardiovascular Prevention and Rehabilitation. Eur J Heart Fail 2011;13(4):347–57. [9] Piotrowicz E, Baranowski R, Bilinska M, et al. A new model of home-based telemonitored cardiac rehabilitation in patients with heart failure: effectiveness, quality of life, and adherence. Eur J Heart Fail 2010;12(2):164–71. [10] Piotrowicz E. How to do — telerehabilitation in heart failure patients. Cardiol J 2012;19(3):243–8.

Please cite this article as: Piotrowicz E, et al, Influence of exercise training on T-wave alternans assessed during exercise test in heart failure patients, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.088