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Microvolt T-wave Alternans in Adult Patients with Repaired Tetralogy of Fallot Agnieszka Bartczak, MD, PhD,* Olga Trojnarska, MD, PhD,* Aleksandra Cieplucha, MD PhD,* Karolina Plaskota, MD,* Lucyna Kramer, PhD,† and Stefan Grajek, MD, PhD* *1st Department of Cardiology and †Department of Statistic & Computers, Poznan University of Medical Sciences, Poznan´, Poland ABSTRACT
Objective. Indications for sudden cardiac death (SCD) primary prevention are unknown in patients with repaired tetralogy of Fallot (ToF). The role of microvolt T-wave alternans (MTWA) in SCD risk stratification was documented. However, the prevalence of spectral MTWA and its association with ventricular arrhythmia (VA) in adults after ToF repair were not elucidated. Design. Microvolt T-wave alternans, electrocardiogram (ECG), ambulatory ECG monitoring, echocardiography, and spiroergometry were evaluated in 102 adults after ToF repair. Microvolt T-wave alternans results were classified as normal: negative(−), abnormal: positive(+), and indeterminate(ind). Owing to similar prognostic significance, MTWA(+) and MTWA(ind) due to patient factors were combined into nonnegative group: MTWA(abnormal). Results. Microvolt T-wave alternans(abnormal) was more frequent in the studied group as compared with controls (P = .0005). The MTWA(abnormal) group had greater right ventricular end-diastolic diameter (P = .005), higher incidence of pulmonary regurgitation (P = .015), lower peak oxygen consumption (P = .01), and higher VE/VCO2 slope (P = .04) in comparison with MTWA(normal). Univariate logistic regression proved pulmonary regurgitation (OR = 3.57, 95% CI 1.27–10.04), VA (OR = 3.26, 95% CI 1.06–10.05), right ventricular end-diastolic enlargement (OR = 1.11, 95% CI 1.03–1.2), increase in VE/VCO2 slope (OR = 1.08, 95% CI 1.01–1.17), and decrease in peak oxygen uptake (OR = .91, 95% CI 0.83–0.99) to increase MTWA(abnormal) prevalence. Conclusions. In adults after ToF repair, abnormal MTWA occurred more often than in controls. Probability of abnormal MTWA did not rise with prevalence of malignant VA; however, presence of abnormal MTWA was associated with VA risk factors: pulmonary regurgitation, right ventricular enlargement, and consequent heart failure. The role of MTWA in selecting patients late after ToF repair at risk of SCD needs further observation. Key Words. Tetralogy of Fallot; Microvolt T-wave Alternans; Congenital Heart Defect; Ventricular Arrhythmia; Sudden Cardiac Death
Introduction
D
espite good results of tetralogy of Fallot (ToF) repair, about 6% of patients are at risk of sudden cardiac death (SCD), mostly due to malignant ventricular arrhythmia (VA).1–5 The studies already performed documented the prognostic significance of: age at surgery,3,5 current patient’s age,2,3,6 history of palliative procedure,3–5,7 and number of reoperations3,5 to increase the risk of Funding: This research received funding from the Polish Society of Cardiology sponsored by Servier. © 2014 Wiley Periodicals, Inc.
SCD. Pulmonary regurgitation2,8,9 caused by transannular patch placement5,7 is also of great importance as it leads to right ventricular enlargement and dysfunction, as well as left ventricular systolic and diastolic dysfunction3,4,10–12 along with QRS complex prolongation.13 The decision on cardioverter-defibrillator implantation in this group is usually based on electrophysiological study.6 Patients with ischemic or nonischemic cardiomyopathy at high risk of SCD can be identified by means of noninvasive tests such as microvolt T-wave alternans (MTWA).14–18 Microvolt T-wave alternans is an electrocardiographic phenomenon Congenit Heart Dis. 2015;10:E89–E97
E90 displaying inhomogeneity of the myocardial repolarization process which leads to reentry phenomenon and, as a consequence, initiation of VA.15 Microvolt T-wave alternans arises from beat-tobeat changes of action potential duration presumably caused at the level of cardiac myocytes by perturbations in intracellular calcium handling. In the diseased heart, MTWA phenomenon occurs at significantly lower heart rate (HR) than in healthy heart; the cutoff value is HR 140 μmol/L (2), serum aspartate transaminase level exceeding twice the upper limit of normal (1). Ultimately, 102 consecutive patients in sinus rhythm (46 men) aged 18–62 years, who underwent ToF repair at the age of 1–25 years, were enrolled in the study group. In 30 (29.4%) patients, palliative surgery (Blalock– Taussig shunt) was performed. According to current recommendation, patients on antiarrhythmic medication were not excluded from our study.22 Pharmacological anti-arrhythmic Congenit Heart Dis. 2015;10:E89–E97
Bartczak et al. therapy included β-blockers in 15 (14.7%), amiodarone in 3 (2.9%), and digoxin in 3 (2.9%). Control group consisted of 45 healthy volunteers (23 men) aged 18–65 years. Echocardiography
Detailed morphologic assessment was performed with VIVID 7 GE Healthcare device (Little Chalfont, Buckinghamshire, United Kingdom), using 1.5–2.5 MHz probe in 2D, M and Doppler modes according to the current recommendations of the European Society of Cardiology and the American Heart Association.23,24 Right ventricular diameter was estimated from right ventricular inlet measurements made at end-diastole from apical four-chamber view (right ventricle focused view). Residual right ventricular outflow tract obstruction was derived from the peak velocity of the right ventricular outflow tract in short axis plane obtained by continuous-wave Doppler trace and calculated from Bernoulli equation. The severity of the pulmonary regurgitation was estimated by continuous-wave Doppler trace method proposed by Li et al.,25 and it was graded as mild, when the retrograde flow to right ventricle was maintained throughout diastole; moderate, when equilibrium between pulmonary artery-right ventricle pressures occurred in the late diastole; severe, when equilibrium took place in the early diastole. At least moderate pulmonary regurgitation was considered significant. Microvolt T-wave alternans was analyzed in 102 consecutive patients during treadmill test while receiving their usual medications, including betablocker therapy.26 After careful skin preparation, high-resolution electrodes (Micro-V Alternans Sensors, Cambridge Heart Inc., Bedford, MA, USA) were applied using standard precordial leads (V1-V6) and Frank orthogonal configuration (X, Y, Z, VM). Microvolt T-wave alternans was recorded during an HR-based exercise protocol applying CH2000 (Cambridge Heart Inc.) with the use of spectral method employing the fast Fourier transform.19 Gradual increase in workload was individually adjusted to obtain at least 2.5 minutes between an HR of 100 and 110 beats per minute (bpm) and at least 1.5 minutes between an HR of 110 and 120 bpm. The test was considered positive if significant sustained MTWA (i.e., alternans voltage ≥1.9 μV and alternans ratio ≥3.0) was present for at least 1 minute with an onset at an HR ≤110 bpm in any orthogonal lead or two adjacent precordial leads. The test was classified as
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MTWA in Tetralogy of Fallot negative (MTWA[normal]) if it did not meet the criteria for a positive test and if there was ≥1 minute at HR ≥105 bpm of artifact-free trace (noise level 50 ms.28
Cardiopulmonary exercise test was performed according to the modified Bruce protocol (adding stage 0–3 minutes, 1.7 km/h, 5% grading) and symptom limited. Patients were encouraged to continue the exercise until the respiratory exchange ratio (RER) exceeded 1. Oxygen uptake and carbon dioxide production were measured with breath by breath technique using Sensor Medics, model Vmax29 (SensorMedics Corporation, Yorba Linda, CA, USA). Peak oxygen uptake was defined as the average for the last 20 seconds of exercise and expressed as mL/kg/ minute and L/minute, as well as the percentage ranges predicted for sex, age, height, and weight according to Wasserman’s equation. A minute ventilation/carbon dioxide production slope (VE/ VCO2 slope) was assessed by linear regression for the whole exercise. Due to mental disability, cardiopulmonary test was not performed in two patients. Serum brain natriuretic peptide (BNP) concentration was measured in the venous blood samples taken to the EDTA tubes after 15 minutes of rest in supine position using the Abbott AxSYM Immunoassay system, Microparticle Enzyme (MEIA) method (Abbott Diagnostics, Abbott Park, IL, USA). Statistical Analysis
Continuous variables were summarized by mean or median and their ranges, depending on normality of distribution assessed with Wilk– Shapiro test. Variables following normal distribution were analyzed using Student’s t-test or Welch’s test, otherwise nonparametric Mann– Whitney U-test was used. Categorical variables were compared by using the chi-square or Fisher’s exact test, where applicable. To assess predictors of MTWA(abnormal), univariate and multivariate logistic regressions were applied. All tests were two-sided and used P ≤ .05 as statistically significant. Statistical analysis was performed using the Statistica 7.0 package (StatSoft, Inc., Tulsa, OK, USA). The study protocol, as approved by our institutional Ethics Committee, conformed to the ethical guidelines set forth by the 1975 Declaration of Helsinki. Results
Microvolt T-wave alternans examination was performed in total of 102 patients and 45 healthy Congenit Heart Dis. 2015;10:E89–E97
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volunteers. Fifteen patients and two controls were excluded from further analysis because of indeterminate MTWA due to technical factors. In the remaining 87 patients, MTWA was classified as abnormal in 23 (26.4%) subjects (positive in 13 [14.9%] and indeterminate owing to patient factors in 10 [11.5%]) and negative (MTWA[normal]) in 64 (73.6%) patients. Out of 43 volunteers enrolled in the study, only one (2.3%) tested MTWA(+) and the rest (42 [97.7%]) had MTWA(normal) result. The analyzed group was characterized by significantly higher prevalence of MTWA(abnormal) (P = .0005) as compared with the controls. The comparison between subgroups (Table 1) revealed that the number of men among MTWA(abnormal) patients was significantly higher than in MTWA(normal) group (P = .05). Malignant VA occurrence did not differ between analyzed subgroups. The prevalence of potentially malignant VA (nsVT/VPB ≥ 10/hour) as well as any form of VA [sVT/nsVT/VPB ≥ 10/hour] (some patients presented with more than one type of arrhythmia) was significantly higher in MTWA(abnormal) subgroup when compared with MTWA(normal) (P = .05) (Table 2). As shown in Table 2, the analysis of echocardiographic parameters revealed that right ventricular end-diastolic diameter in MTWA(abnormal) patients was significantly larger as compared with those MTWA(normal) (P = .005). Subjects characterized by abnormal MTWA result presented with a significant pulmonary regurgitation more often than those MTWA(normal) (P = .015). Cardiopulmonary exercise test results (Table 2) showed significantly lower peak oxygen consumpTable 1.
tion (mL/kg/min) in MTWA(abnormal) patients in comparison with MTWA(normal) subgroup (P = .01). It was also lower when expressed as percentage of predicted values (%) (P = .04). The VE/VCO2 slope values were significantly higher in MTWA(abnormal) patients as compared with MTWA(normal) (P = .05). There was no difference observed between subgroups defined by MTWA result with regard to HRV parameters (Table 2). As shown in univariate logistic regression analysis, the most powerful factors increasing the prevalence of MTWA(abnormal) are: significant pulmonary regurgitation (OR = 3.57; 95% CI 1.27–10.04; P = .017), episodes of any form of VA (sVT/nsVT/VPB ≥ 10/h) (OR = 3.26; 95% CI 1.06–10.05; P = .04), right ventricular enddiastolic enlargement (OR = 1.11; 95% CI 1.03– 1.2; P = .010), decrease in peak oxygen uptake (OR = 0.91; 95% CI 0.83–0.99; P = .044), and increase in VE/VCO2 slope (OR = 1.08; 95% CI 1.01–1.17; P = .037). We did not confirm the prognostic role of any of the studied parameters when introduced into multivariate analysis (Table 3).
Discussion
The prevalence of positive MTWA result in the studied population is comparable with those published in two available studies describing this phenomenon in patients after ToF repair. According to Cheung et al.,21 positive MTWA test was present in 14.2% out of 49 children who underwent that surgery; in the study conducted by
Clinical and Demographic Data in the Analyzed Subgroups Characterized by MTWA Result Analyzed control group (n = 43)
Male (%) Age (years) median (min-max) NYHA >I (%) Age at surgery (years) median (min-max) Palliative surgery (%) Ventriculotomy (%) Transannular patch (%) Reoperation (%) Β-blocker (%) QRS (ms) median (min-max)
Analyzed group (n = 87)
MTWA (abnormal) (n = 23)
MTWA (normal) (n = 64)
MTWA (abnormal) vs. MTWA (normal) P
22 (51.1) 28 (18–65)
41 (47.1) 30 (18–62)
15 (65.2) 30 (23–58)
26 (40.6) 29 (18–62)
.05 .32
0 (0.0)* —
11 (12.6) 6 (1–21)
4 (17.4) 7 (2–21)
7 (10.9) 5 (1–16)
.14 .09
26 (29.9) 82 (94.2) 46 (52.9) 11 (12.6) 15 (17.2) 170 (80–200)
10 (43.5) 21 (91.3) 14 (60.9) 3 (13.0) 7 (30.4) 170 (130–200)
16 (25.0) 61 (95.3) 32 (50.0) 8 (12.5) 8 (12.5) 170 (80–200)
.11 .63 .46 1.0 .06 .15
— — — — — 90 (60–110)*
*P < .00001 comparing analyzed control group vs. analyzed group. MTWA, microvolt T-wave alternans: (abnormal) positive and indeterminate, (normal) negative; NYHA, New York Heart Association class; Ventriculotomy, patients operated by means of right ventriculotomy; Transannular patch, patients operated with transannular patch use; ß-blocker, patients taking ß-blocker.
Congenit Heart Dis. 2015;10:E89–E97
0 (0.0) 0 (0.0) 0 (0.0) 32 (26–41)* 0 (0.0) — 42 ± 5.3 66.0 (60.0–73.0) 16.7 (3.3–98.1)* 32.1 (20.9–47.8)* 89.0 (62.0–115.0)* 179 (151–204) 26.9 (21.3–36.4)* 1.09 (1.0–1.5)* 150.1 ± 30.9 134 (92–222) 34 (14–91) 12 (0–52)
3 (3.4) 17 (19.5) 17 (19.5) 38 (30–61) 41 (47.1) 15 (4–56) 43 ± 5.4 63.0 (53.0–72.0) 35.6 (6.2–271.2) 25.7 (14.1–45) 64.0 (37.0–119.0) 172 (122–226) 32 (21–66) 1.03 (0.95–1.19) 140.4 ± 36.7 120 (54–228) 34 (16–87) 11 (1–39)
2 (8.7) 8 (34.8) 8 (34.8) 41 (32–61) 16 (69.6) 17 (6–35) 44.2 ± 5.9 62.0 (56.0–69.0) 49.6 (9.2–195.4) 23.6 (16.5–38.1) 60.0 (42.0–78.0) 175 (122–202) 35.5 (25–66) 1.04 (1.0–1.13) 133.7 ± 28.2 121 (80–208) 29 (16–59) 9 (1–34)
MTWA (abnormal) (n = 23)
1 (1.6) 9 (14.1) 9 (14.1) 37 (30–53) 25 (39.1) 15 (4–56) 42.5 ± 5.3 63.0 (53.0–72.0) 35.2 (6.2–271.2) 26.9 (14.1–45) 66.0 (37.0–119.0) 171 (139–226) 31 (21–50) 1.02 (0.95–1.19) 142.8 ± 39.2 120 (54–228) 35.5 (18–87) 12 (1–39)
MTWA (normal) (n = 64)
.90 .31 .71 .20 .22
.16 .05 .05 .005 .015 .73 .22 .98 .38 .01 .04 .92
MTWA (abnormal) vs. MTWA (normal) P
*P ≤ .0001 comparing analyzed control group vs. analyzed group. MTWA, microvolt T-wave alternans:(abnormal) positive and indeterminate, (normal) negative; sVT, sustained ventricular tachycardia; nsVT, nonsustained ventricular tachycardia; VPB ≥ 10/h, ventricular premature beats ≥10/hour; RVEDD, right ventricular end-diastolic diameter; PR, pulmonary regurgitation; RVOT gradient, pressure gradient through right ventricular outflow tract; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricle ejection fraction; BNP, brain natriuretic peptide; VO2, peak oxygen consumption; %VO2, percentage of predicted peak oxygen consumption; HRmax, maximal heart rate; VE/VCO2 slope, minute ventilation/carbon dioxide production slope; RER, respiratory exchange ratio; SDNN, standard deviation of all normal sinus RR intervals; SDANN, standard deviation of all average RR intervals calculated over 5-minute segments of the entire recording; rMSSD, square root of the mean squared differences of successive RR intervals; pNN50, the percentages of the number of interval differences of successive RR intervals >50ms.
sVT (%) nsVT/ VPB ≥ 10/h (%) sVT/ nsVT/ VPB ≥ 10/h (%) RVEDD (mm) median (min-max) PR (%) RVOT gradient (mm Hg) median (min-max) LVEDD (mm) mean ± SD LVEF (%) median (min-max) BNP (pg/mL) median (min-max) VO2 (mL/kg/min) median (min-max) %VO2 (%) median(min-max) HR max (/min) median (min-max) VE/VCO2 slope median (min-max) RER median (min-max) SDNN (ms) mean ± SD SDANN (ms) median(min-max) rMSSD (ms) median (min-max) pNN50 (%) median (min-max)
Analyzed control group (n = 43)
Analyzed group (n = 87)
Table 2. Ventricular Arrhythmia, Echocardiographic and Cardiopulmonary Parameters, Serum BNP Concentration, and Heart Rate Variability in the Analyzed Subgroups Characterized by MTWA Result
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Congenit Heart Dis. 2015;10:E89–E97
E94 Table 3.
Bartczak et al. Factors Increasing Probability of Abnormal MTWA in Uni- and Multivariate Logistic Regression Analysis Univariate analysis
PR (%) sVT/nsVT/VPB ≥10/h (%) RVEDD (mm) VE/VCO2 slope VO2 (mL/kg/min)
Multivariate analysis
OR (95% CI)
P
OR (95% CI)
P
3.57 (1.27–10.04) 3.26 (1.06–10.05) 1.11 (1.03–1.2) 1.08 (1.01–1.17) 0.91 (0.83–0.99)
.02 .04 .01 .04 .04
1.79 0.93 1.06 1.07 0.95
.41 .93 .27 .12 .35
(0.44–7.22) (0.18–4.78) (0.95–1.19) (0.98–1.18) (0.86–1.06)
MTWA, microvolt T-wave alternans; PR, pulmonary regurgitation; sVT, sustained ventricular tachycardia; nsVT, nonsustained ventricular tachycardia; VPB ≥ 10/hour, ventricular premature beats ≥10/hour; RVEDD, right ventricular end-diastolic diameter; VE/VCO2 slope, minute ventilation/carbon dioxide production slope; VO2, peak oxygen consumption.
Alexander et al.,20 the phenomenon was observed in 14.0% out of 22 patients with this heart defect. It has also been demonstrated that the predictive value of positive and indeterminate (owing to patient factors) MTWA results is of similar significance27; therefore, in the majority of studies they are interpreted jointly as a “nonnegative” (abnormal) group.14,17 These rules were also applied in our study, and as a consequence 26.4% of the population presented an abnormal MTWA. In a few articles on predominantly pediatric groups quoted above, the authors excluded all patients with indeterminate tests, thus confining its possible meaning.20,21 The outcomes of large studies on SCD high-risk groups with ischemic and nonischemic cardiomyopathy demonstrated an abnormal MTWA phenomenon in as much as 66.0–71.0% of patients which is far more than in our study group. The severity of heart failure as well as age were distinctive features of those populations. The great majority of our patients (87.3%) presented NYHA I functional class and had normal left ventricular systolic function. They were also in their 30s, whereas the groups assessed in the cited publications reached the sixth or seventh decade of life.14,16,17 Our study demonstrated episodes of malignant VA (sVT) only in 3.4% of the patients, which is slightly less than in other analyses concerning repaired ToF, where it accounted for 5.0–14.2%.3,6 This might be associated with the relatively young age of our group, as the incidence of VA has been proven to dramatically increase >45 years of age.3 We have not observed any significant difference in the prevalence of VA between the subgroups defined by the MTWA result. Our analysis was further expanded to evaluate the role of potentially malignant VA in structural heart disease.18 Khairy et al.4 had previously reported the presence of nsVT to be a predictor of appropriate ICD interventions among patients Congenit Heart Dis. 2015;10:E89–E97
after ToF repair which might be suggestive of SCD risk (considering some limitations). The outcomes of our study demonstrated just a poor link of any VA episodes with an abnormal MTWA result. Therefore, we found it impossible to document significant relationship between the MTWA phenomenon and VA in the studied population. However, the attempts to determine SCD risk factors are not limited to arrhythmia monitoring only. Male gender was associated with MTWA phenomenon in our study population. This is congruent with the observation that VA incidence is higher in men,18 including those after ToF repair.3 In the experts’ opinion, the main cause of lifethreatening VA and subsequent SCD in the studied population is a significant pulmonary regurgitation emerging as a result of right ventricular outflow tract widening procedures leading to right ventricular volume overload, enlargement, and systolic dysfunction.1,2,5,8,9 Increased wall strain, presence of fibrotic areas within the myocardium, along with the postoperative scars create substrate for conduction disturbance and reentry circuits.10,11 The outcomes of our analysis confirmed that a significant pulmonary regurgitation and right ventricular enlargement were associated with abnormal MTWA. However, they did not prove as independent predictors of this phenomenon. As a result of biventricular interaction, systolic function of the left ventricle becomes impaired.11,12,29 Subsequently, emerging heart failure is also aggravated by other pathophysiological phenomena like systolic dyssynchrony caused by a patch from the ventricular septal defect repair and inadequate coronary circulation.11,30 However, similarly to the majority of published data concerning patients with this defect, we did not observe impairment of left ventricular ejection fraction.5,10,29,30 Although, some articles prove systolic dysfunction of LV in adults after ToF repair.31,32
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MTWA in Tetralogy of Fallot Out of the analyzed clinical features, previously described as having an indirect pathophysiological impact on the heart failure progress (age at operation,3,5 use of transannular patch, number of reoperations,3,5 serum BNP concentration, undergoing a palliative procedure3–5,7), none was associated with abnormal MTWA in our study. Moreover, according to Gatzoulis et al.,13 QRS complex prolongation above 180 ms (mechanoelectrical interaction) is a risk factor of malignant VA in the studied population. Although not all authors8,10 confirm this phenomenon. Our study did not show the widening of QRS to be a factor increasing probability of abnormal MTWA. Also, HRV parameters reflecting autonomic nervous system activity involved in arrhythmogenesis did not prove as independent predictors of abnormal MTWA. We also observed higher VE/VCO2 slope values along with significantly reduced oxygen uptake among patients after ToF repair with abnormal MTWA result. However, none of these parameters proved as independent predictor of MTWA phenomenon. Heart failure is an undeniable risk factor of SCD.18 Tsai et al.33 have already showed that decreased oxygen uptake was significantly associated with VA in the studied population. Therefore, demonstrating association between heart failure and abnormal MTWA results might be suggestive of prognostic role of the latter for sudden cardiac death stratification in subjects after surgical repair of ToF, just as it has been documented for the overall population with cardiovascular disease. Patients who tested MTWA(abnormal) are subjected to closer follow-up in our outpatient clinic where exercise tests, echocardiographic exams, and 24-hour ECG monitoring are performed. In the case of clinical symptoms of arrhythmia, pharmacological treatment is promptly initiated and electrophysiological study is considered.
annular plane systolic excursion, right ventricle fractional area change, or tricuspid tissue Doppler), which lack solid correlations with MRIderived RV data.34 Lack of prospective analysis seems to be the most important limitation of this study. Therefore, we consider this analysis as a starting point for further observation. At the moment, indirect conclusions may be based only on the available knowledge on SCD and the results obtained from this study.
Limitation of the Study
Accepted in final form October 20, 2014.
Our group of patients after ToF repair is considerably smaller than the cohorts included in the previous studies evaluating prognostic role of MTWA.14,16,17 Given the specificity of population with congenital heart disease, most of the performed clinical trials deal with limited number of patients. We did not apply magnetic resonance imaging (MRI) method of the right ventricle nor other echocardiographic parameters (tricuspid
Conclusions
In adults after ToF repair, abnormal MTWA occurred more often than in controls. The probability of abnormal MTWA did not rise with prevalence of malignant VA; however, presence of abnormal MTWA was associated with VA risk factors: significant pulmonary regurgitation, right ventricular enlargement, and consequent heart failure assesed in cardiopulmonary exercise test. The role of MTWA in selecting patients late after ToF repair at risk of SCD needs further observation. Author Contributions AB, OT, AC, KP, and SG conceived the study idea, and design and performed the data acquisition. AB conducted the literature review. AB, OT, and LK conducted the statistical analysis and interpretation of data. AB and OT drafted the manuscript. All authors were involved in revising the article for important intellectual content and gave final approval of the version to be published.
Corresponding Author: Agnieszka Bartczak, MD, PhD, 1st Department of Cardiology, Poznan University of Medical Sciences, ul. Długa 1/2, 61–848 Poznan´, Poland. Tel: (+48) 603-138-156; Fax: +4861 854 90 85; E-mail: [email protected] Conflict of interest: None.
References
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myocardial infarction and reduced ejection fraction. N Engl J Med. 2002;346:877–883. Kaufman ES, Bloomfield DM, Steinman RC, et al. “Indeterminate” microvolt T-wave alternans tests predict high risk of death or sustained ventricular arrhythmias in patients with left ventricular dysfunction. J Am Coll Cardiol. 2006;48:1399– 1404. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability. Standards of measurement, physiological interpretation and clinical use. Circulation. 1996;93:1043–1065. Kempny A, Diller GP, Orwat S, et al. Right ventricular-left ventricular interaction in adults with tetralogy of Fallot: a combined cardiac magnetic resonance and echocardiographic speckle tracking study. Int J Cardiol. 2012;154:259–264. Trojnarska O, Szyszka A, Gwizdała A, et al. The BNP concentrations and exercise capacity
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assessment with cardiopulmonary stress test in patients after surgical repair of Fallot’s tetralogy. Int J Cardiol. 2006;110:86–92. Broberg CS, Aboulhosn J, Mongeon FP, et al. Prevalence of left ventricular systolic dysfunction in adults with repaired tetralogy of Fallot. Am J Cardiol. 2011;107:1215–1220. Tobler D, Crean AM, Redington AN, et al. The left heart after pulmonary valve replacement in adults late after tetralogy of Fallot repair. Int J Cardiol. 2012;160:165–170. Tsai SF, Chan DP, Ro PS, Boettner B, Daniels CJ. Rate of inducible ventricular arrhythmia in adults with congenital heart disease. Am J Cardiol. 2010;106:730–736. Lai WW, Gauvreau K, Rivera ES, Saleeb S, Powell AJ, Geva T. Accuracy of guideline recommendations for two-dimensional quantification of the right ventricle by echocardiography. Int J Cardiovasc Imaging. 2008;24:691–698.
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Microvolt T-wave Alternans in Adult Patients with Repaired Tetralogy of Fallot Agnieszka Bartczak, MD, PhD,* Olga Trojnarska, MD, PhD,* Aleksandra Cieplucha, MD PhD,* Karolina Plaskota, MD,* Lucyna Kramer, PhD,† and Stefan Grajek, MD, PhD* *1st Department of Cardiology and †Department of Statistic & Computers, Poznan University of Medical Sciences, Poznan´, Poland ABSTRACT
Objective. Indications for sudden cardiac death (SCD) primary prevention are unknown in patients with repaired tetralogy of Fallot (ToF). The role of microvolt T-wave alternans (MTWA) in SCD risk stratification was documented. However, the prevalence of spectral MTWA and its association with ventricular arrhythmia (VA) in adults after ToF repair were not elucidated. Design. Microvolt T-wave alternans, electrocardiogram (ECG), ambulatory ECG monitoring, echocardiography, and spiroergometry were evaluated in 102 adults after ToF repair. Microvolt T-wave alternans results were classified as normal: negative(−), abnormal: positive(+), and indeterminate(ind). Owing to similar prognostic significance, MTWA(+) and MTWA(ind) due to patient factors were combined into nonnegative group: MTWA(abnormal). Results. Microvolt T-wave alternans(abnormal) was more frequent in the studied group as compared with controls (P = .0005). The MTWA(abnormal) group had greater right ventricular end-diastolic diameter (P = .005), higher incidence of pulmonary regurgitation (P = .015), lower peak oxygen consumption (P = .01), and higher VE/VCO2 slope (P = .04) in comparison with MTWA(normal). Univariate logistic regression proved pulmonary regurgitation (OR = 3.57, 95% CI 1.27–10.04), VA (OR = 3.26, 95% CI 1.06–10.05), right ventricular end-diastolic enlargement (OR = 1.11, 95% CI 1.03–1.2), increase in VE/VCO2 slope (OR = 1.08, 95% CI 1.01–1.17), and decrease in peak oxygen uptake (OR = .91, 95% CI 0.83–0.99) to increase MTWA(abnormal) prevalence. Conclusions. In adults after ToF repair, abnormal MTWA occurred more often than in controls. Probability of abnormal MTWA did not rise with prevalence of malignant VA; however, presence of abnormal MTWA was associated with VA risk factors: pulmonary regurgitation, right ventricular enlargement, and consequent heart failure. The role of MTWA in selecting patients late after ToF repair at risk of SCD needs further observation. Key Words. Tetralogy of Fallot; Microvolt T-wave Alternans; Congenital Heart Defect; Ventricular Arrhythmia; Sudden Cardiac Death
Introduction
D
espite good results of tetralogy of Fallot (ToF) repair, about 6% of patients are at risk of sudden cardiac death (SCD), mostly due to malignant ventricular arrhythmia (VA).1–5 The studies already performed documented the prognostic significance of: age at surgery,3,5 current patient’s age,2,3,6 history of palliative procedure,3–5,7 and number of reoperations3,5 to increase the risk of Funding: This research received funding from the Polish Society of Cardiology sponsored by Servier. © 2014 Wiley Periodicals, Inc.
SCD. Pulmonary regurgitation2,8,9 caused by transannular patch placement5,7 is also of great importance as it leads to right ventricular enlargement and dysfunction, as well as left ventricular systolic and diastolic dysfunction3,4,10–12 along with QRS complex prolongation.13 The decision on cardioverter-defibrillator implantation in this group is usually based on electrophysiological study.6 Patients with ischemic or nonischemic cardiomyopathy at high risk of SCD can be identified by means of noninvasive tests such as microvolt T-wave alternans (MTWA).14–18 Microvolt T-wave alternans is an electrocardiographic phenomenon Congenit Heart Dis. 2015;10:E89–E97
E90 displaying inhomogeneity of the myocardial repolarization process which leads to reentry phenomenon and, as a consequence, initiation of VA.15 Microvolt T-wave alternans arises from beat-tobeat changes of action potential duration presumably caused at the level of cardiac myocytes by perturbations in intracellular calcium handling. In the diseased heart, MTWA phenomenon occurs at significantly lower heart rate (HR) than in healthy heart; the cutoff value is HR 140 μmol/L (2), serum aspartate transaminase level exceeding twice the upper limit of normal (1). Ultimately, 102 consecutive patients in sinus rhythm (46 men) aged 18–62 years, who underwent ToF repair at the age of 1–25 years, were enrolled in the study group. In 30 (29.4%) patients, palliative surgery (Blalock– Taussig shunt) was performed. According to current recommendation, patients on antiarrhythmic medication were not excluded from our study.22 Pharmacological anti-arrhythmic Congenit Heart Dis. 2015;10:E89–E97
Bartczak et al. therapy included β-blockers in 15 (14.7%), amiodarone in 3 (2.9%), and digoxin in 3 (2.9%). Control group consisted of 45 healthy volunteers (23 men) aged 18–65 years. Echocardiography
Detailed morphologic assessment was performed with VIVID 7 GE Healthcare device (Little Chalfont, Buckinghamshire, United Kingdom), using 1.5–2.5 MHz probe in 2D, M and Doppler modes according to the current recommendations of the European Society of Cardiology and the American Heart Association.23,24 Right ventricular diameter was estimated from right ventricular inlet measurements made at end-diastole from apical four-chamber view (right ventricle focused view). Residual right ventricular outflow tract obstruction was derived from the peak velocity of the right ventricular outflow tract in short axis plane obtained by continuous-wave Doppler trace and calculated from Bernoulli equation. The severity of the pulmonary regurgitation was estimated by continuous-wave Doppler trace method proposed by Li et al.,25 and it was graded as mild, when the retrograde flow to right ventricle was maintained throughout diastole; moderate, when equilibrium between pulmonary artery-right ventricle pressures occurred in the late diastole; severe, when equilibrium took place in the early diastole. At least moderate pulmonary regurgitation was considered significant. Microvolt T-wave alternans was analyzed in 102 consecutive patients during treadmill test while receiving their usual medications, including betablocker therapy.26 After careful skin preparation, high-resolution electrodes (Micro-V Alternans Sensors, Cambridge Heart Inc., Bedford, MA, USA) were applied using standard precordial leads (V1-V6) and Frank orthogonal configuration (X, Y, Z, VM). Microvolt T-wave alternans was recorded during an HR-based exercise protocol applying CH2000 (Cambridge Heart Inc.) with the use of spectral method employing the fast Fourier transform.19 Gradual increase in workload was individually adjusted to obtain at least 2.5 minutes between an HR of 100 and 110 beats per minute (bpm) and at least 1.5 minutes between an HR of 110 and 120 bpm. The test was considered positive if significant sustained MTWA (i.e., alternans voltage ≥1.9 μV and alternans ratio ≥3.0) was present for at least 1 minute with an onset at an HR ≤110 bpm in any orthogonal lead or two adjacent precordial leads. The test was classified as
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MTWA in Tetralogy of Fallot negative (MTWA[normal]) if it did not meet the criteria for a positive test and if there was ≥1 minute at HR ≥105 bpm of artifact-free trace (noise level 50 ms.28
Cardiopulmonary exercise test was performed according to the modified Bruce protocol (adding stage 0–3 minutes, 1.7 km/h, 5% grading) and symptom limited. Patients were encouraged to continue the exercise until the respiratory exchange ratio (RER) exceeded 1. Oxygen uptake and carbon dioxide production were measured with breath by breath technique using Sensor Medics, model Vmax29 (SensorMedics Corporation, Yorba Linda, CA, USA). Peak oxygen uptake was defined as the average for the last 20 seconds of exercise and expressed as mL/kg/ minute and L/minute, as well as the percentage ranges predicted for sex, age, height, and weight according to Wasserman’s equation. A minute ventilation/carbon dioxide production slope (VE/ VCO2 slope) was assessed by linear regression for the whole exercise. Due to mental disability, cardiopulmonary test was not performed in two patients. Serum brain natriuretic peptide (BNP) concentration was measured in the venous blood samples taken to the EDTA tubes after 15 minutes of rest in supine position using the Abbott AxSYM Immunoassay system, Microparticle Enzyme (MEIA) method (Abbott Diagnostics, Abbott Park, IL, USA). Statistical Analysis
Continuous variables were summarized by mean or median and their ranges, depending on normality of distribution assessed with Wilk– Shapiro test. Variables following normal distribution were analyzed using Student’s t-test or Welch’s test, otherwise nonparametric Mann– Whitney U-test was used. Categorical variables were compared by using the chi-square or Fisher’s exact test, where applicable. To assess predictors of MTWA(abnormal), univariate and multivariate logistic regressions were applied. All tests were two-sided and used P ≤ .05 as statistically significant. Statistical analysis was performed using the Statistica 7.0 package (StatSoft, Inc., Tulsa, OK, USA). The study protocol, as approved by our institutional Ethics Committee, conformed to the ethical guidelines set forth by the 1975 Declaration of Helsinki. Results
Microvolt T-wave alternans examination was performed in total of 102 patients and 45 healthy Congenit Heart Dis. 2015;10:E89–E97
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volunteers. Fifteen patients and two controls were excluded from further analysis because of indeterminate MTWA due to technical factors. In the remaining 87 patients, MTWA was classified as abnormal in 23 (26.4%) subjects (positive in 13 [14.9%] and indeterminate owing to patient factors in 10 [11.5%]) and negative (MTWA[normal]) in 64 (73.6%) patients. Out of 43 volunteers enrolled in the study, only one (2.3%) tested MTWA(+) and the rest (42 [97.7%]) had MTWA(normal) result. The analyzed group was characterized by significantly higher prevalence of MTWA(abnormal) (P = .0005) as compared with the controls. The comparison between subgroups (Table 1) revealed that the number of men among MTWA(abnormal) patients was significantly higher than in MTWA(normal) group (P = .05). Malignant VA occurrence did not differ between analyzed subgroups. The prevalence of potentially malignant VA (nsVT/VPB ≥ 10/hour) as well as any form of VA [sVT/nsVT/VPB ≥ 10/hour] (some patients presented with more than one type of arrhythmia) was significantly higher in MTWA(abnormal) subgroup when compared with MTWA(normal) (P = .05) (Table 2). As shown in Table 2, the analysis of echocardiographic parameters revealed that right ventricular end-diastolic diameter in MTWA(abnormal) patients was significantly larger as compared with those MTWA(normal) (P = .005). Subjects characterized by abnormal MTWA result presented with a significant pulmonary regurgitation more often than those MTWA(normal) (P = .015). Cardiopulmonary exercise test results (Table 2) showed significantly lower peak oxygen consumpTable 1.
tion (mL/kg/min) in MTWA(abnormal) patients in comparison with MTWA(normal) subgroup (P = .01). It was also lower when expressed as percentage of predicted values (%) (P = .04). The VE/VCO2 slope values were significantly higher in MTWA(abnormal) patients as compared with MTWA(normal) (P = .05). There was no difference observed between subgroups defined by MTWA result with regard to HRV parameters (Table 2). As shown in univariate logistic regression analysis, the most powerful factors increasing the prevalence of MTWA(abnormal) are: significant pulmonary regurgitation (OR = 3.57; 95% CI 1.27–10.04; P = .017), episodes of any form of VA (sVT/nsVT/VPB ≥ 10/h) (OR = 3.26; 95% CI 1.06–10.05; P = .04), right ventricular enddiastolic enlargement (OR = 1.11; 95% CI 1.03– 1.2; P = .010), decrease in peak oxygen uptake (OR = 0.91; 95% CI 0.83–0.99; P = .044), and increase in VE/VCO2 slope (OR = 1.08; 95% CI 1.01–1.17; P = .037). We did not confirm the prognostic role of any of the studied parameters when introduced into multivariate analysis (Table 3).
Discussion
The prevalence of positive MTWA result in the studied population is comparable with those published in two available studies describing this phenomenon in patients after ToF repair. According to Cheung et al.,21 positive MTWA test was present in 14.2% out of 49 children who underwent that surgery; in the study conducted by
Clinical and Demographic Data in the Analyzed Subgroups Characterized by MTWA Result Analyzed control group (n = 43)
Male (%) Age (years) median (min-max) NYHA >I (%) Age at surgery (years) median (min-max) Palliative surgery (%) Ventriculotomy (%) Transannular patch (%) Reoperation (%) Β-blocker (%) QRS (ms) median (min-max)
Analyzed group (n = 87)
MTWA (abnormal) (n = 23)
MTWA (normal) (n = 64)
MTWA (abnormal) vs. MTWA (normal) P
22 (51.1) 28 (18–65)
41 (47.1) 30 (18–62)
15 (65.2) 30 (23–58)
26 (40.6) 29 (18–62)
.05 .32
0 (0.0)* —
11 (12.6) 6 (1–21)
4 (17.4) 7 (2–21)
7 (10.9) 5 (1–16)
.14 .09
26 (29.9) 82 (94.2) 46 (52.9) 11 (12.6) 15 (17.2) 170 (80–200)
10 (43.5) 21 (91.3) 14 (60.9) 3 (13.0) 7 (30.4) 170 (130–200)
16 (25.0) 61 (95.3) 32 (50.0) 8 (12.5) 8 (12.5) 170 (80–200)
.11 .63 .46 1.0 .06 .15
— — — — — 90 (60–110)*
*P < .00001 comparing analyzed control group vs. analyzed group. MTWA, microvolt T-wave alternans: (abnormal) positive and indeterminate, (normal) negative; NYHA, New York Heart Association class; Ventriculotomy, patients operated by means of right ventriculotomy; Transannular patch, patients operated with transannular patch use; ß-blocker, patients taking ß-blocker.
Congenit Heart Dis. 2015;10:E89–E97
0 (0.0) 0 (0.0) 0 (0.0) 32 (26–41)* 0 (0.0) — 42 ± 5.3 66.0 (60.0–73.0) 16.7 (3.3–98.1)* 32.1 (20.9–47.8)* 89.0 (62.0–115.0)* 179 (151–204) 26.9 (21.3–36.4)* 1.09 (1.0–1.5)* 150.1 ± 30.9 134 (92–222) 34 (14–91) 12 (0–52)
3 (3.4) 17 (19.5) 17 (19.5) 38 (30–61) 41 (47.1) 15 (4–56) 43 ± 5.4 63.0 (53.0–72.0) 35.6 (6.2–271.2) 25.7 (14.1–45) 64.0 (37.0–119.0) 172 (122–226) 32 (21–66) 1.03 (0.95–1.19) 140.4 ± 36.7 120 (54–228) 34 (16–87) 11 (1–39)
2 (8.7) 8 (34.8) 8 (34.8) 41 (32–61) 16 (69.6) 17 (6–35) 44.2 ± 5.9 62.0 (56.0–69.0) 49.6 (9.2–195.4) 23.6 (16.5–38.1) 60.0 (42.0–78.0) 175 (122–202) 35.5 (25–66) 1.04 (1.0–1.13) 133.7 ± 28.2 121 (80–208) 29 (16–59) 9 (1–34)
MTWA (abnormal) (n = 23)
1 (1.6) 9 (14.1) 9 (14.1) 37 (30–53) 25 (39.1) 15 (4–56) 42.5 ± 5.3 63.0 (53.0–72.0) 35.2 (6.2–271.2) 26.9 (14.1–45) 66.0 (37.0–119.0) 171 (139–226) 31 (21–50) 1.02 (0.95–1.19) 142.8 ± 39.2 120 (54–228) 35.5 (18–87) 12 (1–39)
MTWA (normal) (n = 64)
.90 .31 .71 .20 .22
.16 .05 .05 .005 .015 .73 .22 .98 .38 .01 .04 .92
MTWA (abnormal) vs. MTWA (normal) P
*P ≤ .0001 comparing analyzed control group vs. analyzed group. MTWA, microvolt T-wave alternans:(abnormal) positive and indeterminate, (normal) negative; sVT, sustained ventricular tachycardia; nsVT, nonsustained ventricular tachycardia; VPB ≥ 10/h, ventricular premature beats ≥10/hour; RVEDD, right ventricular end-diastolic diameter; PR, pulmonary regurgitation; RVOT gradient, pressure gradient through right ventricular outflow tract; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricle ejection fraction; BNP, brain natriuretic peptide; VO2, peak oxygen consumption; %VO2, percentage of predicted peak oxygen consumption; HRmax, maximal heart rate; VE/VCO2 slope, minute ventilation/carbon dioxide production slope; RER, respiratory exchange ratio; SDNN, standard deviation of all normal sinus RR intervals; SDANN, standard deviation of all average RR intervals calculated over 5-minute segments of the entire recording; rMSSD, square root of the mean squared differences of successive RR intervals; pNN50, the percentages of the number of interval differences of successive RR intervals >50ms.
sVT (%) nsVT/ VPB ≥ 10/h (%) sVT/ nsVT/ VPB ≥ 10/h (%) RVEDD (mm) median (min-max) PR (%) RVOT gradient (mm Hg) median (min-max) LVEDD (mm) mean ± SD LVEF (%) median (min-max) BNP (pg/mL) median (min-max) VO2 (mL/kg/min) median (min-max) %VO2 (%) median(min-max) HR max (/min) median (min-max) VE/VCO2 slope median (min-max) RER median (min-max) SDNN (ms) mean ± SD SDANN (ms) median(min-max) rMSSD (ms) median (min-max) pNN50 (%) median (min-max)
Analyzed control group (n = 43)
Analyzed group (n = 87)
Table 2. Ventricular Arrhythmia, Echocardiographic and Cardiopulmonary Parameters, Serum BNP Concentration, and Heart Rate Variability in the Analyzed Subgroups Characterized by MTWA Result
MTWA in Tetralogy of Fallot E93
Congenit Heart Dis. 2015;10:E89–E97
E94 Table 3.
Bartczak et al. Factors Increasing Probability of Abnormal MTWA in Uni- and Multivariate Logistic Regression Analysis Univariate analysis
PR (%) sVT/nsVT/VPB ≥10/h (%) RVEDD (mm) VE/VCO2 slope VO2 (mL/kg/min)
Multivariate analysis
OR (95% CI)
P
OR (95% CI)
P
3.57 (1.27–10.04) 3.26 (1.06–10.05) 1.11 (1.03–1.2) 1.08 (1.01–1.17) 0.91 (0.83–0.99)
.02 .04 .01 .04 .04
1.79 0.93 1.06 1.07 0.95
.41 .93 .27 .12 .35
(0.44–7.22) (0.18–4.78) (0.95–1.19) (0.98–1.18) (0.86–1.06)
MTWA, microvolt T-wave alternans; PR, pulmonary regurgitation; sVT, sustained ventricular tachycardia; nsVT, nonsustained ventricular tachycardia; VPB ≥ 10/hour, ventricular premature beats ≥10/hour; RVEDD, right ventricular end-diastolic diameter; VE/VCO2 slope, minute ventilation/carbon dioxide production slope; VO2, peak oxygen consumption.
Alexander et al.,20 the phenomenon was observed in 14.0% out of 22 patients with this heart defect. It has also been demonstrated that the predictive value of positive and indeterminate (owing to patient factors) MTWA results is of similar significance27; therefore, in the majority of studies they are interpreted jointly as a “nonnegative” (abnormal) group.14,17 These rules were also applied in our study, and as a consequence 26.4% of the population presented an abnormal MTWA. In a few articles on predominantly pediatric groups quoted above, the authors excluded all patients with indeterminate tests, thus confining its possible meaning.20,21 The outcomes of large studies on SCD high-risk groups with ischemic and nonischemic cardiomyopathy demonstrated an abnormal MTWA phenomenon in as much as 66.0–71.0% of patients which is far more than in our study group. The severity of heart failure as well as age were distinctive features of those populations. The great majority of our patients (87.3%) presented NYHA I functional class and had normal left ventricular systolic function. They were also in their 30s, whereas the groups assessed in the cited publications reached the sixth or seventh decade of life.14,16,17 Our study demonstrated episodes of malignant VA (sVT) only in 3.4% of the patients, which is slightly less than in other analyses concerning repaired ToF, where it accounted for 5.0–14.2%.3,6 This might be associated with the relatively young age of our group, as the incidence of VA has been proven to dramatically increase >45 years of age.3 We have not observed any significant difference in the prevalence of VA between the subgroups defined by the MTWA result. Our analysis was further expanded to evaluate the role of potentially malignant VA in structural heart disease.18 Khairy et al.4 had previously reported the presence of nsVT to be a predictor of appropriate ICD interventions among patients Congenit Heart Dis. 2015;10:E89–E97
after ToF repair which might be suggestive of SCD risk (considering some limitations). The outcomes of our study demonstrated just a poor link of any VA episodes with an abnormal MTWA result. Therefore, we found it impossible to document significant relationship between the MTWA phenomenon and VA in the studied population. However, the attempts to determine SCD risk factors are not limited to arrhythmia monitoring only. Male gender was associated with MTWA phenomenon in our study population. This is congruent with the observation that VA incidence is higher in men,18 including those after ToF repair.3 In the experts’ opinion, the main cause of lifethreatening VA and subsequent SCD in the studied population is a significant pulmonary regurgitation emerging as a result of right ventricular outflow tract widening procedures leading to right ventricular volume overload, enlargement, and systolic dysfunction.1,2,5,8,9 Increased wall strain, presence of fibrotic areas within the myocardium, along with the postoperative scars create substrate for conduction disturbance and reentry circuits.10,11 The outcomes of our analysis confirmed that a significant pulmonary regurgitation and right ventricular enlargement were associated with abnormal MTWA. However, they did not prove as independent predictors of this phenomenon. As a result of biventricular interaction, systolic function of the left ventricle becomes impaired.11,12,29 Subsequently, emerging heart failure is also aggravated by other pathophysiological phenomena like systolic dyssynchrony caused by a patch from the ventricular septal defect repair and inadequate coronary circulation.11,30 However, similarly to the majority of published data concerning patients with this defect, we did not observe impairment of left ventricular ejection fraction.5,10,29,30 Although, some articles prove systolic dysfunction of LV in adults after ToF repair.31,32
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MTWA in Tetralogy of Fallot Out of the analyzed clinical features, previously described as having an indirect pathophysiological impact on the heart failure progress (age at operation,3,5 use of transannular patch, number of reoperations,3,5 serum BNP concentration, undergoing a palliative procedure3–5,7), none was associated with abnormal MTWA in our study. Moreover, according to Gatzoulis et al.,13 QRS complex prolongation above 180 ms (mechanoelectrical interaction) is a risk factor of malignant VA in the studied population. Although not all authors8,10 confirm this phenomenon. Our study did not show the widening of QRS to be a factor increasing probability of abnormal MTWA. Also, HRV parameters reflecting autonomic nervous system activity involved in arrhythmogenesis did not prove as independent predictors of abnormal MTWA. We also observed higher VE/VCO2 slope values along with significantly reduced oxygen uptake among patients after ToF repair with abnormal MTWA result. However, none of these parameters proved as independent predictor of MTWA phenomenon. Heart failure is an undeniable risk factor of SCD.18 Tsai et al.33 have already showed that decreased oxygen uptake was significantly associated with VA in the studied population. Therefore, demonstrating association between heart failure and abnormal MTWA results might be suggestive of prognostic role of the latter for sudden cardiac death stratification in subjects after surgical repair of ToF, just as it has been documented for the overall population with cardiovascular disease. Patients who tested MTWA(abnormal) are subjected to closer follow-up in our outpatient clinic where exercise tests, echocardiographic exams, and 24-hour ECG monitoring are performed. In the case of clinical symptoms of arrhythmia, pharmacological treatment is promptly initiated and electrophysiological study is considered.
annular plane systolic excursion, right ventricle fractional area change, or tricuspid tissue Doppler), which lack solid correlations with MRIderived RV data.34 Lack of prospective analysis seems to be the most important limitation of this study. Therefore, we consider this analysis as a starting point for further observation. At the moment, indirect conclusions may be based only on the available knowledge on SCD and the results obtained from this study.
Limitation of the Study
Accepted in final form October 20, 2014.
Our group of patients after ToF repair is considerably smaller than the cohorts included in the previous studies evaluating prognostic role of MTWA.14,16,17 Given the specificity of population with congenital heart disease, most of the performed clinical trials deal with limited number of patients. We did not apply magnetic resonance imaging (MRI) method of the right ventricle nor other echocardiographic parameters (tricuspid
Conclusions
In adults after ToF repair, abnormal MTWA occurred more often than in controls. The probability of abnormal MTWA did not rise with prevalence of malignant VA; however, presence of abnormal MTWA was associated with VA risk factors: significant pulmonary regurgitation, right ventricular enlargement, and consequent heart failure assesed in cardiopulmonary exercise test. The role of MTWA in selecting patients late after ToF repair at risk of SCD needs further observation. Author Contributions AB, OT, AC, KP, and SG conceived the study idea, and design and performed the data acquisition. AB conducted the literature review. AB, OT, and LK conducted the statistical analysis and interpretation of data. AB and OT drafted the manuscript. All authors were involved in revising the article for important intellectual content and gave final approval of the version to be published.
Corresponding Author: Agnieszka Bartczak, MD, PhD, 1st Department of Cardiology, Poznan University of Medical Sciences, ul. Długa 1/2, 61–848 Poznan´, Poland. Tel: (+48) 603-138-156; Fax: +4861 854 90 85; E-mail: [email protected] Conflict of interest: None.
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