Late gadolinium enhancement of cardiac magnetic resonance imaging indicates abnormalities of time-domain T-wave alternans in hypertrophic cardiomyopathy with ventricular tachycardia Naka Sakamoto, MD,* Nobuyuki Sato, MD, PhD,* Kensuke Oikawa, MD, PhD,† Ahmed Karim Talib, MD, PhD,* Eitaro Sugiyama, MD,* Akiho Minoshima, MD,* Yasuko Tanabe, MD, PhD,* Toshiharu Takeuchi, MD,* Kazumi Akasaka, MD, PhD,*† Yasuaki Saijo, MD, PhD,‡ Yuichiro Kawamura, MD, PhD,* Naoyuki Hasebe, MD, PhD* From the *Department of Cardiology, †Department of Pathology, and ‡Division of Community Medicine and Epidemiology, Department of Health Science, Asahikawa Medical University, Asahikawa, Japan. BACKGROUND The presence of myocardial scar detected by late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) imaging has been described as a good independent predictor of mortality in patients with hypertrophic cardiomyopathy (HCM). Time-domain T-wave alternans (TWA) is also a potential predictor of cardiac mortality in patients with left ventricular dysfunction. OBJECTIVE The purpose of this study was to elucidate the relationship between LGE distribution and TWA in patients with HCM. METHODS CMR and TWA analyses using Holter monitoring were performed in 42 patients with HCM. The average transmural extent of LGE was scored as 1–4 in each segment, and the sum of the LGE scores (total LGE score) was calculated for each patient. The correlation between the maximal time-domain TWA voltage and LGE findings was analyzed, and the differences in time-domain TWA voltage, total LGE score, and cardiac function assessed by CMR imaging in the presence or absence of ventricular tachycardia (VT) were also compared. RESULTS The total LGE score was significantly and positively correlated with the maximal time-domain TWA voltage (r ¼ 0.59; P o .001). Furthermore, the total LGE score and maximal timedomain TWA voltage were significantly greater in patients who had
Introduction T-wave alternans (TWA) has been shown to be one of the most useful predictive markers for cardiac mortality since it reflects myocardial electrical instability. It has been demonstrated that TWA is increased in various diseases such as heart failure, ischemic heart disease, and nonischemic Address reprint requests and correspondence: Dr Nobuyuki Sato, Department of Cardiology, Asahikawa Medical University, Midorigaoka Higashi 2-1-1, Asahikawa 078-8510, Japan. E-mail address: [email protected].
1547-5271/$-see front matter B 2015 Heart Rhythm Society. All rights reserved.
episodes of VT (n ¼ 21) than in those without VT (23 ⫾ 7 vs 10 ⫾ 8; P o .001 and 87 ⫾ 26 μV vs 62 ⫾ 12 μV; P o .001, respectively). However, the left ventricular ejection fraction did not statistically differ between patients with VT and those without VT (56% ⫾ 14% vs 61% ⫾ 7%; P ¼ .102). CONCLUSION The magnitude of the localized LGE was significantly correlated with abnormalities in ventricular repolarization as assessed by TWA and QT dispersion. KEYWORDS T-wave alternans; Cardiac magnetic resonance imaging; Late gadolinium enhancement; Hypertrophic cardiomyopathy; Ventricular tachycardia; Ventricular fibrillation ABBREVIATIONS CMR ¼ cardiac magnetic resonance; ECG ¼ electrocardiogram/electrocardiographic; EDV ¼ end-diastolic volume; EF ¼ ejection fraction; HCM ¼ hypertrophic cardiomyopathy; LGE ¼ late gadolinium enhancement; LV ¼ left ventricular/ventricle; QTd ¼ QT dispersion; SCD ¼ sudden cardiac death; TD-TWA ¼ time-domain T-wave alternans; TWA ¼ T-wave alternans; VF ¼ ventricular fibrillation; VT ¼ ventricular tachycardia (Heart Rhythm 2015;12:1747–1755) I 2015 Heart Rhythm Society. All rights reserved.
cardiomyopathy.1–8 In hypertrophic cardiomyopathy (HCM), the positive ratio of microvolt TWA has been shown to be higher, and its mechanism is explained by abnormal myocardial arrangement (disarray) and/or fibrosis.8 Indeed, myocardial disarray, ischemia, and fibrosis can modify the electrophysiological properties of the myocardium, which will cause dispersion of the impulse conduction leading to a reentrant phenomenon.9,10 Time-domain TWA using 24-hour Holter electrocardiographic (ECG) recordings has also been available for http://dx.doi.org/10.1016/j.hrthm.2015.04.028
1748 approximately 12 years, and it has been proven to be useful for the risk stratification of sudden cardiac death (SCD) without an exercise test.11 Time-domain TWA is also applied to various diseases such as heart failure, vasospastic angina, and Brugada syndrome and is shown to be a good predictive marker.12–14 In contrast, it has been shown that scar tissue can be detected as late gadolinium enhancement (LGE) on contrastenhanced cardiac magnetic resonance (CMR) imaging even in nonischemic myocardial disease such as HCM15–18 and that the degree of LGE is a predictive factor of cardiac sudden death.15,16,18 Moreover, the presence of myocardial scar detected by LGE has been described as a good independent predictor of all-cause and cardiac mortality in patients with HCM.17 Taken together, we sought to evaluate the relationship between LGE distribution and TWA in patients with HCM who had a history of ventricular tachycardia (VT) and those without VT.
Heart Rhythm, Vol 12, No 8, August 2015 during daily activity. The maximal TD-TWA voltage at a heart rate of o120 beats/min was obtained in these 2 leads. Manual editing was needed to exclude beats with noise and artifact. TWA with a value of 465 μV was defined as positive, which was in accordance with previous reports.12 QT measurements were performed on the standard 12lead ECG with a paper speed of 25 mm/s, and all recordings were magnified by 200% to increase the resolution. The QT interval was defined as the interval from the onset of the QRS complex to the end of the T wave, which was the intersection of the isoelectric line and T wave. If a U wave existed, the end of the QT interval was taken to be the nadir between the T and U wave peaks. For QT dispersion (QTd), the difference between the maximum and the minimum interval on the 12-lead ECG was calculated. The measurements were performed by 2 investigators blinded to the results of other studies, and the average values were used.
CMR imaging protocol
Methods Study patients We analyzed the 24-hour ECG recordings of patients who were referred to our hospital for an evaluation of HCM with or without VT/VF (ventricular fibrillation) from 2004 to 2014. During admission, a standard investigation protocol was performed in each patient, including a 12-lead surface ECG, chest radiography, 2-dimensional echocardiography, 24-hour Holter monitoring, myocardial perfusion imaging, CMR imaging, cardiac catheterization when indicated, endomyocardial biopsy, and an electrophysiological study when appropriate. The participants in this study consisted of 42 patients with HCM. The diagnosis of HCM was based on the demonstration of a hypertrophied left ventricle (LV; wall thickness Z13 mm) associated with a nondilated LV in the absence of another cardiac or systemic disease. In all patients, coronary angiography was performed to certify that no significant coronary artery disease was present. HCM was also histopathologically confirmed by a right ventricular endomyocardial biopsy in 31 patients. All participants gave their written informed consent. The local institutional ethics review board approved this study.
TWA and QT dispersion measurement Time-domain T-wave alternans (TD-TWA) was measured using the modified moving average algorithm in commercial software (MARS, GE Healthcare Inc, Milwaukee, WI). This method has been described in detail in the original report.11,19 Briefly, the modified moving average algorithm continuously streams odd and even beats into separate bins and creates median complexes at any point within the JT segment and it is regarded as the TWA value, which is updated every 15 seconds. The moving average algorithm allows control of the influence of new incoming beats on the median complexes with an adjustable update factor, which was 1/8 in this analysis. The TWA value was measured in leads V2 and V5 from the 24-hour Holter ECG recordings
A 1.5-T scanner (Magnetom Sonata, Siemens Japan K.K., Tokyo, Japan) was used for all CMR imaging examinations. The CMR imaging protocol included a functional study of the LV using an ECG-triggered breath-hold segmented steady-state free-precession cine sequence with a slice thickness of 8 mm. After 3 standard long-axis slices were obtained, contiguous short-axis slices were acquired to cover the entire LV without an interslice gap. The LGE images were acquired 10 minutes after an intravenous administration of 0.15 mmol/kg of gadolinium-diethylenetriamine pentaacetic acid (DTPA) (Magnevist, Bayer Yakuhin, Ltd, Osaka, Japan) with a breath-hold 2-dimensional segmented inversion-recovery sequence (TI 200–350 ms), acquired in the same orientation as the cine images.
CMR analysis The LV volumes, LV mass, LV ejection fraction (EF), and LGE status were assessed via standard planimetry techniques with semi-automated computer software (QMass MR 7.2.2, Medis Medical Imaging Systems, Leiden, The Netherlands) by 2 independent readers blinded to all patient information. We manually traced the LV endocardial border on all shortaxis images. By using a semiautomatic detection algorithm, we applied a signal-intensity threshold of 4 SDs above a reference remote myocardial region on the same slice to define areas of LGE. The LV wall was divided into 4 segments (anterior, septal, inferior, and lateral) in each short axial slice (basal, middle, and apical). Thus, all LV wall views were divided into 12 segments (Figure 1). The segments were classified into those with enhancement (LGE-positive) and those without (LGE-negative). To measure the transmural extent of LGE, radial lines extending from the epicardium to the endocardium were drawn in each sector and the proportion of each line that intersected the LGE area was automatically calculated. The average transmural extent of enhancement in each segment was expressed by using the following scale (score): 0 ¼ none, 1 ¼ 1%–25%, 2 ¼ 26%–
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Figure 1 Myocardial segments and late gadolinium enhancement (LGE) score on cardiac magnetic resonance imaging. A computer-assisted algorithm applied signal-intensity thresholds of 44 SDs above the normal myocardial segment to delineate the scar (red region). SA ¼ short axial.
50%, 3 ¼ 51%–75%, and 4 ¼ 76%–100% of the wall thickness. The sum of LGE transmural scores (total LGE score) was calculated for each patient.
variables, the Pearson correlation method was used. All statistical analyses were performed using SPSS statistical software (version 15.0 for Windows, SPSS, Inc, Chicago, IL).
Histology of endomyocardial biopsy specimens
Results
Right ventricular endomyocardial biopsy specimens were fixed in 10% formalin, paraffin-embedded, and sectioned for light microscopy. The sections were stained with hematoxylin and eosin, Azan, and periodic acid-Schiff stain. The presence or absence of myocyte disarray was determined, and subendocardial fibrosis was excluded from the analyses. Visual estimates of the areas affected (% area) by interstitial or replacement fibrosis were assessed as described by Almaas et al.20 For the quantitative analysis of fibrosis, Azan-stained slides were digitally scanned (at 100 magnification). The digital images were converted into single blue channel images, and the total specimen areas and blue areas were measured to calculate the % area of the total amount of fibrosis by using ImageJ image processing software (US National Institutes of Health). The observers were blinded to the clinical data and outcome. As a representative example, a specimen obtained from a patient with severe interstitial fibrosis is shown in Online Supplemental Figure 1.
Study patients
Statistical analysis Continuous variables are expressed as mean +/- SD or as n (%). The differences in variables between the 2 groups were analyzed using Student t test, Mann-Whitney test, or Fisher exact test, and a probability value of o.05 was considered statistically significant. To test the association between 2
Table 1 summarizes the clinical characteristics, CMR imaging parameters, TWA parameters, and histology parameters of all 42 patients with HCM and 31 patients with HCM with available histology data. The median age was approximately 60 years, and approximately 80% were male patients. The average EF was 58% ⫾ 11%. VT, defined as Z3 consecutive ventricular beats at a rate of 4120 beats/min for nonsustained VT and lasting 430 seconds for sustained VT, was documented on the Holter ECG in 21 patients. In 3 cases in which VT was recorded, VF was also documented on ambulatory ECG monitoring or during the electrophysiological study. LGE was demonstrated in 41 of 42 patients. The average score of the total LGE score was; 17 ⫾ 10, and the average of the maximal TD-TWA voltage was 74 ⫾ 24 μV.
TWA and CMR imaging parameters Figure 2A shows the correlation between the maximal TDTWA voltage and the total LGE score. The total LGE score was significantly and positively correlated with the maximal TD-TWA voltage (r ¼ 0.59; P o .001). A comparison of the variables between patients with and without VT is shown in Table 2. Although there was no significant difference between the values of the CMR
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Table 1 Characteristics of all 42 patients with HCM and the 31 patients with available histological data
Characteristic Sex: male Age (y) Type of HCM HNCM HOCM d-HCM Family history of sudden cardiac death History of atrial fibrillation CMR imaging parameters LV EF (%) LV EDV (mL) LV mass (g) Total LGE score Maximum LV wall thickness (mm) ECG parameters Maximum QT interval (ms) Minimum QT interval (ms) QTd (ms) Heart rate Maximal TD-TWA voltage (μV) Ventricular tachycardia Ventricular fibrillation Histological parameters Disarray present Histological fibrosis present % Area of the total amount of fibrosis Medications at the time of TWA measurements β-Blockers Calcium channel antagonists Antiarrhythmic agents
All patients (N ¼ 42)
Patients with available histological data (n ¼ 31)
33 (79) 59 ⫾ 12
22 (71) 60 ⫾ 12
27 (64) 5 (12) 10 (24) 9 (21)
24 (77) 4 (13) 3 (10) 8 (26)
8 (19)
7 (23)
58 ⫾ 132 ⫾ 158 ⫾ 17 ⫾ 17 ⫾
11 36 58 10 5
479 ⫾ 37 434 ⫾ 39 42 ⫾ 10 59 ⫾ 15 74 ⫾ 24 21 (50) 7 (17)
61 ⫾ 121 ⫾ 155 ⫾ 16 ⫾ 17 ⫾
8 31 53 10 5
475 ⫾ 39 431 ⫾ 41 41 ⫾ 11 59 ⫾ 16 71 ⫾ 23 15 (48) 5 (16) 16 (52) 27 (87) 20 ⫾ 12
was no significant difference between the values of the CMR imaging parameters such as LV EF, LV end-diastolic volume, and LV mass, the total LGE score was significantly greater in TD-TWA–positive patients than in TD-TWA– negative patients (20 ⫾ 8 vs 11 ⫾ 10; P o .001). Furthermore, we evaluated the relationship between QTd and both the TWA value and LGE score. As shown in Figures 2B and 2C, there was a modestly significant correlation between QTd and both the TWA value and LGE score, but the correlation coefficients were not so high (r ¼ 0.53; P o .001) and r ¼ 0.68; P o .001, respectively) and some points were scattered. Figure 3 shows a typical example of a TWA-positive patient who had a history of polymorphic VT. His LGE score was 23 points, and the TWA value was 87 μV. Figure 4 shows a typical example of a TWA-negative patient who did not have a history of polymorphic VT. His LGE score was 3 points, and the TWA value was 53 μV.
Histological parameters Table 3 shows the comparison of the histological and CMR imaging parameters in 31 patients with and without VT. In patients with VT, the total LGE score and % area of the total amount of fibrosis were significantly higher than those in patients without VT. Figure 2D shows the relationship between the total LGE score and % area. There was a significant correlation between the total LGE score and % area.
Discussion 39 (93) 14 (33)
28 (90) 11 (35)
20 (48)
15 (48)
Values are expressed as mean ⫾ SD or as n (%). CMR ¼ cardiac magnetic resonance; d-HCM ¼ dilated phase of hypertrophic cardiomyopathy; ECG ¼ electrocardiographic; EDV ¼ enddiastolic volume; EF ¼ ejection fraction; HCM ¼ hypertrophic cardiomyopathy; HNCM ¼ hypertrophic nonobstructive cardiomyopathy; HOCM ¼ hypertrophic obstructive cardiomyopathy; LGE ¼ late gadolinium enhancement; LV ¼ left ventricle; QTd ¼ QT dispersion; TD-TWA ¼ time-domain T-wave alternans; TWA ¼ T-wave alternans.
imaging parameters such as LV EF, LV end-diastolic volume, and LV mass, the total LGE score was significantly greater in patients who had episodes of VT than in those without VT (23 ⫾ 7 vs 10 ⫾ 8; P o .001). Also, the maximal TD-TWA voltage was significantly greater in patients with VT than in those without VT (87 ⫾ 26 μV vs 62 ⫾ 12 μV; P o .001). Subsequently, we compared the cardiac function, total LGE score, and presence or absence of VT between the TWA-positive group (maximal TD-TWA voltage Z65 μV) and the TWA-negative group (maximal TD-TWA voltage o65 μV). A comparison of the clinical variables between TD-TWA–positive and TD-TWA–negative patients is shown in Online Supplemental Table 1. Although there
In the present study, we demonstrated that myocardial scar detected by LGE was closely related to TWA; namely, the total scar burden correlated with repolarization abnormality, which would enhance reentry, and thus cause severe ventricular arrhythmia. To our knowledge, this is the first study to investigate the relationship between LGE on CMR imaging and TWA and gain an insight into the possible mechanisms. TWA is known to reflect the spatiotemporal heterogeneity of repolarization. Furthermore, TWA reflects not only changes in the action potential duration but also the conduction velocity restitution, and subsequent functional and/or anatomical gradients in the action potential duration can produce a heterogeneous repolarization gradient leading to reentry.8 Chauhan and coworkers21,22 measured local activation times, activation-recovery intervals, and repolarization intervals in humans and found that patients with cardiomyopathy and VT/TWA have greater endocardial and epicardial repolarization heterogeneity than those without VT/TWA; they concluded that steep repolarization gradients may provide a substrate for conduction block and subsequent reentrant arrhythmias. In our study, VT occurred independently of the value of the EF and was closely correlated with TWA. Since TWA correlated with QTd, indicating repolarization heterogeneity, and TWA also correlated with LGE
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Figure 2 A: Correlation between the maximal time-domain T-wave alternans (TD-TWA) voltage and the total late gadolinium enhancement (LGE) score. B: Correlation between QT dispersion and the TD-TWA voltage. C: Correlation between QT dispersion and the LGE score. D: Correlation between the % area of the total amount of fibrosis and the total LGE score.
on CMR imaging, indicating transmural inhomogeneity of the cardiac tissues, our data suggested that TWA, which can reflect endocardial and epicardial repolarization heterogeneity, might be a useful tool to predict VT/VF. In HCM, various conditions such as hypertrophy, fibrosis, ischemia, sympathetic activation, and intracellular calcium handling should be taken into consideration with regard to the pathogenesis. As for hypertrophy, downregulation of repolarization potassium channels is known to occur, which may lead to dispersion of repolarization.23 From a histopathological point of view, it has been shown that fiber disarray and/or fibrosis are correlated with the occurrence of TWA and VT in HCM. Kon-no et al9 investigated TWA in 12 patients with HCM and LV hypertrophy and found that TWA may be related to an abnormal myocardial disarray and/or fibrosis. Kuroda et al10 also reported the relationship between TWA and the histopathological changes in 22 patients with HCM and found that TWA is correlated with myocardial disarray.
In the present study, we analyzed the relationship between the histological findings and LGE. As a result, there was a correlation between the LGE score or VT and the histological findings (the areas affected [%area] by interstitial or replacement fibrosis). Since there was also a correlation between the TWA value and LGE, these findings suggest that TWA values would be high in LGE areas reflecting fibrosis. For the possible ischemia in HCM, exercise-induced myocardial ischemia and a related increase in QTd has been demonstrated using thallium–201 stress myocardial imaging.24 In nonischemic cardiomyopathy, accelerated sympathetic nervous activity is also shown to play an important role in provoking TWA.25,26 Calkins et al27 also found greater mid-myocardial ventricular refractory periods in regions of sympathetic denervation as defined by positron emission tomography imaging, suggesting that altered sympathetic innervation is an important mechanism in TWA. In our study, the close relationship between QTd and TWA might
1752 Table 2
Heart Rhythm, Vol 12, No 8, August 2015 Comparison of the variables between patients with and without VT
Characteristic Sex: male Age (y) Type of HCM HNCM HOCM d-HCM Family history of sudden cardiac death History of atrial fibrillation CMR imaging parameters LV EF (%) LV EDV (mL) LV mass (g) Total LGE score Maximum LV wall thickness (mm) ECG parameters Maximum QT interval (ms) Minimum QT interval (ms) QTd (ms) Heart rate (beats/min) Maximal TD-TWA voltage (μV) Medications at the time of TWA measurements β-Blockers Calcium channel antagonists Antiarrhythmic agents
All patients (N ¼ 42)
Patients with VT (n ¼ 21)
Patients without VT (n ¼ 21)
P
33 (79) 59 ⫾ 12
17 (81) 58 ⫾ 12
16 (76) 60 ⫾ 12
1.000 .676
27 (64) 5 (12) 10 (24) 9 (21) 8 (19)
10 (48) 2 (9) 9 (43) 6 (29) 7 (33)
17 (81) 3 (14) 1 (5) 3 (14) 1 (5)
.011
58 132 158 17 17
⫾ 11 ⫾ 36 ⫾ 58 ⫾ 10 ⫾5
56 ⫾ 140 ⫾ 159 ⫾ 23 ⫾ 16 ⫾
479 434 42 59 74
⫾ 37 ⫾ 39 ⫾ 10 ⫾ 15 ⫾ 24
39 (93) 14 (33) 20 (48)
14 40 47 7 5
61 ⫾ 124 ⫾ 157 ⫾ 10 ⫾ 17 ⫾
.454 .045
7 30 68 8 5
.102 .143 .912 o.001 .432
481 ⫾ 41 429 ⫾ 42 49 ⫾ 8 55 ⫾ 8 87 ⫾ 26
476 ⫾ 33 439 ⫾ 36 36 ⫾ 8 62 ⫾ 18 62 ⫾ 12
.646 .395 o.001 .172 o.001
21 (100) 6 (29) 14 (67)
18 (86) 8 (38) 6 (29)
.232 .744 .029
Values are expressed as mean ⫾ SD or as n (%). CMR ¼ cardiac magnetic resonance; d-HCM ¼ dilated phase of hypertrophic cardiomyopathy; ECG ¼ electrocardiographic; EDV ¼ end-diastolic volume; EF ¼ ejection fraction; HCM ¼ hypertrophic cardiomyopathy; HNCM ¼ hypertrophic nonobstructive cardiomyopathy; HOCM ¼ hypertrophic obstructive cardiomyopathy; LGE ¼ late gadolinium enhancement; LV ¼ left ventricular; QTd ¼ QT dispersion; TD-TWA ¼ time-domain T-wave alternans; TWA ¼ T-wave alternans; VT ¼ ventricular tachycardia.
Figure 3 Representative T-wave alternans (TWA)–positive patient with a history of polymorphic ventricular tachycardia (VT; male patients aged 51 years). Findings from (A) cardiac magnetic resonance (CMR) imaging, (B) electrocardiography, and (C) time-domain T-wave alternans (TD-TWA) assessment. EDV ¼ end-diastolic volume; EF ¼ ejection fraction; LGE ¼ late gadolinium enhancement; LV ¼ left ventricular; SA ¼ short axial.
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Figure 4 Representative T-wave alternans (TWA)–negative patient without a history of polymorphic ventricular tachycardia (VT; male patients aged 57 years). Findings from (A) cardiac magnetic resonance (CMR) imaging, (B) electrocardiography, and (C) time-domain T-wave alternans (TD-TWA) assessment. EDV ¼ end-diastolic volume; EF ¼ ejection fraction; LGE ¼ late gadolinium enhancement; LV ¼ left ventricular; SA ¼ short axial; VF ¼ ventricular fibrillation.
indicate that the presence of an underlying sympathetic activation since sympathetic nerve stimulation could prolong the QT interval and increase QTd. Finally, the precise correlation between QT indices and TWA remains unknown. Armoundas et al28 reported a correlation between the corrected QT interval at rest and TWA, although the majority of patients had coronary heart disease. Kuroda et al29 measured the QT interval at rest and during exercise and found that there was a close relationship between TWA and the prolonged maximum QT interval in
patients with HCM . They speculated that the hypertrophy of myocytes may cause an extension of the action potential duration, and the proliferation of cardiac interstitial tissue may be associated with a shortened action potential duration, which would cause repolarization inhomogeneity. In our study, TWA was correlated with both LGE and VT occurrence. Also, QTd was correlated with both TWA and LGE. Although the power of the QTd measurement for predicting a high risk of VT and SCD may be limited, our study strongly suggested that repolarization abnormality, as
Table 3 Comparison of histological and CMR imaging parameters between the 31 patients with available histological data with and without VT Parameter Histological parameters Disarray present Histological fibrosis present % Area of the total amount of fibrosis CMR imaging parameters LV EF (%) LV EDV (mL) LV mass (g) Total LGE score Maximum LV wall thickness (mm)
Patients with available histological data (n ¼ 31) 16 (52) 27 (87) 20 ⫾ 12 61 ⫾ 121 ⫾ 155 ⫾ 16 ⫾ 17 ⫾
8 31 53 10 5
Patients with VT (n ¼ 15) 6 (40) 15 (100) 24 ⫾ 15 59 ⫾ 125 ⫾ 166 ⫾ 22 ⫾ 17 ⫾
10 33 45 8 6
Patients without VT (n ¼ 16) 10 (63) 12 (75) 15 ⫾ 7 62 ⫾ 117 ⫾ 145 ⫾ 10 ⫾ 17 ⫾
6 29 59 7 5
P .289 .101 .036 .407 .482 .277 o.001 .933
Values are expressed as mean ⫾ SD or as n (%). CMR ¼ cardiac magnetic resonance; EDV ¼ end-diastolic volume; EF ¼ ejection fraction; LGE ¼ late gadolinium enhancement; LV ¼ left ventricular; VT ¼ ventricular tachycardia.
1754 defined by TWA (and QTd) combined with the extent of LGE on CMR imaging, can be a useful tool for the risk stratification in HCM, by reflecting the special dispersion as well as temporal dispersion.
Study limitations The results of this study should be interpreted in light of their limitations. First, the number of patients in the study group was small. Second, although we demonstrated the relationship between TWA and LGE, we did not find any direct evidence that this abnormality was associated with VT. However, we believe that the information provided in this study, indicating that LGE on CMR imaging had a close relationship with TWA, is quite valuable for evaluating patients with lethal arrhythmias. Third, Holter recording was performed in the presence of medications in some cases because of the underlying structural heart disease and primary prevention of lethal arrhythmias. Although β-blockers might decrease TWA, the overall arrhythmic risk and relationship between the LGE score and TWA could be evaluated in either the absence or the presence of prophylactic drugs for lethal arrhythmias, and it is believed to be worthy of evaluation as in the previous clinical trials. Fourth, in this study we did not evaluate LGE of intermediate intensity. In patients with previous myocardial infarction, it is reported that the extent of the peri-infarct region based on a signal-intensity threshold of o3 SD above the mean signal intensity of the remote myocardium provides an incremental prognostic value.30 Thus, there is a possibility that scar heterogeneity may also have been relevant, but that was not evaluated in this study. Furthermore, with the recent advances in cardiac imaging, it has been reported that contrast-enhanced CMR T1 mapping can now identify diffuse fibrosis not detectable by the conventional delayed enhanced CMR imaging.31 Since TWA is considered, at least in part, to reflect repolarization abnormality associated with the scar heterogeneity, further precise studies will be necessary to elucidate that evaluation.
Conclusion This study demonstrated that the magnitude of the localized LGE was significantly correlated with abnormalities in ventricular repolarization as assessed by TWA and QTd. Dispersion of repolarization among healthy and damaged myocardium would account, in part, for the occurrence of VT in HCM.
Appendix Supplementary data Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/j.hrthm. 2015.04.028.
References [1]. Bloomfield DM, Steinman RC, Namerow PB, et al. Microvolt T-wave alternans distinguishes between patients likely and patients not likely to benefit from implanted cardiac defibrillator therapy: a solution to the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II conundrum. Circulation 2004;110: 1885–1889.
Heart Rhythm, Vol 12, No 8, August 2015 [2]. Gehi AK, Stein RH, Metz LD, Gomes JA. Microvolt T-wave alternans for the risk stratification of ventricular tachyarrhythmic events: a meta-analysis. J Am Coll Cardiol 2005;46:75–82. [3]. Chow T, Kereiakes DJ, Bartone C, Booth T, Schloss EJ, Waller T, Chung ES, Menon S, Nallamothu BK, Chan PS. Prognostic utility of microvolt T-wave alternans in risk stratification of patients with ischemic cardiomyopathy. J Am Coll Cardiol 2006;47:1820–1827. [4]. Bloomfield DM, Bigger JT, Steinman RC, Namerow PB, Parides MK, Curtis AB, Kaufman ES, Davidenko JM, Shinn TS, Fontaine JM. Microvolt T-wave alternans and the risk of death or sustained ventricular arrhythmias in patients with left ventricular dysfunction. J Am Coll Cardiol 2006;47:456–463. [5]. Chow T, Kereiakes DJ, Bartone C, Booth T, Schloss EJ, Waller T, Chung E, Menon S, Nallamothu BK, Chan PS. Microvolt T-wave alternans identifies patients with ischemic cardiomyopathy who benefit from implantable cardioverter-defibrillator therapy. J Am Coll Cardiol 2007;49:50–58. [6]. Exner DV, Kavanagh KM, Slawnych MP, et al; REFINE Investigators. Noninvasive risk assessment early after a myocardial infarction: the REFINE study. J Am Coll Cardiol 2007;50:2275–2284. [7]. Salerno-Uriarte JA, De Ferrari GM, Klersy C, et al. Prognostic value of T-wave alternans in patients with heart failure due to nonischemic cardiomyopathy: results of the ALPHA Study. J Am Coll Cardiol 2007;50:1896–1904. [8]. Verrier RL, Klingenheben T, Malik M, El-Sherif N, Exner DV, Hohnloser SH, Ikeda T, Martínez JP, Narayan SM, Nieminen T, Rosenbaum DS. 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;50:1309–1324. [9]. Kon-No Y, Watanabe J, Koseki Y, Koyama J, Yamada A, Toda S, Shinozaki T, Fukuchi M, Miura M, Kagaya Y, Shirato K. Microvolt T wave alternans in human cardiac hypertrophy: electrical instability and abnormal myocardial arrangement. J Cardiovasc Electrophysiol 2001;12:759–763. [10]. Kuroda N, Ohnishi Y, Yoshida A, Kimura A, Yokoyama M. Clinical significance of T-wave alternans in hypertrophic cardiomyopathy. Circ J 2002;66:457–462. [11]. Nearing BD, Verrier RL. Modified moving average analysis of T-wave alternans to predict ventricular fibrillation with high accuracy. J Appl Physiol 2002;92:541–549. [12]. Sasaki K, Ikeda T, Miwa Y, Miyakoshi M, Abe A, Tsukada T, Ishiguro H, Mera H, Yusu S, Yoshino H. Time-domain T-wave alternans measured from Holter electrocardiograms predicts cardiac mortality in patients with left ventricular dysfunction: a prospective study. Heart Rhythm 2009;6:332–337. [13]. Shimada H, Nishizaki M, Fujii H, Yamawake N, Fukamizu S, Sakurada H, Hiraoka M. Ambulatory electrocardiogram-based T-wave alternans in patients with vasospastic angina during asymptomatic periods. Am J Cardiol 2012;110:1446–1451. [14]. Uchimura-Makita Y, Nakano Y, Tokuyama T, et al. Time-domain T-wave alternans is strongly associated with a history of ventricular fibrillation in patients with Brugada syndrome. J Cardiovasc Electrophysiol 2014;25: 1021–1027. [15]. Choudhury L, Mahrholdt H, Wagner A, Choi KM, Elliott MD, Klocke FJ, Bonow RO, Judd RM, Kim RJ. Myocardial scarring in asymptomatic or mildly symptomatic patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 2002;40:2156–2164. [16]. Moon JC, McKenna WJ, McCrohon JA, Elliott PM, Smith GC, Pennell DJ. Toward clinical risk assessment in hypertrophic cardiomyopathy with gadolinium cardiovascular magnetic resonance. J Am Coll Cardiol 2003;41: 1561–1567. [17]. Bruder O, Wagner A, Jensen CJ, Schneider S, Ong P, Kispert EM, Nassenstein K, Schlosser T, Sabin GV, Sechtem U, Mahrholdt H. Myocardial scar visualized by cardiovascular magnetic resonance imaging predicts major adverse events in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 2010;56:875–887. [18]. Chan RH, Maron BJ, Olivotto I, et al. Prognostic value of quantitative contrastenhanced cardiovascular magnetic resonance for the evaluation of sudden death risk in patients with hypertrophic cardiomyopathy. Circulation 2014;130: 484–495. [19]. Nieminen T, Verrier RL. Usefulness of T-wave alternans in sudden death risk stratification and guiding medical therapy. Ann Noninvasive Electrocardiol 2010;15:276–288. [20]. Almaas VM, Haugaa KH, Strøm EH, Scott H, Smith HJ, Dahl CP, Geiran OR, Endresen K, Aakhus S, Amlie JP, Edvardsen T. Noninvasive assessment of myocardial fibrosis in patients with obstructive hypertrophic cardiomyopathy. Heart 2014;100:631–638. [21]. Chauhan VS, Downar E, Nanthakumar K, Parker JD, Ross HJ, Chan W, Picton P. Increased ventricular repolarization heterogeneity in patients with ventricular arrhythmia vulnerability and cardiomyopathy: a human in vivo study. Am J Physiol Heart Circ Physiol 2006;290:H79–H86.
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[22]. Selvaraj RJ, Picton P, Nanthakumar K, Chauhan VS. Steeper restitution slopes across right ventricular endocardium in patients with cardiomyopathy at high risk of ventricular arrhythmias. Am J Physiol Heart Circ Physiol 2007;292:H1262–H1268. [23]. Shi C, Wang X, Dong F, Wang Y, Hui J, Lin Z, Yang J, Xu Y. Temporal alterations and cellular mechanisms of transmural repolarization during progression of mouse cardiac hypertrophy and failure. Acta Physiol (Oxf) 2013;208:95–110. [24]. Yamanari H, Fukushima K, Miyaji K, Miyaji K, Yamamoto M, Nagase S, Misunaga-Otsuka F, Nakayama K, Matsubara H, Emori T, Ohe T. Effects of myocardial perfusion on QT dispersion in patients with hypertrophic cardiomyopathy. Ann Noninvasive Electrocardiol 2000;5:60–67. [25]. Harada M, Shimizu A, Murata M, Ono K, Kubo M, Mitani R, Dairaku Y, Matsumoto T, Yamagata T, Seki K, Matsuzaki M. Relation between microvoltlevel T-wave alternans and cardiac sympathetic nervous system abnormality using iodine-123 metaiodobenzylguanidine imaging in patients with idiopathic dilated cardiomyopathy. Am J Cardiol 2003;92:998–1001. [26]. Selvaraj RJ, Suszko AM, Subramanian A, Nanthakumar K, Chauhan VS. Adrenergic stimulation increases repolarization dispersion and reduces activation-repolarization coupling along the RV endocardium of patients with cardiomyopathy. Europace 2009;11:1529–1535.
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[27]. Calkins H, Allman K, Bolling S, Kirsch M, Wieland D, Morady F, Schwaiger M. Correlation between scintigraphic evidence of regional sympathetic neuronal dysfunction and ventricular refractoriness in the human heart. Circulation 1993;88:172–179. [28]. Armoundas AA, Osaka M, Mela T, Rosenbaum DS, Ruskin JN, Garan H, Cohen RJ. T-wave alternans and dispersion of the QT interval as risk stratification markers in patients susceptible to sustained ventricular arrhythmias. Am J Cardiol 1998;82:1127–1129. [29]. Kuroda N, Ohnishi Y, Adachi K, Yokoyama M. Relationship between the QT indices and the microvolt-level T wave alternans in cardiomyopathy. Jpn Circ J 2001;65:974–978. [30]. Yan AT, Shayne AJ, Brown KA, Gupta SN, Chan CW, Luu TM, Di Carli MF, Reynolds HG, Stevenson WG, Kwong RY. Characterization of the peri-infarct zone by contrast-enhanced cardiac magnetic resonance imaging is a powerful predictor of post-myocardial infarction mortality. Circulation 2006;114:32–39. [31]. Iles L, Pfluger H, Phrommintikul A, Cherayath J, Aksit P, Gupta SN, Kaye DM, Taylor AJ. Evaluation of diffuse myocardial fibrosis in heart failure with cardiac magnetic resonance contrast-enhanced T1 mapping. J Am Coll Cardiol 2008;52:1574–1580.
CLINICAL PERSPECTIVES There have been several reports on the association between late gadolinium enhancement (LGE) and long-term outcomes in patients with hypertrophic cardiomyopathy (HCM), and the data collected support the relationship between LGE and cardiovascular mortality. However, few studies have shown the relationship between LGE and an increased risk of sudden death, although LGE has been shown to be associated with nonsustained ventricular tachycardia on Holter monitoring. Consequently, 2014 ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy state that the extent of LGE on cardiac magnetic resonance imaging has some utility in predicting cardiovascular mortality, but the current evidence does not support the use of LGE in the prediction of the risk of sudden cardiac death. In the present study, for the first time we demonstrated that LGE had a close relationship with abnormalities in ventricular repolarization as assessed by T-wave alternans and QT dispersion, which can lead to lethal ventricular arrhythmias in HCM. Although our study was performed based on a retrospective analysis, a prospective study investigating the correlations among LGE, repolarization electrocardiographic parameters, and sudden cardiac death will provide important information for high-risk HCM patients.
Introduction T-wave alternans (TWA) has been shown to be one of the most useful predictive markers for cardiac mortality since it reflects myocardial electrical instability. It has been demonstrated that TWA is increased in various diseases such as heart failure, ischemic heart disease, and nonischemic Address reprint requests and correspondence: Dr Nobuyuki Sato, Department of Cardiology, Asahikawa Medical University, Midorigaoka Higashi 2-1-1, Asahikawa 078-8510, Japan. E-mail address: [email protected].
1547-5271/$-see front matter B 2015 Heart Rhythm Society. All rights reserved.
episodes of VT (n ¼ 21) than in those without VT (23 ⫾ 7 vs 10 ⫾ 8; P o .001 and 87 ⫾ 26 μV vs 62 ⫾ 12 μV; P o .001, respectively). However, the left ventricular ejection fraction did not statistically differ between patients with VT and those without VT (56% ⫾ 14% vs 61% ⫾ 7%; P ¼ .102). CONCLUSION The magnitude of the localized LGE was significantly correlated with abnormalities in ventricular repolarization as assessed by TWA and QT dispersion. KEYWORDS T-wave alternans; Cardiac magnetic resonance imaging; Late gadolinium enhancement; Hypertrophic cardiomyopathy; Ventricular tachycardia; Ventricular fibrillation ABBREVIATIONS CMR ¼ cardiac magnetic resonance; ECG ¼ electrocardiogram/electrocardiographic; EDV ¼ end-diastolic volume; EF ¼ ejection fraction; HCM ¼ hypertrophic cardiomyopathy; LGE ¼ late gadolinium enhancement; LV ¼ left ventricular/ventricle; QTd ¼ QT dispersion; SCD ¼ sudden cardiac death; TD-TWA ¼ time-domain T-wave alternans; TWA ¼ T-wave alternans; VF ¼ ventricular fibrillation; VT ¼ ventricular tachycardia (Heart Rhythm 2015;12:1747–1755) I 2015 Heart Rhythm Society. All rights reserved.
cardiomyopathy.1–8 In hypertrophic cardiomyopathy (HCM), the positive ratio of microvolt TWA has been shown to be higher, and its mechanism is explained by abnormal myocardial arrangement (disarray) and/or fibrosis.8 Indeed, myocardial disarray, ischemia, and fibrosis can modify the electrophysiological properties of the myocardium, which will cause dispersion of the impulse conduction leading to a reentrant phenomenon.9,10 Time-domain TWA using 24-hour Holter electrocardiographic (ECG) recordings has also been available for http://dx.doi.org/10.1016/j.hrthm.2015.04.028
1748 approximately 12 years, and it has been proven to be useful for the risk stratification of sudden cardiac death (SCD) without an exercise test.11 Time-domain TWA is also applied to various diseases such as heart failure, vasospastic angina, and Brugada syndrome and is shown to be a good predictive marker.12–14 In contrast, it has been shown that scar tissue can be detected as late gadolinium enhancement (LGE) on contrastenhanced cardiac magnetic resonance (CMR) imaging even in nonischemic myocardial disease such as HCM15–18 and that the degree of LGE is a predictive factor of cardiac sudden death.15,16,18 Moreover, the presence of myocardial scar detected by LGE has been described as a good independent predictor of all-cause and cardiac mortality in patients with HCM.17 Taken together, we sought to evaluate the relationship between LGE distribution and TWA in patients with HCM who had a history of ventricular tachycardia (VT) and those without VT.
Heart Rhythm, Vol 12, No 8, August 2015 during daily activity. The maximal TD-TWA voltage at a heart rate of o120 beats/min was obtained in these 2 leads. Manual editing was needed to exclude beats with noise and artifact. TWA with a value of 465 μV was defined as positive, which was in accordance with previous reports.12 QT measurements were performed on the standard 12lead ECG with a paper speed of 25 mm/s, and all recordings were magnified by 200% to increase the resolution. The QT interval was defined as the interval from the onset of the QRS complex to the end of the T wave, which was the intersection of the isoelectric line and T wave. If a U wave existed, the end of the QT interval was taken to be the nadir between the T and U wave peaks. For QT dispersion (QTd), the difference between the maximum and the minimum interval on the 12-lead ECG was calculated. The measurements were performed by 2 investigators blinded to the results of other studies, and the average values were used.
CMR imaging protocol
Methods Study patients We analyzed the 24-hour ECG recordings of patients who were referred to our hospital for an evaluation of HCM with or without VT/VF (ventricular fibrillation) from 2004 to 2014. During admission, a standard investigation protocol was performed in each patient, including a 12-lead surface ECG, chest radiography, 2-dimensional echocardiography, 24-hour Holter monitoring, myocardial perfusion imaging, CMR imaging, cardiac catheterization when indicated, endomyocardial biopsy, and an electrophysiological study when appropriate. The participants in this study consisted of 42 patients with HCM. The diagnosis of HCM was based on the demonstration of a hypertrophied left ventricle (LV; wall thickness Z13 mm) associated with a nondilated LV in the absence of another cardiac or systemic disease. In all patients, coronary angiography was performed to certify that no significant coronary artery disease was present. HCM was also histopathologically confirmed by a right ventricular endomyocardial biopsy in 31 patients. All participants gave their written informed consent. The local institutional ethics review board approved this study.
TWA and QT dispersion measurement Time-domain T-wave alternans (TD-TWA) was measured using the modified moving average algorithm in commercial software (MARS, GE Healthcare Inc, Milwaukee, WI). This method has been described in detail in the original report.11,19 Briefly, the modified moving average algorithm continuously streams odd and even beats into separate bins and creates median complexes at any point within the JT segment and it is regarded as the TWA value, which is updated every 15 seconds. The moving average algorithm allows control of the influence of new incoming beats on the median complexes with an adjustable update factor, which was 1/8 in this analysis. The TWA value was measured in leads V2 and V5 from the 24-hour Holter ECG recordings
A 1.5-T scanner (Magnetom Sonata, Siemens Japan K.K., Tokyo, Japan) was used for all CMR imaging examinations. The CMR imaging protocol included a functional study of the LV using an ECG-triggered breath-hold segmented steady-state free-precession cine sequence with a slice thickness of 8 mm. After 3 standard long-axis slices were obtained, contiguous short-axis slices were acquired to cover the entire LV without an interslice gap. The LGE images were acquired 10 minutes after an intravenous administration of 0.15 mmol/kg of gadolinium-diethylenetriamine pentaacetic acid (DTPA) (Magnevist, Bayer Yakuhin, Ltd, Osaka, Japan) with a breath-hold 2-dimensional segmented inversion-recovery sequence (TI 200–350 ms), acquired in the same orientation as the cine images.
CMR analysis The LV volumes, LV mass, LV ejection fraction (EF), and LGE status were assessed via standard planimetry techniques with semi-automated computer software (QMass MR 7.2.2, Medis Medical Imaging Systems, Leiden, The Netherlands) by 2 independent readers blinded to all patient information. We manually traced the LV endocardial border on all shortaxis images. By using a semiautomatic detection algorithm, we applied a signal-intensity threshold of 4 SDs above a reference remote myocardial region on the same slice to define areas of LGE. The LV wall was divided into 4 segments (anterior, septal, inferior, and lateral) in each short axial slice (basal, middle, and apical). Thus, all LV wall views were divided into 12 segments (Figure 1). The segments were classified into those with enhancement (LGE-positive) and those without (LGE-negative). To measure the transmural extent of LGE, radial lines extending from the epicardium to the endocardium were drawn in each sector and the proportion of each line that intersected the LGE area was automatically calculated. The average transmural extent of enhancement in each segment was expressed by using the following scale (score): 0 ¼ none, 1 ¼ 1%–25%, 2 ¼ 26%–
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Figure 1 Myocardial segments and late gadolinium enhancement (LGE) score on cardiac magnetic resonance imaging. A computer-assisted algorithm applied signal-intensity thresholds of 44 SDs above the normal myocardial segment to delineate the scar (red region). SA ¼ short axial.
50%, 3 ¼ 51%–75%, and 4 ¼ 76%–100% of the wall thickness. The sum of LGE transmural scores (total LGE score) was calculated for each patient.
variables, the Pearson correlation method was used. All statistical analyses were performed using SPSS statistical software (version 15.0 for Windows, SPSS, Inc, Chicago, IL).
Histology of endomyocardial biopsy specimens
Results
Right ventricular endomyocardial biopsy specimens were fixed in 10% formalin, paraffin-embedded, and sectioned for light microscopy. The sections were stained with hematoxylin and eosin, Azan, and periodic acid-Schiff stain. The presence or absence of myocyte disarray was determined, and subendocardial fibrosis was excluded from the analyses. Visual estimates of the areas affected (% area) by interstitial or replacement fibrosis were assessed as described by Almaas et al.20 For the quantitative analysis of fibrosis, Azan-stained slides were digitally scanned (at 100 magnification). The digital images were converted into single blue channel images, and the total specimen areas and blue areas were measured to calculate the % area of the total amount of fibrosis by using ImageJ image processing software (US National Institutes of Health). The observers were blinded to the clinical data and outcome. As a representative example, a specimen obtained from a patient with severe interstitial fibrosis is shown in Online Supplemental Figure 1.
Study patients
Statistical analysis Continuous variables are expressed as mean +/- SD or as n (%). The differences in variables between the 2 groups were analyzed using Student t test, Mann-Whitney test, or Fisher exact test, and a probability value of o.05 was considered statistically significant. To test the association between 2
Table 1 summarizes the clinical characteristics, CMR imaging parameters, TWA parameters, and histology parameters of all 42 patients with HCM and 31 patients with HCM with available histology data. The median age was approximately 60 years, and approximately 80% were male patients. The average EF was 58% ⫾ 11%. VT, defined as Z3 consecutive ventricular beats at a rate of 4120 beats/min for nonsustained VT and lasting 430 seconds for sustained VT, was documented on the Holter ECG in 21 patients. In 3 cases in which VT was recorded, VF was also documented on ambulatory ECG monitoring or during the electrophysiological study. LGE was demonstrated in 41 of 42 patients. The average score of the total LGE score was; 17 ⫾ 10, and the average of the maximal TD-TWA voltage was 74 ⫾ 24 μV.
TWA and CMR imaging parameters Figure 2A shows the correlation between the maximal TDTWA voltage and the total LGE score. The total LGE score was significantly and positively correlated with the maximal TD-TWA voltage (r ¼ 0.59; P o .001). A comparison of the variables between patients with and without VT is shown in Table 2. Although there was no significant difference between the values of the CMR
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Table 1 Characteristics of all 42 patients with HCM and the 31 patients with available histological data
Characteristic Sex: male Age (y) Type of HCM HNCM HOCM d-HCM Family history of sudden cardiac death History of atrial fibrillation CMR imaging parameters LV EF (%) LV EDV (mL) LV mass (g) Total LGE score Maximum LV wall thickness (mm) ECG parameters Maximum QT interval (ms) Minimum QT interval (ms) QTd (ms) Heart rate Maximal TD-TWA voltage (μV) Ventricular tachycardia Ventricular fibrillation Histological parameters Disarray present Histological fibrosis present % Area of the total amount of fibrosis Medications at the time of TWA measurements β-Blockers Calcium channel antagonists Antiarrhythmic agents
All patients (N ¼ 42)
Patients with available histological data (n ¼ 31)
33 (79) 59 ⫾ 12
22 (71) 60 ⫾ 12
27 (64) 5 (12) 10 (24) 9 (21)
24 (77) 4 (13) 3 (10) 8 (26)
8 (19)
7 (23)
58 ⫾ 132 ⫾ 158 ⫾ 17 ⫾ 17 ⫾
11 36 58 10 5
479 ⫾ 37 434 ⫾ 39 42 ⫾ 10 59 ⫾ 15 74 ⫾ 24 21 (50) 7 (17)
61 ⫾ 121 ⫾ 155 ⫾ 16 ⫾ 17 ⫾
8 31 53 10 5
475 ⫾ 39 431 ⫾ 41 41 ⫾ 11 59 ⫾ 16 71 ⫾ 23 15 (48) 5 (16) 16 (52) 27 (87) 20 ⫾ 12
was no significant difference between the values of the CMR imaging parameters such as LV EF, LV end-diastolic volume, and LV mass, the total LGE score was significantly greater in TD-TWA–positive patients than in TD-TWA– negative patients (20 ⫾ 8 vs 11 ⫾ 10; P o .001). Furthermore, we evaluated the relationship between QTd and both the TWA value and LGE score. As shown in Figures 2B and 2C, there was a modestly significant correlation between QTd and both the TWA value and LGE score, but the correlation coefficients were not so high (r ¼ 0.53; P o .001) and r ¼ 0.68; P o .001, respectively) and some points were scattered. Figure 3 shows a typical example of a TWA-positive patient who had a history of polymorphic VT. His LGE score was 23 points, and the TWA value was 87 μV. Figure 4 shows a typical example of a TWA-negative patient who did not have a history of polymorphic VT. His LGE score was 3 points, and the TWA value was 53 μV.
Histological parameters Table 3 shows the comparison of the histological and CMR imaging parameters in 31 patients with and without VT. In patients with VT, the total LGE score and % area of the total amount of fibrosis were significantly higher than those in patients without VT. Figure 2D shows the relationship between the total LGE score and % area. There was a significant correlation between the total LGE score and % area.
Discussion 39 (93) 14 (33)
28 (90) 11 (35)
20 (48)
15 (48)
Values are expressed as mean ⫾ SD or as n (%). CMR ¼ cardiac magnetic resonance; d-HCM ¼ dilated phase of hypertrophic cardiomyopathy; ECG ¼ electrocardiographic; EDV ¼ enddiastolic volume; EF ¼ ejection fraction; HCM ¼ hypertrophic cardiomyopathy; HNCM ¼ hypertrophic nonobstructive cardiomyopathy; HOCM ¼ hypertrophic obstructive cardiomyopathy; LGE ¼ late gadolinium enhancement; LV ¼ left ventricle; QTd ¼ QT dispersion; TD-TWA ¼ time-domain T-wave alternans; TWA ¼ T-wave alternans.
imaging parameters such as LV EF, LV end-diastolic volume, and LV mass, the total LGE score was significantly greater in patients who had episodes of VT than in those without VT (23 ⫾ 7 vs 10 ⫾ 8; P o .001). Also, the maximal TD-TWA voltage was significantly greater in patients with VT than in those without VT (87 ⫾ 26 μV vs 62 ⫾ 12 μV; P o .001). Subsequently, we compared the cardiac function, total LGE score, and presence or absence of VT between the TWA-positive group (maximal TD-TWA voltage Z65 μV) and the TWA-negative group (maximal TD-TWA voltage o65 μV). A comparison of the clinical variables between TD-TWA–positive and TD-TWA–negative patients is shown in Online Supplemental Table 1. Although there
In the present study, we demonstrated that myocardial scar detected by LGE was closely related to TWA; namely, the total scar burden correlated with repolarization abnormality, which would enhance reentry, and thus cause severe ventricular arrhythmia. To our knowledge, this is the first study to investigate the relationship between LGE on CMR imaging and TWA and gain an insight into the possible mechanisms. TWA is known to reflect the spatiotemporal heterogeneity of repolarization. Furthermore, TWA reflects not only changes in the action potential duration but also the conduction velocity restitution, and subsequent functional and/or anatomical gradients in the action potential duration can produce a heterogeneous repolarization gradient leading to reentry.8 Chauhan and coworkers21,22 measured local activation times, activation-recovery intervals, and repolarization intervals in humans and found that patients with cardiomyopathy and VT/TWA have greater endocardial and epicardial repolarization heterogeneity than those without VT/TWA; they concluded that steep repolarization gradients may provide a substrate for conduction block and subsequent reentrant arrhythmias. In our study, VT occurred independently of the value of the EF and was closely correlated with TWA. Since TWA correlated with QTd, indicating repolarization heterogeneity, and TWA also correlated with LGE
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Figure 2 A: Correlation between the maximal time-domain T-wave alternans (TD-TWA) voltage and the total late gadolinium enhancement (LGE) score. B: Correlation between QT dispersion and the TD-TWA voltage. C: Correlation between QT dispersion and the LGE score. D: Correlation between the % area of the total amount of fibrosis and the total LGE score.
on CMR imaging, indicating transmural inhomogeneity of the cardiac tissues, our data suggested that TWA, which can reflect endocardial and epicardial repolarization heterogeneity, might be a useful tool to predict VT/VF. In HCM, various conditions such as hypertrophy, fibrosis, ischemia, sympathetic activation, and intracellular calcium handling should be taken into consideration with regard to the pathogenesis. As for hypertrophy, downregulation of repolarization potassium channels is known to occur, which may lead to dispersion of repolarization.23 From a histopathological point of view, it has been shown that fiber disarray and/or fibrosis are correlated with the occurrence of TWA and VT in HCM. Kon-no et al9 investigated TWA in 12 patients with HCM and LV hypertrophy and found that TWA may be related to an abnormal myocardial disarray and/or fibrosis. Kuroda et al10 also reported the relationship between TWA and the histopathological changes in 22 patients with HCM and found that TWA is correlated with myocardial disarray.
In the present study, we analyzed the relationship between the histological findings and LGE. As a result, there was a correlation between the LGE score or VT and the histological findings (the areas affected [%area] by interstitial or replacement fibrosis). Since there was also a correlation between the TWA value and LGE, these findings suggest that TWA values would be high in LGE areas reflecting fibrosis. For the possible ischemia in HCM, exercise-induced myocardial ischemia and a related increase in QTd has been demonstrated using thallium–201 stress myocardial imaging.24 In nonischemic cardiomyopathy, accelerated sympathetic nervous activity is also shown to play an important role in provoking TWA.25,26 Calkins et al27 also found greater mid-myocardial ventricular refractory periods in regions of sympathetic denervation as defined by positron emission tomography imaging, suggesting that altered sympathetic innervation is an important mechanism in TWA. In our study, the close relationship between QTd and TWA might
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Heart Rhythm, Vol 12, No 8, August 2015 Comparison of the variables between patients with and without VT
Characteristic Sex: male Age (y) Type of HCM HNCM HOCM d-HCM Family history of sudden cardiac death History of atrial fibrillation CMR imaging parameters LV EF (%) LV EDV (mL) LV mass (g) Total LGE score Maximum LV wall thickness (mm) ECG parameters Maximum QT interval (ms) Minimum QT interval (ms) QTd (ms) Heart rate (beats/min) Maximal TD-TWA voltage (μV) Medications at the time of TWA measurements β-Blockers Calcium channel antagonists Antiarrhythmic agents
All patients (N ¼ 42)
Patients with VT (n ¼ 21)
Patients without VT (n ¼ 21)
P
33 (79) 59 ⫾ 12
17 (81) 58 ⫾ 12
16 (76) 60 ⫾ 12
1.000 .676
27 (64) 5 (12) 10 (24) 9 (21) 8 (19)
10 (48) 2 (9) 9 (43) 6 (29) 7 (33)
17 (81) 3 (14) 1 (5) 3 (14) 1 (5)
.011
58 132 158 17 17
⫾ 11 ⫾ 36 ⫾ 58 ⫾ 10 ⫾5
56 ⫾ 140 ⫾ 159 ⫾ 23 ⫾ 16 ⫾
479 434 42 59 74
⫾ 37 ⫾ 39 ⫾ 10 ⫾ 15 ⫾ 24
39 (93) 14 (33) 20 (48)
14 40 47 7 5
61 ⫾ 124 ⫾ 157 ⫾ 10 ⫾ 17 ⫾
.454 .045
7 30 68 8 5
.102 .143 .912 o.001 .432
481 ⫾ 41 429 ⫾ 42 49 ⫾ 8 55 ⫾ 8 87 ⫾ 26
476 ⫾ 33 439 ⫾ 36 36 ⫾ 8 62 ⫾ 18 62 ⫾ 12
.646 .395 o.001 .172 o.001
21 (100) 6 (29) 14 (67)
18 (86) 8 (38) 6 (29)
.232 .744 .029
Values are expressed as mean ⫾ SD or as n (%). CMR ¼ cardiac magnetic resonance; d-HCM ¼ dilated phase of hypertrophic cardiomyopathy; ECG ¼ electrocardiographic; EDV ¼ end-diastolic volume; EF ¼ ejection fraction; HCM ¼ hypertrophic cardiomyopathy; HNCM ¼ hypertrophic nonobstructive cardiomyopathy; HOCM ¼ hypertrophic obstructive cardiomyopathy; LGE ¼ late gadolinium enhancement; LV ¼ left ventricular; QTd ¼ QT dispersion; TD-TWA ¼ time-domain T-wave alternans; TWA ¼ T-wave alternans; VT ¼ ventricular tachycardia.
Figure 3 Representative T-wave alternans (TWA)–positive patient with a history of polymorphic ventricular tachycardia (VT; male patients aged 51 years). Findings from (A) cardiac magnetic resonance (CMR) imaging, (B) electrocardiography, and (C) time-domain T-wave alternans (TD-TWA) assessment. EDV ¼ end-diastolic volume; EF ¼ ejection fraction; LGE ¼ late gadolinium enhancement; LV ¼ left ventricular; SA ¼ short axial.
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Figure 4 Representative T-wave alternans (TWA)–negative patient without a history of polymorphic ventricular tachycardia (VT; male patients aged 57 years). Findings from (A) cardiac magnetic resonance (CMR) imaging, (B) electrocardiography, and (C) time-domain T-wave alternans (TD-TWA) assessment. EDV ¼ end-diastolic volume; EF ¼ ejection fraction; LGE ¼ late gadolinium enhancement; LV ¼ left ventricular; SA ¼ short axial; VF ¼ ventricular fibrillation.
indicate that the presence of an underlying sympathetic activation since sympathetic nerve stimulation could prolong the QT interval and increase QTd. Finally, the precise correlation between QT indices and TWA remains unknown. Armoundas et al28 reported a correlation between the corrected QT interval at rest and TWA, although the majority of patients had coronary heart disease. Kuroda et al29 measured the QT interval at rest and during exercise and found that there was a close relationship between TWA and the prolonged maximum QT interval in
patients with HCM . They speculated that the hypertrophy of myocytes may cause an extension of the action potential duration, and the proliferation of cardiac interstitial tissue may be associated with a shortened action potential duration, which would cause repolarization inhomogeneity. In our study, TWA was correlated with both LGE and VT occurrence. Also, QTd was correlated with both TWA and LGE. Although the power of the QTd measurement for predicting a high risk of VT and SCD may be limited, our study strongly suggested that repolarization abnormality, as
Table 3 Comparison of histological and CMR imaging parameters between the 31 patients with available histological data with and without VT Parameter Histological parameters Disarray present Histological fibrosis present % Area of the total amount of fibrosis CMR imaging parameters LV EF (%) LV EDV (mL) LV mass (g) Total LGE score Maximum LV wall thickness (mm)
Patients with available histological data (n ¼ 31) 16 (52) 27 (87) 20 ⫾ 12 61 ⫾ 121 ⫾ 155 ⫾ 16 ⫾ 17 ⫾
8 31 53 10 5
Patients with VT (n ¼ 15) 6 (40) 15 (100) 24 ⫾ 15 59 ⫾ 125 ⫾ 166 ⫾ 22 ⫾ 17 ⫾
10 33 45 8 6
Patients without VT (n ¼ 16) 10 (63) 12 (75) 15 ⫾ 7 62 ⫾ 117 ⫾ 145 ⫾ 10 ⫾ 17 ⫾
6 29 59 7 5
P .289 .101 .036 .407 .482 .277 o.001 .933
Values are expressed as mean ⫾ SD or as n (%). CMR ¼ cardiac magnetic resonance; EDV ¼ end-diastolic volume; EF ¼ ejection fraction; LGE ¼ late gadolinium enhancement; LV ¼ left ventricular; VT ¼ ventricular tachycardia.
1754 defined by TWA (and QTd) combined with the extent of LGE on CMR imaging, can be a useful tool for the risk stratification in HCM, by reflecting the special dispersion as well as temporal dispersion.
Study limitations The results of this study should be interpreted in light of their limitations. First, the number of patients in the study group was small. Second, although we demonstrated the relationship between TWA and LGE, we did not find any direct evidence that this abnormality was associated with VT. However, we believe that the information provided in this study, indicating that LGE on CMR imaging had a close relationship with TWA, is quite valuable for evaluating patients with lethal arrhythmias. Third, Holter recording was performed in the presence of medications in some cases because of the underlying structural heart disease and primary prevention of lethal arrhythmias. Although β-blockers might decrease TWA, the overall arrhythmic risk and relationship between the LGE score and TWA could be evaluated in either the absence or the presence of prophylactic drugs for lethal arrhythmias, and it is believed to be worthy of evaluation as in the previous clinical trials. Fourth, in this study we did not evaluate LGE of intermediate intensity. In patients with previous myocardial infarction, it is reported that the extent of the peri-infarct region based on a signal-intensity threshold of o3 SD above the mean signal intensity of the remote myocardium provides an incremental prognostic value.30 Thus, there is a possibility that scar heterogeneity may also have been relevant, but that was not evaluated in this study. Furthermore, with the recent advances in cardiac imaging, it has been reported that contrast-enhanced CMR T1 mapping can now identify diffuse fibrosis not detectable by the conventional delayed enhanced CMR imaging.31 Since TWA is considered, at least in part, to reflect repolarization abnormality associated with the scar heterogeneity, further precise studies will be necessary to elucidate that evaluation.
Conclusion This study demonstrated that the magnitude of the localized LGE was significantly correlated with abnormalities in ventricular repolarization as assessed by TWA and QTd. Dispersion of repolarization among healthy and damaged myocardium would account, in part, for the occurrence of VT in HCM.
Appendix Supplementary data Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/j.hrthm. 2015.04.028.
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CLINICAL PERSPECTIVES There have been several reports on the association between late gadolinium enhancement (LGE) and long-term outcomes in patients with hypertrophic cardiomyopathy (HCM), and the data collected support the relationship between LGE and cardiovascular mortality. However, few studies have shown the relationship between LGE and an increased risk of sudden death, although LGE has been shown to be associated with nonsustained ventricular tachycardia on Holter monitoring. Consequently, 2014 ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy state that the extent of LGE on cardiac magnetic resonance imaging has some utility in predicting cardiovascular mortality, but the current evidence does not support the use of LGE in the prediction of the risk of sudden cardiac death. In the present study, for the first time we demonstrated that LGE had a close relationship with abnormalities in ventricular repolarization as assessed by T-wave alternans and QT dispersion, which can lead to lethal ventricular arrhythmias in HCM. Although our study was performed based on a retrospective analysis, a prospective study investigating the correlations among LGE, repolarization electrocardiographic parameters, and sudden cardiac death will provide important information for high-risk HCM patients.
