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Current noninvasive surrogates of cardiac involvement in myotonic muscular dystrophy have low positive predictive value for sudden death. We hypothesized that the cardiac MR signal-to-noise ratio variance (SNRV) is a surrogate of the spatial heterogeneity of myocardial fibrosis and correlates with electrocardiography changes in myotonic muscular dystrophy. The SNRV for contrast enhanced cardiac MR images was calculated over the entire left ventricle in 43 patients with myotonic muscular dystrophy. All patients underwent standard electrocardiography, and a subset of 23 patients underwent signal averaged electrocardiography. After correcting for body mass index, age, and ejection fraction, SNRV was predictive of QRS duration on standard electrocardiography (1.35-msec increased QRS duration/unit increase in SNRV, P < 0.001). SNRV was also predictive of the low-amplitude late-potential duration (1.49-msec increased low-amplitude late-potential duration/unit increase in SNRV, P < 0.001). Ten-fold cross-validation yielded an area under the receiver operating characteristic curve of 0.87 for the predictive value of SNRV for QRS duration greater than 120 msec. The SNRV of the left ventricle is associated with QRS prolongation, likely due to late depolarization of tissue within islands of patchy fibrosis. The association of SNRV with future clinical events warrants further study.
Myotonic muscular dystrophy (MMD), the most common muscular dystrophy in adults, is an inherited multisystem disorder associated with myotonia, progressive skeletal muscle weakness, and sudden death likely due to atrioventricular block and/or ventricular arrhythmia (1,2). Cytosine-thymine-guanine repeats on chromosome 19 in the 3′ untranslated region of a serine-threonine protein kinase gene (MDPK) characterize type I MMD, the more common form of the disease (3). Type II MMD is associated with a cytosine-cytosine-thymine-guanine (CCTG) tetranucleotide repeat in intron 1 of the zinc finger protein 9 gene (ZNF9) (4). In a recent landmark study of adults with type I MMD, electrocardiography (ECG) abnormalities had excellent negative but poor (12.1%) positive predictive value for sudden death (2). The predominant myocardial histologic finding from autopsy studies of patients with MMD is patchy interstitial fibrosis (5–8). Thus, a noninvasive marker of spatially heterogeneous myocardial fibrosis may select patients with high risk of sudden death.
Previous studies have revealed the utility of cardiac MR (CMR) in predicting the risk of arrhythmia based upon the spatial distribution of cohesive myocardial fibrosis (9–13). An important recent study described a global measure of diffuse fibrosis by T1 mapping (14). However, no methods are currently available to measure the spatial heterogeneity of myocardial fibrosis. Spatially heterogeneous fibrosis results in greater variation of the delayed enhancement CMR signal-to-noise ratio. Thus, we hypothesized that the signal-to-noise ratio variance (SNRV) may provide a surrogate measure of spatially heterogeneous myocardial fibrosis. Figure 1 illustrates relationships among variables under present study and other unobserved variables of interest. Importantly, QRS prolongation does not fully mediate the association of myocardial fibrosis and sudden death. Therefore, SNRV may be a better predictor of clinical events than baseline ECG abnormalities. Prior to the availability of long-term clinical results, we sought to assess the association of SNRV with QRS duration in MMD.
The protocol was reviewed and approved by the Johns Hopkins Institutional Review Board. The patient population included 43 patients with MMD (35 with type I and 8 with type II) diagnosed by genetic testing (82%) or by clinical examination plus genetically proven MMD in a first-degree family member (18%). Patients with examination findings of MMD but negative genotype were not included. All consecutive MMD patients who were referred to the electrophysiology service for arrhythmia risk stratification, without history of atrioventricular block, resuscitated sudden death, or contraindications to CMR, were enrolled in the study. All patients underwent CMR and standard 12-lead ECG. Additionally, five control patients without evidence of arrhythmia, structural cardiac disease, or neuromuscular disease underwent CMR and ECG. Twenty-three of 43 total MMD patients underwent signal-averaged ECG with frank orthogonal leads at a sampling rate of 1 kHz/channel and enough QRS complexes to reduce the noise level to <1 mcV (PC ECG 1200; Norav Medical Ltd., Thornhill, Ontario, Canada).
The median time between ECG recording and MRI was 15.5 days (interquartile range 9–50 days). Images were acquired with a 1.5-T (Magnetum Avanto, Syngo MR B13; Siemens Medical Systems, Erlangen, Germany) MR scanner and a six-channel body phased-array surface coil. After localization of the heart, base-to-apex, short-axis, cine, steady-state free precession, gradient echo images (temporal resolution, 46.80–49.14 msec; echo time, 1.1–1.2 msec; image resolution, 256 × 192 pixels; field of view, 360 × 360mm; slice thickness, 8mm; spacing, 2mm; flip angle, 69–80° ; repetition time, 48.2–55 msec; views per segment, 18; breath hold, 6 sec per slice) were obtained with retrospective ECG gating. Patients then received 0.2 mmol/kg intravenous gadodiamide (Omniscan; Amersham Health/General Electric Healthcare, Waukesha, Wisconsin, USA). Fifteen minutes after the contrast bolus, short-axis delayed images were acquired with an inversion recovery fast gradient echo pulse sequence (repetition time, 5.4–7 msec; echo time, 1.3–3 msec; image resolution, 256 × 256 pixels; field of view, 400 × 400mm; slice thickness, 8mm; spacing, 2mm; flip angle, 20–40° ; inversion time, 175 to 250 msec; repetition time, 500–940 msec; views per segment, 24; breath hold, 12–18 sec per slice). Inversion times were optimized for each patient to null normal myocardium. Given the spatially heterogeneous nature of myocardial fibrosis in MMD, the selection of normal areas required particular attention. In our experience, basal lateral areas of left ventricular myocardium were often spared of fibrosis and were used as the standard for null myocardium in selection of inversion times. The number of image planes acquired depended on the length of the ventricular long axis in each patient (six to 10 planes per patient).
The QMass MR Version 6.2.2 (Medis Medical Imaging Systems, Leiden, The Netherlands) software package was used for image analysis. Steady-state free precession images obtained in the short-axis plane were used for functional analysis. The left ventricular endocardium and epicardium were manually contoured at end diastole and end systole at each short-axis level to calculate the left ventricular ejection fraction, end-diastolic volume, and mass. Postcontrast delayed enhancement images in the short-axis plane were analyzed by manual contouring of the left ventricular endocardium and epicardium. The myocardium was then divided into 20 sectors per slice, starting from the posterior right ventricular insertion point (Fig. 2a). The signal-to-noise ratio was used to standardize intensity measurements between patients. The signal-to-noise ratio of each of 20 sectors per inversion-recovery-prepared gradient echo image plane (120–200 sectors per patient, Fig. 2b) was calculated by the dividing the mean sector intensity by the standard deviation of the background noise. Background noise was measured from a large region of interest (3 × 4 cm) placed anterior to the chest wall. The SNRV of the entire left ventricle was calculated by obtaining the variance of the signal-to-noise ratio for all sectors for each patient (Fig. 2c). Contours were reviewed and confirmed by two independent observers who were blinded to patient identities and clinical characteristics. Discrepancies were resolved by the senior observer (D.A.B.) with more than 10 years’ experience in CMR.
Continuous variables are summarized as median and interquartile range. Categorical and dichotomous variables are expressed as percentages. The unpaired Student's t test was used to compare SNRV among MMD and control patients. Univariate and multivariate linear regression were used to assess the association of SNRV with standard and signal-averaged ECG findings while adjusting for potential confounders. Potential confounders (age, left ventricular ejection fraction, and body mass index) were selected a priori due to known associations with both the dependent and independent variables under study (Fig. 1). Ten-fold cross-validation was used to calculate the area under the receiver operator characteristic curve to assess the value of SNRV in predicting effective bundle-branch block (QRS duration >120 msec). To perform 10-fold cross-validation, the sample was partitioned into 10 subsamples. One subsample was retained as the validation data for testing the model, and the remaining nine subsamples were used as training data. The cross-validation process was then repeated 10 times, with each of the 10 subsamples used exactly once as the validation data. The 10 results for the area under the curve were then averaged to produce a single area under the curve. Statistical analyses were performed using R software (version 2.7.1; R Foundation for Statistical Computing, Vienna, Austria).
Baseline characteristics are summarized in Table 1. Eighty-one percent had type I MMD and 19% had type II MMD. Among patients with MMD, 43% were women, median age was 50.5 years, median body mass index was 25.8 kg/m2, median left ventricular ejection fraction was 52.8%, and median QRS duration was 104 msec on both standard and signal averaged electrocardiograms. Compared to controls, the mean SNRV was higher in patients with MMD (mean difference 13.9 ± 6 8.4, P = 0.05). The baseline left ventricular end diastolic volume was greater in male patients with MMD. There were no other statistically significant gender differences at baseline (Table 2).
A linear relationship was observed between the SNRV of the entire left ventricle and QRS duration on the standard ECG (Fig. 3). Simple linear regression of the standard ECG QRS duration on SNRV revealed a 1.36-msec increase in QRS duration per unit increase in SNRV (95% confidence interval for β1: 0.93 to 1.80, P < 0.001). Age and left ventricular ejection fraction were selected as potential confounders of the QRS duration. Body mass index was selected as a potential confounder of SNRV on inversion-prepared gradient echo images. After inclusion of age, left ventricular ejection fraction, and body mass index in the multivariate linear regression model, SNRV remained predictive of QRS duration on standard ECG. After adjusting for potential confounders and the effect of gender, there was 1.35-msec increase in QRS duration per unit increase in SNRV (95% confidence interval for β1: 0.77 to 1.93, P < 0.001).
The matrix plot in Fig. 4 illustrates the relationship between the signal-averaged filtered QRS duration, terminal (40 msec) root mean square voltage, low-amplitude (<40 μV) late-potential duration, and SNRV. The signal-averaged filtered QRS duration and low-amplitude late-potential duration exhibited a positive linear relationship with SNRV, and the terminal root mean square voltage had a negative relationship with SNRV. The signal-averaged filtered QRS duration and low-amplitude late potential duration were colinear (ρ = 0.75, P < 0.001). The terminal root mean square voltage had a negative linear relationship with both the signal-averaged filtered QRS duration (ρ = –0.71, P < 0.001) and low-amplitude late-potential duration (ρ = –0.90, P < 0.001). Given the high degree of colinearity among the signal-averaged ECG variables, as reflected by Fig. 4, only the low-amplitude late-potential duration was used in the SNRV versus late-potential linear regression model. Simple linear regression of the low-amplitude late-potential duration on SNRV yielded a coefficient reflecting a 1.24-msec increase in duration per unit increase in SNRV (95% confidence interval for β1: 0.87 to 1.61, P < 0.001). After adjusting for potential confounders and the effect of gender, the coefficient was a 1.49-msec increase in duration per unit increase in SNRV (95% confidence interval for β1: 0.99 to 1.98, P < 0.001).
Ten-fold cross-validation was used to assess the utility of SNRV for predicting QRS duration >120 msec on 12-lead ECG of patients with MMD. Ten-fold cross-validation yielded the receiver operating characteristic curve displayed in Fig. 5. The average area under the receiver operator characteristic was 0.87. The best classification occurred at an SNRV cut point of ≥25.2, resulting in 86.1% correct classification, 66.7% sensitivity, 96.4% specificity, likelihood ratio positive of 18.7, and likelihood ratio negative of 0.4.
The main finding of this study is that the SNRV of the entire left ventricle, a quantitative measure of the image signal-to-noise ratio statistical dispersion, is associated with QRS duration and late potentials in MMD.
Traditional region-of-interest analyses of myocardial areas with delayed enhancement CMR can be subjective. Intensity threshold techniques have been developed to increase the reproducibility of measurements when cohesive myocardial scar is present on CMR (10,11,15). However, intensity threshold techniques cannot be applied to measurement of scar in patients with diffuse fibrosis because no one area of myocardium can objectively be used as the “null” (normal) myocardium. The recent technique of T1 mapping provides a global measure of diffuse fibrosis (14). However, no methods are currently available to quantify the spatial heterogeneity of diffuse myocardial fibrosis. Given the high signal intensity of fibrotic areas versus the low signal intensity of normal myocardium on delayed enhancement CMR, image intensity variance is a logical feature extraction methodology to estimate the degree of myocardial heterogeneity. In this study, we normalized the arbitrary CMR intensity scale by calculating the signal-to-noise ratio and hypothesized that the SNRV of all left ventricular sectors would provide a measure of spatially heterogeneous myocardial fibrosis. Increased fibrosis is subjectively appreciated with increasing SNRV of the entire left ventricle upon examination of sample image planes from patients with the full range of SNRV (Fig. 6). In this study, SNRV was associated with QRS duration on standard ECG. The area under the receiver operator characteristic curve obtained via 10-fold cross-validation suggested that SNRV is an excellent predictor of prolonged QRS duration on ECG. SNRV also predicted late potentials on signal-averaged ECG, suggesting that late depolarization of tissues within islands of patchy fibrosis may account for its positive association with the surface QRS duration.
QRS prolongation may occur due to conduction delay or block at different levels of the atrioventricular and intraventricular conduction path, depending upon the underlying disease process. The most common cause of QRS prolongation is discrete right or left bundle-branch block. However, invasive electrophysiology studies of patients with MMD have revealed diffuse abnormalities of the entire conduction system in patients with any electrocardiographic manifestation of conduction delay (16). The gradual prolongation of QRS duration in MMD suggests the contribution of progressive fibrosis to conduction delay in this disease (17–20), and an autopsy study of patients with MMD has revealed fibrosis of the ventricular myocardium as the predominant finding in patients with intraventricular conduction delay (8). Similarly, pathology studies in animal models of MMD have confirmed myocardial fibrosis (21), and invasive electrophysiology recordings in such models point predominantly to infra-Hisian conduction delay as the primary contributor to conduction abnormalities in MMD (22). The findings of our study lend further support to the role of diffuse and patchy fibrosis as the primary contributor of conduction delay in MMD.
Myocardial fibrosis in MMD can lead to severe bradyarrhythmia resulting from atrioventricular block, producing asystole and sudden death in both type I (2,23,24) and type II MMD (25,26). Progression to atrioventricular block in MMD can be sudden and unpredictable, and pacemaker implantation has proved beneficial in asymptomatic MMD patients with evidence of infra-Hisian conduction delay (27). Additionally, the presence of late potentials on signal-averaged ECG of patients with MMD has previously been correlated with increased risk of complete atrioventricular block (28–30). Patients with MMD can also present with ventricular tachyarrhythmia leading to sudden death. There is conflicting evidence regarding the utility of standard ECG abnormalities for prediction of ventricular arrhythmias in MMD (2,20,31). Patchy myocardial fibrosis acts as a substrate for ventricular arrhythmia in dilated cardiomyopathy (32), and diffuse fibrosis is a dominant finding in endomyocardial biopsies of patients with spontaneous ventricular fibrillation and no other macroscopic cardiac disease (33). In this study, increased SNRV predicted not only prolonged QRS duration on standard ECG but also late potentials on signal-averaged ECG. QRS prolongation does not fully mediate the association of myocardial fibrosis and sudden death. Therefore, as a surrogate of spatially heterogeneous myocardial fibrosis, the SNRV may provide a better predictor of clinical events than baseline ECG abnormalities. Prospective studies of SNRV are necessary to demonstrate the predictive value of this metric for outcomes.
Patients with both MMD types I and II were included in the study. Since interstitial fibrosis is the final common pathway leading to cardiac dysfunction and arrhythmia in both genetic variants (20), comparison of SNRV to QRS duration and late potentials should be applicable in both cases. When excluding the eight patients with MMD type II and after adjusting for confounders, SNRV remained predictive of the QRS duration (β1: 1.36, P < 0.001).
A random-effects model of individual sector signal-to-noise ratio estimated by patient and sector (reflecting sector orientation with respect to the surface coil and contour inconsistencies) showed that 41.6% of the total variance in signal-to-noise ratio in individual sectors appears to be due to interpatient variability. Factors that affect the signal-to-noise ratio will alter the SNRV. The image signal-to-noise ratio will likely be affected by body size, surface coil position, scanner type, and variations in contrast dose, delay time, and imaging parameters. Therefore, it is important to standardize as many variables as possible to adequately apply this technique to patient care or large-scale research. The SNRV measures the square of the deviation of each sector signal-to-noise ratio from the mean signal-to-noise ratio and provides an indicator of the spread of signal-to-noise ratios across the myocardium. In this study, external variations in signal-to-noise ratio were reduced by (a) consistent use of scanner type, contrast dose, and delay time; (b) minimizing variations in surface coil position and imaging parameters; and (c) consistent contouring by masked and experienced reviewers. The presence of artifacts would likely attenuate SNRV measurements. Minimal artifacts were noted in the present study; however, if present, regions with extensive artifact should be excluded from analysis.
In the current study, SNRV was not directly compared with histologic evidence of diffuse myocardial fibrosis. However, correlation of SNRV to myocardial biopsies would also be limited due to regional variations in diffuse fibrosis and sampling bias. Studies of the association of SNRV with biopsy evidence of diffuse fibrosis in patients, or pathologic evidence of fibrosis in animal models of MMD, may refine our findings. Future studies are also necessary to compare and simulate T1 mapping and SNRV results and to assess the ability of each measure for predicting clinical events in patients with MMD and other infiltrative cardiomyopathies. Long-term outcome results are not yet available on our cohort of patients with MMD. A longitudinal study of atrioventricular block and ventricular arrhythmia event rates among patients stratified by SNRV will be needed to determine predictive value.
We have shown a positive linear association between SNRV on CMR and QRS prolongation in patients with MMD. This observation, at present, has limited clinical value. However, QRS prolongation does not fully mediate the association of myocardial fibrosis and sudden death, and SNRV may provide a better predictor of clinical events than baseline ECG abnormalities. Such a predictor may lead to improved periodic assessment of disease progression and prevention of life-threatening brady- and tachyarrhythmias using implanted pacemakers and cardioverter defibrillators. Future studies to assess the association of SNRV with atrioventricular block, ventricular arrhythmia, and sudden death are warranted.
The SNRV of the entire left ventricle, a measure of image signal-to-noise ratio statistical dispersion, likely reflects the regional heterogeneity of myocardial fibrosis and predicts QRS prolongation. This noninvasive measure may improve the quantification of patchy myocardial fibrosis in MMD and other cardiomyopathies.
Saman Nazarian is funded by the Johns Hopkins Clinician Scientist Award and the NIH Clinical Research Scholars Program (1KL2RR025006-01). Dr. Tomaselli is the Michel Mirowski Professor of Cardiology and Dr. Calkins is the Nicholas Fortuin Professor of Medicine at Johns Hopkins University. Research was partly supported by a grant from the Donald W. Reynolds Foundation.
Disclosures: Drs. Halperin and Berger serve as scientific advisors for Boston Scientific Inc. The Johns Hopkins University Advisory Committee on Conflict of Interest manages all commercial arrangements. The remaining authors report no conflicts.