Prevalence of Left Ventricular Regional Dysfunction in Arrhythmogenic Right Ventricular DysplasiaCLINICAL PERSPECTIVE
A Tagged MRI Study
Background— Although arrhythmogenic right ventricular dysplasia (ARVD) predominantly affects the right ventricle (RV), genetic/molecular and histological changes are biventricular. Regional left ventricular (LV) function has not been systematically studied in ARVD.
Methods and Results— The study population included 21 patients with suspected ARVD who underwent evaluation with MRI including tagging. Eleven healthy volunteers served as control subjects. Peak systolic regional circumferential strain (Ecc, %) was calculated by harmonic phase from tagged MRI based on the 16-segment model. Patients who met ARVD Task Force criteria were classified as definite ARVD, whereas patients with a positive family history who had 1 additional minor criterion and patients without a family history with 1 major or 2 minor criteria were classified as probable ARVD. Of the 21 ARVD subjects, 11 had definite ARVD and 10 had probable ARVD. Compared with control subjects, probable ARVD patients had similar RV ejection fraction (58.9±6.2% versus 53.5±7.6%, P=0.20), but definite ARVD patients had significantly reduced RV ejection fraction (58.9±6.2% versus 45.2±6.0%, P=0.001). LV ejection fraction was similar in all 3 groups. Compared with control subjects, peak systolic Ecc was significantly less negative in 6 of 16 (37.5%) segments in definite ARVD and 3 of 16 segments (18.7%) in probable ARVD (all P<0.05).
Conclusions— ARVD is associated with regional LV dysfunction, which appears to parallel degree of RV dysfunction. Further large studies are needed to validate this finding and to better define implications of subclinical segmental LV dysfunction.
Received September 22, 2009; accepted February 16, 2010.
Arrhythmogenic right ventricular dysplasia (ARVD) is a familial cardiomyopathy that is characterized by predominant right ventricular (RV) dysfunction, myocyte loss, and fibro-fatty infiltration of the myocardium.1 Defective cell-to-cell adhesion caused by mutations in genes encoding desmosomal proteins have been implicated in the pathogenesis of ARVD. The result is disruption of the cardiac gap junction apparatus, which has been thought to result both in the functional impairment and the failure of impulse transmission with subsequent arrhythmogenesis. The ultrastructural and molecular consequences are expressed in both ventricles alike, and this has promoted the notion that ARVD is a biventricular cardiomyopathy, with predominant involvement of the thin-walled RV.1
Clinical Perspective on p 290
Patients with advanced or end-stage ARVD are observed with clinically obvious biventricular dysfunction that can be readily identified using echocardiography or MRI. When present, left ventricular (LV) dysfunction is often associated with significantly more adverse clinical outcomes such as ventricular arrhythmias and heart failure.2,3 LV contraction abnormalities have been demonstrated in ARVD in association with advanced RV disease by previous imaging studies using radionuclide angiography,4,5 echocardiography6,7 and electron-beam computed tomography.8 More recently, ARVD with dominant LV involvement has also been reported in the United Kingdom9,10 but not yet in the United States.
Regional contraction abnormalities often precede global dysfunction but have not previously been quantified using tagged cardiovascular MRI for the RV or LV for ARVD. Unfortunately, the thin wall of the RV makes regional motion tracking extremely challenging. However, tagged MRI of the heart provides objective measurements of regional LV function11 with great precision and reliability.12 The purpose of this study was to quantify regional LV function in patients with high clinical suspicion for ARVD using tagged MRI.
The study population included 21 patients who were evaluated for ARVD at the Johns Hopkins ARVD program with a positive family history (n=13, 62%) or left bundle-branch block morphology ventricular tachycardia (n=8, 38%). Eleven healthy volunteers served as control subjects. All of these patients underwent initial noninvasive testing according to a standardized protocol including an ECG, signal-averaged ECG, Holter monitoring, echocardiography, exercise testing, and cardiac MRI. They underwent further invasive testing at the discretion of the cardiologist, which included electrophysiological study, RV angiography, and endomyocardial biopsy. Diagnosis of ARVD was established based on the results of noninvasive tests including MRI and invasive tests according to the criteria set by the Task Force of the Working Group of Myocardial and Pericardial Disease of the European Society of Cardiology and of the Scientific Council on Cardiomyopathies of the International Society and Federation of Cardiology.13 Among those who did not meet the Task Force criteria, patients with a positive family history who had 1 additional minor criterion and patients without a family history with 1 major or 2 minor criteria were classified as probable ARVD.
MR Imaging Protocol
MR images of study subjects were obtained on 1.5-T scanners (CV/I, GE Medical Systems, Waukesha, Wis, or Philips Medical Systems, Best, The Netherlands) at the Johns Hopkins Hospital and included both fast spin-echo and gradient-echo sequences. Fat-suppressed and non-fat-suppressed fast spin-echo sequences were acquired in the axial and short-axis planes with breath-hold double-inversion recovery blood suppression pulses with repetition time (TR) of 1 or 2 R-R intervals, time to excitation (TE) of 10 to 20 ms, slice thickness of 5 to 10 mm, and slice gap of 2 to 5 mm. The matrix and field of view (FOV) were 256×256 and 24 to 36 cm, respectively. Cine functional images were obtained in the axial and short-axis planes using breath-hold steady-state free precession imaging. The flip angle was 40° to 60° and TE was set to minimum. For steady-state free precession imaging, the slice thickness was 5 to 8 mm, with a slice gap of 2 to 6 mm. The matrix and FOV were 256×160 and 36 to 40 cm, respectively. Inversion recovery prepared breath-hold 2D cine gradient-echo images were obtained 20 minutes after contrast agent injection (0.2 mmol/kg of gadodiamide (Omniscan, Amersham Health, Princeton, NJ)). Imaging parameters included TR/TE, 7.2/3.2; inversion time optimized, 150 to 250 ms; flip angle, 25°; slice thickness, 8 mm; slice gap, 2 mm; number of excitations, 2; matrix, 256×192; and FOV, 36×27 cm. Two-dimensional myocardial delayed enhancement MRI scans were obtained in the short-axis and axial planes at 10-mm intervals, covering the entire RV and LV. All studies used a phased-array surface coil for signal reception. The temporal resolution of the cine images was ≤50 ms.
After completing the standard imaging protocol, 3 tagged short-axis slices (base to apex) were obtained. Parallel striped tags were prescribed in 2 orthogonal orientations (0° and 90°) using ECG-triggered fast gradient-echo sequence with spatial modulation of magnetization.14,15 The parameters for tagged MR images were FOV, 40 cm; slice thickness, 8 to 10 mm; TR, 3.5 to 7.2 ms; echo time, 2.0 to 4.2 ms; flip angle, 10° to 12°; matrix size, 256×96 to 140; temporal resolution, 20 to 40 ms; and tag spacing, 7 mm.
MR Image Analysis
MR images were assessed by experienced cardiac MRI readers at the Johns Hopkins Hospital who were blinded to all clinical and other diagnostic information. MR images were transferred to an Advantage windows workstation (GE Medical Systems, Waukesha, Wis) for analysis. Quantitative analysis was performed using dedicated commercially available MASS software program (Medis, Leiden, The Netherlands). This software was used to view images using standardized window width and level settings. The first image after the R-wave trigger represented the end-diastolic image. End-systolic image was defined visually as the one with the smallest ventricular cavity size. Quantitative MR parameters included end-diastolic volume (EDV), end-systolic volume (ESV), and ejection fraction for both ventricles. Diastolic and systolic ventricular volume measurements were obtained by summation of planimetered areas obtained from serial short-axis images. The MR images were qualitatively assessed for ventricular enlargement, aneurysms, global hypokinesis, regional wall motion abnormalities, intramyocardial fat, and delayed enhancement.
Horizontal and vertical striped tags were superimposed as grid images (Figure 1). Short-axis tagged slices were analyzed for midwall regional circumferential strain (Ecc,%) by the HARP (Figure 1) method (Harmonic Phase, Diagnosoft, Palo Alto, Calif),16,17 based on the 16-segment heart model.18 LV was divided into 3 circular basal, mid, and apical short-axis slices perpendicular to the long axis of the heart; the basal and mid slices were divided into 6 circumferential segments of 60° each—anterior, anteroseptal, inferoseptal, inferior, inferolateral, and anterolateral; and the apical slice was divided into 4 segments of 90° each—anterior, septal, inferior, and lateral. Because Ecc represents circumferential shortening, its value during systole is negative. A more negative value (eg, −25%) reflects greater contraction (healthier), whereas a relatively less negative value (eg, −10%) implies weaker contraction. Peak systolic value of Ecc, which refers to Ecc noted around peak systole, was considered for the analysis as the contractile effort tends to be at its maximum at this phase during the cardiac cycle. One of our previous studies has demonstrated excellent interobserver and intraobserver agreement for peak systolic midwall Ecc (correlation coefficient >0.8 for both) in myocardial tagged MRI analysis using the HARP technique.19
All continuous variables are reported as mean±standard deviation. All categorical variables are reported as frequency (%). The ventricular end-diastolic and end-systolic volumes were indexed to body surface area (in m2). Kruskal-Wallis and single Fisher exact tests were used for overall comparison of continuous and categorical data, respectively, among the 3 study groups. Wilcoxon-Mann-Whitney and Fisher exact tests were used for post hoc pairwise comparisons of continuous and categorical data, respectively, with Bonferroni correction of the α to maintain the overall probability of a type I error at 0.05. Statistical analyses were performed in STATA statistical software (Version 9.0, College Station, Tex). A 2-tailed probability value <0.05 was considered statistically significant. The major goal of this research, as an exploratory study, was hypothesis generation, and no adjustment was made for examining multiple factors.
Table 1 describes the demographics and electrophysiological and structural abnormalities of the study population, which was composed of 21 patients with ARVD and 11 control subjects. Of the 21 patients with ARVD, 11 (52%) were classified as having definite ARVD and 10 (48%) as probable ARVD. Among the definite ARVD group, 45% patients fulfilled 4 Task Force criteria points, and the remaining 55% fulfilled >4. Among the probable ARVD group, 20% patients satisfied 2 points and remaining 80% patients satisfied 3 points. The mean age of the definite ARVD and probable ARVD patients was 41.2±14.2 years and 34.9±12.1 years, and 7 (64%) and 3 (30%) were men, respectively. The mean age of control subjects was 29.8±6.7 years, and 6 (55%) were men. Mean age and sex distribution across all 3 groups of study participants were similar (Kruskal-Wallis, P=0.14; single Fisher exact, P=0.37, respectively). The presence of >1000 premature ventricular contractions on a 24-hour Holter monitor was significantly more often seen in the definite ARVD group as compared with the probable ARVD group (Fisher exact, P=0.004). None of the definite or probable ARVD patients showed evidence of LV wall motion abnormalities on echocardiography. None of the control subjects had any prior symptoms, family history, or electric or structural abnormalities consistent with ARVD.
Characteristics of the RV and LV on MRI
Shown in Table 2 are the detailed MRI findings of subjects included in the study. In general, definite ARVD patients demonstrated a higher degree of RV structural abnormalities on MRI and showed a significantly higher presence of varying degrees of dilatation and delayed enhancement of the RV as compared with patients with probable ARVD (Fisher exact, P=0.001 and P=0.02, respectively). Among the 3 groups of participants, definite ARVD patients had significantly higher RVEDV and RVESV as well as lower RV ejection fraction (EF) than control subjects (Kruskal-Wallis, P=0.006, P=0.0009, and P=0.0007, respectively; post hoc tests, P=0.004, P=0.0009, and P=0.001, respectively). Definite ARVD patients also showed significantly lower RVEF than probable ARVD patients (post hoc test, P=0.04). Probable ARVD patients reported higher global RV volumes and lower RVEF than control subjects, but the differences did not reach statistical significance (post hoc tests, P=0.12, P=0.07, and P=0.20, respectively).
Among the definite ARVD group, the most commonly seen LV abnormality was intramyocardial fat (3/11, 27%), followed by regional wall motion defects (2/11, 18%), dilation (1/11, 9%), and delayed enhancement (1/11, 9%). Similarly, among the probable ARVD group, the LV abnormalities observed were intramyocardial fat (1/10, 10%) and delayed enhancement (1/10, 10%). Quantitatively, LVEDV, LVESV, and LV ejection fraction were similar across all 3 groups (Kruskal-Wallis, P=0.29, P=0.59, and P=0.50, respectively).
Regional LV Systolic Function
Table 3 shows mean (SD) peak systolic Ecc at the 16 myocardial segments by study groups and the corresponding probability values for Kruskal-Wallis and post hoc comparisons. Patients with definite ARVD revealed significantly less negative Ecc (as stated earlier, less negative Ecc denotes weaker contraction) than control subjects in 6 of 16 (37.5%) segments: basal inferior, basal anterolateral, mid inferior, mid inferolateral, mid anterolateral, and apical lateral (Figure 1 and Figure 2). Ecc was significantly less negative in probable ARVD compared with control subjects in 3 of 16 (18.7%) segments: basal anterolateral, mid anterolateral, and apical lateral.
Figure 3a shows mean (95% confidence interval) peak systolic Ecc according to the study groups across myocardial regions along the longitudinal axis of the heart. Definite ARVD patients demonstrated less negative strain at the basal and mid LV slice levels in contrast to control subjects (Kruskal-Wallis, P=0.01 and P=0.009, respectively; post hoc tests, P=0.01 and P=0.01, respectively). No differences in basal, mid, or apical strain were observed between probable ARVD patients and control subjects. Figure 3b depicts distribution of mean (95% confidence interval) peak systolic Ecc circumferentially around the heart in the study population. Of the anterior, septal, inferior, and lateral regions, definite ARVD reported a less negative strain in anterior, inferior, and lateral regions compared with control subjects (Kruskal-Wallis, P=0.04, P=0.005, and P=0.0003, respectively; post hoc tests, P=0.03, P=0.005, and P=0.0006, respectively). This is in contrast to probable ARVD, which showed less negative strain in the lateral region alone (post hoc test, P=0.006). No differences in regional strain were found between definite and probable ARVD patients (Table 3 and Figure 3a and 3b).
To our knowledge, this is the first study to quantitatively assess regional LV function in ARVD using MRI strain analysis. This approach revealed regional LV systolic dysfunction despite a preserved global LV function. Further, the extent of LV dysfunction appeared to parallel RV dysfunction, with definite ARVD showing worse LV regional dysfunction.
Patients with a strong clinical suspicion of ARVD but satisfying less than the required number of Task Force criteria for the definite diagnosis of the disease were considered to have probable ARVD. Probable ARVD may represent an early spectrum of the disease with possible progression to diagnostically more overt forms with time. In a high-risk population (such as positive mutation carrier status or positive family history), the classification of probable ARVD may be particularly relevant. Such patients may not fulfill traditional ARVD criteria but may have a higher pretest probability for disease. In our practice, patients fulfilling several if not all ARVD criteria frequently mandate closer clinical follow-up.
LV Involvement in ARVD
Left-sided involvement in ARVD has been described, but it is frequently considered a late manifestation of advanced disease.20,21 However, the recent and important advances in the field of genetic characterization of the disease led to the hypothesis of a potential LV affliction in ARVD from its early stages.10 Most disease-causing mutations have been found to involve genes encoding different component proteins of the cardiac desmosome such as desmoplakin, plakophilin-2, junctional plakoglobin, desmoglein-2, and desmocollin-2.1 Although different mutations may affect ventricles differentially,10 the spectrum of their phenotypic expression should involve both ventricles concomitantly because right and left sides of the heart are similar with respect to desmosomal structure and gene expression. Our findings are plausible with the purported common genetic substrate between the 2 ventricles. The findings support the emerging evidence in favor of LV involvement and favor the need of a contemporaneous revision of Task Force criteria to include LV descriptions.10,22
With respect to qualitative changes, LV functional abnormalities in ARVD have been previously reported.1,8,23 However, a systematic regional quantification of LV contractile function in context to global function in ARVD has not been previously undertaken. Using myocardial tagging, we discovered decreased regional LV contraction in probable ARVD that had a higher prevalence in definite ARVD. Less negative strain noted first in 3 of 16 myocardial segments in probable ARVD appeared to progress to 6 of 16 segments, with increase in disease severity to definite ARVD. Similarly, less negative strain in the basal and mid slice levels of the LV in definite ARVD was not observed in probable ARVD. The lateral region showed a predilection for less negative strain in probable ARVD patients, whereas definite disease involved the lateral as well as anterior and inferior regions. These subclinical reductions in regional LV contractility as demonstrated by less negative systolic circumferential shortening showed an association with increasing RV impairment and existed without significant morphological abnormalities of the LV in the context of normal global LV function. Regional contraction derangement appears to be a more sensitive indicator of LV involvement, and this may be of great relevance in the classic disease paradigm in which the RV is consistently more severely affected than the LV and conspicuous signs of LV involvement may not set in until later in the course of the disease.9,10
Prognostic Significance of LV Involvement
The “left-sidedness” of ARVD is known to portend an increased likelihood of an eventful clinical course. Prospective and retrospective studies have highlighted LV involvement to be associated with an increased risk of palpitations, syncopal episodes, potentially lethal arrhythmias, and heart failure than isolated RV disease alone, which explains why LV involvement can help in identifying those ARVD patients who would benefit the most from timely implantable cardioverter-defibrillator placement.2,3 In the light of the aforementioned, the interpretation of the findings of our study of a possible LV involvement in ARVD in the form of a subclinical reduction in myocardial contraction may be critical from the prognostic standpoint.
Study Strengths and Limitations
Strengths of this study include nonsubjective analysis of regional LV function by the novel application of myocardial tagging in ARVD, comparative assessment of probable and definite ARVD patients against normal subjects, and cardiac MRI scanning for qualitative and quantitative evaluation of ARVD. One of the main limitations of the study is the small sample size, and the study may not have had sufficient power to detect differences in global LV function between ARVD patients and control subjects. The results should be interpreted in context to this important limitation and validated in a large-scale genotyped cohort of ARVD patients. Although the inclusion of individuals who do not fulfill adequate number of Task Force criteria may imply inclusion of early ARVD patients, it could also lead to a loss of specificity and admittance of false-positively identified patients with similar disorders such as idiopathic ventricular tachycardia and other types of cardiomyopathy. Because of the cross-sectional nature of our study, temporal trends in LV involvement and disease progression in ARVD patients over time could not be addressed.
Although the study is limited by a small sample size, our results for the first time show regional LV dysfunction in patients with ARVD despite preserved global LV systolic function. Even patients with probable ARVD had minor LV regional functional alterations compared with control subjects. These results support the current molecular/genetic basis of ARVD with biventricular disease expression, since early in the course of the disease. Abnormal strain measurements may be the first indication of an incipient overt LV dysfunction, warranting closer clinical follow-up and surveillance. Future longitudinal studies are needed to validate this finding and to better understand the natural history and prognostic implications of this asymptomatic segmental LV dysfunction in ARVD in larger cohorts of patients.
We thank the ARVD patients and families who have made this work possible. More information on the Johns Hopkins ARVD program can be found at www.arvd.com.
Sources of Funding
This study was supported by the National Heart, Lung, and Blood Institute (K23HL093350 to Dr Tandri) and the St Jude Medical Foundation, Medtronic Inc, and Boston Scientific Corp. The Johns Hopkins ARVD Program is supported by the Bogle Foundation, the Healing Hearts Foundation, the Campanella family, and the Wilmerding Endowments.
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Arrhythmogenic right ventricular cardiomyopathy or dysplasia (ARVC/D) predominantly affects the right ventricle; however, histological and molecular involvement of the left ventricle (LV) is well documented. Global LV function is usually affected in the advanced stages and is an important determinant for the need for heart transplantation. We evaluated regional LV strain in ARVC/D patients without overt LV dysfunction using MRI tagging. Patients with definite ARVC/D showed worse regional LV function compared with control subjects. Regional LV function was also significantly decreased in probable ARVC/D patients compared with control subjects, although right ventricular function was comparable between the groups. Thus, we report a high prevalence of regional LV dysfunction in ARVC/D despite preserved global LV function. This is in agreement with the current literature that supports the notion that ARVC/D is a biventricular disease; however, the exact significance of this finding is unclear. It is not known whether LV dysfunction is progressive in these patients, and future long-term studies addressing the prognostic significance of minor LV regional abnormalities are needed.