Author + information
- Received February 24, 2009
- Revision received April 6, 2009
- Accepted April 14, 2009
- Published online July 28, 2009.
- Laurens F. Tops, MD⁎,‡,
- Kalpana Prakasa, MD⁎,
- Harikrishna Tandri, MD⁎,
- Darshan Dalal, MD⁎,
- Rahul Jain, MD⁎,
- Veronica L. Dimaano, MD⁎,
- David Dombroski, MD†,
- Cynthia James, PhD⁎,
- Crystal Tichnell, MGC⁎,
- Amy Daly, MSc⁎,
- Frank Marcus, MD§,
- Martin J. Schalij, MD‡,
- Jeroen J. Bax, MD‡,
- David Bluemke, MD†,
- Hugh Calkins, MD⁎ and
- Theodore P. Abraham, MD⁎,⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Theodore P. Abraham, Johns Hopkins University, 600 North Wolfe Street, Carnegie 568, Baltimore, Maryland 21287
Objectives This study sought to investigate the prevalence and mechanisms underlying right ventricular (RV) dyssynchrony in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) using tissue Doppler echocardiography (TDE).
Background An ARVD/C is characterized by fibrofatty replacement of RV myocardium and RV dilation. These pathologic changes may result in electromechanical dyssynchrony.
Methods Echocardiography, both conventional and TDE, was performed in 52 ARVD/C patients fulfilling Task Force criteria and 25 control subjects. The RV end-diastolic and -systolic areas, right ventricular fractional area change (RVFAC), and left ventricular (LV) volumes and function were assessed. Mechanical synchrony was assessed by measuring differences in time-to-peak systolic velocity (TSV) between the RV free wall, ventricular septum, and LV lateral wall. An RV dyssynchrony was defined as the difference in TSVbetween the RV free wall and the ventricular septum, >2 SD above the mean value for control subjects.
Results The mean difference in RV TSVwas higher in ARVD/C compared with control subjects (55 ± 34 ms vs. 26 ± 15 ms, p < 0.001). Significant RV dyssynchrony was not noted in any of the control subjects. Based on a cutoff value of 56 ms, significant RV dyssynchrony was present in 26 ARVD/C patients (50%). Patients with RV dyssynchrony had a larger RV end-diastolic area (22 ± 5 cm2vs. 19 ± 4 cm2, p = 0.02), and lower RVFAC (29 ± 8% vs. 34 ± 8%, p = 0.03) compared with ARVD/C patients without RV dyssynchrony. No differences in QRS duration, LV volumes, or function were present between the 2 groups.
Conclusions An RV dyssynchrony may occur in up to 50% of ARVD/C patients, and is associated with RV remodeling. This finding may have therapeutic and prognostic implications in ARVD/C.
Arrhythmogenic right ventricular dysplasia cardiomyopathy (ARVD/C) is an inherited disease characterized by fibrofatty replacement of right ventricular (RV) myocardium (1). The diagnosis is established based on the presence of a conglomeration of factors (2,3). Other than ventricular arrhythmias, ARVD/C results in progressive RV dilation and systolic dysfunction leading to heart failure (4,5).
Ventricular electromechanical delay (or mechanical dyssynchrony) has been well described in left ventricular (LV) failure and has formed the basis of cardiac resynchronization therapy leading to significant improvements in symptoms, functional capacity, and survival in heart failure patients (6). Although RV mechanical dyssynchrony has been described in pulmonary hypertension (7), there are no data on whether a primary RV cardiomyopathy such as ARVD/C is associated with mechanical dyssynchrony. Tissue Doppler echocardiography (TDE) and strain echocardiography (SE) have emerged as the predominant means of evaluating ventricular mechanics (8,9).
Several components of the ARVD/C disease process could potentially lead to the development of RV mechanical dyssynchrony. Fibrofatty infiltration could involve the RV conduction system, resulting in electrical and electromechanical delays. Similar to LV failure, RV dilation and dysfunction may cause dyssynchrony. Lastly, other factors such as pulmonary pressures and LV involvement may influence RV mechanical properties. Importantly, ventricular electromechanical dyssynchrony has prognostic and therapeutic implications (10,11).
Accordingly, the aims of this study were to determine the prevalence of mechanical dyssynchrony in a large cohort of ARVD/C patients and to better elucidate the factors influencing RV mechanics in ARVD/C.
Study population and protocol
This study was approved by the institutional review board with written informed consent obtained in all subjects. The study population comprised 52 ARVD/C patients with diagnosis confirmed by Task Force criteria (2) and 25 control subjects. All control subjects were healthy volunteers, recruited on campus, with no history of medical illness, not on any cardioactive medications, and who had a normal echo Doppler examination result (18 men, 7 women; mean age 32 ± 6 years). All patients underwent a detailed history and physical examination, 12-lead electrocardiogram (ECG), signal-averaged ECG, conventional echocardiography, and TDE/SE.
Conventional and TDE/SE images were acquired from at least 3 consecutive heart beats and digitally stored for off-line analysis using a Vivid 7 ultrasound machine (GE Healthcare, Waukesha, Wisconsin). Offline analysis was performed using EchoPAC PC version 6.1 (GE Healthcare). During image acquisition, special care was taken to acquire accurate images of the RV free wall. Off-plane images of the RV were acquired to maximize visualization of RV morphology.
The RV outflow tract dimension was measured in the parasternal short-axis view at the level of the aortic valve plane (12). In addition, right ventricular end-diastolic area (RVEDA) and right ventricular end-systolic area (RVESA) were measured by tracing the RV endocardial border on the apical 4-chamber view and right ventricular fractional area change (RVFAC) was calculated as a measure of RV systolic function using the following equation: RVFAC = (RVEDA − RVESA)/RVEDA × 100% (12). Biplane LV end-diastolic and -systolic volumes were assessed from the apical 2- and 4-chamber images, and LV ejection fraction was calculated using the biplane Simpson formula (13).
Standard apical 4-chamber images and narrow-angle-sector images were acquired for tissue Doppler and strain analysis. Adjustments to the sector width were made to visualize 1 myocardial wall at a time (RV free wall, interventricular septum, LV lateral wall), to obtain an optimal alignment between the wall and the ultrasound beam, and to maximize frame rates (mean frame rate 253 ± 46 frames/s). The gain settings, filters, and pulse repetition frequency were adjusted to optimize color saturation and to avoid aliasing.
Off-line analysis was performed by placing the Doppler sample at the basal segment of the RV free wall, interventricular septum, and LV lateral wall, as previously described (14). Semiautomated tissue tracking was used to maintain the sample area within the region of interest throughout the cardiac cycle. Peak systolic tissue velocity of each segment was obtained and averaged from 3 cardiac cycles. For peak systolic strain analysis, an offset (strain) distance of 12 mm was used; for all segments the time-to-peak systolic strain was similarly assessed. Off-line analyses were performed by 2 observers, blinded to the results of the echocardiographic RV function analysis.
For the assessment of ventricular dyssynchrony, the time from the onset of the QRS complex to the peak systolic tissue velocity of different segments was measured (TSV). The difference between the TSVof the septum and the TSVof the RV free wall was calculated as an indicator of RV dyssynchrony. Significant RV dyssynchrony was defined as a septal to RV free wall TSVdelay exceeding 2 SD above the mean value for the control group.
Similarly, for LV dyssynchrony the difference in TSVbetween the septum and the LV lateral wall was calculated. A value >2 SD above the mean value derived from the control group was used as a cutoff value for the presence of significant LV dyssynchrony. Finally, interventricular dyssynchrony was calculated as the difference in TSVbetween the RV free wall and the LV lateral wall. The cutoff value for significant interventricular dyssynchrony was defined similar to RV and LV dyssynchrony.
Continuous data are presented as mean ± SD; categorical data are presented as frequencies and percentages. Differences between the ARVD/C patients and the control subjects, and between the ARVD/C patients with and without ventricular dyssynchrony, were evaluated using an unpaired Student ttest (continuous variables) or chi-square tests (dichotomous variables). Differences in continuous variables between control subjects and ARVD/C patients with and without ventricular dyssynchrony were evaluated with 1-way analysis of variance. Correlations between echocardiographic variables and the extent of RV dyssynchrony were assessed with a Pearson correlation test.
Interobserver and intraobserver variability for the assessment of TSVof the RV free wall and the interventricular septum and RV dyssynchrony were assessed using Bland-Altman analysis, in 10 random ARVD/C patients that were analyzed by 2 independent observers (interobserver variability) and by a single observer at 2 different time points (intraobserver variability); mean differences ± SD and 95% confidence intervals (CIs) are reported. In addition, the kappa statistic was used to assess the interobserver and intraobserver variability for the classification of the presence or absence of RV dyssynchrony.
All statistical analyses were performed using SPSS software (version 12.0, SPSS Inc., Chicago, Illinois). All statistical tests were 2-sided, and a p value <0.05 was considered statistically significant.
Baseline characteristics of the 52 ARVD/C patients are summarized in Table 1.In none of the patients, symptoms of right-sided heart failure were present. Right ventricular areas (RVEDA and RVESA) were higher and RVFAC was significantly lower in ARVD/C compared with the control subjects (Table 2).There were no significant intergroup differences in LV volumes and function. Peak systolic velocities and strain values in the interventricular septum and the LV lateral wall were comparable between the ARVD/C patients and control subjects (Table 2). In contrast, RV free wall peak systolic velocity (7.4 ± 2.1 cm/s vs. 9.9 ± 1.2 cm/s, p < 0.001) and RV free wall peak systolic strain (−19 ± 7% vs. −25 ± 9%, p = 0.002) were significantly lower in ARVD/C patients compared with control subjects, respectively.
In all subjects, echocardiographic images were of sufficient quality to assess TSV. The mean TSVof the septum and the RV free wall in the ARVD/C patients was 159 ± 40 ms and 210 ± 42 ms, respectively. In the control subjects, the mean TSVof the septum and the RV free wall was 135 ± 39 ms and 160 ± 33 ms, respectively. Mean time-to-peak strain of the septum and RV free wall was 387 ± 67 ms and 434 ± 73 ms in the ARVD/C patients and 345 ± 88 ms and 368 ± 75 ms in the control subjects.
The mean difference in TSVbetween the septum and the RV free wall, representing RV dyssynchrony, was 55 ± 34 ms in the ARVD/C patients and 26 ± 15 ms in the control subjects (p < 0.001). Based on a cutoff value of ≥56 ms, significant RV dyssynchrony was present in 26 ARVD/C patients (50%). In these patients, the mean RV dyssynchrony was 84 ± 20 ms, whereas it was 26 ± 16 ms in the remaining patients (p < 0.001). An example of a patient with significant RV dyssynchrony is shown in Figure 1.
The mean TSVfor the LV lateral wall in the ARVD/C patients and the control subjects was 171 ± 47 ms and 155 ± 47 ms, respectively. Mean time-to-peak strain of the LV lateral wall was 398 ± 70 ms in the ARVD/C patients and 370 ± 86 ms in the control subjects. There was no significant difference in LV dyssynchrony between the ARVD/C patients and the control subjects (21 ± 18 ms vs. 22 ± 19 ms, p = 0.7). Using a cutoff value of ≥60 ms (>2 SD of the control subjects), 2 ARVD/C patients (4%) showed significant LV dyssynchrony.
Interventricular dyssynchrony, calculated as the difference in TSVbetween the RV free wall and the LV lateral wall, was 53 ± 36 ms in the ARVD/C patients and 21 ± 15 ms in the control subjects (p < 0.001). Based on a cutoff value of ≥51 ms (>2 SD of the control subjects), significant interventricular dyssynchrony was present in 22 patients (42%) with ARVD/C. In these patients, mean interventricular dyssynchrony was 88 ± 17 ms, whereas it was 27 ± 21 ms in the remaining patients (p < 0.001). In 19 of the 26 patients with RV dyssynchrony (73%), significant interventricular dyssynchrony was present. Conversely, in 23 of the 26 patients without RV dyssynchrony (88%), no significant interventricular dyssynchrony was present.
Factors influencing RV dyssynchrony
We examined several morphologic and functional factors that could potentially impact RV mechanical synchrony. These included: 1) electrocardiographic: the presence of RV conduction abnormalities as typified by QRS duration and presence of right bundle branch block; 2) morphologic: RV volumes and LV volumes; and 3) functional: RV function and LV function. To study these factors, ARVD/C patients were divided into those with RV dyssynchrony (n = 26) and those without RV dyssynchrony (n = 26).
No differences in RV conduction abnormalities, evaluated by signal-averaged and surface ECG, were noted between the 2 groups: filtered QRS duration on signal averaged ECG was similar in ARVD/C patients with versus those without RV dyssynchrony (134 ± 41 ms vs. 128 ± 32 ms, respectively; p = 0.6). No difference in the prevalence of T-wave inversion in right precordial leads was noted between the 2 groups (with RV dyssynchrony n = 18, without RV dyssynchrony n = 21, p = 0.5). Similarly, there were no differences in the prevalence of right bundle branch block noted in 5 patients (19%) with RV dyssynchrony and in 5 patients (19%) without RV dyssynchrony (p = 1.0). In addition, there was no difference in the number of patients with documented ventricular tachycardia at baseline between the group with and the group without RV dyssynchrony (10 patients vs. 4 patients, p = 0.1).
Compared with patients without RV dyssynchrony, the patients with RV dyssynchrony had a larger RVEDA (Table 3),and a lower RVFAC (Fig. 2).No significant differences in LV volumes, function, and peak systolic velocities and peak systolic strain were noted between patients with and without RV dyssynchrony. In contrast, peak systolic strain of the RV free wall was significantly decreased in patients with RV dyssynchrony compared with patients without RV dyssynchrony (Fig. 2).
A modest but significant correlation was found between RVFAC and RV dyssynchrony (r = −0.38, p = 0.001) and between RVEDA and RV dyssynchrony (r = 0.38, p = 0.001). In addition, a modest but significant correlation was found between peak systolic strain of the RV free wall and RV dyssynchrony (r = 0.40, p < 0.001).
Reproducibility of RV dyssynchrony
The intraobserver and interobserver variability for TSVfor the RV free wall were 1.0 ± 16.6 ms (95% CI: −31.6 to 33.6), and 0 ± 26.7 ms (95% CI: −52.3 to 52.3), respectively. The intraobserver and interobserver variability for RV dyssynchrony were 0 ± 18.9 ms (95% CI: −36.9 to 36.9) and −5.0 ± 29.5 ms (95% CI: −62.9 to 52.9), respectively. For the classification of the presence or absence of RV dyssynchrony, an excellent agreement was noted between the 2 observers (κ = 0.80) and within the same observer (κ = 1.0).
We presented a previously unreported finding of significant ventricular mechanical dyssynchrony in patients with a primary RV cardiomyopathy, ARVD/C. In a relatively large cohort of ARVD/C patients, we have shown RV dyssynchrony in 50% and interventricular dyssynchrony in 42% of the patients. Patients with RV dyssynchrony had larger RV volumes and lower RV function compared with control subjects.
The presence of LV and interventricular dyssynchrony has been studied in a broad spectrum of clinical settings (9). In contrast, RV dyssynchrony has not been studied extensively. The presence of RV dyssynchrony was first reported by Lopez-Candales et al. (7) in 20 patients with pulmonary hypertension. Using time-to-peak strain between the septum and RV free wall, RV dyssynchrony was found to be more pronounced in patients with pulmonary hypertension as compared with control subjects (92 ± 78 ms vs. 11 ± 23 ms, p < 0.001). In contrast, there were no differences in LV dyssynchrony between the 2 groups (7). Similarly, intraobserver and interventricular dyssynchrony was examined in 34 patients with LV systolic heart failure, mean LV ejection fraction 22 ± 7% (56% with nonischemic cardiomyopathy) (15). The mean RV dyssynchrony was 59 ± 45 ms, and the mean LV dyssynchrony was 80 ± 62 ms.
In a larger unselected cohort of patients with a primary RV cardiomyopathy (ARVD/C), we report for the first time the occurrence of significant RV and interventricular mechanical dyssynchrony. As opposed to previous studies, dyssynchrony in this population occurred in the absence of confounding factors such as pulmonary hypertension and LV failure. Our data also established a cutoff value for mechanical dyssynchrony in the RV using 25 healthy control subjects. Interestingly, our cutoff value of 56 ms is close to the previously reported cutoff values for LV dyssynchrony (16).
Factors influencing RV dyssynchrony in ARVD/C
The presence of RV dyssynchrony is not surprising given previous and recent knowledge about the pathophysiology of ARVD/C. Recent data on potential causal genes suggest that most mutations involve genes that encode desmosomal proteins and include but are not limited to desmoplakin, plakophilin 2, and desmoglein (17–19). Thus ARVD/C is considered a desmopathy that is likely associated with abnormal cell-to-cell coupling, both electrically and mechanically, providing the substrate for the RV dyssynchrony.
Akin to LV dysfunction, electrical conduction abnormalities in the RV could be associated with mechanical delays. However, in our cohort we found no differences in QRS duration and/or the presence of right bundle branch block between patients with and without RV dyssynchrony. Although in general the presence of mechanical dyssynchrony is related to intraventricular conduction abnormalities, substantial LV ventricular dyssynchrony has been previously shown in the absence of QRS prolongation (20,21). Thus ARVD/C may be another example of dyssynchrony with a narrow QRS. Another potential explanation is that ventricular dyssynchrony in ARVD/C is related to regional abnormalities and heterogeneities in conduction and contractility, not evident on a surface ECG (22).
In contrast to the lack of association between electrocardiographic abnormalities and dyssynchrony, RV morphology and function seemed to be related to RV dyssynchrony. Larger RVEDA and RVESA were noted in the patients with RV dyssynchrony. However, this relationship was not as strong as previously reported in patients with pulmonary hypertension (r = 0.70, p < 0.001 between RVEDA and RV dyssynchrony) (23). One potential reason for a weaker relationship could be the difference in pathology. An ARVD/C is a patchy infiltrative process with regional dilation, whereas pulmonary hypertension (pressure overload) affects the RV globally and is more likely to cause uniform chamber dilation in the load-sensitive RV (24).
Similar to dyssynchrony associated with LV failure (20,25), our data indicate a relationship between RV function, as determined by RVFAC and RV peak systolic strain, and RV dyssynchrony in ARVD/C. These findings are also in line with previous studies in patients with pulmonary hypertension (7,23) and systolic heart failure (15). Finally, fibrofatty infiltration in ARVD/C could involve the conduction system and thereby introduce electromechanical delays resulting in dyssynchrony. Similar relationships have been examined in ischemic cardiomyopathy, in which significant amounts of fibrosis result in the presence of mechanical dyssynchrony (22).
Our findings present several incremental points of knowledge concerning ARVD/C that could be potentially used for prognostic and therapeutic purposes. In patients with LV failure, the presence of significant ventricular dyssynchrony is associated with a worse prognosis (10). Dyssynchrony in ARVD/C may similarly predict worse clinical outcomes. Serial monitoring of RV dyssynchrony may identify patients at higher risk and deserving of aggressive therapy. Cardiac resynchronization therapy has improved symptoms and survival in dyssynchronous left heart failure (8,26). The presence of significant RV or interventricular dyssynchrony may introduce the possibility of resynchronization therapy for right-sided failure in patients with ARVD/C who would otherwise be transplantation candidates. However, more prospective studies are needed to further elucidate the clinical implications of the presence of RV dyssynchrony in ARVD/C.
The mean age of the control group was lower than the ARVD/C patients. This may affect the definition of RV dyssynchrony for the ARVD/C patients. However, it has been shown that ventricular dyssynchrony does not depend on age (27). In addition, LV dyssynchrony was comparable between the control subjects and the ARVD/C patients in the present study. Lastly, we strictly selected healthy normal control subjects because a previous definition for RV dyssynchrony was not available. Older control subjects tended to have medical conditions such as hypertension and diabetes, which have effects on RV dyssynchrony that are unclear and were therefore excluded from the normal group. Larger studies with the power to assess the influence of other comorbidities should ideally include an age-matched control group.
Furthermore, in the present study only TDE was used to define interventricular dyssynchrony. Interventricular dyssynchrony calculated as the time difference between RV and LV pre-ejection intervals may have also provided additional information. However, RV outflow Doppler studies were not consistently performed in a fair number of subjects, and we are unable to assess this parameter in our population.
Duration of disease is likely an important factor in the development of RV dyssynchrony in ARVD/C. However, determining the onset and duration of disease in this relatively asymptomatic group is challenging. We are therefore unable to evaluate its influence on RV dyssynchrony.
Similarly, the extent of fibrofatty infiltration may be an important factor in the pathogenesis of RV dyssynchrony in ARVD/C patients. In a small subset of patients enrolled in the present study, who also had clinical magnetic resonance imaging, we found no correlation between the extent of fibrofatty infiltration (as assessed by gadolinium enhancement) and RV dyssynchrony. These data were not presented because of the small sample size and lack of statistical power to offer reliable conclusions.
Finally, although the present study is the first observational study that shows the presence of RV dyssynchrony in ARVD/C patients, unfortunately, this cross-sectional analysis does not provide insights into the clinical significance of the presence of RV dyssynchrony, and its exact role in ARVD/C management remains unclear. However, our findings prompt larger longitudinal studies to evaluate the influence of dyssynchrony on diagnosis, treatment, and prognostication of ARVD/C patients, including prediction of clinical outcomes such as heart failure, potential for arrhythmias, and response to treatment. In particular, future studies may allow a more systematic assessment of several important factors including but not limited to duration of disease and genotype.
Significant RV dyssynchrony may occur in up to 50% of ARVD/C patients and is associated with RV remodeling and dysfunction rather than electrocardiographic abnormalities. This finding may have therapeutic and prognostic implications in ARVD/C.
This work was supported by funds from the Bogle Foundation, National Institutes of Health (HL65594 and AG22554), The Netherlands Heart Foundation, Leids Universiteits Fonds, and Foundation De Drie Lichten. Dr. Bax has received grants from Medtronic, Biotronik, Bristol-Myers Squibb Medical Imaging, St. Jude Medical, GE Healthcare, and Edwards Lifesciences. Dr. Abraham has received honoraria and research grants from GE Healthcare. Drs. Tops and Prakasa contributed equally to this work.
- Abbreviations and Acronyms
- arrhythmogenic right ventricular dysplasia/cardiomyopathy
- confidence interval
- left ventricle/ventricular
- right ventricle/ventricular
- right ventricular end-diastolic area
- right ventricular end-systolic area
- right ventricular fractional area change
- strain echocardiography
- tissue Doppler echocardiography
- time-to-peak systolic velocity
- Received February 24, 2009.
- Revision received April 6, 2009.
- Accepted April 14, 2009.
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