2003 ARVD Family Seminar Summary

The 2003 ARVD seminar was held on April 26 in Baltimore and was attended by over 85 people. Dr. Hugh Calkins began the meeting with an overview of ARVD. Crystal Tichnell and Cindy James followed by describing their role in the ARVD program as coordinators and genetic counselors. Some of their roles include managing this website, responding to phone calls and emails, coordinate medical record reviews as well as patient evaluations, identify patients eligible for research studies, coordinate research protocols and write grants, attend national genetics and cardiology meetings, etc.

The remaining talks focused on research at Hopkins and specific topics of ARVD in Newfoundland, Genetics, and Pediatric ARVD. Four researchers from Johns Hopkins shared their research on ARVD. These presentations are summarized below.

 

Dr. Chandra Bomma, a post-doctoral fellow, presented his research on "Misdiagnosis of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C)" and the "Role Of Helical CT In Qualitative & Quantitative Evaluation of Arrhythmogenic Right Ventricular Dysplasia"

SELECTED ABSTRACTS:

Misdiagnosis of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C)

Introduction: The diagnosis of Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) has major implications for the management of patients and their first degree relatives. Diagnosis of ARVD/C is based on a set of criteria proposed by the International Task Force for Cardiomyopathies. In this study we report our experience in providing a re-evaluation for patients who have been previously diagnosed with ARVD/C.

Methods/Results: The study population included 89 patients who requested a re-evaluation at our center for diagnosis of ARVD/C. Detailed results of the initial evaluation and the basis of their ARVD/C diagnosis were analyzed. These patients were re-evaluated with a clinical history, physical exam and by non-invasive testing. Invasive testing including electrophysiology testing, right ventricular angiography and endomyocardial biopsy was performed when clinically indicated. After re-evaluation, only 24 (27%) of the 89 patients met the Task Force criteria for ARVD/C. Each of the remaining 65 patients had been diagnosed with ARVD/C without completing a thorough evaluation, and with the diagnosis often based on minor MRI abnormalities.
Conclusion: Diagnosis of ARVD/C should be entertained only after complete evaluation has been performed and based on International Task Force criteria. Greater awareness of, and reliance on, the International Task Force criteria will also allow greater uniformity in the diagnosis of ARVD/C. This ultimately should help facilitate the care of these patients, as well as improve research efforts on ARVD/C.

Role Of Helical CT In Qualitative & Quantitative Evaluation of Arrhythmogenic Right Ventricular Dysplasia

Objective: Arrhythmogenic right ventricular dysplasia (ARVD) is a cardiomyopathy characterized by fibro-fatty infiltration of the right ventricle (RV), leading to progressive RV failure. Serial morphological evaluation of the RV in ARVD patients is often useful to monitor progression of the disease. Echocardiography often results in sub-optimal visualization of the RV and defibrillator implants preclude the use of MR imaging for follow-up. We studied the role of contrast enhanced computed tomography (CT) in evaluating the right ventricle (RV) in ARVD patients, treated with ICD.

Methods: The study group consists of 13 patients who met the Task force criteria for ARVD and had received ICD implantation. ECG triggered, axial CT images with 0.4s time delay were obtained on 13 patients after injection of 100cc of non-ionic contrast agent, using a 4 detector helical scanner. The CT images were analyzed for morphological abnormalities suggestive of ARVD, which include intra myocardial fat, RV free wall scalloping, increased trabeculations and out flow tract (RVOT) enlargement. Quantitative measurement of RV inflow diameter and outflow area was performed and correlated with the global RV volume.

Results: Fatty infiltration of the RV free wall was observed in 9 (69%), increased trabeculation in 12(92%) and RV free wall scalloping in 7(57%) patients. Intra myocardial fat in the left ventricle was observed in one patient (7%). RV inflow dimension was significantly greater than left ventricular (LV) inflow dimension suggesting RV enlargement (4.6cm ± 0.98 vs. 3.7cm ± 0.56, p=0.01). The mean RV volume was 204.45 ml ± 54ml and the mean RVOT area was 16.1cm2 ± 4.9 cm2. Both the RV inlet dimension and the RVOT area showed good correlation with the global RV volume (r2 = 0.74 and 0.81 respectively).

Conclusion: Contrast enhanced ECG gated CT not only depicts the qualitative findings of ARVD, but also permits quantitative assessment of the RV. This modality may have a role in diagnosis of ARVD, and more importantly in follow-up evaluation of the RV in ARVD patients who receive defibrillator.

Dr. Ariel Roguin, a post-doctoral fellow, presented his research on "Cardioverter-Defibrillators in Patients with Arrhythmogenic Right Ventricular Dysplasia."

Introduction: Arrhythmogenic Right Ventricular Dysplasia (ARVD) is associated with tachyarrhythmia and an increased risk of sudden death. Our aim was to study the outcome of ARVD patients treated with an implantable cardioverter-defibrillator (ICD).
Methods and Results: This study included 64 ARVD patients with ICDs (50% male, ages 6-69, median 37). The mean follow up was 42±26 months (4-135 months). Complications associated with ICD implantation included need for lead repositioning (n=3) and systemic infection (n=2). During follow up, one patient died of a brain malignancy and one had heart transplantation. Lead replacement was required in 6 patients because of lead fracture/insulation damage (n=4) or change in thresholds (n=2). During this period 39/64 (61%) patients received a mean of 3.5 (range 1-75) appropriate ICD shocks . The median period between ICD implantation and the first firing was 9-months (0.1-66 months). ICD firing storms were observed in 5 patients. Inappropriate firings were seen in 14 patients. Predictors of appropriate firing were fulfillment of the ARVD criteria (76% vs. 27%, respectively, p<0.001), induction of VT during EP Study (73% vs. 33%, respectively, p<0.001), detection of spontaneous VT (80% vs. 35%, respectively, p<0.001) and severe right ventricular dysfunction in echocardiography (72% vs. 16%, respectively, p<0.02). No appropriate ICD firings were observed in the group (n=7) who did not have complete fulfillment of the ARVD criteria and no arrhythmia induction during electrophysiology study.

Conclusions: Patients with ARVD have a high arrhythmia rate requiring appropriate ICD interventions. ICD therapy appears to be well tolerated and valuable in the management of patients with ARVD.

Dr. Khurram Nasir, a research fellow, presented his research on "Signal Averaged Electrocardiogram (SAECG) testing in Arrhythmogenic Right Ventricular Dysplasia (ARVD)."

He discussed that SAECG abnormalities are related to severity of disease; with approximately 90% of them seen in severe cases compared to just 1/3 in milder disease. It is also important to note that there are no described criteria as to what an abnormal SAECG constitutes among ARVD patients. One of the most notable findings of research at Hopkins is the development of an "abnormal criteria" for SAECG, which has been shown to be more predictive than the "conventional criteria" for diagnosing ARVD as well as identifying individuals at risk for VT induction and ICD firing.

SELECTED ABSTRACTS:

ECG and SAECG Predictors of Disease Severity, VT Induction and Implantable Defibrillator Firing in Arrhythmogenic Right Ventricle Dysplasia

Background: The value of non-invasive markers reflecting repolarization and/or conduction abnormalities in identifying patients with arrhythmogenic right ventricular dysplasia (ARVD) who have a severe form of disease and are at risk for life-threatening ventricular arrhythmias (VT) is not clear. The purpose of the study is to evaluate ECG and SAECG indicators of severity of the disease and arrhythmic risk in ARVD.

Methods & Results: The study included 33 definite ARVD patients (37 14 years, 64% males). Patients were classified as having diffuse disease (DD) or mild disease (MD) according to McKenna's criteria. Indicators of severity of disease in ARVD are shown in table. A positive (+) EP study was seen in 76%(n=25) patients. Patients with DD compared to MD had a higher prevalence of inducibility during EP study (82% vs. 46%, p=0.03). The following ECG and signal average ECG characteristics were indicative of inducibility of ventricular tachycardia during EP Study: filtered QRS duration (fQRS) 110 ms, QT dispersion (QTd) 60 ms, QRS dispersion (QRSd) 35 ms and JT dispersion (JTd) 35 ms, QRS duration in V1-V3 120 ms and presence of an epsilon wave. T wave inversions in V1-V3 and beyond as well as prolonged S wave upstroke in right precordial leads were not predictive of the EP study result. Stepwise logistic regression analysis of all the variables identified fQRSd (1.7, 95% CI: 1.3-3.7, p=0.001) and QTd (1.3, 1.01-10.3, p=0.04) as the only significant predictors of a positive EP Study. During a follow-up of 21 19 months, 23/29 (79%) ARVD patients had an ICD firing. The sensitivity and specificity were 91% and 73% for fQRS 110 ms and 73% and 82% for QTd 60 ms in predicting ICD firing. FQRS 110 ms and QTd 60 ms on Cox regression had a hazard ratio of 4.5 (95% CI=1.5-13.1) and 2.1 (1.0-3.3) for an ICD firing.

Conclusions: Risk stratification of patients with ARVD is possible by simple and inexpensive means such as SAECG and EKG, which provide sensitive and specific indices.

Filtered QRS Duration Predicts Inducibility of Ventricular Tachycardia in Arrhythmogenic Right Ventricular Dysplasia

The treatment of patients with arrhythmogenic right ventricular dysplasia (ARVD) is mostly based on the prevention of sudden cardiac death that results from cardiac arrhythmias. A clinical history suggestive of ARVD requires careful evaluation including electrophysiological studies (EPS), which play an important role in deciding mode of therapy. However these studies are expensive, require high degree of expertise, and carry some risk. It would be helpful to be able to screen patients prior to performing EPS by non-invasive means in order to select those patients likely to have the highest yield from EPS. The purpose of the study is to evaluate the role of signal average electrocardiogram (SAECG) in predicting inducibility of ventricular arrhythmias (VT) in patients with clinical presentation of ARVD. 30 patients with a clinical suspicion of ARVD were evaluated with time domain SAECG (band pass 40-250 Hz) and EPS. 8 patients with bundle branch were excluded. The EPS was considered positive if uniform sustained VT was induced. VT was induced in 14 patients. The filtered QRS duration (FQRS), amplitude in the last 40 ms of QRS duration (HFLA), and root mean square in last 40 ms of QRS duration (RMS) in patients induced vs. non induced were 117±12 & 105±7 msec (p= 0.01), 42±16 & 32±7 uv (p=0.1), and 23±18 vs. 21±15 msec (p=0.5) respectively. A difference in ejection fraction in both groups was non-significant. FQRS greater than 110 msec had a sensitivity of 92%, specificity of 75%, and a total predictive value of 82% in predicting inducibility in these patients. Measurement of filtered QRS duration with SAECG could be a simple method to detect patients with suspected ARVD prone to VT.

Published in: Pacing and Clinical Electrophysiology. 2003 Oct; 26 (10):1955-1960.

Dr. Hari Tandri, a post-doctoral fellow, presented his research on "MR Imaging Findings In Patients Meeting Task Force Criteria For Arrhythmogenic Right Ventricular Dysplasia"

Background: The diagnosis of arrhythmogenic right ventricular dysplasia (ARVD) is based on a set of criteria encompassing structural, electrocardiographic and histological criteria proposed by the Task Force of the Working Group on Cardiomyopathies. MR imaging findings in patients meeting Task Force criteria have not been systematically described. The purpose of this study is to present qualitative and quantitative MR imaging findings in patients who met Task Force criteria for the diagnosis of ARVD using state of the art MR imaging.

Methods: Between 1999 and 2002, 11 patients meeting the task force criteria for the diagnosis of ARVD were identified from the Johns Hopkins ARVD registry. MR imaging was performed using a 1.5T scanner, and included breath-hold spin echo and gradient echo images. Ventricular volumes and dimensions were compared to 10 age and sex-matched normal volunteers who underwent MR imaging with the same protocol. Results: High intramyocardial T1 signal similar to fat signal was observed in 7 of the 11 patients (72%) and in none of the controls. Right ventricular (RV) hypertrophy was seen in 5 (45%), trabecular hypertrophy/disarray in 7 (63%), and wall thinning in 3 patients (27%). Both the RV end diastolic diameter and the outflow tract area were significantly higher in ARVD patients compared to controls (51.4 mm vs. 43.2 mm, p<0.01; 15.0 cm2 vs. 9.29 cm2, p<0.01). ARVD patients had higher RV end diastolic volume index and lower RV ejection fraction compared with controls (127.8 vs. 87.5, p<0.01; 40.7% vs. 57%).

Conclusions: High intramyocardial T1 signal indicative of fat is seen in a high percentage (72%) but not all patients who meet the Task Force criteria for ARVD. Trabecular disarray is seen more frequently than wall thinning and aneurysms. RV dimensions and volumes differ significantly in ARVD compared to controls, indicating a role for quantitative evaluation in the diagnosis of ARVD.

Published in: Journal of Cardiovascular Electrophysiology. 2003 May; 14(5):476-82.

Cynthia James, Genetic Counselor, gave a review of the inheritance of ARVD, an update on recent genetic discoveries, and a description of ongoing research on the genetics of ARVD.

Inheritance of ARVD
ARVD can run in families. A recent study (Hamid et al, 2002) reported on the cardiac screening of 298 relatives of 67 people with ARVD. 10% of relatives had ARVD and 11% of relatives had abnormal test results but did not meet the formal criteria for ARVD. Over all, slightly more than one-quarter of families wound up having a second family member diagnosed with ARVD and an additional quarter had a person with milder abnormalities. This finding highlights the importance of cardiac screening for all first degree relatives (parents, children, sisters, and brothers) of people who have ARVD.

Genes/loci linked to ARVD
Researchers in groups across the world (Italy, England, Germany, Canada, United States) have been working to find genes associated with ARVD. To date three genes have been found. Changes in the desmoplakin gene can cause typical ARVD. Changes in the cardiac ryanodine receptor gene cause a variant of ARVD called ARVD2 which is characterized by early-onset severe arrhythmias with fewer changes in the structure of the right ventricle. Changes in the plakoglobin gene cause Naxos disease, a rare form of severe ARVD accompanied by unusual hair and skin findings. Naxos disease only occurs in a small area of Greece. Specific changes in each of these three genes can cause ARVD. Research has shown that there are probably at least six other genes associated with ARVD. So far we know what chromosome these genes are on but have not found the genes yet.

What are desmoplakin and plakoglobin?
Desmoplakin and plakoglobin are components of something called the "desmosome-intermediate filament complex." This complex sticks muscle cells of the heart together. This finding helps explain why exercise might trigger ARVD. If muscle cells already have a problem sticking together, the force from exercise might cause the cells to be damaged, resulting in scarring characteristic of ARVD.

What research is happening now?
Research groups are continuing to look for additional genes associated with ARVD. The research group of Jeff Towbin at Baylor (with whom we collaborate) is looking at blood samples of ARVD patients to see whether he can find changes in desmoplakin and other genes. Your donation of blood samples is important to these efforts. To all who have donated, we thank you. If you have not donated a sample please contact us. (Please be aware that we are looking for specific types of families to donate blood right now so you may not be eligible at the moment.)

Dr. Philip Spevak, a pediatric cardiologist at Johns Hopkins, presented his research and recommendations on "Arrhythmogenic Right Ventricular Dysplasia Presenting During Childhood"

Objectives: To characterize the clinical features of arrhythmogenic right ventricular dysplasia (ARVD) in childhood and to develop strategies for reducing the complication of sudden cardiac death or arrest (SCD).

Methods: ARVD, an inheritable form of cardiomyopathy, predominantly affects the right ventricle. Applying strict diagnostic criteria, a retrospective review of children diagnosed with ARVD at Johns Hopkins Hospital and of other pediatric cases reported in the literature was performed to describe presenting features, frequency of abnormalities on diagnostic testing, and characteristics of the patients experiencing SCD.

Results: Forty-three patients (mean age at presentation 14.2 years (range 2.8-18.0)) comprised the study population. The most consistent presenting symptoms and signs were: ventricular arrhythmia 37% (n=13/35), palpitations 31% 9n=11/35), and syncope or presyncope 31% (n=11/35). Cardiac arrest was the presenting finding in 3 children (7%) and 5 others died suddenly during follow-up. The most common criteria achieved for the diagnosed of ARVD were: right ventricular functional or structural abnormality 100% (41/41), repolarization abnormality 92% (22/24), and arrhythmia 85% (34/40). Among patients with SCD, family history was positive for ARVD or SCD in all 6 children where family history was known.

Conclusion: SCD from ARVD does occur during childhood and can be the presenting feature. More aggressive screening of those family members with a positive family history may reduce sudden death since 6 of the 23 patients with a family history had SCD. However, the diagnosis of ARVD is complicated since the most frequent presenting symptoms are non-specific as may be the results of diagnostic testing.

Dr. Spevak also discussed screening recommendations; including who to screen, when to start, what tests to do, and when to repeat testing. In general, the following are indications for screening: first-degree relative with ARVD or cardiomyopathy, syncope or palpitations with exercise, new exertional intolerance in a previously conditioned child, and frequent ventricular ectopy. Screening may begin as early as 2-4 years when risk factors are present and at age 8 with no risk factors. Children younger than 8 years should be screened with an ECG, signal averaged ECG, 24-hour Holter monitor, and echocardiogram. Children 8 years and older should be screened with an ECG, signal averaged ECG, 24 hour Holter monitor, echocardiogram, exercise stress test, and cardiac MRI. If results are within normal limits, screening should be repeated every three years. If results are abnormal, repeat screening is generally recommended between 1 and 3 years depending on the results.

Kathy Hodgkinson discussed the Newfoundland Experience with ARVD

Clinical Diagnosis: Diagnosis is difficult. Criteria defined in 1994 (based on structural, functional and electrocardiographic features, with major and minor categories, in which the gold standard for diagnosis was defined as the presence of fat and fibrous tissue on cardiac biopsy or autopsy) to aid in the diagnosis of ARVC have little relevance to the Newfoundland population. Diagnostic tests include routine 12-lead Electrocardiogram (EKG), Signal averaged EKG, Echocardiography, Magnetic Resonance Imaging (MRI), and Holter monitoring. These tests have been analysed and we have found subtle differences with the findings and those published. We currently have a database comprising all family members with a risk of 50% or above and have analysed the issue of diagnostic utility of current cardiac testing for some of the routine cardiac tests. It is clear that although subtle signs occur, they would be considered normal in a general population sample, and are only of relevance when the individual being assessed has a high a-priori risk of having the ARVC gene. The most useful diagnostic predictor is the genetic locus, but it has several limitations. These relate to the research nature of the testing, the inherent error related to a linked locus, and the ever present possibility of sample mix-up. However, given all these issues the DNA test is conservatively assumed to be 95% accurate when available. Once a mutation for ARVC is defined a 100% DNA test result will be available.

Treatment: Current treatment utilizes both antiarrhythmic drug therapy and Implantable Cardioverter defibrillator (ICD) therapy with the latter considered the treatment of choice based on randomized control trials, both primary (assessment of those at high risk of MI or death from cardiac compromise before the first MI) and secondary (assessment of those given drug or ICD therapy following a previous MI.) prevention studies. There are no long term studies utilizing a large patient group that have looked at the efficacy of ICD implants in ARVC. We have 31 treated individuals with ARVC to date (another 10 individuals whose families may be ARVC but await confirmation), and 10/30 for whom it has been a life saver.

Possible requirement for ICD therapy in Newfoundland
Current figures have not been assessed. However, three years ago when we had only 6 families linked to the chromosome 3 locus, there were 655 living individuals at above a 12.5% risk (1 in 8) of inheriting ARVC. This translates to an expected number of gene carriers of 173. Since this time 5 additional linked families have been ascertained, and 6 others await assessment.

Health Care Model
ARVC is a progressive disorder, where negative tests do not always exclude the disease. The first symptom for many individuals with ARVC has been their last. This condition is an ideal model for preventative medicine: assess those at highest risk, define affected status, treat, move on to the next generation of those at risk. Prevent early death with true multi-disciplinary, stand alone clinics, with accurate recall and appropriate staff. Newfoundland is in an ideal position to appropriately care for and prevent the seemingly unremitting numbers of young deaths which have occurred.

This year we invited a number of individuals to share their experiences with ARVD. Their experiences were deeply felt by all those attended. It was our hope that this would initiate discussion among families and it did exactly that. It also helped families to realize the importance of screening for ARVD, as we have had a number of referrals over the past few months.

Tracy Church took a few minutes to discuss the importance of donating funds to the ARVD project for continued research. Donations can be made through our website.

After a lunch reception, individuals diagnosed with ARVD and their family members were invited to participate in various research studies. Over 40 individuals participated in blood drawings, electrocardiograms, signal averaged electrocardiograms, Holter monitors, strain rate echocardiograms, and body surface electrocardiograms. We would like to thank all of you who participated in these research projects!

We look forward to seeing you at the next ARVD Family Seminar to be held on May 15, 2004!