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Background: A novel risk calculator based on clinical characteristics and noninvasive tests that predicts the onset of clinical sustained ventricular arrhythmias (VA) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) has been proposed and validated by recent studies. It remains unknown whether programmed ventricular stimulation (PVS) provides additional prognostic value. Methods: All patients with a definite ARVC diagnosis, no history of sustained VAs at diagnosis, and PVS performed at baseline were extracted from 6 international ARVC registries. The calculator-predicted risk for sustained VA (sustained or implantable cardioverter defibrillator treated ventricular tachycardia [VT] or fibrillation, [aborted] sudden cardiac arrest) was assessed in all patients. Independent and combined performance of the risk calculator and PVS on sustained VA were assessed during a 5-year follow-up period. Results: Two hundred eighty-eight patients (41.0 +/- 14.5 years, 55.9% male, right ventricular ejection fraction 42.5 +/- 11.1%) were enrolled. At PVS, 137 (47.6%) patients had inducible ventricular tachycardia. During a median of 5.31 [2.89-10.17] years of follow-up, 83 (60.6%) patients with a positive PVS and 37 (24.5%) with a negative PVS experienced sustained VA (PFunding Agencies|Leonie-Wild Foundation; Leyla Erkan Family Fund for ARVD Research; Hugh Calkins, Marvin H. Weiner, and Jacqueline J. Bernstein Cardiac Arrhythmia Center; Marvin H. Weiner, and Jacqueline J. Bernstein Cardiac Arrhythmia Center; Dr. Francis P. Chiramonte Private Foundation; Dr. Satish, Rupal, and Robin Shah ARVD Fund at Johns Hopkins; Bogle Foundation; Healing Hearts Foundation; Campanella Family; Patrick J. Harrison Family; Peter French Memorial Foundation; Wilmerding Endowments; Fondation Leducq; National Center for Advancing Translational Sciences [UL1TR001079]; Philippa and Marvin Carsley cardiology research chair; Montreal Heart Institute Foundation; Georg und Bertha Schwyzer-Winiker Foundation; Baugarten Foundation; Swiss Heart Foundation [FF17019, FF21073]; Swiss National Science Foundation [160327]; Swedish Heart Lung Foundation [20200674]; Swedish state under the Avtal om lakarutbildning och forsknin (ALF)-agreement; Netherlands Cardiovascular Research Initiative; Dutch Heart Foundation [CVON201512/2018-30]

Introduction: Few intraprocedural localization systems have been developed to predict idiopathic ventricular arrhythmia (IVA) source sites. However, an accurate and bi-ventricular patient-specific automated site of origin localization system remains elusive. To address this issue, we have developed a new automatic arrhythmia origin localization (AAOL) system that determines the sites of earliest activation in both ventricles and provides superior accuracy. Hypothesis: We hypothesized that the AAOL system can use electroanatomic mapping (EAM) geometry and accurately localize IVA source sites on patient-specific geometry of LV, RV and neighboring vessels using 3-lead ECGs. Methods: Twenty patients undergoing IVA catheter ablation had a 12-lead ECG recorded during clinical arrhythmia and during pacing at various locations identified on EAM geometries. The AAOL system combined 3-lead (III, V2, V6) 120-ms QRS integrals and patient-specific EAM geometry with intracardiac pacing to predict the site of earliest ventricular activation. The predicted site was projected onto the EAM geometry using the EAM triangular-mesh site nearest to the tip of the predicted site. Results: Twenty-three IVA source sites were clinically identified by activation mapping and/or pace mapping (8 RV, 15 LV, including 8 from the posteromedial papillary muscle; 2 from the aortic root; and 1 from the distal coronary sinus). The new system achieved a mean localization accuracy of 3.6 mm for the 23 mapped IVAs (Figure 1D), better than that achieved by previous systems. Conclusions: The new AAOL system offers highly accurate localization of IVA source sites in both ventricles and neighboring vessels, which could facilitate ablation procedures for patients with IVAs.

Introduction: With improved survival of sudden cardiac death in arrhythmogenic right ventricular cardiomyopathy (ARVC), progressive heart failure is increasingly recognized. Cardiopulmonary exercise testing (CPET) can play a role in prognostication. However, correlation of morphologic disease severity and exercise capacity is lacking. Hypothesis: Increased RV size and decreased RV function measured by two-dimensional echocardiography (2D echo) are associated with impaired exercise capacity parameters (peak oxygen consumption (pVO 2 ) and ventilator efficiency (VE/VCO 2 slope)). Methods: We retrospectively examined 21 patients who underwent 25 echocardiography and cardiopulmonary exercise testing (CPET) studies within 6 months of each other. A Spearman rank correlation was used to determine the relationship between RV dimensions and CPET parameters. Seven (28%) had submaximal effort defined as respiratory exchange ratio 2 . Results: Patients’ mean age was 44 ± 11 years and 28% were women. Despite more than half of patients (54%) being New York Heart Association Class I, mean pVO 2 was decreased at 19 ± 5 mL/kg per minute (63% ± 22% predicted for age and sex). There was a moderate negative correlation between pVO 2 and RV basal diameter ( r s = -0.46, p =0.05) and RV area in diastole ( r s = -0.55, p =0.02). There was no significant correlation between RV size or function with VE/VCO 2 slope. Conclusion: In this small study of ARVC patients, abnormalities on echo including increased RV basal diameter and RV diastolic area were associated with worse pVO 2 but not VE/VCO 2 slope. These findings suggest that RV structural abnormalities are related to reduced oxygen uptake on CPET, and larger studies are warranted to investigate the prognostic value and clinical course of ARVC patients with regards to the development of heart failure.

Introduction: High transnasal airflow at ambient temperature increases evaporative cooling of the nasal passages and drives a countercurrent heat exchange between cooled venous blood draining the nasal turbinates with cephalic arterial blood. Hypothesis: High transnasal airflow is not inferior to standard surface cooling in protecting the brain in an infant swine model of asphyxic cardiac arrest. Methods: Arterial O2 saturation was decreased to ~35% for 45 min followed by 7 min airway occlusion to produce asphyxic cardiac arrest in 2-week-old anesthetized piglets (4 kg). Viable neuronal counts were assessed at 6 days of recovery in 6 groups (n=5-9): 1) sham surgery, 2) normothermic recovery, 3) surface cooling to decrease rectal temperature from 38.5 to 34C between 10-120 min 4) transnasal cooling with airflow of 32 L/min from 10-120 min, 5) surface cooling onset delayed until 120 min ROSC, and 6) transnasal cooling delayed by 120 min ROSC. In all 4 cooling groups, hypothermia was sustained at 34C with surface cooling until 20 h ROSC followed by 6-8 h of rewarming. Results: Nasal airflow of 32 L/min decreased brain temperature from 38.3±0.3°C to 33.8±0.6 within 60 min without spatial temperature gradients in these 45-g brains. Surface cooling and transnasal airflow rescued the number of viable neurons in putamen from 38±23% (% of sham viable neurons; ±SD) in the normothermic group to 67±33% and 76±36%, respectively, when initiated at 10 min ROSC, and to 72±30% and 61±25%, respectively, when initiated at 120 min. In sensorimotor cortex, surface cooling and transnasal airflow rescued neurons from 56±36% in the normothermic group to 89±37% and 89±29%, respectively, when initiated at 10 min ROSC, and to 84±19% and 81±28%, respectively, when initiated at 120 min. Conclusions: The use of a high transnasal airflow is as effective as standard surface cooling when initiated at 10 or 120 min after ROSC in protecting vulnerable putamen and sensorimotor cortex from asphyxic cardiac arrest in infant piglets. Because of its simplicity, portability, and low cost, we postulate that transnasal cooling potentially could be deployed in the field by first responders for early initiation of brain cooling prior to maintenance with standard surface cooling after pediatric cardiac arrest.

Background: Targeted temperature management (TTM) is recommended as a standard of care for post cardiac arrest patients. Current TTM methods have significant limitations to be used in an ambulatory setting. We explored the efficacy and safety of a novel non-invasive transnasal evaporative cooling device (CoolStat™). Methods: Eleven pigs underwent hypothermia therapy using a transnasal cooling device (CoolStat™). CoolStat™ induces evaporative cooling by blowing de-humidified ambient air over the nose in a unidirectional fashion. CoolStat’s efficacy and safety were assessed by applying different cooling strategies (Groups A, B and C). In group A (efficacy study; n=5, TTM for 8h), time to achieve brain target temperature, and the percentage of time in which the temperature ranged within 0.5 o C after reaching the target temperature were investigated. In the safety assessment (Groups B and C), two worst-case therapy situations were reproduced: in group B (n=3), continuous maximum air flow (65L/min) was applied without temperature control and, in group C (n=3), subjects underwent 24-hour TTM (prolonged therapy). Hemodynamic and respiratory parameters, nasal mucosa integrity (endoscopic assessment) and other therapy-related adverse effects were evaluated. Results: Efficacy study. CoolStat™ cooling therapy successfully induced and sustained managed hypothermia in all subjects. Brain target temperature was achieved in 0.5±0.6h and kept within a ±0.5 o C range for the therapy duration (99.9±0.1%). All animals completed the safety studies. Maximum air flow (Group B) and 24-hour (Group C) therapies were well-tolerated and no significant damage was observed on nasal mucosa for neither of the groups. Conclusion: CoolStat™ was able to efficiently induce and maintain hypothermia using unidirectional high flow of dry air into the nostrils of porcine models. CoolStat therapy was well-tolerated and might account for early hypothermia in cardiac arrest settings.

The diagnosis of cardiac sarcoidosis (CS), especially in cases where there is limited or no extracardiac involvement, is challenging. Patients with CS are at increased risk of ventricular arrhythmias and sudden cardiac death. Several techniques for risk stratification for sudden cardiac death have been proposed in this population, including advanced cardiac imaging and electrophysiology study. Clinical ventricular arrhythmias in patients with CS may be treated with immunosuppressant therapy, antiarrhythmic drugs, catheter ablation, or implantable cardioverter-defibrillator placement. This article will provide an update on techniques for diagnosing CS, risk stratifying patients with CS for sudden cardiac death, and treating patients with CS with ventricular arrhythmias, focusing on evidence that has become available since publication of the 2014 Heart Rhythm Society Expert Consensus Statement on the Diagnosis and Management of Arrhythmias Associated With Cardiac Sarcoidosis.

Background— Changes in right ventricular (RV) morphology are associated with morbidity and mortality in heart and lung disease. We examined the association of abnormal RV structure and function with the risk of heart failure or cardiovascular death in a population-based multiethnic sample free of clinical cardiovascular disease at baseline. Methods and Results— The Multi-Ethnic Study of Atherosclerosis (MESA) performed cardiac magnetic resonance imaging on 5098 participants between 2000 and 2002 with follow-up for incident heart failure and cardiovascular death (“death”) until January 2008. RV volumes and mass were available for 4204 participants. The study sample (n=4144) was 61.4±10.1 years old and 47.6% male. The presence of RV hypertrophy (increased RV mass) was associated with more than twice the risk of heart failure or death after adjustment for demographics, body mass index, education, C-reactive protein level, hypertension, and smoking status (hazard ratio, 2.52; 95% confidence interval, 1.55–4.10; P P for interaction=0.05). Conclusions— RV hypertrophy was associated with the risk of heart failure or death in a multiethnic population free of clinical cardiovascular disease at baseline.

We appreciated the interest of Barison and colleagues in our International Consensus Statement on the treatment of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D).1 Our document provided a comprehensive overview and recommendations for risk stratification and therapy of patients fulfilling the diagnostic criteria for ARVC/D. These criteria had been addressed by a previous International Task Force consensus document dedicated to diagnosis of ARVC/D.2 According to the revised criteria proposed by the International Task Force in 2010, the diagnosis of ARVC/D is based on the presence of major and minor criteria encompassing electrocardiographic, arrhythmic, morphological, histopathologic, and genetic factors. Diagnosis of definite ARVC/D is fulfilled in the presence of 2 major criteria or 1 major plus 2 minor or 4 minor criteria from different groups; the ARVC/D diagnosis is possible or borderline in the presence of insufficient criteria. In their Letter to the Editor, Barison and colleagues emphasized the valuable role of cardiac magnetic resonance (CMR) for diagnosis of ARVC/D, which relies on its ability to combine evaluation of ventricular size, function, and regional wall motion with characterization by late-gadolinium enhancement (LGE) of fibro-fatty myocardial scar, which is the hallmark lesion of ARVC/D. We totally agree that CMR is becoming the gold standard tool for detection of structural and functional ventricular abnormalities in ARVC/D. In the 2010 International Task Force consensus document, CMR was appropriately included among the diagnostic imaging techniques, and specific CMR reference values for normal (and abnormal) ventricular size, systolic function, and regional dyssynergy were provided. Tissue characterization by LGE was not included among these diagnostic criteria because of the potential risk of misdiagnosis of ARVC/D related to the difficulty of assessing LGE at the level of the thin right ventricular wall and possible confusion with normal epicardial fat tissue. More recently, the frequent involvement by the disease of the left ventricular wall in the form of epicardial-mediomural LGE has been recognized. As pointed out by the authors, LV LGE may enhance sensitivity for early/minor or predominant left variants of the ARVC/D; however, its diagnostic accuracy remains to be established. The prognostic role of CMR and, in particular, of postcontrast sequences for tissue characterization in patients with a diagnosis of definitive ARVC/D remains elusive. In our consensus statement on the treatment of ARVC/D, we performed a systematic review of outcome studies on ARVC/D available in the literature to identify predictor variables that were associated with an increased risk of major arrhythmic events (ie, sudden cardiac death, appropriate defibrillator interventions, or defibrillator therapy on fast ventricular tachycardia/ventricular fibrillation), nonsudden cardiac death, or heart transplantation in at least 1 published multivariable analysis. Although the predicting value of CMR for worse arrhythmic outcome was shown in the general population of patients showing premature ventricular beats with a left bundle branch morphology4 and in patients with suspected diagnosis of ARVC/D,5 no specific features of CMR, either alone or in combination, have been reported yet as independent predictors of life-threatening arrhythmic events in patients with a definite diagnosis of ARVC/D. This lack of evidence underscores the importance of undertaking future studies on this field.

Introduction: The phenotypic features and clinical course of elderly Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) patients (age> 50 years at diagnosis) is unknown. Methods: Demographic, phenotypic and genotypic data of 502 patients with ARVC diagnosis (2010 Task Force Criteria) from Johns Hopkins and Utrecht (NL) ARVD/C registries was obtained and long term clinical outcomes ascertained. Results: Late presentation was seen in 104 (21%) patients (38% with PKP2 mutation; no DSP or DSG2 mutation carrier) with 3% being ≥ 65 years at diagnosis. Sustained ventricular tachycardia (VT) is the major (43%) mode of presentation in the elderly while cardiac syncope is infrequent (p Conclusion: One fifth of all ARVD/C patients present after 50 years of age, often with sustained VT and are less likely to have prior syncope or identifiable pathogenic mutation. In ARVD/C, late presentation does not confer a benign prognosis and is associated with high arrhythmic risk. Electrocardiographic changes and ventricular ectopy are significantly less common in the elderly and are not associated with arrhythmic events.

Background— Right ventricular (RV) morphology is an important predictor of outcomes in heart and lung disease; however, determinants of RV anatomy have not been well studied. We examined the demographic factors associated with RV morphology and function in a population-based multiethnic sample free of clinical cardiovascular disease. Methods and Results— In the Multi-Ethnic Study of Atherosclerosis (MESA), cardiac magnetic resonance imaging was performed on 5098 participants. Right ventricular volumes and mass were available for 4204 participants. Normative equations for RV parameters were derived with an allometric approach. The study sample (n=4123) was 61.5±10.1 years of age and 47.5% men. Older age was associated with lower RV mass (≈5% lower mass per decade), with larger age-related decrements in men than in women ( P P ≤0.01 for interaction). Overall, men had greater RV mass (≈8%) and larger RV volumes than women, but had lower RV ejection fraction (4% in absolute terms; P P ≤0.002), whereas Hispanics had higher RV mass ( P ≤0.02). When the derived normative equations were used, 7.3% (95% confidence interval, 6.5 to 8.1) met the criteria for RV hypertrophy, and 5.9% (95% confidence interval, 5.2 to 6.6) had RV dysfunction. Conclusion— Age, sex, and race are associated with significant differences in RV mass, RV volumes, and RV ejection fraction, potentially explaining distinct responses of the RV to cardiopulmonary disease.

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an inheritable heart muscle disease that predominantly affects the right ventricle (RV) and predisposes to ventricular arrhythmias and sudden cardiac death (SCD).1–17 In the last three decades, there have been a significant number of studies defining the pathogenesis, genetic aspects, and clinical manifestations of the disease (See ‘Etiology, pathogenesis, diagnosis and natural history’ in the online-only Data Supplement). In 1994 and 2010, an International Task Force (ITF) document proposed guidelines for the standardized diagnosis of ARVC/D based on electrocardiographic (ECG), arrhythmic, morphological, histopathologic, and clinico-genetic factors.18,19 The growing knowledge regarding arrhythmic outcome, risk factors, and life-saving therapeutic interventions, make it particularly timely to critically address and place into perspective the issues relevant to the clinical management of ARVC/D patients. The present ITF consensus statement is a comprehensive overview of currently used risk stratification algorithms and approaches to therapy, either pharmacological or nonpharmacological, which often poses a clinical challenge to cardiovascular specialists and other practitioners, particularly those infrequently engaged in the management of ARVC/D. This document should be regarded as a guide to clinical practice where rigorous evidence is still lacking, because of the relatively low disease prevalence and the absence of controlled studies. Recommendations are based on available data derived from nonrandomized and observational studies and consensus within the conference panellists. When development of prognostic-therapeutic algorithms was controversial, management decisions were recommended to be individualized. Recommendation and level of evidence of specific management options were classified according to predefined scales, as outlined in Tables 1 and 2 (http://www.escardio.org/guidelines-surveys/esc-guidelines/about/Pages/rules-writing.aspx). Because randomized studies are not available, most consensus recommendations on treatment of ARVC/D are based on data derived from follow-up registries and/or experts opinions (ie, level of evidence B or C). View this table: Table 1. Classes of Recommendations View this table: Table 2. Levels of Evidence All members of …

Introduction: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by regional wall motion abnormalities of the right ventricle (RV) that have not previously been quantified, resulting in challenges / errors in diagnosis of the disease. RV strain is poorly assessed with tagged cardiac magnetic resonance (CMR) due to the thin RV wall. We applied novel feature tracking analysis to assess RV strain in patients with ARVC. Methods: 106 subjects (30 controls, 37 preclinical ARVC [mutation+], and 39 overt ARVC [mutation+, Task Force+] patients) underwent 4 chamber and axial cine imaging using SSFP sequences. The RV was divided into subtricuspid (ST), anterior wall (AW), and apical (Ap) regions. Each region was analyzed to determine peak longitudinal strain and strain-rate using Multimodality Tissue Tracking (MTT) software (MTT Version 6.0.4725, Toshiba Medical Systems Corporation, Tokyo, Japan). Results: Average age was 33.6 ± 16.1 years (48.2% women); there were no differences between groups. In the 4 chamber view, mean global and segmental strain and strain rates decreased in magnitude from control (-37.7% ± 11.2) to preclinical (-32.2% ± 11.5) to overt ARVC (mean -22.2% ± 11.9). Differences between groups most pronounced in the subtricuspid segment, and reached statistical significance between overt ARVC and both control and preclinical ARVC (p < 0.01). A similar trend was observed in longitudinal strain measured in the axial view, but these trends were inconsistent; statistical significance was met globally, but most individual segments did not reach statistical significance. Conclusions: Longitudinal RV strain as measured by CMR feature tracking in ARVC appears able to quantify wall motion abnormalities in overt ARVC, as well as define subtle abnormalities in patients with preclinical ARVC.

Background: Depolarization abnormalities in the terminal portion of the QRS are frequently seen in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C). The purpose of this study was to correlate the electroanatomic activation pattern of the RV endocardium and epicardium to the surface ECG. Methods: Thirty consecutive ARVD/C patients (Mean age 33.1 +/- 11.2 years, 16 (53%) men) underwent detailed endocardial and epicardial electroanatomical mapping (EAM). Local sinus rhythm activation was annotated at the sharpest intrinsic deflection of the bipolar electrogram, including late potentials. ECG features were classified into 5 major patterns; 1. Normal QRS (12 patients) 2. Epsilon wave (5 patients) 3. Incomplete RBBB (5 patients) 4. Atypical complete RBBB (6 patients) and 5. Prolonged terminal activation duration (TAD) (2 patients) Results: The earliest endocardial and epicardial RV activation occurred on the mid anteroseptal wall on all ECG patterns. Figure 1 represented activation area (purple) after the QRS or during the delayed depolarization phase. Nearly all endocardial and epicardial RV was activated well within the QRS duration in patients with normal QRS but was activated during R’ in patients with CRBBB. The delayed activation during Epsilon wave consistently occurred in basal anterior wall and basal angle of RV. In patients with TAD, the activation of RVOT and basal angle RV represented slurred S wave. Conclusion: ECG features in ARVD/C are correlated with late activation in specific regions of RV and total endocardial activation time. The delay activation of basal anterior wall and basal angle of RV represents the Epsilon wave in the right precordial ECG.

Introduction: Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) is a hereditary progressive cardiomyopathy. We aimed to define long-term outcome in a transatlantic ARVD/C cohort of 1001 individuals. Methods: Clinical/genetic characteristics and follow-up data of ARVD/C index patients (n=439, fulfillment of 2010 criteria in all) and family members (n=562) were assessed. Genetic screening of desmosomal and TMEM43 and PLN genes was performed in index patients. Results: Mutations, predominantly in PKP2, were identified in 276/439 (63%). Index patients presented mostly with sustained ventricular arrhythmias (VA) (268/439, 61%). Recurrent sustained VA (in 301/416 (72%) patients presenting alive) characterized follow-up (median 7 years) with 10/63 (16%) sudden cardiac deaths (SCD) in patients without implantable cardioverter-defibrillators (ICDs) versus 2/335 (0.6%) in those with ICDs. Overall, cardiac mortality during follow-up (6%) and cardiac transplantation rate (4%) were low. Although disease onset was significantly earlier in index patients with mutations (first presentation 34 vs.38 years old, p Conclusions: Long-term outcome in ARVD/C index patients was favorable when diagnosed and treated. Prognosis in family members was determined by symptoms and mutation status. One in three family members, including asymptomatic mutation carriers, developed ARVD/C.

Background: Endurance exercise is associated with adverse arrhythmic outcomes and development of heart failure in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C)-associated desmosomal mutation carriers. However studies comparing exercise participation in family members with desmosomal mutations are lacking. Methods: Structured exercise interviews were performed focusing on duration, intensity and timing among ten families with 37 patients (9 probands, 28 family members) carrying a pathogenic plakophilin ( PKP2 ) mutation. Exercise was classified based on 36 th Bethesda Conference into endurance/dynamic sports and static sports. Baseline characteristics, non-invasive and invasive clinical data, family history data and occurrence of ventricular tachycardia/appropriate defibrillator intervention (VT/VF) were collected. Results: Exercise duration (hours/year) at last follow up was highest among probands. Family members meeting 2010 Task Force Criteria [TFC] had significantly higher exercise duration (Figure 1-A), were more likely to be endurance athletes (77% vs. 33%, p=0.03), and had significantly higher participation in sports with high dynamic component (Median 416[IQR:123-864] vs. 214[IQR:48-408] hours/year; p=0.046) than family members not meeting TFC. Family members who were endurance athletes had worse arrhythmic course (Figure 1-B), were more likely to meet a major or minor 2010 TFC for depolarization/repolarization abnormalities (p=0.05), 2010 TFC for structural abnormalities (p=0.024) and had significantly lower right ventricular ejection fraction (48% vs. 57%; p=0.007). Conclusion: Mutation carrier family members of probands who are endurance athletes have increased penetrance, worse arrhythmic outcomes and greater structural changes compared with family members who are not endurance athletes and should be advised to restrict participation in exercise, especially with a high dynamic component.

Background— The purpose of this study was to systematically study diagnostic and prognostic electrocardiographic (ECG) characteristics of arrhythmogenic right ventricle dysplasia/cardiomyopathy (ARVD/C). Methods and Results— The patient population included 50 patients with ARVD/C (27 males, 23 females; mean age 38±15 years). We also analyzed the ECG of 50 age- and gender-matched normal control subject and 28 consecutive patients who presented with right ventricular outflow tract (RVOT) tachycardia. Right bundle-branch block (RBBB) was present in 11 patients (22%). T-wave inversions in V 1 through V 3 were observed in 85% of ARVD/C patients in the absence of RBBB compared with none in RVOT and normal controls, respectively ( P 1 through V 3 was present in 64% of patients. Among those without RBBB, our newly proposed criterion of “prolonged S-wave upstroke in V 1 through V 3” ≥55 ms was the most prevalent ECG feature (95%) and correlated with disease severity and induction of VT on electrophysiological study. This feature also best distinguished ARVD/C (diffuse and localized) from RVOT. Conclusions— A prolonged S-wave upstroke in V 1 through V 3 is the most frequent ECG finding in ARVD/C and should be considered as a diagnostic ECG marker.

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited progressive disease of the heart muscle that can cause dangerous heart rhythms (arrhythmias). Significant advances over the past 10 years have changed how we diagnose and manage patients with ARVD/C and at-risk family members. In this guide, we review key information that every family affected by ARVD/C should know (Table 1). View this table: Table 1. ARVD/C Fast Facts The majority of patients with ARVD/C have abnormalities of the right ventricle. However, abnormalities of the left ventricle are more common than once thought. Recently, the main areas of the heart involved in ARVD/C, referred to as the triangle of dysplasia, have been redefined as noted in Figure 1.1 ARVD/C, if severe, may impair the ability of the heart to pump blood as needed. ARVD/C is a genetic disease and often runs in families, making evaluation of first-degree relatives essential. Figure 1. Three-dimensional cardiac image showing typical areas of involvement of the right ventricle (RV) and left ventricle (LV). It has been shown that ARVD/C is often a disease of the cardiac desmosome. Desmosomes are proteins that connect heart muscle cells and hold them together (Figure 2). Changes (mutations) in the genes ( Plakophilin-2 [ PKP2 ], Desmoglein-2 [ DSG2 ], Desmocollin-2 [ DSC2 ], Plakoglobin [ JUP ], Desmoplakin [ DSP ]) that make desmosome proteins can result in weakened desmosomes.2,3 When this happens, heart muscle cells become disconnected and die, particularly when the heart is stretched during vigorous exercise. Damaged heart muscle is ultimately replaced with fat and scar tissue. Figure 2. Model of the desmosome proteins linking heart muscle cells together. Genetic testing of the desmosomal genes is now available through several clinical laboratories. Genetic tests including even more genes associated with ARVD/C, as well as other inherited heart diseases, are available and may …

Background: Left ventricular hypertrophy (LVH) is a strong predictor of cardiovascular event risk. We evaluated the ethnicity-specific diagnostic utility of ECG in the detection of LVH measured by MRI as a gold standard. Methods: 12-lead ECG and MRI of 4498 asymptomatic subjects in the MESA study (49% males, mean age 61 ± 10 years) with no prior cardiovascular disease were analyzed. Left ventricular mass (LVM) was determined from MRI. Body-size predicted LV mass (pLVM) was determined from an allometric height-weight index derived from a subpopulation of 822 normal-weight, normotensive, non-diabetic MESA participants with LVH defined as LVM/pLVM > 1.31 (>95 th percentile). Prediction of absolute LV mass by ECG was also assessed for whites and blacks based on previously validated prediction models for these groups. Results: The study population consisted of 39% Whites, 12% Chinese, 27% Blacks and 22% Hispanics. ECG detection rate for LVH as determined by MRI was significantly more in women than men (12.3% vs 3.9% respectively, p< 0.02). For a specificity >= 90%, the highest overall sensitivity for LVH was shown by Perguia score (28.7%) which increased from the first (17.9%) to fourth quartile (45.3%) of LV mass. At a fixed specificity of 90%, the highest sensitivity was shown by Sokolow-Lyon voltage duration product (SLP) (38.2%). Neither Perguia nor SLP differed significantly across the four ethnic groups with respect to sensitivity and area under the ROC curve (p< 0.27, p< 0.52; p< 0.35, p< 0.88 respectively). Presence of LV strain pattern on ECG showed the highest adjusted odds ratio for LVH across all ethnic groups. ECG predicted LVM correlated significantly with MRI-determined LVM for both whites and blacks (r=0.74, p< 0.001 and r=0.70, p< 0.001 respectively) with no significant difference in LVH detection rates (6.1% vs 9.4% respectively, p< 0.35) Conclusion: Based on LVM prediction models, ECG correlates well with MRI. ECG sensitivity to detect LVH is low and it does not differ significantly between whites and blacks. Based on individual criteria like Perguia and SLP, sensitivity and diagnostic performance of ECG did not vary significantly across different ethnic groups.

Right ventricular (RV) mass reflects response to afterload, whereas RV ejection fraction (RVEF) is an indicator of RV function. Pulmonary vascular disease is characterized by hemostatic abnormalities and inflammation and may affect RV mass and function. We hypothesized that increased levels of inflammatory markers (ICAM-1, TNF-α, E-Selectin, MMP-3, and MMP-9) would be associated with higher RV mass and lower RVEF, and increased levels of hemostatic markers (tissue factor, PAI-1, and CD40L) and decreased levels of TFPI would be associated with higher RV mass and lower RVEF. The Multi-Ethnic Study of Atherosclerosis (MESA) performed interpretable cardiac MRIs on 5,004 participants without clinical cardiovascular disease at six field centers. 785 randomly selected patients had plasma biomarkers measured, 730 of whom had complete interpretation of RV measures. Endocardial margins of the RV were manually contoured on diastolic and systolic images. End-diastolic volume (EDV) and end-systolic volume (ESV) were calculated by using a summation of disks method (“Simpson’s Rule”). RVEF was calculated from (EDV-ESV)/EDV. RV mass was determined from cine images of the heart. Biomarkers were analyzed in quintiles using multivariate linear regression. The 730 participants in the study sample were 59 ± 10 (mean ± SD) years old, 58% female, 45% Caucasian, 21% African-American, 11% Chinese-American, and 23% Hispanic. The RV mass was 22 g ± 5 g and RVEF was 69% ± 7%. Higher PAI-1 levels were associated with lower RV mass, after adjustment for age, gender, race, height, and weight (test for trend, p = 0.036, n = 710). Higher MMP-9 levels were associated with lower RV mass (test for trend, p = 0.006). Neither hemostatic nor inflammatory biomarkers were associated with RVEF. RV mass was inversely associated with PAI-1, a serine protease which inhibits thrombolysis, and MMP-9, which breaks down the extracellular matrix. The mechanism of these determinants of RV structure and function should be investigated.

Background: In this report we present the prevalence and significance of a novel MRI abnormality that we identified in desmosomal mutation positive asymptomatic relatives of arrhythmogenic right ventricular dysplasia (ARVD) patients. Methods: MRI of 38 first-degree relatives was analyzed for abnormalities blinded to the mutation status. Focal crinkling of the right ventricle (accordion sign) was observed in 15/25 mutation positive vs. 0/13 mutation negative patients. The presence of this finding was sought in 207 patients evaluated for ARVD blinded to clinical history and was correlated with electrophysiologic findings. Results: Mean age of the population was 32±16, 61% had a family history of ARVD. Based on non-invasive testing the 207 patients were classified into 4 groups 1) 106 normal, 2) 57 Idiopathic ventricular tachycardia (VT), 3) 33 probable ARVD, 4) 11 definite ARVD. A family history of ARVD was present in 74%, 0%, 67% and 36% respectively. 43 patients had the “accordion sign” and the prevalence in the four groups was 10%, 5%, 70% and 100% respectively. The abnormality was seen in the sub-tricuspid region in 62%, outflow tract in 30% in both regions in 8%. After excluding group 4, 48% of patients with the accordion sign had T wave inversion’s beyond V1 compared with 7% of those without the sign (p Conclusion: Focal crinkling of the RV termed “Accordion sign” may represent an early manifestation of ARVD that correlates with mutation positive status and predicts inducibility of ventricular arrhythmias.

Abstract 1768 Harikrishna Tandri, Darshan Dalal, Aditya Jain, Daniel P Judge, Theodore Abraham, Cynthia James, Samanthapudi K Daya, Crystal Tichnell, Stuart Russell, Hugh Calkins, David A Bluemke, Johns Hopkins University, Baltimore, MD Harikrishna Tandri, 2007 Finalist and Presenting Author

Background— Arrhythmogenic right ventricular dysplasia (ARVD) is an inherited cardiomyopathy characterized by right ventricular dysfunction and ventricular arrhythmias. The purpose of our study was to describe the presentation, clinical features, survival, and natural history of ARVD in a large cohort of patients from the United States. Methods and Results— The patient population included 100 ARVD patients (51 male; median age at presentation, 26 [interquartile range {IQR}, 18 to 38; range, 2 to 70] years). A familial pattern was observed in 32 patients. The most common presenting symptoms were palpitations, syncope, and sudden cardiac death (SCD) in 27%, 26%, and 23% of patients, respectively. Among those who were diagnosed while living (n=69), the median time between first presentation and diagnosis was 1 (range, 0 to 37) year. During a median follow-up of 6 (IQR, 2 to 13; range, 0 to 37) years, implantable cardioverter/defibrillators (ICD) were implanted in 47 patients, 29 of whom received an appropriate ICD discharge, including 3 patients who received the ICD for primary prevention. At follow-up, 66 patients were alive, of whom 44 had an ICD in place, 5 developed signs of heart failure, 2 had a heart transplant, and 18 were on drug therapy. Thirty-four patients died either at presentation (n=23: 21 SCD, 2 noncardiac deaths) or during follow-up (n=11: 10 SCD, 1 of biventricular heart failure), of whom only 3 were diagnosed while living and 1 had an ICD implanted. On Kaplan-Meier analysis, the median survival in the entire population was 60 years. Conclusions— ARVD patients present between the second and fifth decades of life either with symptoms of palpitations and syncope associated with ventricular tachycardia or with SCD. Diagnosis is often delayed. Once diagnosed and treated with an ICD, mortality is low. There is a wide variation in presentation and course of ARVD patients, which can likely be explained by the genetic heterogeneity of the disease.