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ABSTRACT: Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a genetically transmitted disease. However the genetics are more complex than in other inherited conditions wherein a single gene abnormal mutation may be causative. In ARVC, five causative desmosomal genes have been identified but, since only 30-50% of patients with ARVC have one of these gene abnormalities, it is assumed that there are other genes not yet identified. Frequently patients with ARVC have more than one genetic defect in the same gene (compound heterozygosity) or in a second complementary gene (digenic heterozygosity). In addition, a family member may have an ARVC gene defect and develop the disease or have no or minimal manifestations of the disease. Clinical genetic testing is commercially available. It is beneficial for first degree family members of an individual with ARVC to have genetic testing but only if there is a known genetic abnormality in the affected individual. If the affected family member (proband) with ARVC does not have a genetic defect identified, then it will not be identified in the family member. Genetic counseling is strongly advised for family members of the proband.
Journal of the American College of Cardiology 03/2013; · 14.16 Impact Factor
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ABSTRACT: The duration of the cholesterol-lowering effect of statins is considerably longer than the duration of the pharmacokinetic half-life of these drugs. The long duration of pharmacologic effects provides the rational for the efficacy of intermittent dosing that provides nearly the equivalent low-density lipoprotein cholesterol reduction compared with daily dosing. Review of studies comparing alternate-day dosing with daily dosing of statins indicates that the magnitude of low-density lipoprotein cholesterol reduction with alternate-day dosing is nearly the same, with obvious cost savings. It is possible that the adverse effects of statins, such as myalgia or diabetes, may be related to the cumulative amount of drug ingested over time, and if so, the adverse effects may be decreased by alternate-day dosing.
The American journal of medicine 02/2013; 126(2):99-104. · 4.47 Impact Factor
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Angeliki Asimaki,
Harikrishna Tandri,
Elizabeth R Duffy,
Jeffrey R Winterfield,
Shannon Mackey-Bojack,
Maria M Picken,
Leslie T Cooper,
David J Wilber, Frank I Marcus,
Cristina Basso,
Gaetano Thiene,
Adalena Tsatsopoulou,
Nikos Protonotarios,
William G Stevenson,
William J McKenna,
Shiva Gautam,
Daniel G Remick,
Hugh Calkins,
Jeffrey E Saffitz
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ABSTRACT: Immunoreactive signal for the desmosomal protein plakoglobin (γ-catenin) is reduced at cardiac intercalated disks in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), a highly arrhythmogenic condition caused by mutations in genes encoding desmosomal proteins. Previously, we observed a false-positive case in which plakoglobin signal was reduced in a patient initially believed to have ARVC but who actually had cardiac sarcoidosis. Sarcoidosis can masquerade clinically as ARVC but has not been previously associated with altered desmosomal proteins.
We observed marked reduction in immunoreactive signal for plakoglobin at cardiac myocyte junctions in patients with sarcoidosis and giant cell myocarditis, both highly arrhythmogenic forms of myocarditis associated with granulomatous inflammation. In contrast, plakoglobin signal was not depressed in lymphocytic (nongranulomatous) myocarditis. To determine whether cytokines might promote dislocation of plakoglobin from desmosomes, we incubated cultures of neonatal rat ventricular myocytes with selected inflammatory mediators. Brief exposure to low concentrations of interleukin (IL)-17, tumor necrosis factor-α (TNF-α), and IL-6 (cytokines implicated in granulomatous myocarditis) caused translocation of plakoglobin from cell-cell junctions to intracellular sites, whereas other potent cytokines implicated in nongranulomatous myocarditis had no effect, even at much higher concentrations. We also observed myocardial expression of IL-17 and TNF-α and elevated levels of serum inflammatory mediators, including IL-6R, IL-8, monocyte chemoattractant protein 1, and macrophage inflammatory protein 1β, in patients with ARVC (all P<0.0001 compared with controls).
The results suggest novel disease mechanisms involving desmosomal proteins in granulomatous myocarditis and implicate cytokines, perhaps derived in part from the myocardium, in disruption of desmosomal proteins and arrhythmogenesis in ARVC.
Circulation Arrhythmia and Electrophysiology 08/2011; 4(5):743-52. · 6.46 Impact Factor
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Kurt S Hoffmayer,
Orlando N Machado,
Gregory M Marcus,
Yanfei Yang,
Colleen J Johnson,
Simon Ermakov,
Eric Vittinghoff,
Ulhas Pandurangi,
Hugh Calkins,
David Cannom,
Kathleen C Gear,
Crystal Tichnell,
Young Park,
Wojciech Zareba, Frank I Marcus,
Melvin M Scheinman
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ABSTRACT: The purpose of this study was to evaluate whether electrocardiographic characteristics of ventricular arrhythmias distinguish patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) from those with right ventricular outflow tract tachycardia (RVOT-VT).
Ventricular arrhythmias in RVOT-VT and ARVD/C-VT patients can share a left bundle branch block/inferior axis morphology.
We compared the electrocardiographic morphology of ventricular tachycardia or premature ventricular contractions with left bundle branch block/inferior axis pattern in 16 ARVD/C patients with that in 42 RVOT-VT patients.
ARVD/C patients had a significantly longer mean QRS duration in lead I (150 ± 31 ms vs. 123 ± 34 ms, p = 0.006), more often exhibited a precordial transition in lead V(6) (3 of 17 [18%] vs. 0 of 42 [0%] with RVOT-VT, p = 0.005), and more often had at least 1 lead with notching (11 of 17 [65%] vs. 9 of 42 [21%], p = 0.001). The most sensitive characteristics for the detection of ARVD/C were a QRS duration in lead I of ≥120 ms (88% sensitivity, 91% negative predictive value). QRS transition at V(6) was most specific at 100% (100% positive predictive value, 77% negative predictive value). The presence of notching on any QRS complex had 79% sensitivity and 65% specificity of (55% positive predictive value, 85% negative predictive value). In multivariate analysis, QRS duration in lead I of ≥120 ms (odds ratio [OR]: 20.4, p = 0.034), earliest onset QRS in lead V(1) (OR: 17.0, p = 0.022), QRS notching (OR: 7.7, p = 0.018), and a transition of V(5) or later (OR: 7.0, p = 0.030) each predicted the presence of ARVD/C.
Several electrocardiographic criteria can help distinguish right ventricular outflow tract arrhythmias originating from ARVD/C compared with RVOT-VT patients.
Journal of the American College of Cardiology 08/2011; 58(8):831-8. · 14.16 Impact Factor
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ABSTRACT: Imaging of the right ventricle (RV) for the diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is commonly performed by echocardiography or magnetic resonance imaging (MRI). Angiography is an alternative modality, particularly when MRI cannot be performed. We hypothesized that RV volume and ejection fraction computed by angiography would correlate with these quantities as computed by MRI. RV volumes and ejection fraction were computed for subjects enrolled in the North American ARVC/D Registry, with both RV angiography and MRI studies. Angiography was performed in the 30° right anterior oblique (RAO) and 60° left anterior oblique (LAO) views. Angiographic volumes were computed by RAO view and two-view (RAO and LAO) formulae. 17 subjects were analyzed (11 men and 6 women), with 15 subjects classified as affected, and two as unaffected by modified Task Force criteria. The correlation coefficient of MRI to the two-view angiographic analysis was 0.72 (P = 0.003) for end-diastolic volume and 0.68 (P = 0.005) for ejection fraction. Angiographically derived volumes were larger than MRI derived volume (P = 0.009) and with the slope in a linear relationship equal to 0.8 for end diastolic volume, and 0.9 for RV ejection fraction (P < 0.001), computed by the two view formula. End-diastolic volumes and ejection fractions of the RV obtained by dual view angiography correlate with these quantities by MRI. RV end-diastolic volumes are larger by RV angiography in comparison with MRI.
The international journal of cardiovascular imaging 06/2011; 28(5):995-1001. · 2.15 Impact Factor
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Journal of the American College of Cardiology 04/2011; 57(15):1636-7; author reply 1637-8. · 14.16 Impact Factor
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European Heart Journal 01/2011; 32(8):931-3. · 10.48 Impact Factor
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Domenico Corrado,
Hugh Calkins,
Mark S Link,
Loira Leoni,
Stefano Favale,
Michela Bevilacqua,
Cristina Basso,
Deirdre Ward,
Giuseppe Boriani,
Renato Ricci,
Jonathan P Piccini,
Darshan Dalal,
Massimo Santini,
Gianfranco Buja,
Sabino Iliceto,
N A Mark Estes,
Thomas Wichter,
William J McKenna,
Gaetano Thiene, Frank I Marcus
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ABSTRACT: The role of implantable cardioverter-defibrillator (ICD) in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia and no prior ventricular fibrillation (VF) or sustained ventricular tachycardia is an unsolved issue.
We studied 106 consecutive patients (62 men and 44 women; age, 35.6±18 years) with arrhythmogenic right ventricular cardiomyopathy/dysplasia who received an ICD based on 1 or more arrhythmic risk factors such as syncope, nonsustained ventricular tachycardia, familial sudden death, and inducibility at programmed ventricular stimulation. During follow-up of 58±35 months, 25 patients (24%) had appropriate ICD interventions and 17 (16%) had shocks for life-threatening VF or ventricular flutter. At 48 months, the actual survival rate was 100% compared with the VF/ventricular flutter-free survival rate of 77% (log-rank P=0.01). Syncope significantly predicted any appropriate ICD interventions (hazard ratio, 2.94; 95% confidence interval, 1.83 to 4.67; P=0.013) and shocks for VF/ventricular flutter (hazard ratio, 3.16; 95% confidence interval, 1.39 to 5.63; P=0.005). The positive predictive value of programmed ventricular stimulation was 35% for any appropriate ICD intervention and 20% for shocks for VF/ventricular flutter, with a negative predictive value of 70% and 74%. None of the 27 asymptomatic patients with isolated familial sudden death had appropriate ICD therapy. Twenty patients (19%) had inappropriate ICD interventions, and 18 (17%) had device-related complications.
One fourth of patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia and no prior sustained ventricular tachycardia or VF had appropriate ICD interventions. Syncope was an important predictor of life-saving ICD intervention and is an indication for ICD. Prophylactic ICD may not be indicated in asymptomatic patients because of their low arrhythmic risk regardless of familial sudden death and programmed ventricular stimulation findings. Programmed ventricular stimulation had a low predictive accuracy for ICD therapy.
Circulation 09/2010; 122(12):1144-52. · 14.74 Impact Factor
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ABSTRACT: The 2 predominant causes of ventricular tachycardia (VT) arising from the right ventricle are arrhythmogenic right ventricular cardiomyopathy (ARVC) and idiopathic VT arising from the right ventricular outflow tract (RVOT). These arrhythmias can be adrenergically mediated and may be difficult to distinguish clinically. A minor criterion for the diagnosis of ARVC is T-wave inversion (TWI) in the right precordial leads during sinus rhythm. However, there have been reports of precordial TWI identified in patients with RVOT tachycardia. The purpose of this study was to determine whether patterns of precordial TWI could differentiate between the 2 groups. A multicenter registry of 229 patients with VT of right ventricular origin was evaluated. After appropriate exclusions (n = 29), 79 patients (58% men, mean age 40 +/- 14 years) had ARVC, and 121 patients (41% men, mean age 48 +/- 14 years) had RVOT tachycardia. During sinus rhythm, 37 patients (47%) with ARVC and 5 patients (4%) with RVOT tachycardia had TWI in leads V(1) to V(3). For the diagnosis of ARVC, TWI in leads V(1) to V(3) had sensitivity of 47% and specificity of 96%. In conclusion, in patients with VT of right ventricular origin, the presence of TWI in electrocardiographic leads V(1) to V(3) supports the diagnosis of ARVC.
The American journal of cardiology 06/2010; 105(12):1821-4. · 3.58 Impact Factor
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Frank I Marcus,
William J McKenna,
Duane Sherrill,
Cristina Basso,
Barbara Bauce,
David A Bluemke,
Hugh Calkins,
Domenico Corrado,
Moniek G P J Cox,
James P Daubert, [......],
Nikos Protonotarios,
Jeffrey E Saffitz,
Danita M Yoerger Sanborn,
Jonathan S Steinberg,
Harikrishna Tandri,
Gaetano Thiene,
Jeffrey A Towbin,
Adalena Tsatsopoulou,
Thomas Wichter,
Wojciech Zareba
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ABSTRACT: In 1994, an International Task Force proposed criteria for the clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) that facilitated recognition and interpretation of the frequently nonspecific clinical features of ARVC/D. This enabled confirmatory clinical diagnosis in index cases through exclusion of phenocopies and provided a standard on which clinical research and genetic studies could be based. Structural, histological, electrocardiographic, arrhythmic, and familial features of the disease were incorporated into the criteria, subdivided into major and minor categories according to the specificity of their association with ARVC/D. At that time, clinical experience with ARVC/D was dominated by symptomatic index cases and sudden cardiac death victims-the overt or severe end of the disease spectrum. Consequently, the 1994 criteria were highly specific but lacked sensitivity for early and familial disease.
Revision of the diagnostic criteria provides guidance on the role of emerging diagnostic modalities and advances in the genetics of ARVC/D. The criteria have been modified to incorporate new knowledge and technology to improve diagnostic sensitivity, but with the important requisite of maintaining diagnostic specificity. The approach of classifying structural, histological, electrocardiographic, arrhythmic, and genetic features of the disease as major and minor criteria has been maintained. In this modification of the Task Force criteria, quantitative criteria are proposed and abnormalities are defined on the basis of comparison with normal subject data.
The present modifications of the Task Force Criteria represent a working framework to improve the diagnosis and management of this condition. Clinical Trial Registration clinicaltrials.gov Identifier: NCT00024505.
European Heart Journal 02/2010; 31(7):806-14. · 10.48 Impact Factor
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Frank I Marcus,
Wojciech Zareba,
Hugh Calkins,
Jeffrey A Towbin,
Cristina Basso,
David A Bluemke,
N A Mark Estes,
Michael H Picard,
Danita Sanborn,
Gaetano Thiene, [......],
Bruce B Lerman,
Charles Kerr,
Jack Kron,
Jonathan S Steinberg,
Duane Sherrill,
Kathleen Gear,
Mary Brown,
Patricia Severski,
Slava Polonsky,
Scott McNitt
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ABSTRACT: Prior reports on patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) focused on individuals with advanced forms of the disease. Data on the diagnostic performance of various testing modalities in newly identified individuals suspected of having ARVC/D are limited.
The purpose of the Multidisciplinary Study of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia was to study the clinical characteristics and diagnostic evaluation of a large group of patients newly identified with ARVC/D.
A total of 108 newly diagnosed patients with suspected ARVC/D were prospectively enrolled in the United States and Canada. The patients underwent noninvasive and invasive tests using standardized protocols that initially were interpreted by the enrolling center and adjudicated by blind analysis in six core laboratories. Patients were followed for a mean of 27 +/- 16 months (range 0.2-63 months).
The clinical profile of these newly diagnosed patients differs from the profile of reported patients with more advanced disease. There was considerable difference in the initial and final classification of the presence of ARVC/D after the diagnostic tests were evaluated by the core laboratories. Final clinical diagnosis was 73 affected, 28 borderline, and 7 unaffected. Individual tests agreed with the final diagnosis in 50% to 70% of the 73 patients with a final classification of affected.
The clinical profile of 108 newly diagnosed probands with suspected ARVC/D indicates that a combination of diagnostic tests is needed to evaluate the presence of right ventricular structural, functional, and electrical abnormalities. Echocardiography, right ventricular angiography, signal-averaged ECG, and Holter monitoring provide optimal clinical evaluation of patients suspected of ARVC/D.
Heart rhythm: the official journal of the Heart Rhythm Society 08/2009; 6(7):984-92. · 4.56 Impact Factor
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ABSTRACT: Arrhythmogenic right ventricular cardiomyopathy is a rare inherited heart-muscle disease that is a cause of sudden death in young people and athletes. Causative mutations in genes encoding desmosomal proteins have been identified and the disease is nowadays regarded as a genetically determined myocardial dystrophy. The left ventricle is so frequently involved as to support the adoption of the broad term arrhythmogenic cardiomyopathy. Clinical diagnosis can be achieved by demonstrating function and structure changes of the right ventricle, electrocardiogram depolarisation and repolarisation abnormalities, ventricular arrhythmias, and fibrofatty replacement through endomyocardial biopsy. Although specific, the standardised diagnostic criteria lack sensitivity for early disease and their primary application remains in establishing the diagnosis in probands. However, the main clinical targets are early detection of concealed forms and risk stratification for preventive strategies, which include physical exercise restriction, antiarrhythmic drugs, and implantable cardioverter-defibrillator therapy. Cascade genetic screening of family members of gene-positive probands allows the identification of asymptomatic carriers who would require lifelong follow-up due to the age-related penetrance.
The Lancet 05/2009; 373(9671):1289-300. · 38.28 Impact Factor
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ABSTRACT: The electrocardiogram (ECG) provides important information to aid in the diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). The ECG changes may be explained by the pathophysiology of the disease. The proximity of the right ventricle (RV) to the anterior chest leads (V(1) to V(4)) explains why the characteristic ECG abnormalities are most prominent in those lends. The specific ECG abnormalities reflect the pathophysiology of the disease including T-wave inversion due to scarring of the free wall of the RV, prolonged S-wave duration due to slow depolarization of the terminal part of the QRS because the RV is the last part of the heart to undergo depolatization, and epsilon waves due to slow conduction in the RV. The extent of ECG abnormalities correlate with the degree of structural change in the RV.
Journal of electrocardiology 03/2009; 42(2):136.e1-5. · 1.08 Impact Factor
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Barbara Bauce,
Gianfranco Frigo, Frank I Marcus,
Cristina Basso,
Alessandra Rampazzo,
Francesco Maddalena,
Domenico Corrado,
Mikolaj Winnicki,
Luciano Daliento,
Ilaria Rigato,
Alexandros Steriotis,
Elisa Mazzotti,
Gaetano Thiene,
Andrea Nava
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ABSTRACT: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart muscle disease characterized by myocardial necrosis followed by fibrous-fatty replacement. The pathologic process constitutes the basis for ventricular arrhythmias due to re-entrant circuits. Even if this genetic disease is transmitted in the majority of cases with autosomal dominant trait, in all reported series ARVC is prevalent in men. In this study we investigate the impact that gender may have on clinical presentation in a large series of patients with ARVC. A total of 171 consecutive patients (mean 29 +/- 12 years, range 13 to 65) affected by ARVC were examined with family and personal history, 12-lead electrocardiogram (ECG), 24-hour ECG, signal-averaged ECG, and echocardiogram. Moreover, electrophysiological study and ventricular angiography were performed in selected cases. In the 171 subjects, 71% were men and 29% women (p = 0.02). No gender differences were found considering the age at the time of diagnosis and of study enrolment and the prevalence of index cases and family members. The genders differed in prevalence of abnormal ECG (69% vs 52%, p = 0.036) and presence of late potentials (60% vs 40%, p = 0.01). Moreover, men had larger right ventricular dimensions and practiced competitive sports more frequently (26% vs 14%, p <0.001). Nonetheless, gender was not associated with a high incidence of life-threatening ventricular arrhythmias or with a poor outcome. In conclusion, our data show that diagnosis of ARVC is less common in female patients, who present a higher prevalence of mild forms. Nonetheless, the degree of electrical instability does not differ significantly between genders in affected subjects. Even if ARVC remains mainly a male disease, gender does not have a role in patients' outcome. The cause of the under-representation of women is not clear, even if potentially important factors such as sexual hormones and physical activity could play a role.
The American journal of cardiology 11/2008; 102(9):1252-7. · 3.58 Impact Factor
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Frank I Marcus
Journal of Cardiovascular Electrophysiology 08/2008; 19(11):1186-7. · 3.06 Impact Factor
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Heart rhythm: the official journal of the Heart Rhythm Society 06/2008; 5(10):1455-7. · 4.56 Impact Factor
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ABSTRACT: Angiography of the right ventricle (RV) is a standard, reference technique to diagnose wall motion abnormalities in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). RV wall motion is usually assessed by qualitative, visual impression, and has lacked a quantitative basis for defining abnormalities. Since the normal RV has a markedly asymmetric movement, angiographic interpretation can differ, even among experienced clinicians. The purpose of this study was to quantify RV wall motion based on contrast ventriculography in patients with ARVD/C and to specify the severity and location of wall motion abnormalities, as compared with normal subjects.
We analyzed the angiographic contours of the RV in three views from 19 normal subjects and 23 subjects with ARVD/C. Contour area movement during contraction was calculated circumferentially and further analyzed in nine zones. RV ejection fraction was also computed. Wall motion in ARVD/C was depressed by more than 30% at the tricuspid valve and inferior wall regions (P < 0.001) and significantly reduced at the apex (P = 0.003). However, the RVOT and anterior wall motion were not significantly reduced. RV ejection fraction was depressed from 60 +/- 11% in normal subjects to 41 +/- 12% in ARVD/C patients (P < 0.001).
Wall motion abnormalities in ARVD/C can be quantified and compared with normal controls, showing primarily reduced movement in the tricuspid and inferior wall regions. This study delineates objective measurements that can be used to aid in the diagnosis of ARVD/C. In addition, they may be incorporated in future refinements of criteria to diagnose ARVD/C.
Journal of Cardiovascular Electrophysiology 02/2008; 19(1):39-45. · 3.06 Impact Factor
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ABSTRACT: Changes due to biventricular pacing have been documented by shortening of QRS duration and echocardiography. Compared to normal ventricular activation, the presence of left bundle branch block (LBBB) results in a significant change in cardiac cycle time intervals. Some of these have been used to quantify the underlying cardiac dyssynchrony, assess the effects of biventricular pacing, and guide programming of ventricular pacing devices. This study evaluates a simple noninvasive method using accelerometers attached to the skin to measure cardiac time intervals in biventricularly paced patients.
Ten patients with biventricular pacemakers previously implanted for congestive heart failure were paced in the AAI mode, then in atrioventricular (AV) sequential mode from the right and left ventricles followed by biventricular pacing. Simultaneous recordings were obtained by 2D, Doppler echocardiography as well as by accelerometers. Similar recordings were obtained from 10 gender, aged matched, normal controls during sinus rhythm.
Compared to normals, heart failure patients paced in AAI mode had prolonged isovolumetric contraction time (IVCT), shorter ventricular ejection time (LVET), and prolonged isovolumetric relaxation (IVRT). With biventricular pacing the IVCT decreased, but the LVET and IVRT did not change significantly. There was excellent correlation between the echo and accelerometer-measured intervals.
Shortening of the IVCT measured by an accelerometer is a consistent time interval change due to biventricular pacing that probably reflects more rapid acceleration of left ventricular ejection. The accelerometer may be useful to assess immediate efficacy of biventricular pacing during device implantation and optimize programmable time intervals such as AV and interventricular (VV) delays.
Pacing and Clinical Electrophysiology 01/2008; 30(12):1476-81. · 1.35 Impact Factor
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Journal of Cardiovascular Electrophysiology 03/2007; 18(2):231-3. · 3.06 Impact Factor
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ABSTRACT: The 12-lead ECG has limited utility to predict the risk for sudden cardiac death in common cardiac diseases such as coronary artery disease and idiopathic dilated cardiomyopathy. However, it is quite useful in diagnosing less common cardiac conditions that are associated with an increased risk for sudden death.
Cardiology Clinics 09/2006; 24(3):453-69, x. · 1.36 Impact Factor
