Magnetic Resonance Imaging Assessment of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia in Children

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a genetically determined disease that progresses continuously from conception and throughout life. ARVC/D manifests predominantly in young adulthood. Early identification of the concealed cases in childhood is of utmost importance for the prevention of sudden cardiac death later in life. Magnetic resonance imaging (MRI) is routinely requested in patients with a confirmed or suspected diagnosis of ARVC/D and in family members of the patients with ARVC/D. Although the utility of MRI in the assessment of ARVC/D is well recognized in adults, MRI is a low-yield test in children as the anatomical, histological, and functional changes are frequently subtle or not present in the early phase of the disease. MRI findings of ARVC/D include morphologic changes such as right ventricular dilatation, wall thinning, and aneurismal outpouchings, as well as abnormal tissue characteristics such as myocardial fibrosis and fatty infiltration, and functional abnormalities such as global ventricular dysfunction and regional wall motion abnormalities. Among these findings, regional wall motion abnormalities are the most reliable MRI findings both in children and adults, while myocardial fibrosis and fat infiltration are rarely seen in children. Therefore, an MRI protocol should be tailored according to the patient's age and compliance, as well as the presence of other findings, instead of using the protocol that is used for adults. We propose that MRI in children with ARVC/D should focus on the detection of regional wall motion abnormalities and global ventricular function by using a cine imaging sequence and that the sequences for myocardial fat and late gadolinium enhancement of the myocardium are reserved for those who show abnormal findings at cine imaging. Importantly, MRI should be performed and interpreted by experienced examiners to reduce the number of false positive and false negative readings

Clinical expression of plakophilin-2 mutations in familial arrhythmogenic right ventricular cardiomyopathy

Background - Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disorder characterized by loss of cardiomyocytes and their replacement by adipose and fibrous tissue. It is considered a disease of cell adhesion because mutations in desmosomal genes, desmoplakin and plakoglobin, have been implicated in the pathogenesis of ARVC. In a recent report, mutations in plakophilin-2, a gene highly expressed in cardiac desmosomes, have been shown to cause ARVC.Methods and Results - We investigated 100 white patients with ARVC for mutations in plakophilin-2. Nine different mutations were identified by direct sequencing in 11 cases. Five of these mutations are novel (A733fsX740, L586fsX658, V570fsX576, R413X, and P533fsX561) and predicted to cause a premature truncation of the plakophilin-2 protein. Family studies showed incomplete disease expression in mutation carriers and identified a number of individuals who would be misdiagnosed with the existing International Task Force and modified diagnostic criteria for ARVC.Conclusions - In this study, we provide new evidence that mutations in the desmosomal plakophilin-2 gene can cause ARVC. A systematic clinical evaluation of mutation carriers within families demonstrated variable phenotypic expression, even among individuals with the same mutation, and highlighted the need for a more accurate set of diagnostic criteria for ARVC

The multi-modality cardiac imaging approach to the Athlete's heart: an expert consensus of the European Association of Cardiovascular Imaging

The term 'athlete's heart' refers to a clinical picture characterized by a slow heart rate and enlargement of the heart. A multi-modality imaging approach to the athlete's heart aims to differentiate physiological changes due to intensive training in the athlete's heart from serious cardiac diseases with similar morphological features. Imaging assessment of the athlete's heart should begin with a thorough echocardiographic examination. Left ventricular (LV) wall thickness by echocardiography can contribute to the distinction between athlete's LV hypertrophy and hypertrophic cardiomyopathy (HCM). LV end-diastolic diameter becomes larger (>55 mm) than the normal limits only in end-stage HCM patients when the LV ejection fraction is <50%. Patients with HCM also show early impairment of LV diastolic function, whereas athletes have normal diastolic function. When echocardiography cannot provide a clear differential diagnosis, cardiac magnetic resonance (CMR) imaging should be performed. With CMR, accurate morphological and functional assessment can be made. Tissue characterization by late gadolinium enhancement may show a distinctive, non-ischaemic pattern in HCM and a variety of other myocardial conditions such as idiopathic dilated cardiomyopathy or myocarditis. The work-up of athletes with suspected coronary artery disease should start with an exercise ECG. In athletes with inconclusive exercise ECG results, exercise stress echocardiography should be considered. Nuclear cardiology techniques, coronary cardiac tomography (CCT) and/or CMR may be performed in selected cases. Owing to radiation exposure and the young age of most athletes, the use of CCT and nuclear cardiology techniques should be restricted to athletes with unclear stress echocardiography or CMR

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) in clinical practice

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an inherited myocardial disease characterized by fibro-fatty replacement of the right ventricular myocardium, and associated with paroxysmal ventricular arrhythmias and sudden cardiac death (SCD). It is currently the second most common cause of SCD after hypertrophic cardiomyopathy in young people <35 years of age, causing up to 20% of deaths in this patient population. This condition has a male preponderance and is more commonly found in individuals of Italian and Greek descent. To date, there is no single diagnostic test for ARVC/D and the diagnosis is made based on clinical, electrocardiographic, and radiological findings according to the Revised 2010 Task Force Criteria. In this review, we will discuss the mainstay treatment which includes pharmacotherapy, implantable cardioverter-defibrillator insertion for abortion of sudden cardiac death, and in the advanced stages of the disease cardiac transplantation

Image quality assessment of the right ventricle with three different delayed enhancement sequences in patients suspected of ARVC/D

Histopathologic findings in arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) are replacement of the normal myocardium with fatty and fibrous elements with preferential involvement of the right ventricle. The right ventricular fibrosis can be visualised by post-gadolinium delayed enhancement inversion recovery imaging (DE imaging). We compared the image quality of three different gradient echo MRI sequences for short axis DE imaging of the right ventricle (RV). We retrospectively analysed MRI scans performed between February 2005 and December 2008 in 97 patients (mean age: 41.2 years, 67% men) suspected of ARVC/D. For DE imaging either a 2D Phase Sensitive (PSIR), a 2D (2D) or a 3D (3D) inversion recovery sequence was used in respectively 38, 32 and 27 MRI-examinations. The RV, divided in 10 segments, was assessed for image quality by two radiologists in random sequence. A consensus reading was performed if results differed between the two readings. Image quality was good in 24% of all segments in the 3D group, 66% in the 2D group and 79% in the PSIR group. Poor image quality was observed in 51% (3D), 10% (2D), and 2% (PSIR) of all segments. Exams were considered suitable for clinical use in 7% of exams in the 3D group, 75% of exams in the 2D group and 90% of exams of the PSIR group. Breathing-artifacts occurred in 22% (3D), 59% (2D) and 53% (PSIR). Motion-artifacts occurred in 56% (3D), 28% (2D) and 29% (PSIR). Post-gadolinium imaging using the PSIR sequence results in better and more consistent image quality of the RV compared to the 2D and 3D sequences

Diastolic Ventricular Interaction in Heart Failure With Preserved Ejection Fraction

Background Exercise‐induced pulmonary hypertension is common in heart failure with preserved ejection fraction (HFpEF). We hypothesized that this could result in pericardial constraint and diastolic ventricular interaction in some patients during exercise. Methods and Results Contrast stress echocardiography was performed in 30 HFpEF patients, 17 hypertensive controls, and 17 normotensive controls (healthy). Cardiac volumes, and normalized radius of curvature (NRC) of the interventricular septum at end‐diastole and end‐systole, were measured at rest and peak‐exercise, and compared between the groups. The septum was circular at rest in all 3 groups at end‐diastole. At peak‐exercise, end‐systolic NRC increased to 1.47±0.05 (P<0.001) in HFpEF patients, confirming development of pulmonary hypertension. End‐diastolic NRC also increased to 1.54±0.07 (P<0.001) in HFpEF patients, indicating septal flattening, and this correlated significantly with end‐systolic NRC (ρ=0.51, P=0.007). In hypertensive controls and healthy controls, peak‐exercise end‐systolic NRC increased, but this was significantly less than observed in HFpEF patients (HFpEF, P=0.02 versus hypertensive controls; P<0.001 versus healthy). There were also small, non‐significant increases in end‐diastolic NRC in both groups (hypertensive controls, +0.17±0.05, P=0.38; healthy, +0.06±0.03, P=0.93). In HFpEF patients, peak‐exercise end‐diastolic NRC also negatively correlated (r=−0.40, P<0.05) with the change in left ventricular end‐diastolic volume with exercise (ie, the Frank‐Starling mechanism), and a trend was noted towards a negative correlation with change in stroke volume (r=−0.36, P=0.08). Conclusions Exercise pulmonary hypertension causes substantial diastolic ventricular interaction on exercise in some patients with HFpEF, and this restriction to left ventricular filling by the right ventricle exacerbates the pre‐existing impaired Frank‐Starling response in these patients

Dynamic Conduction and Repolarisation Changes in Early Arrhythmogenic Right Ventricular Cardiomyopathy versus Benign Outflow Tract Ectopy Demonstrated by High Density Mapping and Paced Surface ECG Analysis

Aims: The concealed phase of arrhythmogenic right ventricular cardiomyopathy (ARVC) may initially manifest electrophysiologically. No studies have examined dynamic conduction/repolarization kinetics to distinguish benign right ventricular outflow tract ectopy (RVOT ectopy) from ARVC's early phase. We investigated dynamic endocardial electrophysiological changes that differentiate early ARVC disease expression from RVOT ectopy. Methods: 22 ARVC (12 definite based upon family history and mutation carrier status, 10 probable) patients without right ventricular structural anomalies underwent high-density non-contact mapping of the right ventricle. These were compared to data from 14 RVOT ectopy and 12 patients with supraventricular tachycardias and normal hearts. Endocardial & surface ECG conduction and repolarization parameters were assessed during a standard S1-S2 restitution protocol. Results: Definite ARVC without RV structural disease could not be clearly distinguished from RVOT ectopy during sinus rhythm or during steady state pacing. Delay in Activation Times at coupling intervals just above the ventricular effective refractory period (VERP) increased in definite ARVC (43±20 ms) more than RVOT ectopy patients (36±14 ms, p = 0.03) or Normals (25±16 ms, p = 0.008) and a progressive separation of the repolarisation time curves between groups existed. Repolarization time increases in the RVOT were also greatest in ARVC (definite ARVC: 18±20 ms; RVOT ectopy: 5±14, Normal: 1±18, p<0.05). Surface ECG correlates of these intracardiac measurements demonstrated an increase of greater than 48 ms in stimulus to surface ECG J-point pre-ERP versus steady state, with an 88% specificity and 68% sensitivity in distinguishing definite ARVC from the other groups. This technique could not distinguish patients with genetic predisposition to ARVC only (probable ARVC) from controls. Conclusions: Significant changes in dynamic conduction and repolarization are apparent in early ARVC before detectable RV structural abnormalities, and were present to a lesser degree in probable ARVC patients. Investigation of dynamic electrophysiological parameters may be useful to identify concealed ARVC in patients without disease pedigrees by using endocardial electrogram or paced ECG parameters

Novel desmoplakin mutation: juvenile biventricular cardiomyopathy with left ventricular non-compaction and acantholytic palmoplantar keratoderma

Two sons of a consanguineous marriage developed biventricular cardiomyopathy. One boy died of severe heart failure at the age of 6 years, the other was transplanted because of severe heart failure at the age of 10 years. In addition, focal palmoplantar keratoderma and woolly hair were apparent in both boys. As similar phenotypes have been described in Naxos disease and Carvajal syndrome, respectively, the genes for plakoglobin (JUP) and desmoplakin (DSP) were screened for mutations using direct genomic sequencing. A novel homozygous 2 bp deletion was identified in an alternatively spliced region of DSP. The deletion 5208_5209delAG led to a frameshift downstream of amino acid 1,736 with a premature truncation of the predominant cardiac isoform DSP-1. This novel homozygous truncating mutation in the isoform-1 specific region of the DSP C-terminus caused Carvajal syndrome comprising severe early-onset heart failure with features of non-compaction cardiomyopathy, woolly hair and an acantholytic form of palmoplantar keratoderma in our patient. Congenital hair abnormality and manifestation of the cutaneous phenotype in toddler age can help to identify children at risk for cardiac death

Mutations with pathogenic potential in proteins located in or at the composite junctions of the intercalated disk connecting mammalian cardiomyocytes: a reference thesaurus for arrhythmogenic cardiomyopathies and for Naxos and Carvajal diseases

In the past decade, an avalanche of findings and reports has correlated arrhythmogenic ventricular cardiomyopathies (ARVC) and Naxos and Carvajal diseases with certain mutations in protein constituents of the special junctions connecting the polar regions (intercalated disks) of mature mammalian cardiomyocytes. These molecules, apparently together with some specific cytoskeletal proteins, are components of (or interact with) composite junctions. Composite junctions contain the amalgamated fusion products of the molecules that, in other cell types and tissues, occur in distinct separate junctions, i.e. desmosomes and adherens junctions. As the pertinent literature is still in an expanding phase and is obviously becoming important for various groups of researchers in basic cell and molecular biology, developmental biology, histology, physiology, cardiology, pathology and genetics, the relevant references so far recognized have been collected and are presented here in the following order: desmocollin-2 (Dsc2, DSC2), desmoglein-2 (Dsg2, DSG2), desmoplakin (DP, DSP), plakoglobin (PG, JUP), plakophilin-2 (Pkp2, PKP2) and some non-desmosomal proteins such as transmembrane protein 43 (TMEM43), ryanodine receptor 2 (RYR2), desmin, lamins A and C, striatin, titin and transforming growth factor-β3 (TGFβ3), followed by a collection of animal models and of reviews, commentaries, collections and comparative studies