Relationship between electrocardiographic findings and cardiac magnetic resonance phenotypes in arrhythmogenic cardiomyopathy

Background-\u2014The new designation of arrhythmogenic cardiomyopathy defines a broader spectrum of disease phenotypes, which include right dominant, biventricular, and left dominant variants. We evaluated the relationship between electrocardiographic findings and contrast-enhanced cardiac magnetic resonance phenotypes in arrhythmogenic cardiomyopathy. Methods and Results-\u2014We studied a consecutive cohort of patients with a definite diagnosis of arrhythmogenic cardiomyopathy, according to 2010 International Task Force criteria, who underwent electrocardiography and contrast-enhanced cardiac magnetic resonance. Both depolarization and repolarization electrocardiographic abnormalities were correlated with the severity of dilatation/dysfunction, either global or regional, of both ventricles and the presence and regional distribution of late gadolinium enhancement. The study population included 79 patients (60% men). There was a statistically significant relationship between the presence and extent of T-wave inversion across a 12-lead ECG and increasing values of median right ventricular (RV) end-diastolic volume (P55 ms in the right precordial leads (V1-V3) was associated with higher RV volume (P=0.014) and lower RV ejection fraction (P=0.053). Low QRS voltages in limb leads predicted the presence (P=0.004) and amount (P<0.001) of left ventricular late gadolinium enhancement. Conclusions-\u2014The study results indicated that electrocardiographic abnormalities predict the arrhythmogenic cardiomyopathy phenotype in terms of severity of RV disease and left ventricular involvement, which are among the most important determinants of the disease outcome

Arrhythmogenic Right Ventricular Cardiomyopathy: Characterization of Left Ventricular Phenotype and Differential Diagnosis With Dilated Cardiomyopathy

Background This study assessed the prevalence of left ventricular (LV) involvement and characterized the clinical, electrocardiographic, and imaging features of LV phenotype in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). Differential diagnosis between ARVC-LV phenotype and dilated cardiomyopathy (DCM) was evaluated. Methods and Results The study population included 87 ARVC patients (median age 34\ua0years) and 153 DCM patients (median age 51\ua0years). All underwent cardiac magnetic resonance with quantitative tissue characterization. Fifty-eight ARVC patients (67%) had LV involvement, with both LV systolic dysfunction and LV late gadolinium enhancement (LGE) in 41/58 (71%) and LV-LGE in isolation in 17 (29%). Compared with DCM, the ARVC-LV phenotype was statistically significantly more often characterized by low QRS voltages in limb leads, T-wave inversion in the inferolateral leads and major ventricular arrhythmias. LV-LGE was found in all ARVC patients with LV systolic dysfunction and in 69/153 (45%) of DCM patients. Patients with ARVC and LV systolic dysfunction had a greater amount of LV-LGE (25% versus 13% of LV mass; P<0.01), mostly localized in the subepicardial LV wall layers. An LV-LGE 6520% had a 100% specificity for diagnosis of ARVC-LV phenotype. An inverse correlation between LV ejection fraction and LV-LGE extent was found in the ARVC-LV phenotype (r=-0.63; P<0.01), but not in DCM (r=-0.01; P=0.94). Conclusions LV involvement in ARVC is common and characterized by clinical and cardiac magnetic resonance features which differ from those seen in DCM. The most distinctive feature of ARVC-LV phenotype is the large amount of LV-LGE/fibrosis, which impacts directly and negatively on the LV systolic function

Morphofunctional abnormalities of mitral annulus and arrhythmic mitral valve prolapse

Background\u2014Arrhythmic mitral valve prolapse (MVP) is characterized by myxomatous leaflets and left ventricular (LV) fibrosis of papillary muscles and inferobasal wall. We searched for morphofunctional abnormalities of the mitral valve that could explain a regional mechanical myocardial stretch. Methods and Results\u2014Thirty-six (27 female patients; median age: 44 years) arrhythmic MVP patients with LV late gadolinium enhancement on cardiac magnetic resonance and no or trivial mitral regurgitation, and 16 (6 female patients; median age: 40 years) MVP patients without LV late gadolinium enhancement were investigated by morphofunctional cardiac magnetic resonance. Mitral annulus disjunction (median: 4.8 versus 1.8 mm; P1.5 (22 [61%] versus 4 [25%]; P=0.016) were higher in MVP patients with late gadolinium enhancement than in those without. A linear correlation was found between mitral annulus disjunction and curling (R=0.85). A higher prevalence of auscultatory midsystolic click (26 [72%] versus 6 [38%]; P=0.018) was also noted. Histology of the mitral annulus showed a longer mitral annulus disjunction in 50 sudden death patients with MVP and LV fibrosis than in 20 patients without MVP (median: 3 versus 1.5 mm; P<0.001). Conclusions\u2014Mitral annulus disjunction is a constant feature of arrhythmic MVP with LV fibrosis. The excessive mobility of the leaflets caused by posterior systolic curling accounts for a mechanical stretch of the inferobasal wall and papillary muscles, eventually leading to myocardial hypertrophy and scarring. These mitral annulus abnormalities, together with auscultatory midsystolic click, may identify MVP patients who would need arrhythmic risk stratification

Nonischemic left ventricular scar as a substrate of life-threatening ventricular arrhythmias and sudden cardiac death in competitive athletes

Background\u2014The clinical profile and arrhythmic outcome of competitive athletes with isolated nonischemic left ventricular (LV) scar as evidenced by contrast-enhanced cardiac magnetic resonance remain to be elucidated. Methods and Results\u2014We compared 35 athletes (80% men, age: 14\u201348 years) with ventricular arrhythmias and isolated LV subepicardial/midmyocardial late gadolinium enhancement (LGE) on contrast-enhanced cardiac magnetic resonance (group A) with 38 athletes with ventricular arrhythmias and no LGE (group B) and 40 healthy control athletes (group C). A stria LGE pattern with subepicardial/midmyocardial distribution, mostly involving the lateral LV wall, was found in 27 (77%) of group A versus 0 controls (group C; P<0.001), whereas a spotty pattern of LGE localized at the junction of the right ventricle to the septum was respectively observed in 11 (31%) versus 10 (25%; P=0.52). All athletes with stria pattern showed ventricular arrhythmias with a predominant right bundle branch block morphology, 13 of 27 (48%) showed ECG repolarization abnormalities, and 5 of 27 (19%) showed echocardiographic hypokinesis of the lateral LV wall. The majority of athletes with no or spotty LGE pattern had ventricular arrhythmias with a predominant left bundle branch block morphology and no ECG or echocardiographic abnormalities. During a follow-up of 38\ub125 months, 6 of 27 (22%) athletes with stria pattern experienced malignant arrhythmic events such as appropriate implantable cardiac defibrillator shock (n=4), sustained ventricular tachycardia (n=1), or sudden death (n=1), compared with none of athletes with no or LGE spotty pattern and controls. Conclusions\u2014Isolated nonischemic LV LGE with a stria pattern may be associated with life-threatening arrhythmias and sudden death in the athlete. Because of its subepicardial/midmyocardial location, LV scar is often not detected by echocardiography

Coronary artery calcium score: we know where we are but not where we may be

Cardiac computed tomography angiography (CCTA) has emerged as a cost-effective and time-saving technique for excluding coronary artery disease. One valuable tool obtained by CCTA is the coronary artery calcium (CAC) score. The use of CAC scoring has shown promise in risk assessment and stratification of cardiovascular disease. CAC scores can be complemented by plaque analysis to assess vulnerable plaque characteristics and further refine risk assessment. This paper aims to provide a comprehensive understanding of the value of the CAC as a prognostic tool and its implications for patient risk assessment, treatment strategies and outcomes. CAC scoring has demonstrated superior ability in stratifying patients, especially asymptomatic individuals, compared to traditional risk factors and scoring systems. The main evidence suggests that individuals with a CAC score of 0 had a good long-term prognosis, while elevated CAC score is associated with increased cardiovascular risk. Finally, the clinical power of CAC scoring and the develop of new models for risk stratification could be enhanced by machine learning algorithms

Correlazione gentotipo-fenotipo in pazienti affetti da cardiomiopatia aritmogena del ventricolo destro portatori di mutazioni di geni codificanti per le proteine di giunzione intercellulare

Background: Arrhymogenic Right Ventricular Cardiomyopathy (ARVC) is an inherited primary heart muscle disease characterized by progressive myocardial atrophy and progressive fibrofatty tissue replacement. Familiar occurrence with an autosomal dominant pattern of inheritance and variable penetrance is proven, although recessive forms exist. ARVC affects primarily the right ventricle even if a left ventricular involvement is frequently described. The disease often presents with ventricular arrhythmias that can also lead to sudden death. A recent molecular classification defines ARVC as a “Desmosomal Cardiomyopathy” due to the identification of causative mutations in genes encoding for components of the desmosome, the specialized intercellular junctions that anchor intermediate filaments to the cytoplasmatic membrane in adjoining cells. This defect in desmosome components seems to predispose to myocyte detachment and death. Available genotype-phenotype correlation studies analysed the phenotypic features associated with mutations of a single disease-gene, although a comparison among clinical phenotype of patients with mutation on different genes is still missing. Objectives we sought to provide a detailed analysis of the genotype-phenotype correlation in subjects carrying a causative mutation of the different disease-genes encoding for desmosome components (Plakophillin2-PKP2, Desmoglein2-DSG2, Desmoplakin-DSP, Desmoglein2-DSG2, Multiple mutations-MM) Materials and Methods a total of 38 families (257 patients-128 women and 129 men- mean age at first evaluation 35±18 years) affected by ARVC and in whom mutations of a known ARVC-gene has been identified were analysed. The study population was divided into 4 groups according to the disease-gene: PKP2 (n=46), DSP (n=37), DSG2 (n=59) and those with MM (n=28). The instrumental and clinical features detected at first and at last examination were compared. Clinical evaluation included a detailed familial pedigree, medical history, 12- lead ECG, signal-averaged ECG, two-dimensional echocardiography, 24-hour ambulatory ECG monitoring. Moreover, in selected cases a cardiac magnetic resonance with gadolinium injection was performed. Results: a total of 170 patients was found to carry a mutation in a desmosomal gene (DSP=59, PKP2= 46, DGS2=37,MM=22 had). Moreover, 48% of patients fulfilled the established diagnostic criteria of ARVC (M/F 2,8/1). Analysis of clinical and instrumental data showed a greater extent of the disease in PKP2 and MM groups, defined a larger right ventricular dimensions and more frequent left ventricular involvement. During follow- up patients carrying a DSP mutation showed a greater progression of the disease, with particular regard to the left ventricle. Nonetheless, survival analysis didn't show a significant difference of major events in patients carrying distinct genes mutations. Conclusions: the study demonstrated the presence of gene-specific features in ARVC patients, with particular regard to right ventricular dilatation and left ventricular involvement. Nevertheless the prognosis doesn't seem to be different among mutation carriers of different genes. Thus the genetic characterization seems not to modify the therapeutic strategies and the risk stratification of patients. Finally, the different clinical expression of this disease in subjects carrying the same mutation suggests a possible role of modifying factor in the clinical phenotype.Introduzione: la Cardiomiopatia Aritmogena del Ventricolo Destro (Arrythmogenic Right Ventricular Cardiomyopaty: ARVC) è una malattia ereditaria del muscolo cardiaco, spesso familiare, caratterizzata da un’atrofia miocardica progressiva con sostituzione fibro-adiposa. Il coinvolgimento ventricolare destro è predominante e più evidente ma anche il ventricolo sinistro viene colpito dalla malattia in maniera significativa. Clinicamente si manifesta con aritmie ventricolari che possono portare anche a morte improvvisa. Una recente classificazione molecolare definisce l’ARVC una “Cardiomiopatia delle giunzioni intercellulari” o “Cardiomiopatia Desmosomiale”, dato che i geni-malattia codificano per proteine delle giunzioni intercellulari (desmosomi e giunzioni adherens) con rimodellamento dei dischi intercalari, così da rendere i miociti più suscettibili allo stress parietale con morte miocellulare e sostituzione fibroadiposa . Gli studi di correlazione genotipo- fenotipo finora eseguiti hanno esaminato il fenotipo dei pazienti portatori dei vari geni malattia, senza tuttavia paragonare gli aspetti clinici di pazienti portatori di mutazioni genetiche a carico di geni diversi. Scopo dello Studio: lo studio si propone di eseguire una correlazione genotipo- fenotipo in soggetti affetti e nei familiari non affetti dalla malattia, portatori di mutazioni di geni che codificano per le proteine desmosomiali finora identificati nella nostra casistica (Plakofillina-2: PKP2; Desmogleina-2: DSG2; Desmoplachina: DSP) Materiali e Metodi: abbiamo studiato le famiglie di 38 probandi affetti da ARVC per un totale di 257 soggetti (128 femmine e 129 maschi età media 35±18 anni). I soggetti analizzati sono stati suddivisi in 3 gruppi in base alla alterazione genetica individuata (PKP2, DSP e DSG2); un quarto gruppo comprendeva pazienti portatori di una mutazione multipla (MM). Sono stati raccolti i dati relativi alla prima visita e all’ultima visita di follow-up. Il protocollo di studio prevedeva l’anamnesi personale e familiare, l’ecocardiografia mono e bidimensionale color Doppler, l’elettrocardiogramma di base, i SAECG (potenziali tardivi ad alta risoluzione), l’ECG Holter delle 24h. In casi selezionati si acquisivano i dati di Risonanza Magnetica Cardiaca. Risultati: un totale di 170 (51%) soggetti è risultato essere portatore di mutazione genetica. Si trattava di mutazioni della DSP (n.59), PKP2 (n. 46), DSG2 (n.37) e di doppie mutazioni (MM= n.28). Una diagnosi clinica con i criteri della Task Force era possibile nel 48% dei soggetti con mutazione, con una netta prevalenza maschile (M/F 2,8/1). L’analisi dei dati clinico- strumentali mostrava alla prima visita una maggiore estensione della malattia, in termini di dilatazione del ventricolo destro e di interessamento del ventricolo sinistro, nei soggetti portatori di mutazione PKP2 e MM. Durante il follow up i pazienti con mutazione DSP mostravano una maggiore progressione della malattia in particolare a carico del ventricolo sinistro. L’analisi di sopravvivenza non mostrava differenze significative nei pazienti portatori di mutazioni dei diversi geni. Conclusioni: I dati ottenuti evidenziano delle caratteristiche gene- specifiche dell’ARVC in particolare al grado di dilatazione del ventricolo destro e del coinvolgimento ventricolare sinistro. Tuttavia la prognosi non sembra essere diversa nei portatori di mutazioni di geni diversi. Pertanto al momento attuale la caratterizzazione genetica non modifica l’approccio clinico- diagnostico e la stratificazione del rischio nei pazienti. La diversa espressione clinica della malattia in famiglie portatrici della stessa mutazione suggeriscono che il fenotipo è in larga misura influenzato anche da fattori ambientali

Desmoplakin Cardiomyopathy: Comprehensive Review of an Increasingly Recognized Entity

Desmoplakin (DSP) is a desmosomal protein that plays an essential role for cell-to-cell adhesion within the cardiomyocytes. The first association between DSP genetic variants and the presence of a myocardial disease referred to patients with Carvajal syndrome. Since then, several reports have linked the DSP gene to familial forms of arrhythmogenic (ACM) and dilated cardiomyopathies. Left-dominant ACM is the most common phenotype in individuals carrying DSP variants. More recently, a new entity—“Desmoplakin cardiomyopathy”—was described as a distinct form of cardiomyopathy characterized by frequent left ventricular involvement with extensive fibrosis, high arrhythmic risk, and episodes of acute myocardial injury. The purpose of this review was to summarize the available evidence on DSP cardiomyopathy and to identify existing gaps in knowledge that need clarification from upcoming research

Why and how to support screening strategies to prevent sudden death in athletes.

Sudden death in athletes occurs because of the existence of hidden cardiovascular disorders which, during effort, may jeopardize the electrical stability of the heart, triggering ventricular tachycardia and/or fibrillation. Apart from rare conditions of ion channel diseases in the setting of a structurally normal heart, in which the disorder may be easily diagnosed on basal or stress test ECG, cardiac abnormalities at risk of causing sudden death may affect the aorta (Marfan syndrome), the coronary arteries (congenital coronary artery anomalies, premature coronary atherosclerosis), the myocardium (hypertrophic and arrhythmogenic cardiomyopathy), the valves (bicuspid aortic valve, mitral valve prolapse) and the conduction system (pre-excitation syndromes). These structural heart disorders may be detected by ECG and/or echo. The employment of these tools at pre-participation screening can help to identify concealed anomalies, which may play a major role in early diagnosis, risk stratification, and prevention of sudden death