Arrhythmogenic cardiomyopathy (ACM) is a familial heart disease characterized by cardiac dysfunction, arrhythmias, and myocardial inflammation. Exercise and stress can influence the disease\'s progression. Thus, an investigation of whether a high-fat diet (HFD) contributes to ACM pathogenesis is warranted. In a robust ACM mouse model, 8-week-old Desmoglein-2 mutant (Dsg2mut/mut) mice were fed either an HFD or rodent chow for 8 weeks. Chow-fed wildtype (WT) mice served as controls. Echo- and electrocardiography images pre- and post-dietary intervention were obtained, and the lipid burden, inflammatory markers, and myocardial fibrosis were assessed at the study endpoint. HFD-fed Dsg2mut/mut mice showed numerous P-wave perturbations, reduced R-amplitude, left ventricle (LV) remodeling, and reduced ejection fraction (%LVEF). Notable elevations in plasma high-density lipoprotein (HDL) were observed, which correlated with the %LVEF. The myocardial inflammatory adipokines, adiponectin (AdipoQ) and fibroblast growth factor-1, were substantially elevated in HFD-fed Dsg2mut/mut mice, albeit no compounding effect was observed in cardiac fibrosis. The HFD not only potentiated cardiac dysfunction but additionally promoted adverse cardiac remodeling. Further investigation is warranted, particularly given elevated AdipoQ levels and the positive correlation of HDL with the %LVEF, which may suggest a protective effect. Altogether, the HFD worsened some, but not all, disease phenotypes in Dsg2mut/mut mice. Notwithstanding, diet may be a modifiable environmental factor in ACM disease progression.

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Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiomyopathy associated with fibrofatty tissue replacement of the ventricular tissue. The disease can cause ventricular dysfunction and arrhythmias and can increase the risk of sudden cardiac death. This cardiomyopathy can have variable clinical presentations, especially in the pediatric and young adult populations. In this report, we describe the case of an 18-year-old female with myocarditis as the initial presentation of ACM. She presented following a resuscitated cardiac arrest due to ventricular arrhythmia. On arrival, myocardial edema and delayed gadolinium enhancement were present on cardiac magnetic resonance imaging, with no ventricular changes observed, making the diagnosis consistent with myocarditis. Genetic testing revealed a pathogenic mutation in the desmoplakin gene consistent with ACM. Given the unconventional initial presentation of this patient\'s disease, early consideration of genetic testing may be beneficial to aid in the early diagnosis and management of ACM in young patients.

暂无摘要。

Arrhythmogenic cardiomyopathy (ACM) is an inherited myocardial disease at risk of sudden death. Genetic testing impacts greatly in ACM diagnosis, but gene-disease associations have yet to be determined for the increasing number of genes included in clinical panels. Genetic variants evaluation was undertaken for the most relevant non-desmosomal disease genes. We retrospectively studied 320 unrelated Italian ACM patients, including 243 cases with predominant right-ventricular (ARVC) and 77 cases with predominant left-ventricular (ALVC) involvement, who did not carry pathogenic/likely pathogenic (P/LP) variants in desmosome-coding genes. The aim was to assess rare genetic variants in transmembrane protein 43 (TMEM43), desmin (DES), phospholamban (PLN), filamin c (FLNC), cadherin 2 (CDH2), and tight junction protein 1 (TJP1), based on current adjudication guidelines and reappraisal on reported literature data. Thirty-five rare genetic variants, including 23 (64%) P/LP, were identified in 39 patients (16/243 ARVC; 23/77 ALVC): 22 FLNC, 9 DES, 2 TMEM43, and 2 CDH2. No P/LP variants were found in PLN and TJP1 genes. Gene-based burden analysis, including P/LP variants reported in literature, showed significant enrichment for TMEM43 (3.79-fold), DES (10.31-fold), PLN (117.8-fold) and FLNC (107-fold). A non-desmosomal rare genetic variant is found in a minority of ARVC patients but in about one third of ALVC patients; as such, clinical decision-making should be driven by genes with robust evidence. More than two thirds of non-desmosomal P/LP variants occur in FLNC.

Arrhythmogenic cardiomyopathy (ACM) is a rare genetic cardiac disease characterized by the progressive substitution of myocardium with fibro-fatty tissue. Clinically, ACM shows wide variability among patients; symptoms can include syncope and ventricular tachycardia but also sudden death, with the latter often being its sole manifestation. Approximately half of ACM patients have been found with variations in one or more genes encoding cardiac intercalated discs proteins; the most involved genes are plakophilin 2 (PKP2), desmoglein 2 (DSG2), and desmoplakin (DSP). Cardiac intercalated discs provide mechanical and electro-metabolic coupling among cardiomyocytes. Mechanical communication is guaranteed by the interaction of proteins of desmosomes and adheren junctions in the so-called area composita, whereas electro-metabolic coupling between adjacent cardiac cells depends on gap junctions. Although ACM has been first described almost thirty years ago, the pathogenic mechanism(s) leading to its development are still only partially known. Several studies with different animal models point to the involvement of the Wnt/β-catenin signaling in combination with the Hippo pathway. Here, we present an overview about the existing murine models of ACM harboring variants in intercalated disc components with a particular focus on the underlying pathogenic mechanisms. Prospectively, mechanistic insights into the disease pathogenesis will lead to the development of effective targeted therapies for ACM.

Arrhythmias account for over 300,000 annual deaths in the United States, and approximately half of all deaths are associated with heart disease. Mechanisms underlying arrhythmia risk are complex; however, work in humans and animal models over the past 25 years has identified a host of molecular pathways linked with both arrhythmia substrates and triggers. This chapter will focus on select arrhythmia pathways solved by linking human clinical and genetic data with animal models.

Special Operations Servicemembers presenting with palpitations, pre-syncope, or exertional syncope during rigorous physical training are often experiencing a benign condition; however, life-threatening etiologies should be considered. We describe a 43-year-old Special Operator who presented to his medics during selection physical assessment testing with palpitations and lightheadedness, with a subsequent workup revealing arrhythmogenic right ventricular cardiomyopathy (ARVC). His initial electrocardiogram was unremarkable without characteristic ARVC changes. Outpatient evaluation with ambulatory cardiac monitoring recorded numerous episodes of non-sustained ventricular tachycardia. Transthoracic echocardiography demonstrated findings concerning for ARVC, with subsequent cardiac MRI confirming the diagnosis via the 2020 Padua criteria. Management includes activity modification, class III anti-arrhythmic medications, and possible placement of an implantable cardioverter defibrillator to prevent sudden cardiac death. This case demonstrates the importance of maintaining high clinical suspicion for rare diagnoses that present with exertional palpitations, such as arrhythmogenic right ventricular cardiomyopathy, in even our fittest Special Operators.

BACKGROUND: Arrhythmogenic left ventricular cardiomyopathy (ALVC) is characterized by fibrofatty myocardial replacement demonstrated on cardiac magnetic resonance by late gadolinium enhancement (LGE) mainly involving the subepicardium. The aims of this study were to describe the layer-specific strain (LSS) echocardiography phenotype of ALVC and to compare it with LGE features.
METHODS: All consecutive ALVC pathogenic genetic variant carriers and noncarrier relatives were separated into four prespecified groups (overt ALVC [group 1], isolated LGE [group 2], pathogenic genetic variant carrier without ALVC phenotype [group 3], and no genetic variant carrier [group 4]) and studied accordingly using cardiac magnetic resonance and LSS echocardiography.
RESULTS: Eighty-five individuals were included. Endocardial global longitudinal strain (GLS)-epicardial GLS (GLSepi) gradient was altered predominantly in group 1, illustrating transmural strain alteration in overt ALVC (3.8 ± 1.1 in group 1, 4.3 ± 2.2 in group 2, 5.2 ± 1.2 in group 3, and 5.4 ± 1.6 in group 4; P = .0017), whereas GLSepi was impaired predominantly in group 2 (endocardial GLS and GLSepi were 15.0 ± 4.1% and 11.2 ± 3.3%, respectively, in group 1; 20.5 ± 2.8% and 16.2 ± 5.5% in group 2; 23.4 ± 3.3% and 18.2 ± 2.7% in group 3; and 24.6 ± 2.8% and 19.2 ± 1.9% in group 4; P < .0001 for all). GLSepi was able to detect subepicardial LGE in genetic variant carriers without overt ALVC with an area under curve of 0.84 (95% CI, 0.73-0.95). However, segmental epicardial and endocardial strain behaved similarly and showed comparable diagnostic values for segmental LGE detection (areas under the curve, 0.72; [95% CI, 0.69-0.76] and 0.73 [95% CI, 0.70-0.76], respectively, P = .40).
CONCLUSIONS: LSS alteration in ALVC progresses from the epicardium to the endocardium along with disease severity. Irrespective of LSS analysis, which did not provide incremental diagnostic value for the detection and localization of LGE, strain echocardiography was shown to be a potential surrogate marker of LGE, including in apparently healthy individuals with isolated LV fibrosis.

Desmoglein-2 mutations are detected in 5-10% of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). Endurance training accelerates the development of the ARVC phenotype, leading to earlier arrhythmic events. Homozygous Dsg2 mutant mice develop a severe ARVC-like phenotype. The phenotype of heterozygous mutant (Dsg2mt/wt) or haploinsufficient (Dsg20/wt) mice is still not well understood. To assess the effects of age and endurance swim training, we studied cardiac morphology and function in sedentary one-year-old Dsg2mt/wt and Dsg20/wt mice and in young Dsg2mt/wt mice exposed to endurance swim training. Cardiac structure was only occasionally affected in aged Dsg20/wt and Dsg2mt/wt mice manifesting as small fibrotic foci and displacement of Connexin 43. Endurance swim training increased the right ventricular (RV) diameter and decreased RV function in Dsg2mt/wt mice but not in wild types. Dsg2mt/wt hearts showed increased ventricular activation times and pacing-induced ventricular arrhythmia without obvious fibrosis or inflammation. Preload-reducing therapy during training prevented RV enlargement and alleviated the electrophysiological phenotype. Taken together, endurance swim training induced features of ARVC in young adult Dsg2mt/wt mice. Prolonged ventricular activation times in the hearts of trained Dsg2mt/wt mice are therefore a potential mechanism for increased arrhythmia risk. Preload-reducing therapy prevented training-induced ARVC phenotype pointing to beneficial treatment options in human patients.