High-Fat Diet Augments Myocardial Inflammation and Cardiac Dysfunction in Arrhythmogenic Cardiomyopathy.

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.

Clinical and echocardiographic evolution of patients with arrhythmogenic cardiomyopathy before heart transplantation.

BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiomyopathy characterized by fibrofatty myocardial replacement, and accurate diagnosis can be challenging. The clinical course of patients expressing a severe phenotype of the disease needing heart transplantation (HTx) is not well described in the literature. Therefore, this study aims to describe the clinical and echocardiographic evolution of patients with ACM necessitating HTx. METHODS: We retrospectively studied all patients who underwent HTx in our institution between 1998 and 2019 with a definite diagnosis of ACM according to the explanted heart examination. RESULTS: Ten patients with confirmed ACM underwent HTx. Only four of them had a diagnosis of ACM before HTx. These patients were 28 ± 15 years old at the time of their first symptoms. Patients received a diagnosis of heart failure (HF) after 5.9 ± 8.7 years of symptom evolution. The mean age at transplantation was 40 ± 17 years old. All the patients experienced ventricular tachycardia (VT) at least once before their HTx and 50% were resuscitated after sudden death. The mean left ventricular ejection at diagnosis and before transplantation was similar (32% ± 21% vs. 35.0% ± 19.3%, p = NS). Right ventricular dysfunction was present in all patients at the time of transplantation. CONCLUSION: Patients with ACM necessitating HTx show a high burden of ventricular arrhythmias and frequently present a biventricular involvement phenotype, making early diagnosis challenging. HF symptoms are the most frequent reason leading to the decision to transplant.

Age-related differences and associated mid-term outcomes of subcutaneous implantable cardioverter-defibrillators: A propensity-matched analysis from a multicenter European registry.

BACKGROUND: A few limited case series have shown that the subcutaneous implantable cardioverter-defibrillator (S-ICD) system is safe for teenagers and young adults, but a large-scale analysis currently is lacking. OBJECTIVES: The purpose of this study was to compare mid-term device-associated outcomes in a large real-world cohort of S-ICD patients, stratified by age at implantation. METHODS: Two propensity-matched cohorts of teenagers + young adults (≤30 years old) and adults (>30 years old) were retrieved from the ELISIR Registry. The primary outcome was the comparison of inappropriate shock rate. Complications, freedom from sustained ventricular arrhythmias, and overall and cardiovascular mortality were deemed secondary outcomes. RESULTS: Teenagers + young adults represented 11.0% of the entire cohort. Two propensity-matched groups of 161 patients each were used for the analysis. Median follow-up was 23.1 (13.2-40.5) months. In total, 15.2% patients experienced inappropriate shocks, and 9.3% device-related complications were observed, with no age-related differences in inappropriate shocks (16.1% vs 14.3%; P = .642) and complication rates (9.9% vs 8.7%; P = .701). At univariate analysis, young age was not associated with increased rates of inappropriate shocks (hazard ratio [HR] 1.204 [0.675-2.148]: P = .529). At multivariate analysis, use of the SMART Pass algorithm was associated with a strong reduction in inappropriate shocks (adjusted HR 0.292 [0.161-0.525]; P <.001), whereas arrhythmogenic right ventricular cardiomyopathy (ARVC) was associated with higher rates of inappropriate shocks (adjusted HR 2.380 [1.205-4.697]; P = .012). CONCLUSION: In a large multicenter registry of propensity-matched patients, use of the S-ICD in teenagers/young adults was safe and effective. The rates of inappropriate shocks and complications between cohorts were not significantly different. The only predictor of increased inappropriate shocks was a diagnosis of ARVC.

Inflammation and Immune Response in Arrhythmogenic Cardiomyopathy: State-of-the-Art Review.

Arrhythmogenic cardiomyopathy (ACM) is a primary disease of the myocardium, predominantly caused by genetic defects in proteins of the cardiac intercalated disc, particularly, desmosomes. Transmission is mostly autosomal dominant with incomplete penetrance. ACM also has wide phenotype variability, ranging from premature ventricular contractions to sudden cardiac death and heart failure. Among other drivers and modulators of phenotype, inflammation in response to viral infection and immune triggers have been postulated to be an aggravator of cardiac myocyte damage and necrosis. This theory is supported by multiple pieces of evidence, including the presence of inflammatory infiltrates in more than two-thirds of ACM hearts, detection of different cardiotropic viruses in sporadic cases of ACM, the fact that patients with ACM often fulfill the histological criteria of active myocarditis, and the abundance of anti-desmoglein-2, antiheart, and anti-intercalated disk autoantibodies in patients with arrhythmogenic right ventricular cardiomyopathy. In keeping with the frequent familial occurrence of ACM, it has been proposed that, in addition to genetic predisposition to progressive myocardial damage, a heritable susceptibility to viral infections and immune reactions may explain familial clustering of ACM. Moreover, considerable in vitro and in vivo evidence implicates activated inflammatory signaling in ACM. Although the role of inflammation/immune response in ACM is not entirely clear, inflammation as a driver of phenotype and a potential target for mechanism-based therapy warrants further research. This review discusses the present evidence supporting the role of inflammatory and immune responses in ACM pathogenesis and proposes opportunities for translational and clinical investigation.

Cardiac Biomarkers and Autoantibodies in Endurance Athletes: Potential Similarities with Arrhythmogenic Cardiomyopathy Pathogenic Mechanisms.

The "Extreme Exercise Hypothesis" states that when individuals perform training beyond the ideal exercise dose, a decline in the beneficial effects of physical activity occurs. This is due to significant changes in myocardial structure and function, such as hemodynamic alterations, cardiac chamber enlargement and hypertrophy, myocardial inflammation, oxidative stress, fibrosis, and conduction changes. In addition, an increased amount of circulating biomarkers of exercise-induced damage has been reported. Although these changes are often reversible, long-lasting cardiac damage may develop after years of intense physical exercise. Since several features of the athlete's heart overlap with arrhythmogenic cardiomyopathy (ACM), the syndrome of "exercise-induced ACM" has been postulated. Thus, the distinction between ACM and the athlete's heart may be challenging. Recently, an autoimmune mechanism has been discovered in ACM patients linked to their characteristic junctional impairment. Since cardiac junctions are similarly impaired by intense physical activity due to the strong myocardial stretching, we propose in the present work the novel hypothesis of an autoimmune response in endurance athletes. This investigation may deepen the knowledge about the pathological remodeling and relative activated mechanisms induced by intense endurance exercise, potentially improving the early recognition of whom is actually at risk.

Spatial and transmural properties of the reentrant ventricular tachycardia circuit in arrhythmogenic right ventricular cardiomyopathy: Simultaneous epicardial and endocardial recordings.

BACKGROUND: While advances in the characterization of the structural substrate in arrhythmogenic right ventricular cardiomyopathy (ARVC) have been made, the ventricular tachycardia (VT) circuit remains incompletely described. OBJECTIVE: The purpose of this study was to delineate the reentrant VT circuit with simultaneous epicardial and endocardial mapping (SEEM) in ARVC. METHODS: Twenty-three consecutive patients with ARVC and VT underwent SEEM at 4 centers between 2014 and 2020. Retrospective analysis was performed on combined isochronal activation maps. RESULTS: Of the 30 VT circuits, 24 were delineated with SEEM (956 [341-1843] endocardial points and 1763 [882-3054] epicardial points). The apex and outflow tract rarely harbored VT circuits, with 50% distributed in the inferior wall and 43% in the free wall. The entire tachycardia cycle length was recorded from the epicardium in 71% of circuits. In all circuits, a large proportion of the tachycardia cycle length was recorded from the epicardium relative to the endocardium. Localized epicardial reentry was observed in 35% of patients (14 mm × 15 mm), which was associated with smaller endocardial low voltage area (39 cm2 vs 104 cm2; P = .002) and preserved right ventricular ejection fraction (35% vs 25%; P = .046) compared with those with larger circuit dimensions. Seventy percent of termination sites were achieved from the epicardium. CONCLUSION: High-resolution recordings from both myocardial surfaces confirm a consistent predominance of epicardial participation during reentry in ARVC. Only the perivalvular inflow region of the "triangle of dysplasia" had a strong propensity to harbor VT circuits, with the greatest proportion located in the inferior wall. Localized epicardial reentry may be a manifestation of earlier stage disease with a relative paucity of endocardial substrate.

Miocardiopatía arritmogénica del ventrículo derecho en pacientes jóvenes con miocarditis: una asociación oculta / Arrhythmogenic right ventricular cardiomyopathy presenting as myocarditis in young patients: a concealed relationship

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Special Article - Exercise-induced right ventricular injury or arrhythmogenic cardiomyopathy (ACM): The bright side and the dark side of the moon.

There is still debate on the range of normal physiologic changes of the right ventricle or ventricular (RV) function in athletes. Genetic links to arrhythmogenic cardiomyopathy (ACM) are well-established. There is no current consensus on the importance of extensive exercise and exercise-induced injury to the RV. During the intensive exercise of endurance sports, the cardiac structures adapt to athletic load over time. Some athletes develop RV cardiomyopathy possibly caused by genetic predisposition, whilst others develop arrhythmias from the RV. Endurance sports lead to increased volume and pressure load in both ventricles and increased myocardial mass. The extent of volume increase and changes in myocardial structure contribute to impairment of RV function and pose a challenge in cardiovascular sports medicine. Genetic predisposition to ACM may play an important role in the risk of sudden cardiac death of athletes. In this review, we discuss and evaluate existing results and opinions. Intensive training in competitive dynamic/power and endurance sports leads to specific RV adaptation, but physiological adaptation without genetic predisposition does not necessarily lead to severe complications in endurance sports. Discriminating between physiological adaptation and pathological form of ACM or RV impairment provoked by reinforced exercise presents a challenge to clinical sports cardiologists.

Arrhythmogenic right ventricular cardiomyopathy or athlete's heart? Challenges in assessment of right heart morphology and function.

The incidence of sudden cardiac death (SCD) in young athletes varies among studies, due to the disagreement in the definitions and the lack of information in this field.

Arrhythmogenic cardiomyopathy: what blood can reveal?

Blood, serum and plasma represent accessible sources of data about physiological and pathologic status. In arrhythmogenic cardiomyopathy (ACM), circulating nucleated cells are routinely used for detection of germinal genetic mutations. In addition, different biomarkers have been proposed for diagnostic purposes and for monitoring disease progression, including inflammatory cytokines, markers of myocardial dysfunction and damage, and microRNAs. This review summarizes the current information that can be retrieved from the blood of ACM patients and considers the future prospects. Improvements in current knowledge of circulating factors may provide noninvasive means to simplify and improve the diagnosis, prognosis prediction, and management of ACM patients.

Prevalence of 18F-fluorodeoxyglucose positron emission tomography abnormalities in patients with arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable heart muscle disease that causes sudden cardiac death in the young. Inflammatory myocardial infiltrates have been described at autopsy and on biopsy, but there are few data on the presence of myocarditis in living patients with ARVC using non-invasive imaging techniques. FDG-PET is a validated technique for detecting myocardial inflammation in clinically suspected myocarditis. We aimed to determine the prevalence of myocardial inflammation in patients with ARVC using 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). METHODS AND RESULTS: We performed a retrospective analysis of a single centre cohort of patients with ARVC referred for FDG-PET scans between 2012 and 2017 for investigation of symptoms or suspected device infection. Sixteen patients (12 male; age 42 ±â€¯13 years) with a definite diagnosis of ARVC were identified. Seven had positive FDG-PET scans, two of whom had cardiac sarcoidosis on endomyocardial biopsy. Of the remaining five, two carried pathogenic desmoplakin mutations. FDG uptake was found in the left ventricular myocardium in all cases. One patient also had right ventricular uptake. CONCLUSION: In this exploratory study, we show that some patients with ARVC have evidence for myocardial inflammation on FDG-PET, suggesting that myocarditis plays a role in disease pathogenesis.

Sex hormones affect outcome in arrhythmogenic right ventricular cardiomyopathy/dysplasia: from a stem cell derived cardiomyocyte-based model to clinical biomarkers of disease outcome.

AIMS: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is characterized by fibrofatty infiltration of the myocardium and ventricular arrhythmias that may lead to sudden cardiac death. It has been observed that male patients develop the disease earlier and present with more severe phenotypes as compared to females. Thus, we hypothesized that serum levels of sex hormones may contribute to major arrhythmic cardiovascular events (MACE) in patients with ARVC/D. METHODS AND RESULTS: The serum levels of five sex hormones, sex hormone-binding globulin, high sensitivity troponin T, pro-brain natriuretic peptide, cholesterol, triglycerides, insulin, and glucose were measured in 54 ARVC/D patients (72% male). Twenty-six patients (48%) experienced MACE. Total and free testosterone levels were significantly increased in males with MACE as compared to males with a favourable outcome, whereas estradiol was significantly lower in females with MACE as compared to females with a favourable outcome. Increased testosterone levels remained independently associated with MACE in males after adjusting for age, body mass index, Task Force criteria, ventricular function, and desmosomal mutation status. Furthermore, an induced pluripotent stem cell-derived ARVC/D cardiomyocyte model was used to investigate the effects of sex hormones. In this model, testosterone worsened and estradiol improved ARVC/D-related pathologies such as cardiomyocyte apoptosis and lipogenesis, strongly supporting our clinical findings. CONCLUSIONS: Elevated serum testosterone levels in males and decreased estradiol levels in females are independently associated with MACE in ARVC/D, and directly influence disease pathology. Therefore, determining the levels of sex hormones may be useful for risk stratification and may open a new window for preventive interventions.

RV Remodeling in Olympic Athletes.

OBJECTIVES: The aim of this study was to assess the impact of sex and different sports on right ventricular (RV) remodeling and compare the derived upper limits with widely used revised Task Force (TF) reference values. BACKGROUND: Uncertainties exist regarding the extent and physiological determinants of RV remodeling in highly trained athletes. The issue is important, considering that in athletes RV size occasionally exceeds the cutoff limits proposed to diagnose arrhythmogenic RV cardiomyopathy. METHODS: A total of 1,009 Olympic athletes (mean age 24 ± 6 years; n = 647 [64%] males) participating in skill, power, mixed, and endurance sport were evaluated by 2-dimensional echocardiography and Doppler/tissue Doppler imaging. The right ventricular outflow tract (RVOT) in parasternal long-axis (PLAX) and short-axis views, fractional area change, s' velocity, and morphological features were assessed. RESULTS: Indexed RVOT PLAX was greater in females than in males (15.3 ± 2.2 mm/m2 vs. 14.4 ± 1.9 mm/m2; p < 0.001). Both RVOT PLAX and parasternal short-axis view were significantly different among skill, power, mixed, and endurance sports: 14.3 ± 2.1 mm/m2 versus 14.7 ± 1.9 mm/m2 versus 14.0 ± 1.8 mm/m2 versus 15.7 ± 2.2 mm/m2, respectively (p < 0.001); and 15.2 ± 2.7 mm/m2 versus 15.3 ± 2.4 mm/m2 versus 14.8 ± 2.1 mm/m2 versus 16.2 ± 2.5 mm/m2, respectively (p < 0.001). The 95th percentile for indexed RVOT PLAX and parasternal short-axis view was 18 mm/m2 and 20 mm/m2, respectively. Fractional area change and s' velocity did not differ among the groups (p = 0.34 for both). RV enlargement compatible with major and minor TF diagnostic criteria for arrhythmogenic RV cardiomyopathy was observed in 41 (4%) and 319 (32%) athletes. A rounded apex was described in 823 (81%) athletes, prominent trabeculations in 378 (37%) athletes, and a prominent/hyperreflective moderator band in 5 (0.5%) athletes. CONCLUSIONS: RV remodeling occurs in Olympic athletes, with male sex and endurance practice playing the major impact. A significant subset (up to 32%) of athletes exceeds the normal TF limits; therefore, we recommend referring to the 95th percentiles here reported as referral values; alternatively, only major diagnostic TF criteria for arrhythmogenic RV cardiomyopathy may be appropriate.

Current aspects of pulmonary arterial hypertension and therapeutics.

The pulmonary arterial hypertension (PAH) patients have high rate of mortality due to right ventricle (or ventricular) (RV) failures. A lot of research work is being carried out in the area, however no treatment is available that could contrast the rise in mortality rates in PAH patients. ß1-adrenoceptor blockers (ß-blockers, BB) reduced mortality in left heart failure, but they do not explored much at clinical level. Recent studies suggest ß-blockers might be beneficial in PAH; however the mechanisms remain unknown. The present review article would put light on all these aspects of PAH along with latest ways for the management of PAH.