Background Patients with Fontan circulation are known to be at high risk for developing atrial tachyarrhythmias (AAs). Our objective was to examine the efficacy and safety of amiodarone in the management of ATs in adult Fontan patients. Methods Primary outcomes of this single-centre, retrospective study included freedom from AAs and incidence of adverse effects of amiodarone on Fontan patients. Heart failure (HF) events and composite outcomes of death from any cause, Fontan revision and heart transplantation were evaluated as secondary outcomes. Predictors of HF and discontinuing amiodarone were also evaluated. Results A total of 61 patients (mean age 31.6±11.3 years, 40.9% female), who were treated with amiodarone in between 1995 and 2018, were included. AAs free survival at 1, 3 and 5 years were 76.2%, 56.9% and 30.6%, respectively. During a median follow-up of 50.5 months, 34 (55.7%) patients developed side effects, and 20 (32.8%) patients discontinued amiodarone due to side effects. Thyroid dysfunction was the most common side effect (n=26, 76.5%), amiodarone-induced thyrotoxicosis (AIT) (n=16, 27.1%) being most common thyroid dysfunction. Young age (age <28.5 years) was associated with discontinuing amiodarone (HR 5.50, 95% CI 1.19 to 25.4, p=0.029). AIT significantly increased risk of HF (HR 4.82, 95% CI 1.71 to 13.6, p=0.003). Conclusions Short-term efficacy of amiodarone in Fontan physiology is acceptable. However, long-term administration is associated with a reduction of efficacy and a significant prevalence of non-cardiac side effects. AIT is associated with exacerbation of HF. The judicious use of amiodarone administration should be considered in this population.

Background Doxorubicin (Dox) is a potent chemotherapeutic agent, but its usage is limited by dose-dependent cardiotoxicity. Intracellular calcium dysregulation has been reported to be involved in doxorubicin-induced cardiomyopathy (DICM). The cardioprotective role of RyR stabilizer dantrolene (Dan) on the calcium dynamics of DICM has not yet been explored. Objective To evaluate the effects of dantrolene on intracellular calcium dysregulation and cardiac contractile function in a DICM model. Methods Adult male C57BL/6 mice were randomized into 4 groups: (1) Control, (2) Dox Only, (3) Dan Only, and (4) Dan + Dox. Fractional shortening (FS) and left ventricular ejection fraction (LVEF) were assessed by echocardiography. In addition, mice were sacrificed 2 weeks after doxorubicin injection for optical mapping of the heart in a Langendorff setup. Results Treatment with Dox was associated with a reduction in both FS and LVEF at 2 weeks (P < .0001) and 4 weeks (P < .006). Dox treatment was also associated with prolongation of calcium transient durations CaTD₅₀ (P = .0005) and CaTD₈₀ (P < .0001) and reduction of calcium amplitude alternans ratio (P < .0001). Concomitant treatment with Dan prevented the Dox-induced decline in FS and LVEF (P < .002 at both 2 and 4 weeks). Dan also prevented Dox-induced prolongation of CaTD₅₀ and CaTD₈₀ and improved the CaT alternans ratio (P < .0001). Finally, calcium transient rise time was increased in the doxorubicin-treated group, indicating RyR2 dyssynchrony, and dantrolene prevented this prolongation (P = .02). Conclusion Dantrolene prevents cardiac contractile dysfunction following doxorubicin treatment by mitigating dysregulation of calcium dynamics.

Ventricular fibrillation induced by short-coupled premature ventricular complex is an uncommon cause of cardiac arrest in young individuals with no structural heart disease. The genetic substrate of this condition is heterogeneous and remains incompletely defined. We describe a case of short-coupled premature ventricular complex–triggered ventricular fibrillation with a likely pathogenic variant in the titin (TTN) gene. (Level of Difficulty: Advanced.)

Background: We recently demonstrated that acute administration of ibrutinib, a Bruton's tyrosine kinase inhibitor used in chemotherapy for blood malignancies, increases ventricular arrhythmia (VA) vulnerability. A pathway of ibrutinib‐induced vulnerability to VA that can be modulated for cardioprotection remains unclear. Methods and Results: The effects of ibrutinib on cardiac electrical activity and Ca ²⁺ dynamics were investigated in Langendorff‐perfused hearts using optical mapping. We also conducted Western blotting analysis to evaluate the impact of ibrutinib on various regulatory and Ca ²⁺ ‐handling proteins in rat cardiac tissues. Treatment with ibrutinib (10 mg/kg per day) for 4 weeks was associated with an increased VA inducibility (72.2%±6.3% versus 38.9±7.0% in controls, P <0.002) and shorter action potential durations during pacing at various frequencies ( P <0.05). Ibrutinib also decreased heart rate thresholds for beat–to–beat duration alternans of the cardiac action potential ( P <0.05). Significant changes in myocardial Ca ²⁺ transients included lower amplitude alternans ratios ( P <0.05), longer times‐to‐peak ( P <0.05), and greater spontaneous intracellular Ca ²⁺ elevations ( P <0.01). We also found lower abundance and phosphorylation of myocardial AMPK (5′‐adenosine monophosphate‐activated protein kinase), indicating reduced AMPK activity in hearts after ibrutinib treatment. An acute treatment with the AMPK activator 5‐aminoimidazole‐4‐carboxamide‐1‐β‐D‐ribofuranoside ameliorated abnormalities in action potential and Ca ²⁺ dynamics, and significantly reduced VA inducibility (37.1%±13.4% versus 72.2%±6.3% in the absence of 5‐aminoimidazole‐4‐carboxamide‐1‐β‐D‐ribofuranoside, P <0.05) in hearts from ibrutinib‐treated rats. Conclusions: VA vulnerability inflicted by ibrutinib may be mediated in part by an impairment of myocardial AMPK activity. Pharmacological activation of AMPK may be a protective strategy against ibrutinib‐induced cardiotoxicity.