In heart failure (HF), Ca²⁺/calmodulin kinase II (CaMKII) expression is increased. Altered Na⁺ channel gating is linked to and may promote ventricular tachyarrhythmias (VTs) in HF. Calmodulin regulates Na⁺ channel gating, in part perhaps via CaMKII. We investigated effects of adenovirus-mediated (acute) and Tg (chronic) overexpression of cytosolic CaMKIIδ_C on Na⁺ current (I_Na) in rabbit and mouse ventricular myocytes, respectively (in whole-cell patch clamp). Both acute and chronic CaMKIIδ_C overexpression shifted voltage dependence of Na⁺ channel availability by –6 mV (P < 0.05), and the shift was Ca²⁺ dependent. CaMKII also enhanced intermediate inactivation and slowed recovery from inactivation (prevented by CaMKII inhibitors autocamtide 2–related inhibitory peptide [AIP] or KN93). CaMKIIδ_C markedly increased persistent (late) inward I_Na and intracellular Na⁺ concentration (as measured by the Na⁺ indicator sodium-binding benzofuran isophthalate [SBFI]), which was prevented by CaMKII inhibition in the case of acute CaMKIIδ_C overexpression. CaMKII coimmunoprecipitates with and phosphorylates Na⁺ channels. In vivo, transgenic CaMKIIδ_C overexpression prolonged QRS duration and repolarization (QT intervals), decreased effective refractory periods, and increased the propensity to develop VT. We conclude that CaMKII associates with and phosphorylates cardiac Na⁺ channels. This alters I_Na gating to reduce availability at high heart rate, while enhancing late I_Na (which could prolong action potential duration). In mice, enhanced CaMKIIδ_C activity predisposed to VT. Thus, CaMKII-dependent regulation of Na⁺ channel function may contribute to arrhythmogenesis in HF.

Background— Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disorder that causes sudden death and right ventricular heart failure in the young. Clinical data suggest that competitive sports may provoke ARVC in susceptible persons. Genetically, loss-of-function mutations in desmosomal proteins (plakophilin, desmoplakin, or plakoglobin) have been associated with ARVC. To test the hypothesis that reduced desmosomal protein expression causes ARVC, we studied the cardiac effects of heterozygous plakoglobin deficiency in mice. Methods and Results— Ten-month-old heterozygous plakoglobin-deficient mice (plakoglobin ^+/− ) had increased right ventricular volume, reduced right ventricular function, and spontaneous ventricular ectopy (all P <0.05). Left ventricular size and function were not altered. Isolated, perfused plakoglobin ^+/− hearts had spontaneous ventricular tachycardia of right ventricular origin and prolonged right ventricular conduction times compared with wild-type hearts. Endurance training accelerated the development of right ventricular dysfunction and arrhythmias in plakoglobin ^+/− mice. Histology and electron microscopy did not identify right ventricular abnormalities in affected animals. Conclusions— Heterozygous plakoglobin deficiency provokes ARVC. Manifestation of the phenotype is accelerated by endurance training. This suggests a functional role for plakoglobin and training in the development of ARVC.

Background—: Intergenic variations on chromosome 4q25, close to the PITX2 transcription factor gene, are associated with atrial fibrillation (AF). We therefore tested whether adult hearts express PITX2 and whether variation in expression affects cardiac function. Methods and Results—: mRNA for PITX2 isoform c was expressed in left atria of human and mouse, with levels in right atrium and left and right ventricles being 100-fold lower. In mice heterozygous for Pitx2c ( Pitx2c ^+/− ), left atrial Pitx2c expression was 60% of wild-type and cardiac morphology and function were not altered, except for slightly elevated pulmonary flow velocity. Isolated Pitx2 c ^+/− hearts were susceptible to AF during programmed stimulation. At short paced cycle lengths, atrial action potential durations were shorter in Pitx2c ^+/− than in wild-type. Perfusion with the β-receptor agonist orciprenaline abolished inducibility of AF and reduced the effect on action potential duration. Spontaneous heart rates, atrial conduction velocities, and activation patterns were not affected in Pitx2c ^+/− hearts, suggesting that action potential duration shortening caused wave length reduction and inducibility of AF. Expression array analyses comparing Pitx2c ^+/− with wild-type, for left atrial and right atrial tissue separately, identified genes related to calcium ion binding, gap and tight junctions, ion channels, and melanogenesis as being affected by the reduced expression of Pitx2c. Conclusions—: These findings demonstrate a physiological role for PITX2 in the adult heart and support the hypothesis that dysregulation of PITX2 expression can be responsible for susceptibility to AF.

Background: Adherence rates of preventative medication for cardiovascular disease (CVD) have been reported as 57%, and approximately 9% of all CVD events in Europe are attributable to poor medication adherence. Mobile health technologies, particularly mobile apps, have the potential to improve medication adherence and clinical outcomes.Objective: The objective of this study is to assess the effects of mobile health care apps on medication adherence and health-related outcomes in patients with CVD. This study also evaluates apps’ functionality and usability and the involvement of health care professionals in their use.Methods: Electronic databases (MEDLINE [Ovid], PubMed Central, Cochrane Library, CINAHL Plus, PsycINFO [Ovid], Embase [Ovid], and Google Scholar) were searched for randomized controlled trials (RCTs) to investigate app-based interventions aimed at improving medication adherence in patients with CVD. RCTs published in English from inception to January 2020 were reviewed. The Cochrane risk of bias tool was used to assess the included studies. Meta-analysis was performed for clinical outcomes and medication adherence, with meta-regression analysis used to evaluate the impact of app intervention duration on medication adherence.Results: This study included 16 RCTs published within the last 6 years. In total, 12 RCTs reported medication adherence as the primary outcome, which is the most commonly self-reported adherence. The duration of the interventions ranged from 1 to 12 months, and sample sizes ranged from 24 to 412. Medication adherence rates showed statistically significant improvements in 9 RCTs when compared with the control, and meta-analysis of the 6 RCTs reporting continuous data showed a significant overall effect in favor of the app intervention (mean difference 0.90, 95% CI 0.03-1.78) with a high statistical heterogeneity (I2=93.32%). Moreover, 9 RCTs assessed clinical outcomes and reported an improvement in systolic blood pressure, diastolic blood pressure, total cholesterol, and low-density lipoprotein cholesterol levels in the intervention arm. Meta-analysis of these clinical outcomes from 6 RCTs favored app interventions, but none were significant. In the 7 trials evaluating app usability, all were found to be acceptable. There was a great variation in the app characteristics. A total of 10 RCTs involved health care professionals, mainly physicians and nurses, in the app-based interventions. The apps had mixed functionality: 2 used education, 7 delivered reminders, and 7 provided reminders in combination with educational support.Conclusions: Apps tended to increase medication adherence, but interventions varied widely in design, content, and delivery. Apps have an acceptable degree of usability; yet the app characteristics conferring usability and effectiveness are ill-defined. Future large-scale studies should focus on identifying the essential active components of successful apps.Trial Registration: PROSPERO International Prospective Register of Systematic Reviews CRD42019121385; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=121385

Macrolide antibiotics are known to have a different proarrhythmic potential in the presence of comparable QT prolongation in the surface ECG. Because the extent of QT prolongation has been used as a surrogate marker for cardiotoxicity, we aimed to study the different electrophysiological effects of the macrolide antibiotics erythromycin, clarithromycin, and azithromycin in a previously developed experimental model of proarrhythmia. In 37 Langendorff-perfused rabbit hearts, erythromycin (150–300 μM, n = 13) clarithromycin (150–300 μM, n = 13), and azithromycin (150–300 μM, n = 11) led to similar increases in QT interval and monophasic action potential (MAP) duration. In bradycardic (atrioventricular-blocked) hearts, eight simultaneously recorded epi- and endocardial MAPs demonstrated increased dispersion of repolarization in the presence of all three antibiotics. Erythromycin and clarithromycin led to early afterdepolarizations (EADs) and torsade de pointes (TdP) after lowering of potassium concentration. In the presence of azithromycin, no EAD or TdP occurred. Erythromycin and clarithromycin changed the MAP configuration to a triangular pattern, whereas azithromycin caused a rectangular pattern of MAP prolongation. In 13 additional hearts, 150 μM azithromycin was administered after previous treatment with 300 μM erythromycin and suppressed TdP provoked by erythromycin. In conclusion, macrolide antibiotics lead to similar prolongation of repolarization but show a different proarrhythmic potential (erythromycin > clarithromycin > azithromycin). In the presence of azithromycin, neither EAD nor TdP occur. This effect may be related to a rectangular pattern of action potential prolongation, whereas erythromycin and clarithromycin cause triangular action potential prolongation and induce TdP.

Cardiac pacemaker cells create rhythmic pulses that control heart rate; pacemaker dysfunction is a prevalent disorder in the elderly, but little is known about the underlying molecular causes. Popeye domain containing (Popdc) genes encode membrane proteins with high expression levels in cardiac myocytes and specifically in the cardiac pacemaking and conduction system. Here, we report the phenotypic analysis of mice deficient in Popdc1 or Popdc2. ECG analysis revealed severe sinus node dysfunction when freely roaming mutant animals were subjected to physical or mental stress. In both mutants, bradyarrhythmia developed in an age-dependent manner. Furthermore, we found that the conserved Popeye domain functioned as a high-affinity cAMP-binding site. Popdc proteins interacted with the potassium channel TREK-1, which led to increased cell surface expression and enhanced current density, both of which were negatively modulated by cAMP. These data indicate that Popdc proteins have an important regulatory function in heart rate dynamics that is mediated, at least in part, through cAMP binding. Mice with mutant Popdc1 and Popdc2 alleles are therefore useful models for the dissection of the mechanisms causing pacemaker dysfunction and could aid in the development of strategies for therapeutic intervention.