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In heart failure (HF), Ca 2+ /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 Ca 2+ 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, CaMKIIdependent regulation of Na + channel function may contribute to arrhythmogenesis in HF.

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.

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 Pitx2c ϩ/Ϫ hearts were susceptible to AF during programmed stimulation. At short paced cycle lengths, atrial action potential durations were shorter in Pitx2c ϩ/Ϫ than in wild-type. Perfusion with the ␤-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 ϩ/Ϫ hearts, suggesting that action potential duration shortening caused wave length reduction and inducibility of AF. Expression array analyses comparing Pitx2c ϩ/Ϫ 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. (Circ Cardiovasc Genet. 2011;4:123-133.)Key Words: action potentials Ⅲ atrium Ⅲ fibrillation Ⅲ genes Ⅲ transgenic mice Ⅲ genetic predisposition A trial fibrillation (AF) is by far the most common sustained arrhythmia and causes important morbidity and mortality. 1,2 Unfortunately, the causes of the arrhythmia are not sufficiently understood to allow effective therapy to prevent AF. 3,4 Both rare and common forms of AF can be heritable, and the genes responsible may provide important clues toward therapy. Familial forms of AF associate with mutations in genes encoding sodium and potassium ion channels, connexin40, the natriuretic peptide precursor A (NPPA) but also transcription factor genes, either in candidate or genome-wide association studies. 3,[5][6][7][8] Editorial see p 105 Clinical Perspective on p 133A polymorphic locus on chromosome 4q25 (SNP rs2200733) associates with AF, particularly of early onset, in several independent studies of European and Asian populations 9,10 and conveys an approximately 1.7-fold risk of developing AF. 11 This locus is intergenic, with the gene in closest proximity being PITX2, which encodes a homeobox transcription factor of the paired type. Mutations of PITX2 are responsible for autosomal dominant anterior eye defects, including the Axenfeld-Rieger syndrome, 12 albeit without reports of AF in affected patients.During embryonic development in ...

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 ϩ/Ϫ ) had increased right ventricular volume, reduced right ventricular function, and spontaneous ventricular ectopy (all PϽ0.05). Left ventricular size and function were not altered. Isolated, perfused plakoglobin ϩ/Ϫ 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 ϩ/Ϫ 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.

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 M, n ϭ 13) clarithromycin (150 -300 M, n ϭ 13), and azithromycin (150 -300 M, n ϭ 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 M azithromycin was administered after previous treatment with 300 M erythromycin and suppressed TdP provoked by erythromycin. In conclusion, macrolide antibiotics lead to similar prolongation of repolarization but show a different proarrhythmic potential (erythromycin Ͼ clarithromycin Ͼ 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.

Background-Potassium currents contribute to action potential duration (APD) and arrhythmogenesis. In heart failure, Ca/calmodulin-dependent protein kinase II (CaMKII) is upregulated and can alter ion channel regulation and expression. Methods and Results-We examine the influence of overexpressing cytoplasmic CaMKII␦ C , both acutely in rabbit ventricular myocytes (24-hour adenoviral gene transfer) and chronically in CaMKII␦ C -transgenic mice, on transient outward potassium current (I to ), and inward rectifying current (I K1 ). Acute and chronic CaMKII overexpression increases I to,slow amplitude and expression of the underlying channel protein K V 1.4. Chronic but not acute CaMKII overexpression causes downregulation of I to,fast , as well as K V 4.2 and KChIP2, suggesting that K V 1.4 expression responds faster and oppositely to K V 4.2 on CaMKII activation. These amplitude changes were not reversed by CaMKII inhibition, consistent with CaMKII-dependent regulation of channel expression and/or trafficking. CaMKII (acute and chronic) greatly accelerated recovery from inactivation for both I to components, but these effects were acutely reversed by AIP (CaMKII inhibitor), suggesting that CaMKII activity directly accelerates I to recovery. Expression levels of I K1 and Kir2.1 mRNA were downregulated by CaMKII overexpression. CaMKII acutely increased I K1 , based on inhibition by AIP (in both models). CaMKII overexpression in mouse prolonged APD (consistent with reduced I to,fast and I K1 ), whereas CaMKII overexpression in rabbit shortened APD (consistent with enhanced I K1 and I to,slow and faster I to recovery). Computational models allowed discrimination of contributions of different channel effects on APD. Key Words: action potentials Ⅲ potassium Ⅲ arrhythmia Ⅲ electrophysiology Ⅲ heart failure H eart failure (HF) is accompanied by arrhythmogenic changes related to electric remodeling. This is associated with prolongation of action potential duration (APD) 1 and downregulation of transient outward K-current (I to ) and inward rectifying K-current (I K1 ). I K1 is responsible for stabilizing the diastolic membrane potential (E m ), such that decreased I K1 increases the propensity for triggered arrhythmias. 2 I to is important in early repolarization and influences the effects of other currents and transporters by affecting AP voltage-time trajectory. There are at least 2 components of I to generated by different K-channel isoforms, which can be distinguished according to their recovery and inactivation kinetics. 3,4 The fast component (I to,fast ) recovers and inactivates with time constants () of Ͻ100 ms, whereas the slow component (I to,slow ) recovers with of hundreds of milliseconds up to several seconds and inactivates with of Ϸ200 ms. 3-5 Downregulation of I to has been described in animal models of hypertrophy and human HF, 2,6,7 is associated with APD prolongation, 8 and predisposes to early afterdepolarizations. Conclusion-CaMKII Clinical Perspective on p 294In HF, expression and activity of Ca/cal...

Atrial natriuretic peptide (ANP), via its vasodilating and diuretic effects, has an important physiological role in the maintenance of arterial blood pressure and volume. Its guanylyl cyclase-A (GC-A) receptor is highly expressed in vascular endothelium, but the functional relevance of this is controversial. To dissect the endothelium-mediated actions of ANP in vivo, we inactivated the GC-A gene selectively in endothelial cells by homologous loxP/Tie2-Cre-mediated recombination. Notably, despite full preservation of the direct vasodilating effects of ANP, mice with endothelium-restricted deletion of the GC-A gene (EC GC-A KO) exhibited significant arterial hypertension and cardiac hypertrophy. Echocardiographic and Doppler flow evaluations together with the Evan's blue dilution technique showed that the total plasma volume of EC GC-A KO mice was increased by 11-13%, even under conditions of normal dietary salt intake. Infusion of ANP caused immediate increases in hematocrit in control but not in EC GC-A KO mice, which indicated that ablation of endothelial GC-A completely prevented the acute contraction of intravascular volume produced by ANP. Furthermore, intravenous ANP acutely enhanced the rate of clearance of radio-iodinated albumin from the circulatory system in control but not in EC GC-A KO mice. We conclude that GC-A-mediated increases in endothelial permeability are critically involved in the hypovolemic, hypotensive actions of ANP.