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Background: Catheter ablation for ventricular tachycardia (VT) reduces the recurrence of VT in patients with implantable cardioverter-defibrillators (ICDs). The appropriate timing of VT ablation and its effects on mortality and heart failure progression remain a matter of debate. In patients with life-threatening arrhythmias necessitating ICD implantation, we compared outcomes of preventive VT ablation (undertaken before ICD implantation to prevent ICD shocks for VT) and deferred ablation after 3 ICD shocks for VT. Methods: The BERLIN VT study (Preventive Ablation of Ventricular Tachycardia in Patients With Myocardial Infarction) was a prospective, open, parallel, randomized trial performed at 26 centers. Patients with stable ischemic cardiomyopathy, a left ventricular ejection fraction between 30% and 50%, and documented VT were randomly assigned 1:1 to a preventive or deferred ablation strategy. The primary outcome was a composite of all-cause death and unplanned hospitalization for either symptomatic ventricular arrhythmia or worsening heart failure. Secondary outcomes included sustained ventricular tachyarrhythmia and appropriate ICD therapy. We hypothesized that preventive ablation strategy would be superior to deferred ablation strategy in the intention-to-treat population. Results: During a mean follow-up of 396±284 days, the primary end point occurred in 25 (32.9%) of 76 patients in the preventive ablation group and 23 (27.7%) of 83 patients in the deferred ablation group (hazard ratio, 1.09 [95% CI, 0.62–1.92]; P =0.77). On the basis of prespecified criteria for interim analyses, the study was terminated early for futility. In the preventive versus deferred ablation group, 6 versus 2 patients died (7.9% versus 2.4%; P =0.18), 8 versus 2 patients were admitted for worsening heart failure (10.4% versus 2.3%; P =0.062), and 15 versus 21 patients were hospitalized for symptomatic ventricular arrhythmia (19.5% versus 25.3%; P =0.27). Among secondary outcomes, the proportions of patients with sustained ventricular tachyarrhythmia (39.7% versus 48.2%; P =0.050) and appropriate ICD therapy (34.2% versus 47.0%; P =0.020) were numerically reduced in the preventive ablation group. Conclusions: Preventive VT ablation before ICD implantation did not reduce mortality or hospitalization for arrhythmia or worsening heart failure during 1 year of follow-up compared with the deferred ablation strategy. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02501005.

Background: Myocardial injury, defined by elevated troponin levels, is associated with adverse outcome in patients with coronavirus disease 2019 (COVID-19). The frequency of cardiac injury remains highly uncertain and confounded in current publications; myocarditis is one of several mechanisms that have been proposed. Methods: We prospectively assessed patients with myocardial injury hospitalized for COVID-19 using transthoracic echocardiography, cardiac magnetic resonance imaging, and endomyocardial biopsy. Results: Eighteen patients with COVID-19 and myocardial injury were included in this study. Echocardiography revealed normal to mildly reduced left ventricular ejection fraction of 52.5% (46.5%–60.5%) but moderately to severely reduced left ventricular global longitudinal strain of −11.2% (−7.6% to −15.1%). Cardiac magnetic resonance showed any myocardial tissue injury defined by elevated T1, extracellular volume, or late gadolinium enhancement with a nonischemic pattern in 16 patients (83.3%). Seven patients (38.9%) demonstrated myocardial edema in addition to tissue injury fulfilling the Lake-Louise criteria for myocarditis. Combining cardiac magnetic resonance with speckle tracking echocardiography demonstrated functional or morphological cardiac changes in 100% of investigated patients. Endomyocardial biopsy was conducted in 5 patients and revealed enhanced macrophage numbers in all 5 patients in addition to lymphocytic myocarditis in 1 patient. SARS-CoV-2 RNA was not detected in any biopsy by quantitative real-time polymerase chain reaction. Finally, follow-up measurements of left ventricular global longitudinal strain revealed significant improvement after a median of 52.0 days (−11.2% [−9.2% to −14.7%] versus −15.6% [−12.5% to −19.6%] at follow-up; P =0.041). Conclusions: In this small cohort of COVID-19 patients with elevated troponin levels, myocardial injury was evidenced by reduced echocardiographic left ventricular strain, myocarditis patterns on cardiac magnetic resonance, and enhanced macrophage numbers but not predominantly lymphocytic myocarditis in endomyocardial biopsies.

In this issue of Circulation Cardiovascular Genetics, Weng et al1 present an interesting study evaluating the heritability of atrial fibrillation (AF). See Article by Weng et al AF is the most common arrhythmia worldwide, and substantial efforts have been made to elucidate mechanisms underlying its onset and progression.2 Over the past years, a growing body of evidence demonstrated that AF is heritable. Besides rare genetic mutations with strong effects and a clear phenotype, such as gain- or loss-of-function mutations in ion channel genes,3–5 there are common genetic variants or single nucleotide polymorphisms that have been shown to be associated with AF although a causal mechanistic role has not been identified for most of the risk variants.6–11 Several studies tried to evaluate the degree of heritability by family-based or population-based studies, such as the Danish twin study that reported an AF heritability of 62% or the Framingham Heart Study that showed a 40% risk to develop AF if a first-degree relative is affected.12,13 Those numbers raised some concerns because studies performed in families might not adequately mirror the situation in the general population and might hence overestimate the true heritability. Also, it is in contrast to the experience from daily clinical practice where AF is predominantly seen in older patients with comorbidities, that is, in patients with several likely causes for AF, making a genetic cause of the disease less likely. It, therefore, remained unclear to which degree AF can be …

Background— Congestive heart failure (CHF) causes atrial fibrotic remodeling, a substrate for atrial fibrillation (AF) maintenance. MicroRNA29 (miR29) targets extracellular matrix proteins. In the present study, we examined miR29b changes in patients with AF and/or CHF and in a CHF-related AF animal model and assessed its potential role in controlling atrial fibrous tissue production. Methods and Results— Control dogs were compared with dogs subjected to ventricular tachypacing for 24 hours, 1 week, or 2 weeks to induce CHF. Atrial miR29b expression decreased within 24 hours in both whole atrial tissue and atrial fibroblasts (−87% and −92% versus control, respectively; p p p p p p p p p p p Conclusions— MiR29 likely plays a role in atrial fibrotic remodeling and may have value as a biomarker and/or therapeutic target.

Rationale: Autoantibodies directed against the second extracellular loop of the cardiac β1-adrenergic receptor (β1-AR) are thought to contribute to the pathogenesis of dilated cardiomyopathy (DCM) and Chagas heart disease. Various approaches have been used to detect such autoantibodies; however, the reported prevalence varies largely, depending on the detection method used. Objective: We analyzed sera from 167 DCM patients (ejection fraction Methods and Results: The novel assay was designed according to the currently most reliable anti-TSH receptor antibody-ELISA used to diagnose Graves disease (“third-generation assay”) and also detects the target antibodies by competition with a specific monoclonal anti–β1-AR antibody (β1-AR MAb) directed against the functionally relevant β1-AR epitope. Anti–β1-AR antibodies were detected in ≈60% of DCM patients and in ≈8% of healthy volunteers using the same cutoff values. The prevalence of these antibodies was 17% in patients with hypertensive heart disease. Anti–β1-AR antibody titers (defined as inhibition of β1-AR MAb-binding) were no longer detected after depleting sera from IgG antibodies by protein G adsorption. In contrast, a previously used ELISA conducted with a linear 26-meric peptide derived from the second extracellular β1-AR loop yielded a high number of false-positive results precluding any specific identification of DCM patients. Conclusions: We established a simple and efficient screening assay detecting disease-relevant β1-AR autoantibodies in patient sera yielding a high reproducibility also in high throughput screening. The assay was validated according to “good laboratory practice” and can serve as a companion biodiagnostic assay for the development and evaluation of antibody-directed therapies in antibody-positive heart failure.

Background— Recent evidence suggests a genetic component for sudden cardiac death (SCD) in subjects with coronary artery disease (CAD). We conducted a systematic candidate-gene approach using haplotype-tagging single nucleotide polymorphisms (htSNPs) to identify genes associated with SCD risk in the context of CAD. Methods and Results— We investigated 1424 htSNPs representing 18 genes with mutations described in patients with ventricular arrhythmias in 291 subjects from the Oregon Sudden Unexpected Death Study (Ore-SUDS). The Ore-SUDS is an ongoing prospective investigation of SCD in the Portland, OR, metropolitan area (population, 1 000 000). SCD cases were ascertained from multiple sources and medical records were reviewed to determine the presence of CAD. A total of 36 SNPs were associated with risk of SCD (uncorrected probability values P =0.04; rs3010396, P =0.007; rs7366407; P =0.04), NOS1AP (rs12084280, P =0.04; rs10918859, P =0.02), and 1 SNP located ≈26 kb upstream of GPD1L (rs9862154, P =0.04). Conclusions— Common variations in or near CASQ2, GPD1L , and NOS1AP are associated with increased risk of SCD in patients with CAD. These findings provide further evidence for overlap between the genetic architecture of rare and common forms of SCD, and replication in additional populations is warranted.

Atrial fibrillation (AF) was first described in humans approximately 100 years ago,1 and familial forms of AF were reported more than 70 years ago.2,3 Within the last 10 years, 3 critical developments have advanced our understanding of the genetic basis of AF. First, multiple epidemiological studies have demonstrated that AF is heritable. Second, rare mutations predisposing to AF have been identified in potassium and sodium channels, gap junction proteins, and signaling molecules. Finally, population-based, genome-wide association studies (GWAS) have implicated novel biological pathways responsible for AF. The molecular biology of established mutations underlying AF has been well summarized.4,5 In this report, we focus on the approaches used to identify AF susceptibility loci and describe the findings from recent GWAS of AF. We also address future directions in the field of AF genetics that may improve our understanding of AF pathophysiology, risk prediction, prevention, and patient treatment. We searched entries in PubMed from 1948 through April 1, 2010, with the key words “atrial fibrillation” and “genetic,” “genetics,” or “gene” published in English, yielding 833 references. We scanned the titles and abstracts of these references to select relevant articles for full-text review. We reviewed the reference lists of retrieved articles to identify any additional relevant articles for inclusion. Case reports and abstracts were excluded. Association-based studies reporting genetic associations with AF were included if associations between the same variants and AF were replicated in an independent sample. Thus, the list of references reflects an overview of existing literature relevant to AF genetics. Whereas individual cases of familial AF were recognized in the mid-20th century,2,3 a widespread heritable component underlying AF was reported only recently. In 2004, investigators from the Framingham Heart Study described …

Background— Atrial fibrillation (AF) is the most common adverse event following coronary artery bypass graft surgery. A recent study identified chromosome 4q25 variants associated with AF in ambulatory populations. However, their role in postoperative AF is unknown. We hypothesized that genetic variants in the 4q25 chromosomal region are independently associated with postoperative AF after coronary artery bypass graft surgery. Methods and Results— Two prospectively collected cohorts of patients undergoing coronary artery bypass graft surgery, with or without concurrent valve surgery, at 3 US centers. From a discovery cohort of 959 patients, clinical and genomic multivariate predictors of postoperative AF were identified by genotyping 45 single-nucleotide polymorphisms (SNPs) encompassing the 4q25 locus. Three SNPs were then assessed in a separately collected validation cohort of 494 patients. After adjustment for clinical predictors of postoperative AF and multiple comparisons, rs2200733, rs13143308, and 5 other linked SNPs independently predicted postoperative AF in the discovery cohort. Additive odds ratios for the 7 associated 4q25 SNPs ranged between 1.57 and 2.17 ( P =8.0�10 −4 to 3.4�10 −6 ). Association with postoperative AF were measured and replicated for rs2200733 and rs13143308 in the validation cohort. Conclusions— In 2 independently collected cardiac surgery cohorts, noncoding SNPs within the chromosome 4q25 region are independently associated with postoperative AF after coronary artery bypass graft surgery after adjusting for clinical covariates and multiple comparisons.

Background— Cardiac repolarization, the process by which cardiomyocytes return to their resting potential after each beat, is a highly regulated process that is critical for heart rhythm stability. Perturbations of cardiac repolarization increase the risk for life-threatening arrhythmias and sudden cardiac death. Although genetic studies of familial long-QT syndromes have uncovered several key genes in cardiac repolarization, the major heritable contribution to this trait remains unexplained. Identification of additional genes may lead to a better understanding of the underlying biology, aid in identification of patients at risk for sudden death, and potentially enable new treatments for susceptible individuals. Methods and Results— We extended and refined a zebrafish model of cardiac repolarization by using fluorescent reporters of transmembrane potential. We then conducted a drug-sensitized genetic screen in zebrafish, identifying 15 genes, including GINS3 , that affect cardiac repolarization. Testing these genes for human relevance in 2 concurrently completed genome-wide association studies revealed that the human GINS3 ortholog is located in the 16q21 locus, which is strongly associated with QT interval. Conclusions— This sensitized zebrafish screen identified 15 novel myocardial repolarization genes. Among these genes is GINS3 , the human ortholog of which is a major locus in 2 concurrent human genome-wide association studies of QT interval. These results reveal a novel network of genes that regulate cardiac repolarization.

Background— Spatial and timely variations in QT interval, even within its normal range, may underlie susceptibility to cardiac arrhythmias and sudden cardiac death. Given its important role in cardiac electrophysiology, we hypothesized that common genetic variation in ankyrin-B gene ( ANK2 ) might modify QT interval length. Methods and Results— The study population consisted of 1188 participants of the World Health Organizational Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (WHO MONICA) general population survey Cooperative Health Research in the Region of Augsburg (KORA S3). Corrected QT interval was calculated using population specific linear regression formulas. A total of 22 single-nucleotide polymorphisms in the genomic region of ANK2 gene were genotyped using TaqMan technology. In a replication study, 6 single nucleotide polymorphisms were genotyped in 3890 individuals from a second population study (KORA S4). The rare variant of the single-nucleotide polymorphism rs6850768 (allele frequency, 0.28) significantly influenced duration of the QT interval, both in KORA S3 and KORA S4 populations. In homozygotes, the shortening of the QT interval was 3.79 ms (95% CI, 1.48 to 5.58; P =0.001 and P =0.0008 for log-additive and dominant model, respectively) in KORA S3 and 2.94 ms (95% CI, 1.11 to 4.77; P =0.001 and P =0.006 for log-additive and dominant genetic model, respectively) in KORA S4. A common 2-locus haplotype (rs11098171-rs6850768; population frequency, 28%) was associated with a QT interval difference of 2.85 ms (permutation; P =0.006) in KORA S3 and 1.23 ms (permutation; P =0.009) in KORA S4. Reverse transcription–polymerase chain reaction expression analysis of the human ANK2 5′ genomic region in the human left ventricular tissue revealed 2 previously unidentified ANK2 5′ exons in the proximity of the identified variants. Conclusions— Common genetic variants juxtaposed with novel exons in the distant 5′ genomic region of ANK2 influence the QT interval length in the general population. These findings support the role of ankyrin-B in normal cardiac electric activity.

Background— Congestive heart failure (CHF) is a common cause of atrial fibrillation. Focal sources of unknown mechanism have been described in CHF-related atrial fibrillation. The authors hypothesized that abnormal calcium (Ca 2+ ) handling contributes to the CHF-related atrial arrhythmogenic substrate. Methods and Results— CHF was induced in dogs by ventricular tachypacing (240 bpm �2 weeks). Cellular Ca 2+ -handling properties and expression/phosphorylation status of key Ca 2+ handling and myofilament proteins were assessed in control and CHF atria. CHF decreased cell shortening but increased left atrial diastolic intracellular Ca 2+ concentration ([Ca 2+ ] i ), [Ca 2+ ] i transient amplitude, and sarcoplasmic reticulum (SR) Ca 2+ load (caffeine-induced [Ca 2+ ] i release). SR Ca 2+ overload was associated with spontaneous Ca 2+ transient events and triggered ectopic activity, which was suppressed by the inhibition of SR Ca 2+ release (ryanodine) or Na + /Ca 2+ exchange. Mechanisms underlying abnormal SR Ca 2+ handling were then studied. CHF increased atrial action potential duration and action potential voltage clamp showed that CHF-like action potentials enhance Ca 2+ i loading. CHF increased calmodulin-dependent protein kinase II phosphorylation of phospholamban by 120%, potentially enhancing SR Ca 2+ uptake by reducing phospholamban inhibition of SR Ca 2+ ATPase, but it did not affect phosphorylation of SR Ca 2+ -release channels (RyR2). Total RyR2 and calsequestrin (main SR Ca 2+ -binding protein) expression were significantly reduced, by 65% and 15%, potentially contributing to SR dysfunction. CHF decreased expression of total and protein kinase A–phosphorylated myosin-binding protein C (a key contractile filament regulator) by 27% and 74%, potentially accounting for decreased contractility despite increased Ca 2+ transients. Complex phosphorylation changes were explained by enhanced calmodulin-dependent protein kinase IIδ expression and function and type-1 protein-phosphatase activity but downregulated regulatory protein kinase A subunits. Conclusions— CHF causes profound changes in Ca 2+ -handling and -regulatory proteins that produce atrial fibrillation–promoting atrial cardiomyocyte Ca 2+ -handling abnormalities, arrhythmogenic triggered activity, and contractile dysfunction.

Atrial fibrillation is associated with increased expression of ventricular myosin isoforms in atrial myocardium, regarded as part of a dedifferentiation process. Whether reexpression of ventricular isoforms in atrial fibrillation is restricted to transcripts encoding for contractile proteins is unknown. Therefore, this study compares atrial mRNA expression in patients with permanent atrial fibrillation to atrial mRNA expression in patients with sinus rhythm and to ventricular gene expression using Affymetrix U133 arrays. In atrial myocardium, we identified 1434 genes deregulated in atrial fibrillation, the majority of which, including key elements of calcium-dependent signaling pathways, displayed downregulation. Functional classification based on Gene Ontology provided the specific gene sets of the interdependent processes of structural, contractile, and electrophysiological remodeling. In addition, we demonstrate for the first time a prominent upregulation of transcripts involved in metabolic activities, suggesting an adaptive response to increased metabolic demand in fibrillating atrial myocardium. Ventricular-predominant genes were 5 times more likely to be upregulated in atrial fibrillation (174 genes upregulated, 35 genes downregulated), whereas atrial-specific transcripts were predominantly downregulated (56 genes upregulated, 564 genes downregulated). Overall, in fibrillating atrial myocardium, functional classes of genes characteristic of ventricular myocardium were found to be upregulated (eg, metabolic processes), whereas functional classes predominantly expressed in atrial myocardium were downregulated (eg, signal transduction and cell communication). Therefore, dedifferentiation with adoption of a ventricular-like signature is a general feature of the fibrillating atrium.

Altered myocardial repolarization is one of the important substrates of ventricular tachycardia and fibrillation. The influence of rare gene variants on repolarization is evident in familial long QT syndrome. To investigate the influence of common gene variants on the QT interval we performed a linkage disequilibrium based SNP association study of four candidate genes. Using a two-step design we analyzed 174 SNPs from the KCNQ1, KCNH2, KCNE1, and KCNE2 genes in 689 individuals from the population-based KORA study and 14 SNPs with results suggestive of association in a confirmatory sample of 3277 individuals from the same survey. We detected association to a gene variant in intron 1 of the KCNQ1 gene (rs757092, +1.7 ms/allele, P =0.0002) and observed weaker association to a variant upstream of the KCNE1 gene (rs727957, +1.2 ms/allele, P =0.0051). In addition we detected association to two SNPs in the KCNH2 gene, the previously described K897T variant (rs1805123, −1.9 ms/allele, P =0.0006) and a gene variant that tags a different haplotype in the same block (rs3815459, +1.7 ms/allele, P =0.0004). The analysis of additive effects by an allelic score explained a 10.5 ms difference in corrected QT interval length between extreme score groups and 0.95% of trait variance ( P

In this issue of Circulation: Cardiovascular Genetics , Kirchhof et al1 present an interesting study on the expression of the developmental transcription factor Pitx2c in adult heart and its potential role in atrial fibrillation (AF). AF is the most common sustained cardiac arrhythmia, with a prevalence that increases with age and affects 1% to 2% of the general population.2 Despite recent advances in AF research, underlying pathophysiologic mechanisms are not fully understood. In general, initiation and perpetuation of AF needs a trigger for its onset and a vulnerable substrate for its maintenance.3 Focal ectopic activity can act as a trigger to initiate AF on the basis of a single- or multiple-circuit reentry.4 Especially, cardiomyocyte sleeves around the pulmonary veins have been shown as an origin of focal activity.5 Underlying mechanisms are early and delayed after depolarizations as a result of disturbances in depolarizing inward (Na+ or Ca2+) or repolarizing outward (K+) currents.6 Article see p 123 Once initiated, AF itself induces structural and electric remodeling, which stabilizes reentry and AF maintenance.6 Structural remodeling due to signaling through angiotensin, profibrotic cytokines like transforming growth factor-β, or microRNAs leads to upregulation of extracellular matrix proteins (eg, collagen) and downregulation of matrix-degrading enzymes (eg, matrix metalloproteinase), resulting in progressive atrial fibrosis. Electric remodeling is caused by expressional changes in ion channel subunits. AF induces calcium overload and increases activity of protein phosphatases, leading to downregulation of depolarizing L-type calcium channels and upregulation of repolarizing potassium channels. Measurable substrate of these changes in atrial electric properties is the shortening of action potential duration (APD), leading to shortening of refractory period and enabling reentry mechanisms. In most cases, therefore, AF is self-terminating (paroxysmal) in the beginning, developing to more sustained forms (persistent and permanent) over …

Abstract Membrane current abnormalities have been described in human heart failure. To determine whether similar current changes are observed in a large animal model of heart failure, we studied dogs with pacing-induced cardiomyopathy. Myocytes isolated from the midmyocardium of 13 dogs with heart failure induced by 3 to 4 weeks of rapid ventricular pacing and from 16 nonpaced control dogs did not differ in cell surface area or resting membrane potential. Nevertheless, action potential duration (APD) was significantly prolonged in myocytes isolated from failing ventricles (APD at 90% repolarization, 1097±73 milliseconds [failing hearts, n=30] versus 842±56 milliseconds [control hearts, n=25]; P 2+ current and whole-cell Na + current did not differ in cells from failing and from control hearts, but significant differences in K + currents were observed. The density of the inward rectifier K + current (I K1 ) was reduced in cells from failing hearts at test potentials below −90 mV (at −150 mV, −19.1±2.2 pA/pF [failing hearts, n=18] versus −32.2±5.1 pA/pF [control hearts, n=15]; P K1 was also reduced in cells from failing hearts (at −60 mV, 1.7±0.2 pA/pF [failing hearts] versus 2.5±0.2 pA/pF [control hearts]; P 2+ -independent transient outward current (I to ) was dramatically reduced in myocytes isolated from failing hearts compared with nonfailing control hearts (at +80 mV, 7.0±0.9 pA/pF [failing hearts, n=20] versus 20.4±3.2 pA/pF [control hearts, n=15]; P to kinetics or single-channel conductance. A reduction in the number of functional I to channels was demonstrated by nonstationary fluctuation analysis (0.4±0.03 channels per square micrometer [failing hearts, n=5] versus 1.2±0.1 channels per square micrometer [control hearts, n=3]; P to by 4-aminopyridine in control myocytes decreased the notch amplitude and prolonged the APD. Current clamp–release experiments in which current was injected for 8 milliseconds to reproduce the notch sufficed to shorten the APD significantly in cells from failing hearts. These data support the hypothesis that downregulation of I to in pacing-induced heart failure is at least partially responsible for the action potential prolongation. Because the repolarization abnormalities mimic those in cells isolated from failing human ventricular myocardium, canine pacing-induced cardiomyopathy may provide insights into the development of repolarization abnormalities and the mechanisms of sudden death in patients with heart failure.

Introduction: Heart failure (HF) frequently causes atrial fibrillation (AF) and focal sources of unknown mechanism have been implicated. Here, we studied the potential role and molecular mechanisms of Ca 2+ handling abnormalities. Methods: Ca 2+ handling (microfluorescence, Indo-1 AM) and related protein expression (Western blot) were assessed in left atria of 20 dogs with ventricular tachypacing (240 bpm × 2 wks)-induced HF and 20 controls (CTLs). Whole-cell perforated-patch was used to record action potentials (APs), delayed afterdepolarizations (DADs) and triggered activity. Results : HF increased [Ca 2+ ] i transient amplitude from 239±24 to 444±43* nM (*P2+ ] i release by 10 mM local caffeine puffs (an index of SR Ca 2+ content) from 849±71 (CTL) to 1574±169* nM (HF). Spontaneous Ca 2+ release events increased from 1.8±0.5 (CTL) to 10.7±2.1* events/run (HF). HF significantly increased APD (by ~40% at 1 Hz). DADs and triggered activity were more common in HF (15.2±2.6 triggered APs/run, vs CTL 0.4±0.2*), and were abolished by ryanodine (10 μM), but not by the I f -blocker Cs + (2 mM). HF caused profound changes in protein expression of key Ca 2+ handling and regulatory proteins (Table ). Calsequestrin, the major SR Ca 2+ -binding protein, was reduced by 32%*. Fractional RYR2 PKA (Ser2809) phosphorylation decreased by 63%*, whereas CaMKII (Ser2815) RYR2 phosphorylation increased by 221%*. The catalytic and regulatory (RII) PKA subunits were downregulated by 15%* and 73%*, whereas expression and autophosphorylation (Thr287) of CaMKIIδ were increased by 45%* and 81%* respectively. NCX1, SERCA and total, PKA and CaMKII phosphorylated SERCA-regulatory phospholamban were unchanged by HF. Conclusions: HF causes profound changes in regulation and expression of atrial Ca 2+ handling proteins, producing increased SR Ca 2+ load and release, along with DADs and triggered activity that may account for focal mechanisms that initiate and/or sustain HF-related AF.

See related article, pages 1384–1393 In this issue Tellez et al1 give a detailed analysis of differentially expressed genes regulating excitation and conduction in the sinoatrial node (SAN) in rabbit. Quantitative PCR and in situ hybridization, as well as action potential recordings, enabled the investigators to assign specific patterns to central and peripheral regions of SAN, and to compare these with the corresponding properteis of atrial tissue. Cluster analysis revealed that the SAN transcript profile is significantly different from that of atrial muscle. More importantly, there are apparent isoform switches on moving from atrial muscle to the SAN center: RYR2 to RYR3, Nav1.5 to Nav1.1, Cav1.2 to Cav1.3 and Kv1.4 to Kv4.2. In this context the transcript profile of the SAN periphery represents an intermediate pattern between that of central SAN and atrial muscle. Differential expression of a variety of genes has been demonstrated in anatomically distinct regions of the heart, for example atrial …

See related article, pages 386–393 Reduction in density of the cardiac calcium-independent transient outward potassium current ( I to1) is one of the most consistent findings in electrophysiological remodeling observed in animal models of left ventricular hypertrophy and failure as well as in the human heart under pathological conditions.1 Initially attributed to downregulation of the mRNA of pore-forming Kv4 subunits,2 a more complex picture emerged over time as several auxiliary subunits were identified, offering new potential regulatory elements for controlling I to1 density. KChIP2 is a dazzling member of this group of beta-subunits which assembles with pore-forming Kv4 subunits in 4:4 complexes to produce native I to1 channels.3 Several different KChIP2 splice variants are expressed in the human heart and the major KChIP2 isoform (KChIP2c) has been found to boost I to1 current density and to speed up recovery from inactivation, thereby recapitulating several, albeit not all, features of native I to1 channels.4 Importantly, myocytes isolated from KChIP2 knock-out mice exhibited a complete, selective loss of I to1, whereas an ≈50% reduction was observed in cardiomyocytes from heterozygous animals, indicating that KChIP2 can quantitatively regulate I to1.5 In line with this finding, KChIP2 mRNA typically distributes across the myocardial wall in a fashion paralleling the gradient of the transient outward current with fast recovery from inactivation encoded by Kv4 channels, with largest concentrations in subepicardium (EPI) and smallest in subendocardium (ENDO) in human and canine hearts.6 This suggests that KChIP2 is the limiting factor in cell surface expression of I to1 channels, rather than the pore-forming Kv4 subunits which are expressed at equal levels …