Telemedical cardiac risk assessment by implantable cardiac monitors in patients after myocardial infarction with autonomic dysfunction (SMART-MI-DZHK9): a prospective investigator-initiated, randomised, multicentre, open-label, diagnostic trial.

BACKGROUND: Cardiac autonomic dysfunction after myocardial infarction identifies patients at high risk despite only moderately reduced left ventricular ejection fraction. We aimed to show that telemedical monitoring with implantable cardiac monitors in these patients can improve early detection of subclinical but prognostically relevant arrhythmic events. METHODS: We did a prospective investigator-initiated, randomised, multicentre, open-label, diagnostic trial at 33 centres in Germany and Austria. Survivors of acute myocardial infarction with left ventricular ejection fraction of 36-50% had biosignal analysis for assessment of cardiac autonomic function. Patients with abnormal periodic repolarisation dynamics (≥5·75 deg2) or abnormal deceleration capacity (≤2·5 ms) were randomly assigned (1:1) to telemedical monitoring with implantable cardiac monitors or conventional follow-up. Primary endpoint was time to detection of serious arrhythmic events defined by atrial fibrillation 6 min or longer, atrioventricular block class IIb or higher and fast non-sustained (>187 beats per min; ≥40 beats) or sustained ventricular tachycardia or fibrillation. This study is registered with ClinicalTrials.gov, NCT02594488. FINDINGS: Between May 12, 2016, and July 20, 2020, 1305 individuals were screened and 400 patients at high risk were randomly assigned (median age 64 years [IQR 57-73]); left ventricular ejection fraction 45% [40-48]) to telemedical monitoring with implantable cardiac monitors (implantable cardiac monitor group; n=201) or conventional follow-up (control group; n=199). During median follow-up of 21 months, serious arrhythmic events were detected in 60 (30%) patients of the implantable cardiac monitor group and 12 (6%) patients of the control group (hazard ratio 6·33 [IQR 3·40-11·78]; p<0·001). An improved detection rate by implantable cardiac monitors was observed for all types of serious arrhythmic events: atrial fibrillation 6 min or longer (47 [23%] patients vs 11 [6%] patients; p<0·001), atrioventricular block class IIb or higher (14 [7%] vs 0; p<0·001) and ventricular tachycardia or ventricular fibrillation (nine [4%] patients vs two [1%] patients; p=0·054). INTERPRETATION: In patients at high risk after myocardial infarction and cardiac autonomic dysfunction but only moderately reduced left ventricular ejection fraction, telemedical monitoring with implantable cardiac monitors was highly effective in early detection of subclinical, prognostically relevant serious arrhythmic events. FUNDING: German Centre for Cardiovascular Research (DZHK) and Medtronic Bakken Research Center.

App-Based Tracking of Self-Reported COVID-19 Symptoms: Analysis of Questionnaire Data.

BACKGROUND: COVID-19 is an infectious disease characterized by various clinical presentations. Knowledge of possible symptoms and their distribution allows for the early identification of infected patients. OBJECTIVE: To determine the distribution pattern of COVID-19 symptoms as well as possible unreported symptoms, we created an app-based self-reporting tool. METHODS: The COVID-19 Symptom Tracker is an app-based daily self-reporting tool. Between April 8 and May 15, 2020, a total of 22,327 individuals installed this app on their mobile device. An initial questionnaire asked for demographic information (age, gender, postal code) and past medical history comprising relevant chronic diseases. The participants were reminded daily to report whether they were experiencing any symptoms and if they had been tested for SARS-CoV-2 infection. Participants who sought health care services were asked additional questions regarding diagnostics and treatment. Participation was open to all adults (≥18 years). The study was completely anonymous. RESULTS: In total, 11,829 (52.98%) participants completed the symptom questionnaire at least once. Of these, 291 (2.46%) participants stated that they had undergone an RT-PCR (reverse transcription-polymerase chain reaction) test for SARS-CoV-2; 65 (0.55%) reported a positive test result and 226 (1.91%) a negative one. The mean number of reported symptoms among untested participants was 0.81 (SD 1.85). Participants with a positive test result had, on average, 5.63 symptoms (SD 2.82). The most significant risk factors were diabetes (odds ratio [OR] 8.95, 95% CI 3.30-22.37) and chronic heart disease (OR 2.85, 95% CI 1.43-5.69). We identified chills, fever, loss of smell, nausea and vomiting, and shortness of breath as the top five strongest predictors for a COVID-19 infection. The odds ratio for loss of smell was 3.13 (95% CI 1.76-5.58). Nausea and vomiting (OR 2.84, 95% CI 1.61-5.00) had been reported as an uncommon symptom previously; however, our data suggest a significant predictive value. CONCLUSIONS: Self-reported symptom tracking helps to identify novel symptoms of COVID-19 and to estimate the predictive value of certain symptoms. This aids in the development of reliable screening tools. Clinical screening with a high pretest probability allows for the rapid identification of infections and the cost-effective use of testing resources. Based on our results, we suggest that loss of smell and taste be considered cardinal symptoms; we also stress that diabetes is a risk factor for a highly symptomatic course of COVID-19 infection.

Mutations in the mitochondrial thioredoxin reductase gene TXNRD2 cause dilated cardiomyopathy.

AIMS: Cardiac energy requirement is met to a large extent by oxidative phosphorylation in mitochondria that are highly abundant in cardiac myocytes. Human mitochondrial thioredoxin reductase (TXNRD2) is a selenocysteine-containing enzyme essential for mitochondrial oxygen radical scavenging. Cardiac-specific deletion of Txnrd2 in mice results in dilated cardiomyopathy (DCM). The aim of this study was to investigate whether TXNRD2 mutations explain a fraction of monogenic DCM cases. METHODS AND RESULTS: Sequencing and subsequent genotyping of TXNRD2 in patients diagnosed with DCM (n = 227) and in DCM-free (n = 683) individuals from the general population sample KORA S4 was performed. The functional impact of observed mutations on Txnrd2 function was tested in mouse fibroblasts. We identified two novel amino acid residue-altering TXNRD2 mutations [175G > A (Ala59Thr) and 1124G > A (Gly375Arg)] in three heterozygous carriers among 227 patients that were not observed in the 683 DCM-free individuals. Both DCM-associated mutations result in amino acid substitutions of highly conserved residues in helices contributing to the flavin-adenine dinucleotide (FAD)-binding domain of TXNRD2. Functional analysis of both mutations in Txnrd2(-/-) mouse fibroblasts revealed that contrasting to wild-type (wt) Txnrd2, neither mutant did restore Txnrd2 function. Mutants even impaired the survival of Txnrd2 wt cells under oxidative stress by a dominant-negative mechanism. CONCLUSION: For the first time, we describe mutations in DCM patients in a gene involved in the regulation of cellular redox state. TXNRD2 mutations may explain a fraction of human DCM disease burden.

Ivabradine in patients with inappropriate sinus tachycardia.

Inappropriate sinus tachycardia (IST) is characterized by paroxysmal tachycardia originating in the sinus nodal area. IST predominately affects young, female patients. Current antiarrhythmic drug treatment (ß-blockers, calcium antagonists), frequently complicated by side effects, is often not successful. Ivabradine, approved for angina pectoris, selectively reduces heart rate by blocking the "funny current" in the sinus node. We therefore evaluated the effect of ivabradine in patients with symptomatic IST. Ten female patients (median age 32.5 years, range 12-57) suffering from symptomatic IST who had either failed (n = 8) or refused (n = 2) conventional therapy were analyzed. Symptoms included palpitations, pre-syncope, syncope, dyspnea, and exercise intolerance. After obtaining informed consent for individual off-label therapy, patients were treated with ivabradine (5-7.5 mg bid) in addition to beta-blocker therapy (n = 3) or as mono- therapy (n = 7). Therapy was monitored by 72-h Holter ECG and a symptoms questionnaire. Ivabradine significantly reduced maximum and mean heart rate (baseline, maximal heart rate 176 ± 45/min, mean heart rate 84 ± 11/min; ivabradine, maximal heart rate 137 ± 36/min, mean HR 74 ± 8/min, both p < 0.05, all values as mean ± SD). Minimum heart rate was not significantly changed. Three patients reported transient phosphene-like phenomena without discontinuation of ivabradine while on therapy. IST-associated symptoms were ameliorated (3 pts) or suppressed (5 pts) in all eight patients who could be contacted after a mean follow-up of 16 ± 9 months. Ivabradine appears effective and safe in patients with symptomatic inappropriate sinus tachycardia.

Usefulness of short-term variability of QT intervals as a predictor for electrical remodeling and proarrhythmia in patients with nonischemic heart failure.

The high incidence of sudden cardiac death in heart failure (HF) reflects electrophysiologic changes in response to myocardial failure. We previously showed that short-term variability of QT intervals (STV(QT)) identifies latent repolarization disorders in patients with drug-induced or congenital long QT syndrome. This study sought to determine (1) if STV(QT) is increased in patients with dilated cardiomyopathy (DC) and moderate congestive HF and (2) if increased STV(QT) is associated with ventricular arrhythmia in patients with HF. Sixty patients (53 +/- 12 years of age, 14 women) with DC and moderate HF (New York Heart Association classes II to III) were compared to matched controls. Twenty patients had implantable cardiac defibrillators secondary to a history of ventricular tachycardia (VT). Two cardiologists blinded to diagnosis manually measured QT intervals. Beat-to-beat variability of repolarization was determined from Poincaré plots of 30 consecutive QT intervals as was STV(QT). QTc intervals were comparable in patients and controls (419 +/- 36 vs 415 +/- 32 ms, respectively, p >0.05), whereas STV(QT) was significantly higher in patients with HF (7.8 +/- 3 vs 4.1 +/- 2 ms, respectively, p <0.05). STV(QT) was more increased in patients with a history of VT compared to those without VT (10.1 +/- 2 vs 6.6 +/- 2 ms, respectively, p <0.05). Increased STV(QT) and decreased ejection fraction were associated with a history of VT; however, STV(QT) was the strongest indicator. In conclusion, the present study demonstrates for the first time that STV(QT) is increased in patients with DC with HF. Patients with DC and HF and implantable cardiac defibrillators for secondary prevention had the highest STV(QT). Thus, increased STV(QT) in the context of moderate HF may reflect a latent repolarization disorder and increased susceptibility to sudden death in patients with DC, which is not identified by a prolonged QT interval.

Adult presentation of combined unilateral atresia of the right proximal pulmonary artery and left patent ductus arteriosus: case report and embryological considerations.

We report on a rare case of combined unilateral atresia of the proximal right pulmonary artery (PA) and left patent ductus arteriosus (PDA). A 46 year-old female patient with known PDA and associated advanced pulmonary arterial hypertension presented with progressive hemoptysis and increasing exertional dyspnea. Computed tomography of the chest proved the presence of the known PDA but surprisingly failed to demonstrate an extrapulmonary proximal right PA. We show the imaging features and discuss the embryological background of this rare congenital cardiovascular malformation.

Relation of increased short-term variability of QT interval to congenital long-QT syndrome.

Apart from clinical symptoms the diagnosis and risk stratification in long-QT syndrome (LQTS) is usually based on the surface electrocardiogram. Studies have indicated that not only prolongation of the QT interval but also an increased short-term variability of QT interval (STV(QT)) is a marker for a decreased repolarization reserve in patients with drug-induced LQTS. The aims of this study were to determine if STV(QT) (1) is higher in patients with LQTS compared with controls, (2) if this effect is more pronounced in a high-risk LQTS population, and (3) could increase the diagnostic power of the surface electrocardiogram in identifying mutation carriers. Forty mutation carriers were compared with age- and gender-matched control subjects in the absence of beta-receptor-blocking agents. Lead II or V(5) RR and QT intervals from 30 consecutive beats were manually measured. STV(QT) was determined from Poincaré plots of QT intervals (STV(QT) = Sigma|QTn + 1 - QTn|/[30 x radical2]). Compared with controls, patients with LQTS had a prolonged QTc interval (449 +/- 41 vs 411 +/- 32 ms, p = 0.00049) and increased STV(QT) (6.4 +/- 3.2 vs 4.1 +/- 1.6 ms, p = 0.005). In patients with the highest risk of clinical events, defined as a QTc interval >500 ms or symptoms before beta-blocker therapy, STV(QT) was 9 +/- 4 ms. QTc interval had a sensitivity of 43% and a specificity of 97% in identifying mutation carriers (thresholds 450 ms for men and 460 ms for women). Receiver operator characteristic analysis showed that an STV(QT) of 4.9 ms was the optimal cut-off value to predict mutation carriers. When incorporating an STV(QT) >4.9 ms for those whose QTc interval was within the normal limits, sensitivity to distinguish mutation carriers increased to 83% with a specificity of 68%, so that another 15 mutation carriers could be identified. In conclusion, these are the first results in humans showing that STV(QT) is increased in congenital LQTS, this effect is increased in patients with symptoms before therapy, and, hence, STV(QT) could prove to be a useful noninvasive additive marker for diagnostic screening to bridge the gap before results of genetic testing are available.

Baseline values and sotalol-induced changes of ventricular repolarization duration, heterogeneity, and instability in patients with a history of drug-induced torsades de pointes.

The authors investigated whether computerized parameters quantifying ventricular repolarization delay, heterogeneity, and instability characterize individuals who developed drug-induced Torsades de Pointes. Assessing an individual's propensity to Torsades de Pointes when exposed to a QT-prolonging drug is challenging because baseline QT prolongation has limited predictive value. Five-minute digital 12-lead electrocardiograms were acquired at baseline and after a sotalol challenge in 16 patients who had a history of Torsades de Pointes in the context of a QT-prolonging drug and 17 patients who did not have such history. Computerized measurements of QTc, T peak to T end intervals (TpTe), TpTe/QTc, and QT variability were implemented, and novel quantifiers of ventricular repolarization heterogeneity from the early (ERD) and late (LRD) part of the T wave were investigated. Compared with electrocardiograms of patients without a history of Torsades de Pointes, the baseline electrocardiograms of patients with a history of Torsades de Pointes had a longer QTc and an increased repolarization heterogeneity of the early part of the T wave (ERD30%: 44 +/- 13 vs 35 +/- 8 ms, P = .02). On sotalol, the electrocardiograms from individuals with Torsades de Pointes revealed a delay of the terminal part of the T wave that was not present in patients without Torsades de Pointes (TpTe: 27 +/- 40 vs -2 +/- 21 ms, P = .02; LRD70%: 20 +/- 29 vs 2 +/- 4 ms, P = .04). Results suggest that the electrocardiogram abnormalities characterizing patients with a history of Torsades de Pointes are (1) an increased repolarization heterogeneity at baseline and (2) a sotalol-induced prolongation of the terminal part of the T wave.

Atrial Arrhythmias in long-QT syndrome under daily life conditions: a nested case control study.

BACKGROUND: The long-QT syndromes (LQTS) are inherited electrical cardiomyopathies characterized by prolonged ventricular repolarization and ventricular arrhythmias. Several genetic reports have associated defects in LQTS-causing genes with atrial fibrillation (AF). We therefore studied whether atrial arrhythmias occur in patients with LQTS under daily-life conditions. METHODS: We systematically assessed atrial arrhythmias in LQTS patients and matched controls using implanted defibrillators or pacemakers as monitors of atrial rhythm in a nested case-control study. Twenty-one LQTS patients (3 male; 39 +/- 18 years old; 18 on beta blocker, ICD therapy duration 6.3 +/- 2.7 years; 4 LQT1, 6 LQT2, 2 LQT3) were matched to 21 control subjects (13 male; 50 +/- 19 years old; 3 on beta blocker; pacemaker therapy duration 8.5 +/- 5.5 years; 19 higher-degree AV block, 2 others). LQTS patients were identified by a systematic search of the LQTS patient databases in Münster and Munich. RESULTS: One-third (7 of 21) of the LQTS patients developed self-terminating atrial arrhythmias (atrial cycle lengths <250 ms). Only one control patient developed a single episode of postoperative AF (P < 0.05 vs LQTS). CONCLUSIONS: LQTS patients at high risk for ventricular arrhythmias may develop short-lasting atrial arrhythmias under daily-life conditions, suggesting that prolonged atrial repolarization may contribute to the initiation of AF.

Patch closure of muscular ventricular septal defects with a new hybrid therapy in a pig model.

OBJECTIVES: We evaluated a novel technique for hybrid patch closure of muscular ventricular septal defects (mVSDs) without cardiopulmonary bypass (CPB) in a pig model. BACKGROUND: So far, surgical and interventional therapies for mVSDs have been associated with significant morbidity, especially in newborns and infants. Thus, it is essential to develop new techniques. Hybrid therapy is an innovative approach for mVSDs that combines the advantages of surgical and interventional techniques. METHODS: Six pigs underwent left anterolateral thoracotomy to expose the left ventricle (LV). The mVSDs were created under echocardiographic guidance with a 7.5-mm sharp punch instrument that was forwarded via an LV incision. A special designed patch system composed of a patch with a Nitinol frame was passed across the carotid artery into the LV and positioned in front of the mVSD. An instrument resembling a stapler was introduced across the LV wall on the beating heart without use of CPB. The patch was fixed with Nitinol anchors on the septum under echocardiographic and fluoroscopic guidance. Finally, the Nitinol frame was detached from the patch. RESULTS: The locations of the defects were apical (n = 1), midmuscular (n = 3), and anterior muscular (n = 2). Closure of the mVSD was successful in 5 of 6 animals confirmed by echocardiography, hemodynamic measurements, and explantation of the heart. Animals were hemodynamically stable throughout the experiment. CONCLUSIONS: Here, we present a novel technique for hybrid closure of mVSDs without use of CPB. Further development of the patch system is necessary to assess applicability in humans, especially for the target group of newborns and infants.

The non-synonymous coding IKr-channel variant KCNH2-K897T is associated with atrial fibrillation: results from a systematic candidate gene-based analysis of KCNH2 (HERG).

AIMS: Atrial fibrillation (AF) is the most frequent arrhythmia in humans. Rare familial forms exist. Recent evidence indicates a genetic susceptibility to common forms of AF. The alpha-subunit of the myocardial I(Kr)-channel, encoded by the KCNH2 gene, is crucial to ventricular and atrial repolarization. Patients with mutations in KCNH2 present with higher incidence of AF. Common variants in KCNH2 have been shown to modify ventricular repolarization. We intended to investigate, whether such variants may also modulate atrial repolarization and predispose to AF. METHODS AND RESULTS: In a two-stage association study we analysed 1207 AF-cases and 2475 controls. In stage I 40 tagSNPs (single nucleotide polymorphisms) from the KCNH2 genomic region were genotyped in 671 AF-cases and 694 controls. Of five associated variants, the common K897-allele of the KCNH2-K897T variant was replicated in n = 536 independent AF cases and n = 1781 controls in stage II [overall odds ratio 1.25, 95% confidence interval 1.11-1.41, P = 0.00033]. This association remained significant after adjustment for gender and age. CONCLUSION: We report a genetic association finding including positive replication between the K897-allele and higher incidence of AF. This provides a molecular correlate for complex genetic predispositions to AF. The consequences of the K897T variant at the atrial level will require further functional investigations.

Beat-to-beat variability of QT intervals is increased in patients with drug-induced long-QT syndrome: a case control pilot study.

AIMS: Torsades de pointes arrhythmias (TdP) occur by definition in the setting of prolonged QT intervals. Animal models of drug induced Long-QT syndrome (dLQTS) have shown higher predictive value for proarrhythmia with beat-to-beat variability of repolarization duration (BVR) when compared with QT intervals. Here, we evaluate variability of QT intervals in patients with a history of drug-induced long QT syndrome (dLQTS) and TdP in absence of a mutation in any of the major LQTS genes. METHODS AND RESULTS: Twenty patients with documented TdP under drugs with QT-prolonging potential were compared with 20 matched control individuals. An observer blinded to diagnosis manually measured lead-II, RR, and QT intervals from 30 consecutive beats. BVR was determined from Poincaré plots of QT intervals as short-term variability (STV(QT) = Sigma|QT(n)(+1) - QT(n)|/[30 x radical2]). QRS interval and cycle length was comparable between study groups and controls. No difference was found in QTc between dLQTS and controls (428 +/- 25 vs. 421 +/- 34 ms, P = 0.26), whereas STV(QT) was significantly higher in dLQTS when compared with controls (8.1 +/- 3.7 vs. 3.6 +/- 1.3 ms, P = 0.001). Proarrhythmic predictive power of STV(QT) was superior to that of the QTc interval (AUC: 0.89 vs. 0.57, 95% CI: 0.79-0.99 vs. 0.39-0.75). CONCLUSION: In the absence of QTc prolongation, baseline STV(QT) characterized patients with documented drug-induced proarrhythmia. STV(QT) could prove to be a useful non-invasive, easily obtainable parameter aiding the identification of the patient at risk for potentially life threatening arrhythmia in the context of drugs with QT prolonging potential.

Analyses of dynamic beat-to-beat QT-TQ interval (ECG restitution) changes in humans under normal sinus rhythm and prior to an event of torsades de pointes during QT prolongation caused by sotalol.

BACKGROUND: Restitution through intracardiac pacing has been used to assess arrhythmia vulnerability. We examined whether analyses of sequential beat-to-beat QT and TQ interval measures can be used to quantify ECG restitution changes under normal sinus rhythm. METHODS: The QT, R-R and TQ intervals were examined 22.5 hour Holter monitoring before and after oral sotalol in normal male and female volunteers. Additionally, comparisons were made to those observed in the time-matched dataset prior to torsades de pointes in a heart diseased patient that received a single dose of sotalol. RESULTS: Sotalol increased QT, R-R and TQ intervals 71, 101, and 125 ms after 160 mg (n = 38) and 194, 235, and 135 ms after 320 mg (n = 19) during maximum plasma concentrations, respectively. The percentage of beats with a QT/TQ ratio >1 was reduced 25% over the entire 22.5 hours after sotalol and the lower TQ interval boundary (5th quantile) was increased 22-30%. In contrast, 99% of the beats prior to torsades de pointes had a QT/TQ ratio > 1 and the median TQ interval was below the lower 98% confidence bounds of normals before and after sotalol. CONCLUSIONS: ECG restitution changes are quantifiable under varying states (nocturnally, beta-adrenergic blockade, QT prolongation) in healthy subjects.

Diagnostic criteria for congenital long QT syndrome in the era of molecular genetics: do we need a scoring system?

AIMS: Previously published diagnostic systems, based on ECG analysis and clinical parameters (Schwartz criteria and Keating criteria), have been used to estimate the probability of inherited long QT syndrome (LQTS). Nowadays, a certain diagnosis can often be made by DNA testing. We aimed to establish the predictive power of the Schwartz and Keating criteria, using DNA testing as a reference, and to determine the best diagnostic strategy. METHODS AND RESULTS: We studied 513 relatives (aged >10 years) of 77 consecutive LQTS probands with a known disease-causing mutation. The Schwartz criteria identified 'high probability of LQTS' (score >or=4) in 41 of 208 mutation carriers, yielding 19% sensitivity and 99% specificity. The Keating criteria had 36% sensitivity and 99% specificity. Alternatively, by analysing QTc duration alone, we found that 430 ms is the optimal cut-off value to distinguish carriers (>or=430 ms) from non-carriers (<430 ms), yielding 72% sensitivity and 86% specificity (area under the curve 0.788). CONCLUSION: The existing clinical criteria have good specificity in identifying mutation carriers. However, their sensitivity is too low for clinical use. Analysis of QTc duration alone is more useful to screen for LQTS carriership (QTc >or= 430 ms) as its sensitivity is far superior, although its specificity remains acceptable. In genotyped families, genetic testing is the preferred diagnostic test.

Torsades de Pointes: a rare complication of an extra-adrenal pheochromocytoma.

Pheochromocytoma is an infrequent secondary cause of arterial hypertension, often associated with paroxysmal headache, sweating, weight loss, and palpitations. Cardiovascular complications of pheochromocytoma include sudden death, heart failure due to toxic cardiomyopathy, and hypertensive encephalopathy. Here we report the case of a female with an acquired long-QT-syndrome as a rare complication of an extra-adrenal pheochromocytoma. Diagnosis was made after sotalol-induced Torsades de Pointes.

Reprogramming of the human atrial transcriptome in permanent atrial fibrillation: expression of a ventricular-like genomic signature.

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.