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Background: Suboptimal device programming is among the reasons for reduced response to cardiac resynchronization therapy (CRT). However, whether systematic optimization is beneficial remains unclear, particularly late after CRT implantation. The aim of this single-center cohort study was to assess the effect of systematic atrioventricular delay (AVD) optimization on echocardiographic and device parameters. Methods: Patients undergoing CRT optimization at the University Hospital Zurich between March 2011 and January 2013, for whom a follow-up was available, were included. AVD optimization was based on 12-lead electrocardiography (ECG) and echocardiographic left ventricular inflow characteristics. Parameters were assessed at the time of CRT optimization and follow-up, and were compared between patients with AVD optimization (intervention group) and those for whom no AVD optimization was deemed necessary (control group). Results: Eighty-one patients with a mean age of 64 ± 11 years were included in the analysis. In 73% of patients, AVD was deemed suboptimal and was changed accordingly. After a median follow-up time of 10.4 (IQR 6.2 to 13.2) months, the proportion of patients with sufficient biventricular pacing (> 97% pacing) was greater in the intervention group (78%) compared to controls (50%). Furthermore, AVD adaptation was associated with an improvement in interventricular mechanical delay (decrease of 6.6 ± 26.2 ms vs. increase of 4.3 ± 17.7 ms, p = 0.034) and intraventricular septal-to-lateral delay (decrease of 0.9 ± 48.1 ms vs. increase of 15.9 ± 15.7 ms, p = 0.038), as assessed by tissue Doppler imaging. Accordingly, a reduction was observed in mitral regurgitation along with a trend towards reduced left ventricular volumes. Conclusions: In this “real-world” setting systematic AVD optimization was associated with beneficial effects regarding biventricular pacing and left ventricular remodeling. These data show that AVD optimization may be advantageous in selected CRT patients.

INTRODUCTION Sotalol and flecainide are used as second line agents in children for the treatment of supraventricular arrhythmias (SA) refractory to anti-beta adrenergic antiarrhythmics or digoxin. Efficacy and adverse events in this cohort have not been well described. Here, we report our institutional experience of second line treatment initiation for SA in children. METHODS AND RESULTS Utilizing an institutional database, 247 patients initiated on sotalol and 81 patients initiated on flecainide were identified. Congenital heart disease (CHD) was present in 40% of patients. Arrhythmia-free discharge on single or dual agent therapy (in combination with other antiarrhythmics) was 87% for sotalol and 91% for flecainide. Neither age, sex, dosing, presence of CHD nor arrhythmia subtype were associated with alterations in in-hospital efficacy. Compared to baseline, QTc intervals in sotalol patients (436 [416-452 ms] vs. 415 [400-431 ms], p

AIMS: Cardiac resynchronization therapy (CRT) has become an important therapy in patients with heart failure with reduced left ventricular ejection fraction (LVEF). The effect of diabetes on long-term outcome in these patients is controversial. We assessed the effect of diabetes on long-term outcome in CRT patients and investigated the role of diabetes in ischaemic and non-ischaemic cardiomyopathy. METHODS AND RESULTS: All patients undergoing CRT implantation at our institution between November 2000 and January 2015 were enrolled. The study endpoints were (i) a composite of ventricular assist device (VAD) implantation, heart transplantation, or all-cause mortality; and (ii) reverse remodelling (improvement of LVEF ≥ 10% or reduction of left ventricular end-systolic volume ≥ 15%). Median follow-up of the 418 patients (age 64.6 ± 11.6 years, 22.5% female, 25.1% diabetes) was 4.8 years [inter-quartile range: 2.8;7.4]. Diabetic patients had an increased risk to reach the composite endpoint [adjusted hazard ratio (aHR) 1.48 [95% CI 1.12-2.16], P = 0.041]. Other factors associated with an increased risk to reach the composite endpoint were a lower body mass index or baseline LVEF (aHR 0.95 [0.91; 0.98] and 0.97 [0.95; 0.99], P < 0.01 each), and a higher New York Heart Association functional class or creatinine level (aHR 2.14 [1.38; 3.30] and 1.04 [1.01; 1.05], P < 0.05 each). Early response to CRT, defined as LVEF improvement ≥ 10%, was associated with a lower risk to reach the composite endpoint (aHR 0.60 [0.40; 0.89], P = 0.011). Reverse remodelling did not differ between diabetic and non-diabetic patients with respect to LVEF improvement ≥ 10% (aHR 0.60 [0.32; 1.14], P = 0.118). However, diabetes was associated with decreased reverse remodelling with respect to a reduction of left ventricular end-systolic volume ≥ 15% (aHR 0.45 [0.21; 0.97], P = 0.043). In patients with ischaemic cardiomyopathy, survival rates were not significantly different between diabetic and non-diabetic patients (HR 1.28 [0.83-1.97], P = 0.101), whereas in patients with non-ischaemic cardiomyopathy, diabetic patients had a higher risk of reaching the composite endpoint (HR 1.65 [1.06-2.58], P = 0.027). The latter effect was dependent on other risk factors (aHR 1.47 [0.83-2.61], P = 0.451). The risk of insulin-dependent patients was not significantly higher than in patients under oral antidiabetic drugs (HR 1.55 [95% CI 0.92-2.61], P = 0.102). CONCLUSIONS: Long-term follow-up revealed diabetes mellitus as independent risk factor for all-cause mortality, heart transplantation, or VAD in heart failure patients undergoing CRT. The detrimental effect of diabetes appeared to weigh heavier in patients with non-ischaemic compared with ischaemic cardiomyopathy. ispartof: ESC HEART FAILURE vol:7 issue:5 pages:2773-2783 ispartof: location:England status: published

Background Cardiac-resynchronization therapy (CRT) reduces morbidity and mortality in selected symptomatic patients with reduced left ventricular ejection fraction (LVEF) and wide QRS complex. While many patients demonstrate a response to CRT within the first year of follow-up, sustained or late response to CRT is highly relevant but poorly characterized. Purpose To characterize the patient population that demonstrates improvements of LVEF late after CRT implantation, irrespective of the primary response, and to identify factors associated with beneficial long-term outcome. Methods All patients undergoing CRT implantation at our institution between Nov 2000 and Jan 2015 with at least two follow-up echocardiographic studies were included. Primary follow-up (FU1) was performed within one year after CRT implantation (median 6.1 months [IQR: 3.5–10.7]). The most recent echocardiography at a median follow-up time of 3.9 years [27.3–70.4] was considered as long-term follow-up (FU2). LVEF-based response to CRT was stratified into 4 categories: non-response (ΔLVEF +15%). Primary study endpoint was the composite of all-cause death, heart transplantation or implantation of a ventricular assist device. Results Out of 362 patients (median age 65.9 years, 23% female, 41% with ischemic cardiomyopathy), 99 (27.3%) demonstrated LVEF improvements beyond their primary response to CRT (blue bars in figure). At baseline, late responders demonstrated lower LVEF (23.4% [19.0–30.0] vs. 27.0 [22.0–32.0], p=0.005) and an increased prevalence of non-ischemic cardiomyopathy (67.8% vs. 55.9%, p=0.042) compared to the remaining patients. Reduction in LVEDV(I) at FU1 correlated positively with late response (ΔLVEDV −28.5 ml [−71.8; −3.25] vs. 18.0 [−46.0; 3.0], p=0.033). Importantly, late responders were seen amongst all types of primary response, including patients demonstrating a negative response with substantially worsened LVEF at first follow-up after CRT implantation. Finally, patients with late response demonstrated significantly better survival compared to patients with late progression of heart failure or continued non-progression (median survival 7.8 [7.1–8.5] vs. 7.0 [6.6–7.5] years, aHR 0.54 [0.33–0.88] p=0.013 on multivariate cox regression analysis). Conclusions A significant proportion of patients achieves LVEF improvements beyond the initial phase after CRT implantation indicating a substantial limitation in categorizing patients into “responders” and “non-responders” based on the initial response to CRT. Further prospective studies are required to validate these findings and optimize treatment strategies for CRT patients.

Background Cardiac-resynchronization therapy (CRT) reduces morbidity and mortality in selected symptomatic patients with reduced left ventricular ejection fraction (LVEF) and wide QRS complex. However, some patients fail to benefit from CRT. Data on the differential role of baseline and follow-up left ventricular ejection fraction (LVEF) on outcome in patients with ischemic compared to non-ischemic cardiomyopathy (ICM, N-ICM) is controversial. Purpose To test, whether ICM and N-ICM patients differ in outcome after CRT during long-term follow-up and whether predictors for survival after CRT differ between the two groups. Methods All patients undergoing CRT implantation at our institution between November 2000 and January 2015 were evaluated (n=418). All ICM/N-ICM patients with follow-up echocardiography within 1 year after CRT implantation (FU1) and a second echocardiography >1 year after FU1 (FU2) were included in the analysis (n=253). Primary post-hoc defined study endpoint was the composite of all-cause death, heart transplantation or implantation of a ventricular assist device. Results Compared to patients with N-ICM (n=160, median age 64 years [IQR 54–71], 71% male), ICM patients (n=93, median age 70 years [IQR 61–75], 84% male) were significantly older and had a higher prevalence of male gender, concomitant diabetes mellitus and arterial hypertension. There were no significant differences in pre-implantation echocardiographic features (LVEF, LVEDV, RV-FAC, severity of mitral regurgitation), QRS width and NT-proBNP levels between the groups. However, the hazard for reaching the primary endpoint was significantly higher in patients with ICM compared to N-ICM both on univariate analysis (HR 1.62 [95% CI 1.09–2.42], p=0.018) and after multivariate correction (aHR 2.13 [1.24–3.66], p=0.006). While higher NT-proBNP levels and greater right ventricular fractional area change were positively correlated with the hazard of death in both ICM and N-ICM (see Figure), lower LVEF at baseline was associated with an increased risk of death only in ICM but not in N-ICM (HR 0.95 [0.91–0.99], p=0.029 vs. HR 1.00 [0.96–1.04], p=0.945). Male gender, lower BMI and NYHA class ≥ III were positively correlated with the endpoint in N-ICM, but not in ICM. Importantly, LVEF at FU1 (median 4.7 months after implantation) and FU2 (median 47.1 months after implantation) were found to correlate signficantly with the endpoint in both ICM and N-ICM. Conclusion Our findings highlight important differences in ischemic and non-ischemic patient populations undergoing CRT. While overall survival of patients with N-ICM exceeds survival in ICM, several other factors (including LVEF) have differential effects on response to CRT in these two patient groups.

Zusammenfassung. Die konstriktive Perikarditis stellt als seltene und gefürchtete Komplikation einer akuten Perikarditis eine schwere und ungewöhnliche Form einer diastolischen Herzinsuffizienz dar bei primär erhaltener systolischer Pumpfunktion. Häufigste Ursache ist die virale/idiopathische Perikarditis, gefolgt von spezifischen Ursachen (postoperativ nach herzchirurgischer Operation, postaktinisch nach mediastinaler Radiotherapie und weitere Ursachen). Durch das steife, unelastische Perikard ist die diastolische Füllung des Herzens eingeschränkt, was zum klinischen Bild einer Rechtsherzinsuffizienz führt und sich mit erhöhten Füllungsdrücken und spezifischen respiratorischen Phänomenen in der klinischen und apparativ-technischen Untersuchung manifestiert (Kussmaul-Zeichen, Pulsus paradoxus, vermehrte interventrikuläre Interdependenz, Annulus reversus, Quadratwurzelzeichen). Differenzialdiagnostisch müssen die restriktive Kardiomyopathie, die schwere Trikuspidalinsuffizienz und die Perikardtamponade ausgeschlossen werden. Die Therapie der Wahl ist zumeist eine chirurgische Perikardektomie, in Einzelfällen kann auch eine spezifische Therapie oder eine medikamentös-antiinflammatorische Therapie erfolgen. Obwohl die konstriktive Perikarditis unbehandelt eine schlechte Prognose hat, ist die Erkrankung potenziell kurativ therapierbar. Die Prognose ist vor allem von der Ursache der konstriktiven Perikarditis abhängig.

Background: Colorectal cancer (CRC) is a common and potentially preventable malignancy. Evidence has emerged that coronary artery disease patients are at increased risk for developing CRC by shared risk factors. Here we investigated an association between CRC and atrial fibrillation (AF), a surrogate marker of cardiovascular risk, in the setting of routine screening colonoscopy. Methods: We investigated 1949 asymptomatic participants (median age 61 [54&ndash, 67] years, 49% females) undergoing screening colonoscopy within the SAKKOPI registry (Salzburg Colon Cancer Prevention Initiative). Forty-six participants with AF (2.4%) were identified, and colonoscopy findings were compared to non-AF participants. Propensity Score Matching (PSM) was used to create 1:1 and 3:1 age- and gender-matched couples. Results: Abnormal findings on screening colonoscopy (any form of adenoma or carcinoma) were more common in AF participants with an odds ratios (OR) of 2.4 [1.3&ndash, 4.3] in the unmatched analysis, and 2.6 [1.1&ndash, 6.3] and 2.0 [1.1&ndash, 4.0] in the 1:1 and 3:1 matched groups, respectively. Correspondingly, the odds of finding advanced adenomas or carcinomas was elevated about three-fold across the different matched and unmatched analyses (OR 3.3 [1.1&ndash, 10.8] for 3:1 matched participants). At the same time, the prevalence and number of colonic lesions were significantly higher in AF participants (63.0% vs. 33.4% for 3:1 matched participants, p &lt, 0.001). Non-CRC related findings on colonoscopy, like diverticulosis, were non-different between groups. Conclusion: Participants with AF had a higher burden of advanced premalignant adenomas and CRC in routine colonoscopy screening. Our data suggest that practitioners should monitor the CRC screening status, especially in AF patients.

Background Patients are commonly affected by ventricular dysfunction and heart failure after Fontan palliation. Reliable quantification of ventricular function is of interest but hampered by complex ventricular anatomy and physiology. Objectives We aimed to assess myocardial function using a novel cardiac magnetic resonance imaging (CMR)-based feature-tracking (FT) technique and to study its clinical utility in Fontan patients. Methods Retrospective study in consecutive patients attending our service. Results We included 15 adult Fontan patients (age 27 ± 7 years) who underwent a standardized transthoracic echocardiographic investigation (TTE) with measurement of global strain using speckle tracking. Thirteen patients also underwent CMR, with assessment of myocardial deformation by FT, providing longitudinal and circumferential global strain for the single ventricle. The value of TTE-based strain measurements was limited by the fact that in 63% of patients at least one myocardial segment could not be adequately quantified due to limited acoustic windows. In contrast, CMR allowed for a complete visualization of all wall segments. Not surprisingly, there was poor agreement between the techniques but good or moderate interobserver variability for FT (coefficients of variability 6.6% and 14.3% for circumferential and longitudinal strain). Unlike ejection fraction, FT parameters correlated significantly with age at Fontan completion, New York Heart Association (NYHA) class, and peak oxygen uptake on cardiopulmonary exercise testing. Conclusions Assessment of myocardial function using CMR cine-based feature tracking is feasible in Fontan patients. Unlike echocardiographic techniques, FT is independent of inadequate acoustic windows and FT measurements relate to clinical parameters, suggesting that this approach could have clinical relevance in future.

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.

Ovaj almanah sažima važne članke o prirođenim srčanim greškama objavljene od 2012. do 2014. godine u časopisu „Heart“ i ostalim većim kardiološkim časopisima. Navest ćemo članke koje smatramo veoma važnima u ovom području. Iako je svrha bila pružiti sveobuhvatan pregled područja, bilo je potrebno usredotočiti se na određene teme. Izbor je članaka dakle nužno subjektivan., This Almanac summarises important congenital heart disease articles published between 2012 and 2014 in Heart and other major cardiac journals. It highlights what the authors perceive to be highly relevant articles in the field. While the aim was to provide a comprehensive overview of the area, a focus on certain areas of interest was required. The selection is, therefore, by necessity a subjective one.

This study aims at documenting the changes in ventricular tissue velocities, longitudinal strain and electromechanical coupling during the first month of life. During the neonatal period, when the ventricular myocardium is not yet fully maturated, the heart is subjected to significant hemodynamic changes. We studied the ventricular performance of 16 healthy neonates at three time points over the first month of life: on days 2 (IQR [2;2]), 13 [12;14] and 27 [25;29]. We found that systolic and diastolic tissue velocities increased significantly in both left and right ventricle (by 1.2-1.7 times, p < 0.001). Congruently, we found that peak systolic longitudinal strain of the right and left ventricles increased significantly. However, no significant changes in longitudinal strain rate were observed. Finally, QS-intervals shortened during the neonatal period: being measured at 12 points throughout the left ventricle, time to peak systolic velocity decreased on average to 89 % in the second and to 80 % in the fourth week of life (22.3 ± 0.2 vs. 19.8 ± 0.3 vs. 17.8 ± 0.5 ms, r = -0.564, p < 0.001). When comparing opposing walls of the left ventricle, no dyssynchrony in left ventricular contraction was found. In addition to increasing systolic and diastolic tissue velocities during the first month of life, the time to peak systolic contraction shortens in the neonatal heart, which may reflect an increasing efficiency of the excitation-contraction coupling in the maturing myocardium. While there appears to be no dyssynchrony in ventricular contraction, these findings may extend our appreciation of the immature neonatal heart and certain disease states.

Background As a consequence of heterogeneous results of relatively small individual trials, the impact of congenital heart defects (CHD) and the effect of disease severity on patient reported outcome measures (PROs) of quality of life (QoL) remains uncertain. We aimed to systematically summarize QoL data in CHD patients using meta-analytic methods. Methods and results We performed a systematic review of the literature focusing on QoL in CHD. The search yielded 234 publications meeting the inclusion criteria, with a median of 88 patients per study (46% females, average age 24years). In total, QoL was reported using PROs in 47,471 CHD-patients. More than 95 different PROs were used to evaluate QoL. The most commonly used tool was the SF36 form (69 publications). Analysis of available quantitative QoL data from SF36 publications (n=4217 CHD patients) showed that QoL was reduced in patients with moderate or complex cardiac disease (e.g. relative physical functioning scores 0.96 [0.93–0.99] and 0.91 [0.88–0.95] compared with controls), while no such effect was evident in those patients with simple cardiac lesions. Similar results were found for the general health domain of the SF36 domain. Conclusions Despite the proliferation of QoL-studies in CHD no standardized approach for measuring and reporting QoL has emerged and the published results are heterogeneous. In aggregation, however, the results of this study suggest that QoL is impaired in moderate or complex CHD, while no such impact of CHD on QoL could be established — on average — in patients with simple defects.

Arrhythmogenic cardiomyopathy (AC) is a rare mostly hereditary disease, in which fibro-fatty tissue replaces cardiomyocytes. Typically, the first alterations of the disease can be encountered in the epicardium of the right ventricle in adolescent patients. From there, the disease usually progresses over time. Besides the development of heart failure, the clinical significance of the disease is determined by the predisposition to potentially lethal ventricular arrhythmias. Hence, a majority of patients with AC require an implantable cardioverter-defibrillator (ICD) to be protected from sudden cardiac death. A recently developed alternative to transvenous systems are subcutaneous ICDs (S-ICD), associated with a lower risk of device-related complications such as endocarditis since no foreign material is implanted within the heart and vascular system. In this report, we describe and discuss our experience with the implantation of a S-ICD in a patient with AC, who had low QRS voltage and persistent atrial fibrillation precluding successful S-ICD implantation, as well as the challenges encountered during subsequent transvenous lead implantation.

Background Cardiothoracic surgery can have adverse effects on the patients' psychosocial well-being which may influence the overall prognosis. In this study, we tested the use of a seven-item screening instrument for the preoperative identification of need for psychosocial assistance in cardiothoracic patients. Methods and Results A total of 297 consecutive patients (69% male) with a median age of 70 years (59;75) completed the seven-item Hornheide Screening Instrument (HSI) on the day of admission. According to questionnaire scores predefined in the literature (cutoff ≥ 4), 130 patients (44%) exhibited a need for psychosocial support. We found female patients to have significantly higher need for psychosocial support than male patients, irrespective of their age, New York Heart Association classification or Canadian Cardiovascular Society classification, and the type of surgery they were undergoing (53 vs. 41%, p = 0.034). In addition, we found that preoperative need for psychosocial support, using the predefined cutoff criterion as well as a higher absolute score, was associated with a prolonged length of hospitalization ( p Conclusion We found the HSI to be a suitable tool to identify psychosocial need in cardiothoracic patients. The relatively high incidence of these patients in our study concurs with previous studies, which generally used more complex instruments. In addition, we found that preoperative scores were associated with prolonged length of stay. Therefore, the use of this questionnaire could represent an alternative, more rapid tool for the psychosocial assessment of cardiothoracic patients in daily routine.

Background Double-chambered right ventricle (DCRV) is a rare form of congenital heart disease. Little is known about the outcome during adult life. Here we report the combined experience of two tertiary Adult Congenital Heart Disease Centres and systematically review the published literature. Results 50 patients (32 female, median age 39years [IQR: 27;53]) with DCRV under follow-up could be identified. A retrospective review of medical records was performed. Almost all patients (96%) had ventricular septal defects as underlying diagnosis. Eight patients remained completely asymptomatic during follow-up and have been managed conservatively thus far. The remaining patients developed symptoms at a median age of 26years. Surgical correction was performed in 33 patients (median age at operation 27years). No residual intraventricular gradient was present at the latest follow-up in 91% of operated patients and functional class improved significantly with only 6 patients remaining in NYHA class 2. There was no early or late operative mortality and no patient required re-operation for DCRV during a median follow-up of 8years. Conclusions Contemporary adult DCRV patients have good survival prospects and low long-term morbidity. Despite occasionally presenting with considerable intraventricular gradients we could not identify any case of sudden death in our unoperated adult sub-population. Although asymptomatic adults may be encountered even with severe obstruction, symptom development is common during adult life. Cardiac surgery in this cohort is inherently low risk and offers good long-term haemodynamic and functional results justifying early intervention in consideration of the progressive nature of this rare congenital lesion.

BackgroundNormal development of the atria requires left-right differentiation during embryonic development. Reduced expression of Pitx2c (paired-like homeodomain transcription factor 2, isoform c), a key regulator of left-right asymmetry, has recently been linked to atrial fibrillation. We therefore systematically studied the molecular composition of left and right atrial tissue in adult murine and human atria.MethodsWe compared left and right atrial gene expression in healthy, adult mice of different strains and ages by employing whole genome array analyses on freshly frozen atrial tissue. Selected genes with enriched expression in either atrium were validated by RT-qPCR and Western blot in further animals and in shock-frozen left and right atrial appendages of patients undergoing open heart surgery.ResultsWe identified 77 genes with preferential expression in one atrium that were common in all strains and age groups analysed. Independent of strain and age, Pitx2c was the gene with the highest enrichment in left atrium, while Bmp10, a member of the TGFβ family, showed highest enrichment in right atrium. These differences were validated by RT-qPCR in murine and human tissue. Western blot showed a 2-fold left-right concentration gradient in PITX2 protein in adult human atria. Several of the genes and gene groups enriched in left atria have a known biological role for maintenance of healthy physiology, specifically the prevention of atrial pathologies involved in atrial fibrillation, including membrane electrophysiology, metabolic cellular function, and regulation of inflammatory processes. Comparison of the array datasets with published array analyses in heterozygous Pitx2c(+/-) atria suggested that approximately half of the genes with left-sided enrichment are regulated by Pitx2c.ConclusionsOur study reveals systematic differences between left and right atrial gene expression and supports the hypothesis that Pitx2c has a functional role in maintaining "leftness" in the atrium in adult murine and human hearts.