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The cardiac conduction system is a network of heterogeneous cell population that initiates and propagates electric excitations in the myocardium. Purkinje fibers, a network of specialized myocardial cells, comprise the distal end of the conduction system in the ventricles. The developmental origins of Purkinje fibers and their roles during cardiac physiology and arrhythmia have been reported. However, it is not clear if they play a role during ischemic injury and heart regeneration. Here we introduce a novel tamoxifen-inducible Cre allele that specifically labels a broad range of components in the cardiac conduction system while excludes other cardiac cell types and vital organs. Using this new allele, we investigated the cellular and molecular response of Purkinje fibers to myocardial injury. In a neonatal mouse myocardial infarction model, we observed significant increase in Purkinje cell number in regenerating myocardium. RNA-Seq analysis using laser-captured Purkinje fibers showed a unique transcriptomic response to myocardial infarction. Our finds suggest a novel role of cardiac Purkinje fibers in heart injury.

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.

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.

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.

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.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.Retrospective study in consecutive patients attending our service.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.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.

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.