Rationale: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA... Show moreRationale: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored. Objective: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA. Methods and Results: We conducted a genome-wide association study in an international set of 1,237 patients with D-TGA and identified a genome-wide significant susceptibility locus on chromosome 3p14.3, which was subsequently replicated in an independent case-control set (rs56219800, meta-analysis P=8.6x10(-10), OR=0.69 per C allele). SNP-based heritability analysis showed that 25% of variance in susceptibility to D-TGA may be explained by common variants. A genome-wide polygenic risk score derived from the discovery set was significantly associated to D-TGA in the replication set (P=4x10(-5)). The genome-wide significant locus (3p14.3) co-localizes with a putative regulatory element that interacts with the promoter of WNT5A, which encodes the Wnt Family Member 5A protein known for its role in cardiac development in mice. We show that this element drives reporter gene activity in the developing heart of mice and zebrafish and is bound by the developmental transcription factor TBX20. We further demonstrate that TBX20 attenuates Wnt5a expression levels in the developing mouse heart. Conclusions: This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 near WNT5A. Genomic and functional data support a causal role of WNT5A at the locus. Show less
Background-The role, interplay, and relative importance of the multifactorial hemodynamic and myocardial mechanisms causing dysfunction of the Fontan circulation remain incompletely understood.... Show moreBackground-The role, interplay, and relative importance of the multifactorial hemodynamic and myocardial mechanisms causing dysfunction of the Fontan circulation remain incompletely understood. Methods and Results-Using an MRI catheterization technique, we performed a differential analysis of pulmonary vascular resistance and aortopulmonary collateral blood flow in conjunction with global ventricular pump function, myocontractility (end-systolic pressure-volume relation), and diastolic compliance (end-diastolic pressure-volume relation) in 10 patients with a Fontan circulation at rest and during dobutamine stress. Pulmonary and ventricular pressures were measured invasively and synchronized with velocity-encoded MRI-derived pulmonary and aortic blood flows and cine MRI-derived ventricular volumes. Pulmonary vascular resistance and end-systolic and end-diastolic pressure-volume relations were then determined. Aortopulmonary collateral flow was calculated as the difference between aortic and pulmonary flow. Compared to rest, dobutamine caused a small increase in mean pulmonary pressures (P < 0.05). Collateral flow was significantly augmented (P < 0.001) and contributed importantly to an increase in pulmonary flow (P < 0.01). Pulmonary vascular resistance decreased significantly (P < 0.01). Dobutamine did not increase stroke volumes significantly despite slightly enhanced contractility (end-systolic pressure-volume relation). Active early relaxation (tau) was inconspicuous, but the end-diastolic pressure-volume relation shifted upward, indicating reduced compliance. Conclusions-In patients with a Fontan circulation, aortopulmonary collateral flow contributes substantially to enhanced pulmonary flow during stress. Our data indicate that pulmonary vascular response to augmented cardiac output was adequate, but decreased diastolic compliance was identified as an important component of ventricular dysfunction. (Circ Cardiovasc Imaging. 2010;3:623-631.) Show less
Riesenkampff, E.; Mengelkamp, L.; Mueller, M.; Kropf, S.; Abdul-Khaliq, H.; Sarikouch, S.; ... ; Kuehne, T. 2010
Riesenkampff E, Mengelkamp L, Mueller M, Kropf S, Abdul-Khaliq H, Sarikouch S, Beerbaum P, Hetzer R, Steendijk P, Berger F, Kuehne T. Integrated analysis of atrioventricular interactions in... Show moreRiesenkampff E, Mengelkamp L, Mueller M, Kropf S, Abdul-Khaliq H, Sarikouch S, Beerbaum P, Hetzer R, Steendijk P, Berger F, Kuehne T. Integrated analysis of atrioventricular interactions in tetralogy of Fallot. Am J Physiol Heart Circ Physiol 299: H364-H371, 2010. First published May 21, 2010; doi:10.1152/ajpheart.00264.2010.-The atria play an important role in cardiac performance. We evaluated their function and the atrioventricular interaction in operated patients with tetralogy of Fallot (TOF). Twenty patients who had undergone surgical repair of TOF and seven controls were investigated. Patients had residual pulmonary but no major tricuspid valve insufficiency. Atrial and ventricular strain rates were obtained by echocardiographic speckle tracking. Cine MRI-derived volumetric analysis provided atrial and ventricular time volume and time volume change curves yielding emptying and filling parameters. In addition, at the atrial level, reservoir, conduit and pump function, and cyclic volume change were calculated. At the atrioventricular valve level, tricuspid and mitral annular plane systolic excursion (TAPSE and MAPSE, respectively) were measured by two-dimensional echocardiography. In the patients compared with controls, right ventricular end-diastolic volumes were increased and biventricular ejection fraction was decreased (all P < 0.05). Biventricular measures of early diastolic ventricular filling were at control levels, but in late diastole, right ventricular filling parameters and strain rates were decreased (P < 0.001). The maximal right atrial size was slightly but not significantly diminished, but cyclic volume change was significantly reduced (P < 0.0001). Pump and reservoir function were decreased (P < 0.05), and conduit function was elevated (P < 0.001). The left atrium showed reduced reservoir function and cyclic volume change (P < 0.05). TAPSE and MAPSE were also decreased (P < 0.05). There were statistically significant interdependencies between RV ejection fraction, TAPSE, and right atrial filling and emptying parameters (all P < 0.05). In TOF patients, moderate systolic and diastolic right ventricular dysfunction is associated with clearly impaired right atrial function. The left atrium is affected to a lesser extent. Show less
