Total anomalous pulmonary venous connection (TAPVC) is a potentially lethal congenital disorder that occurs when the pulmonary veins do not connect normally to the left atrium, allowing mixing of pulmonary and systemic blood1. In contrast to the extensive knowledge of arterial vascular patterning, little is known about the patterning of veins. Here we show that the secreted guidance molecule semaphorin 3d (Sema3d) is crucial for the normal patterning of pulmonary veins. Prevailing models suggest that TAPVC occurs when the midpharyngeal endothelial strand (MES), the precursor of the common pulmonary vein, does not form at the proper location on the dorsal surface of the embryonic common atrium2,3. However, we found that TAPVC occurs in Sema3d mutant mice despite normal formation of the MES. In these embryos, the maturing pulmonary venous plexus does not anastomose uniquely with the properly formed MES. In the absence of Sema3d, endothelial tubes form in a region that is normally avascular, resulting in aberrant connections. Normally, Sema3d provides a repulsive cue to endothelial cells in this area, establishing a boundary. Sequencing of SEMA3D in individuals with anomalous pulmonary veins identified a phenylalanine-to-leucine substitution that adversely affects SEMA3D function. These results identify Sema3d as a crucial pulmonary venous patterning cue and provide experimental evidence for an alternate developmental model to explain abnormal pulmonary venous connections.

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Background: Challenges to cardiac PET-CT include patient motion, prolonged image acquisition and a reduction of counts due to gating. We compared two analytical tools, FusionQuant and OsiriX, for quantification of gated cardiac 18F-sodium fluoride (18F-fluoride) PET-CT imaging. Methods: Twenty-seven patients with aortic stenosis were included, 15 of whom underwent repeated imaging 4 weeks apart. Agreement between analytical tools and scan-rescan reproducibility were determined using the Bland-Altman method and Lin's concordance correlation coefficients (CCC). Results: Image analysis was faster with FusionQuant (median time [IQR] 7:10 [6:40-8:20] minutes) compared with OsiriX (8:30 [8:00-10:10] minutes, p=0.002). Agreement of uptake measurements between programs was excellent, CCC=0.972 (95% CI 0.949-0.995) for mean tissue-to-background ratio (TBR mean) and 0.981 (95% CI 0.965-0.997) for maximum tissue-tobackground ratio (TBR max). Mean noise decreased from 11.7% in the diastolic gate to 6.7% in motion-corrected images (p=0.002); SNR increased from 25.41 to 41.13 (p=0.0001). Aortic valve scan-rescan reproducibility for TBR max was improved with FusionQuant using motion correction compared to OsiriX (error ±36% vs. ±13%, p<0.001) while reproducibility for TBR mean was similar (±10% vs. ±8% p=0.252).

Background: Mitral annular calcification (MAC) is associated with cardiovascular events and mitral valve dysfunction. However, the underlying pathophysiology remains incompletely understood. In this prospective longitudinal study, we used a multimodality approach including positron emission tomography, computed tomography, and echocardiography to investigate the pathophysiology of MAC and assess factors associated with disease activity and progression. Methods: A total of 104 patients (age 72±8 years, 30% women) with calcific aortic valve disease, therefore predisposed to MAC, underwent 18 F-sodium fluoride (calcification activity) and 18 F-Fluorodeoxyglucose (inflammation activity) positron emission tomography, computed tomography calcium scoring, and echocardiography. Sixty patients underwent repeat computed tomography and echocardiography after 2 years. Results: MAC (mitral annular calcium score >0) was present in 35 (33.7%) patients who had increased 18 F-fluoride (tissue-to-background ratio, 2.32 [95% CI, 1.81–3.27] versus 1.30 [1.22–1.49]; P <0.001) and 18 F-Fluorodeoxyglucose activity (tissue-to-background ratio, 1.44 [1.37–1.58] versus 1.17 [1.12–1.24]; P <0.001) compared with patients without MAC. MAC activity ( 18 F-fluoride uptake) was closely associated with the local calcium score and 18 F-Fluorodeoxyglucose uptake, as well as female sex and renal function. Similarly, MAC progression was closely associated with local factors, in particular, baseline MAC. Traditional cardiovascular risk factors and calcification activity in bone or remote atherosclerotic areas were not associated with disease activity nor progression. Conclusions: MAC is characterized by increased local calcification activity and inflammation. Baseline MAC burden was associated with disease activity and the rate of subsequent progression. This suggests a self-perpetuating cycle of calcification and inflammation that may be the target of future therapeutic interventions.

Background: Epicardium-derived cells undergo EMT and differentiate into smooth muscle of the developing coronary vasculature. The role of Dicer in this process is unknown. Results: Dicer mutants displayed impaired epicardial EMT, reduced epicardial cell proliferation, and differentiation into coronary smooth muscle cells. Conclusion: Dicer is essential for epicardium development. Significance: This represents the first evidence for the involvement of Dicer, and by implication miRNAs, in epicardial development.

In late postmenopausal women, lower OC and CTX levels were associated with similarly increased risks of insulin resistance at baseline and incident diabetes over long-term follow-up. Further research to delineate the mechanisms linking abnormal bone homeostasis and energy metabolism could uncover new approaches for the prevention of these age-related disorders.

ObjectivesNon-contrast CT aortic valve calcium scoring ignores the contribution of valvular fibrosis in aortic stenosis. We assessed aortic valve calcific and non-calcific disease using contrast-enhanced CT.MethodsThis was a post hoc analysis of 164 patients (median age 71 (IQR 66–77) years, 78% male) with aortic stenosis (41 mild, 89 moderate, 34 severe; 7% bicuspid) who underwent echocardiography and contrast-enhanced CT as part of imaging studies. Calcific and non-calcific (fibrosis) valve tissue volumes were quantified and indexed to annulus area, using Hounsfield unit thresholds calibrated against blood pool radiodensity. The fibrocalcific ratio assessed the relative contributions of valve fibrosis and calcification. The fibrocalcific volume (sum of indexed non-calcific and calcific volumes) was compared with aortic valve peak velocity and, in a subgroup, histology and valve weight.ResultsContrast-enhanced CT calcium volumes correlated with CT calcium score (r=0.80, p<0.001) and peak aortic jet velocity (r=0.55, p<0.001). The fibrocalcific ratio decreased with increasing aortic stenosis severity (mild: 1.29 (0.98–2.38), moderate: 0.87 (1.48–1.72), severe: 0.47 (0.33–0.78), p<0.001) while the fibrocalcific volume increased (mild: 109 (75–150), moderate: 191 (117–253), severe: 274 (213–344) mm3/cm2). Fibrocalcific volume correlated with ex vivo valve weight (r=0.72, p<0.001). Compared with the Agatston score, fibrocalcific volume demonstrated a better correlation with peak aortic jet velocity (r=0.59 and r=0.67, respectively), particularly in females (r=0.38 and r=0.72, respectively).ConclusionsContrast-enhanced CT assessment of aortic valve calcific and non-calcific volumes correlates with aortic stenosis severity and may be preferable to non-contrast CT when fibrosis is a significant contributor to valve obstruction.