Faculty Bibliography

Hemodynamic shear force has been implicated as modulating Notch signaling-mediated cardiac trabeculation. Whether the spatiotemporal variations in wall shear stress (WSS) coordinate the initiation of trabeculation to influence ventricular contractile function remains unknown. Using light-sheet fluorescent microscopy, we reconstructed the 4D moving domain and applied computational fluid dynamics to quantify 4D WSS along the trabecular ridges and in the groves. In WT zebrafish, pulsatile shear stress developed along the trabecular ridges, with prominent endocardial Notch activity at 3 days after fertilization (dpf), and oscillatory shear stress developed in the trabecular grooves, with epicardial Notch activity at 4 dpf. Genetic manipulations were performed to reduce hematopoiesis and inhibit atrial contraction to lower WSS in synchrony with attenuation of oscillatory shear index (OSI) during ventricular development. γ-Secretase inhibitor of Notch intracellular domain (NICD) abrogated endocardial and epicardial Notch activity. Rescue with NICD mRNA restored Notch activity sequentially from the endocardium to trabecular grooves, which was corroborated by observed Notch-mediated cardiomyocyte proliferations on WT zebrafish trabeculae. We also demonstrated in vitro that a high OSI value correlated with upregulated endothelial Notch-related mRNA expression. In silico computation of energy dissipation further supports the role of trabeculation to preserve ventricular structure and contractile function. Thus, spatiotemporal variations in WSS coordinate trabecular organization for ventricular contractile function.

OBJECTIVE:Systemic to pulmonary arterial collateral flow (CollF) is common in single ventricle patients with superior cavopulmonary connections (SCPC), although associations with CollF are not well understood. We previously described a method to quantify CollF by cardiac MRI (CMR). We sought to identify factors associated with CollF in a large cross section of patients with SCPC. METHODS:A retrospective observational cohort study of events from birth to study CMR was performed for all patients with SCPC who had CollF quantified by CMR. RESULTS:CollF was quantified in 96 patients at a median age of 2.6 (IQR 1.9-3.1) years and 2.1 (1.4-2.7) years after SCPC and measured 1.6±0.7 L/min/m(2) (33±11% of aortic flow and 48±16% of pulmonary venous flow). Significantly higher amounts of indices of CollF were associated with: duration of chest tubes (p≤0.05 for all), intensive care unit and hospital length of stay (p≤0.04 for all), higher O2 saturation at Stage 2 discharge (p=0.04 for CollF/aortic), female sex (p≤0.007 for CollF/aortic and CollF/pulmonary venous), and history of a Blalock-Taussig shunt (p<0.04 for CollF and CollF/aortic). Multivariable models were constructed to identify factors independently associated with CollF measures and included: female sex (p≤0.006 for all), O2 saturation at Stage 2 discharge (p=0.013 for CollF/aortic) and total chest tube days (p=0.001 for all). These models explained 20-22% of the variance in the outcomes. CONCLUSIONS:These data support hypotheses that perioperative morbidity and pleural inflammation play a role in CollF development and that CollF affects pulmonary blood flow.

BACKGROUND:Systemic-pulmonary collateral (SPC) flow occurs commonly in single ventricle patients after superior cavo-pulmonary connection, with unclear clinical significance. We sought to evaluate the association between SPC flow and acute post-Fontan clinical outcomes using a novel method of quantifying SPC flow by cardiac magnetic resonance (CMR) imaging. METHODS AND RESULTS/RESULTS:All patients who had SPC flow quantified by CMR imaging before Fontan were retrospectively reviewed to assess for acute clinical outcomes after Fontan completion. Forty-four subjects were included who had Fontan completion between May 2008 and September 2010. SPC flow prior to Fontan measured 1.5±0.9 L/min/m(2), accounting for 31±11% of total aortic flow and 44±15% of total pulmonary venous flow. There was a significant linear association between natural log-transformed duration of hospitalization and SPC flow as a proportion of total aortic (rho=0.31, P=0.04) and total pulmonary venous flow (rho=0.29, P=0.05). After adjustment for Fontan type and presence of a fenestration, absolute SPC flow was significantly associated with hospital duration ≥7 days (odds ratio [OR]=9.2, P=0.02) and chest tube duration ≥10 days (OR=22.7, P=0.009). Similar associations exist for SPC flow as a percentage of total aortic (OR=1.09, P=0.048 for hospitalization ≥7 days; OR=1.24, P=0.007 for chest tube duration ≥10 days) and total pulmonary venous flow (OR=1.07, P=0.048 for hospitalization ≥7 days; OR=1.18, P=0.006 for chest tube duration ≥10 days). CONCLUSIONS:Increasing SPC flow before Fontan, as measured by CMR imaging, is associated with increased duration of hospitalization and chest tube following Fontan completion.