A theoretical framework for retrospective T2∗ correction to the arterial input function in quantitative myocardial perfusion MRI.

PURPOSE: To develop and evaluate a flexible, Bloch-equation based framework for retrospective T2∗ correction to the arterial input function (AIF) obtained with quantitative cardiac perfusion pulse sequences. METHODS: Our framework initially calculates the gadolinium concentration [Gd] based on T1 measurements alone. Next, T2∗ is estimated from this initial calculation of [Gd] while assuming fast water exchange and using the literature native T2 and static magnetic field variation (ΔB0 ) values. Finally, the [Gd] is recalculated after performing T2∗ correction to the Bloch equation signal model. Using this approach, we performed T2∗ correction to historical phantom and in vivo, dual-imaging perfusion data sets from 3 different patient groups obtained using different pulse sequences and imaging parameters. Images were processed to quantify both the AIF and resting myocardial blood flow (MBF). We also performed a sensitivity analysis of our T2∗ correction to ±20% variations in native T2 and ΔB0 . RESULTS: Compared with the ground truth [Gd] of phantom, the normalized root-means-square-error (NRMSE) in measured [Gd] was 5.1%, 1.3%, and 0.6% for uncorrected, our corrected, and Kellman's corrected, respectively. For in vivo data, both the peak AIF (7.0 ± 3.0 mM vs. 8.6 ± 7.1 mM, 7.2 ± 0.9 mM vs. 8.6 ± 1.7 mM, 7.7 ± 1.8 mM vs. 10.3 ± 5.1 mM, P < .001) and resting MBF (1.3 ± 0.1 mL/g/min vs. 1.1 ± 0.1 mL/g/min, 1.3 ± 0.1 mL/g/min vs. 1.1 ± 0.1 mL/g/min, 1.2 ± 0.1 mL/g/min vs. 0.9 ± 0.1 mL/g/min, P < .001) values were significantly different between uncorrected and corrected for all 3 patient groups. Both the peak AIF and resting MBF values varied by <5% over the said variations in native T2 and ΔB0 . CONCLUSION: Our theoretical framework enables retrospective T2∗ correction to the AIF obtained with dual-imaging, cardiac perfusion pulse sequences.

Highly Accelerated Real-Time Free-Breathing Cine CMR for Patients With a Cardiac Implantable Electronic Device.

RATIONALE AND OBJECTIVES: To develop a 16-fold accelerated real-time, free-breathing cine cardiovascular magnetic resonance (CMR) pulse sequence with compressed sensing reconstruction and test whether it is capable of producing clinically acceptable summed visual scores (SVS) and accurate left ventricular ejection fraction (LVEF) in patients with a cardiac implantable electronic device (CIED). MATERIALS AND METHODS: A 16-fold accelerated real-time cine CMR pulse sequence was developed using gradient echo readout, Cartesian k-space sampling, and compressed sensing. We scanned 13 CIED patients (mean age = 59 years; 9/4 males/females) using clinical standard, breath-hold cine and real-time, free-breathing cine. Two clinical readers performed a visual assessment of image quality in four categories (conspicuity of endocardial wall at end diastole, temporal fidelity of wall motion, any artifact level on the heart, noise) using a five-point Likert scale (1: worst; 3: clinically acceptable; 5: best). SVS was calculated as the sum of 4 individual scores, where 12 was defined as clinical acceptable. The Wilcoxon signed-rank test was performed to compare SVS, and the Bland-Altman analysis was conducted to evaluate the agreement of LVEF. RESULTS: Median scan time was 3.7 times shorter for real-time (3.5 heartbeats per slice) than clinical standard (13 heartbeats per slice, excluding nonscanning time between successive breath-hold acquisitions). Median SVS was not significantly different between clinical standard (15.0) and real-time (14.5). The mean difference in LVEF was -2% (4.7% of mean), and the limits of agreement was 5.8% (13.5% of mean). CONCLUSION: This study demonstrates that the proposed real-time cine method produces clinically acceptable SVS and relatively accurate LVEF in CIED patients.

Left Atrial Dilation and Risk of One-Year Readmission after Embolic Stroke of Undetermined Source.

BACKGROUND: Structural left atrial and ventricular abnormalities on the electrocardiogram (ECG) and transthoracic echocardiogram (TTE) at the time of ischemic stroke have been associated with morbidity and mortality. Yet, the prognostic impact of the same in embolic stroke of undetermined source (ESUS), a relevant subtype of ischemic stroke with a unique pathophysiology, has not been well studied to date. Our aim was to assess the predictive impact of left atrio-ventricular ECG and TTE abnormalities on one-year hospital readmission after ESUS from an ongoing single center prospective stroke registry in the U.S. METHODS: We identified 369 ESUS patients who had at least 1 year of complete follow-up between 2013 and 2018. We examined the association of abnormal left atrio-ventricular findings on ECG and TTE, as well as basic demographic and clinical characteristics, measured at index admission with time to 1-year hospital readmission using Kaplan-Meier curves, log-rank tests, and Cox proportional hazards regression. RESULTS: Recurrent ischemic stroke and cardiovascular causes constituted 60% of all readmissions. Patients with left atrial dilation on TTE were more likely to readmitted within 1 year (HR 1.51; 95% CI, 1.04-2.21). Bundle branch block, pathologic Q-wave, and troponin elevation curves diverged, but were not significantly associated with readmission (log-rank p=0.34, p=0.08, p=0.42, respectively). CONCLUSIONS: Following ESUS, left atrial dilation on TTE was associated with 1-year overall hospital readmission, of which cardiovascular and cerebrovascular ischemic events, and heart failure were a notable proportion. Our data support ongoing studies of atrial cardiopathy in ESUS patients.

Ypt4 and lvs1 regulate vacuolar size and function in Schizosaccharomyces pombe.

The yeast vacuole plays key roles in cellular stress responses. Here, we show that deletion of lvs1, the fission yeast homolog of the Chediak-Higashi Syndrome CHS1/LYST gene, increases vacuolar size, similar to deletion of the Rab4 homolog ypt4. Overexpression of lvs1-YFP rescued vacuolar size in ypt4Δ cells, but ypt4-YFP did not rescue lvs1Δ, suggesting that lvs1 may act downstream of ypt4. Vacuoles were capable of hypotonic shock-induced fusion and recovery in both ypt4Δ and lvs1Δ cells, although recovery may be slightly delayed in ypt4Δ. Endocytic and secretory trafficking were not affected, but ypt4Δ and lvs1Δ strains were sensitive to neutral pH and CaCl2, consistent with vacuolar dysfunction. In addition to changes in vacuolar size, deletion of ypt4 also dramatically increased cell size, similar to tor1 mutants. These results implicate ypt4 and lvs1 in maintenance of vacuolar size and suggest that ypt4 may link vacuolar homeostasis to cell cycle progression.

Foxc1 and Foxc2 deletion causes abnormal lymphangiogenesis and correlates with ERK hyperactivation.

The lymphatic vasculature is essential for maintaining interstitial fluid homeostasis, and dysfunctional lymphangiogenesis contributes to various pathological processes, including inflammatory disease and tumor metastasis. Mutations in FOXC2 are dominantly associated with late-onset lymphedema; however, the precise role of FOXC2 and a closely related factor, FOXC1, in the lymphatic system remains largely unknown. Here we identified a molecular cascade by which FOXC1 and FOXC2 regulate ERK signaling in lymphatic vessel growth. In mice, lymphatic endothelial cell-specific (LEC-specific) deletion of Foxc1, Foxc2, or both resulted in increased LEC proliferation, enlarged lymphatic vessels, and abnormal lymphatic vessel morphogenesis. Compared with LECs from control animals, LECs from mice lacking both Foxc1 and Foxc2 exhibited aberrant expression of Ras regulators, and embryos with LEC-specific deletion of Foxc1 and Foxc2, alone or in combination, exhibited ERK hyperactivation. Pharmacological ERK inhibition in utero abolished the abnormally enlarged lymphatic vessels in FOXC-deficient embryos. Together, these results identify FOXC1 and FOXC2 as essential regulators of lymphangiogenesis and indicate a new potential mechanistic basis for lymphatic-associated diseases.

Murine Notch1 is required for lymphatic vascular morphogenesis during development.

BACKGROUND: The transmembrane receptor Notch1 is a critical regulator of arterial differentiation and blood vessel sprouting. Recent evidence shows that functional blockade of Notch1 and its ligand, Dll4, leads to postnatal lymphatic defects in mice. However, the precise role of the Notch signaling pathway in lymphatic vessel development has yet to be defined. Here we show the developmental role of Notch1 in lymphatic vascular morphogenesis by analyzing lymphatic endothelial cell (LEC)-specific conditional Notch1 knockout mice crossed with an inducible Prox1CreER(T2) driver. RESULTS: LEC-specific Notch1 mutant embryos exhibited enlarged lymphatic vessels. The phenotype of lymphatic overgrowth accords with increased LEC sprouting from the lymph sacs and increased filopodia formation. Furthermore, cell death was significantly reduced in Notch1-mutant LECs, whereas proliferation was increased. RNA-seq analysis revealed that expression of cytokine/chemokine signaling molecules was upregulated in Notch1-mutant LECs isolated from E15.5 dorsal skin, whereas VEGFR3, VEGFR2, VEGFC, and Gja4 (Connexin 37) were downregulated. CONCLUSIONS: The lymphatic phenotype of LEC-specific conditional Notch1 mouse mutants indicates that Notch activity in LECs controls lymphatic sprouting and growth during development. These results provide evidence that similar to postnatal and pathological lymphatic vessel formation, the Notch signaling pathway plays a role in inhibiting developmental lymphangiogenesis.