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Painful vaso-occlusive crisis (VOC), a complication of sickle cell disease (SCD), occurs when sickled red blood cells obstruct flow in the microvasculature. We postulated that exaggerated sympathetically mediated vasoconstriction, endothelial dysfunction and the synergistic interaction between these two factors act together to reduce microvascular flow, promoting regional vaso-occlusions, setting the stage for VOC. We previously found that SCD subjects had stronger vasoconstriction response to pulses of heat-induced pain compared to controls but the relative degrees to which autonomic dysregulation, peripheral vascular dysfunction and their interaction are present in SCD remain unknown. In the present study, we employed a mathematical model to decompose the total vasoconstriction response to pain into: 1) the neurogenic component, 2) the vascular response to blood pressure, 3) respiratory coupling and 4) neurogenic-vascular interaction. The model allowed us to quantify the contribution of each component to the total vasoconstriction response. The most salient features of the components were extracted to represent biophysical markers of autonomic and vascular impairment in SCD and controls. These markers provide a means of phenotyping severity of disease in sickle-cell anemia that is based more on underlying physiology than on genotype. The marker of the vascular component (BMv) showed stronger contribution to vasoconstriction in SCD than controls (p = 0.0409), suggesting a dominant myogenic response in the SCD subjects as a consequence of endothelial dysfunction. The marker of neurogenic-vascular interaction (BMn-v) revealed that the interaction reinforced vasoconstriction in SCD but produced vasodilatory response in controls (p = 0.0167). This marked difference in BMn-v suggests that it is the most sensitive marker for quantifying combined alterations in autonomic and vascular function in SCD in response to heat-induced pain.

Background In the Fontan palliation for single ventricle heart disease (SVHD), pulmonary blood flow is non-pulsatile/passive, low velocity, and low shear, making viscous power loss a critical determinant of cardiac output. The rheologic properties of blood in SVHD patients are essential for understanding and modulating their limited cardiac output and they have not been systematically studied. We hypothesize that viscosity is decreased in single ventricle circulation. Methods We evaluated whole blood viscosity, red blood cell (RBC) aggregation, and RBC deformability to evaluate changes in healthy children and SVHD patients. We altered suspending media to understand cellular and plasma differences contributing to rheologic differences. Results Whole blood viscosity was similar between SVHD and healthy at their native hematocrits, while viscosity was lower at equivalent hematocrits for SVHD patients. RBC deformability is increased, and RBC aggregation is decreased in SVHD patients. Suspending SVHD RBCs in healthy plasma resulted in increased RBC aggregation and suspending healthy RBCs in SVHD plasma resulted in lower RBC aggregation. Conclusions Hematocrit corrected blood viscosity is lower in SVHD vs. healthy due to decreased RBC aggregation and higher RBC deformability, a viscous adaptation of blood in patients whose cardiac output is dependent on minimizing viscous power loss. Impact Patients with single ventricle circulation have decreased red blood cell aggregation and increased red blood cell deformability, both of which result in a decrease in blood viscosity across a large shear rate range. Since the unique Fontan circulation has very low-shear and low velocity flow in the pulmonary arteries, blood viscosity plays an increased role in vascular resistance, therefore this work is the first to describe a novel mechanism to target pulmonary vascular resistance as a modifiable risk factor. This is a novel, modifiable risk factor in this patient population.

The Pediatric Heart Network’s Fontan Udenafil Exercise Longitudinal (FUEL) Trial (Mezzion Pharma Co. Ltd., NCT 02741115) demonstrated improvements in some measures of exercise capacity and in the myocardial performance index following 6 months of treatment with udenafil (87.5 mg twice daily). In this post hoc analysis, we evaluate whether subgroups within the population experienced a differential effect on exercise performance in response to treatment. The effect of udenafil on exercise was evaluated within subgroups defined by baseline characteristics, including peak oxygen consumption (VO 2 ), serum brain-type natriuretic peptide level, weight, race, gender, and ventricular morphology. Differences among subgroups were evaluated using ANCOVA modeling with fixed factors for treatment arm and subgroup and the interaction between treatment arm and subgroup. Within-subgroup analyses demonstrated trends toward quantitative improvements in peak VO 2 , work rate at the ventilatory anaerobic threshold (VAT), VO 2 at VAT, and ventilatory efficiency (VE/VCO 2 ) for those randomized to udenafil compared to placebo in nearly all subgroups. There was no identified differential response to udenafil based on baseline peak VO 2 , baseline BNP level, weight, race and ethnicity, gender, or ventricular morphology, although participants in the lowest tertile of baseline peak VO 2 trended toward larger improvements. The absence of a differential response across subgroups in response to treatment with udenafil suggests that the treatment benefit may not be restricted to specific sub-populations. Further work is warranted to confirm the potential benefit of udenafil and to evaluate the long-term tolerability and safety of treatment and to determine the impact of udenafil on the development of other morbidities related to the Fontan circulation. Trial Registration NCT0274115.

Sickle cell disease is an inherited blood disorder characterized by vasoocclusive crises. Although hypoxia and pulmonary disease are known risk factors for these crises, the mechanisms that initiate vasoocclusive events are not well known. To study the relationship between transient hypoxia, respiration, and microvascular blood flow in patients with sickle cell. We established a protocol that mimics nighttime hypoxic episodes and measured microvascular blood flow to determine if transient hypoxia causes a decrease in microvascular blood flow. Significant desaturations were induced safely by five breaths of 100% nitrogen. Desaturation did not induce change in microvascular perfusion; however, it induced substantial transient parasympathetic activity withdrawal in patients with sickle cell disease, but not controls subjects. Marked periodic drops in peripheral microvascular perfusion, unrelated to hypoxia, were triggered by sighs in 11 of 11 patients with sickle cell and 8 of 11 control subjects. Although the sigh frequency was the same in both groups, the probability of a sigh inducing a perfusion drop was 78% in patients with sickle cell and 17% in control subjects (P < 0.001). Evidence for sigh-induced sympathetic nervous system dominance was seen in patients with sickle cell (P < 0.05), but was not significant in control subjects. These data demonstrate significant disruption of autonomic nervous system balance, with marked parasympathetic withdrawal in response to transient hypoxia. They draw attention to an enhanced autonomic nervous system–mediated sigh–vasoconstrictor response in patients with sickle cell that could increase red cell retention in the microvasculature, promoting vasoocclusion.

Contemporary 0.55T magnetic resonance imaging (MRI) is promising for fetal MRI, due to the larger bore, reduced safety concerns, lower acoustic noise, and improved fast imaging capability. In this work, we explore improved fetal cardiovascular magnetic resonance (CMR) without relying on any synchronizing devices, prospective, or retrospective gating, to determine the feasibility of real-time MRI evaluation of fetal cardiac function as well as cardiac and great vessel anatomies by using spiral balanced steady-state free precession (bSSFP) at 0.55T. A real-time spiral bSSFP pulse sequence for fetal CMR was implemented and optimized on a 0.55T whole-body MRI. Fetal CMR was prospectively performed between May 2022 and August 2023. The protocol included (1) real-time images at standard cardiac views, for 10–20 s/view and 40–43.6 ms/frame and (2) 4–9 stacks of slices at standard cardiac views that each cover the whole heart, with 15–30 slices/stack, and 2–5 s/slice, at 320–349 ms/frame. Images were evaluated by a fetal cardiologist. Quantitative measurements of cardiothoracic area ratio and cardiac axis were compared with previous reports. Diagnostic accuracy was compared against postnatal echocardiographic findings. Twenty-nine participants were enrolled for 32 CMR exams, with mean maternal age 33.6 ± 5.8 years (range 22–44 years) and mean gestational age 32.8 ± 3.9 weeks (range 23–38 weeks). The proposed sequence enabled evaluation of the fetal heart in <30 min in all cases (average 22 min). Real-time MRI allowed easy adjustment of scan plan, automatic whole-heart volumetric sweeping, and flexible choice of reconstruction temporal resolution. For key cardiac anatomic features, 60% (315/527) were delineated well. Mean cardiothoracic area ratio and cardiac axis were 0.27 ± 0.04 and 45.8 ± 7.8 degrees. Diagnostic agreement with postnatal echocardiographic findings was 84% (26/31). A spiral real-time bSSFP pulse sequence at 0.55T can provide both low-framerate and high-framerate fetal heart images without relying on maternal breath-hold, specialized gating devices, or cardiac gating. The low-framerate images offer high diagnostic quality structural evaluations of the fetal heart, while the high-framerate images capture fetal heart motion and may enable functional assessments. [Display omitted]

Dynamic fetal cardiovascular MRI (CMR) enables visualization of moving structures to assess congenital heart disease and plan treatment. Low field MRI systems can provide more comfortable platforms for fetal CMR. Here, we demonstrate the feasibility and utility of motion corrected fetal cardiac cine CMR and compare it with real-time CMR at multiple spatial resolutions at 0.55 T. Ten human pregnancies were scanned at 0.55T on a derated MAGNETOM Aera (Siemens Healthineers, Erlangen, Germany) with spiral steady-state free precession imaging. Real-time images were reconstructed and used for motion correction and fetal cardiac gating followed by cine reconstructions. The signal-to-noise ratio (SNR), image quality, blood-to-myocardium contrast, and contrast-to-noise ratio (CNR) from real-time and cine reconstructions were compared. The effect of acceleration on cine accuracy was assessed by retrospectively undersampling the data and measuring the reconstruction error with the normalized root-mean-squared difference (NRMSD) in five fetuses. Reproducibility of the measurements was assessed by reconstructing cines from two independent windows of data and computing the NRMSD relative to the reference image in five fetuses. The SNR, CNR, and image quality were better for cines than their corresponding real-time reconstructions. The blood-to-myocardium contrast had no significant difference between real-time and cine reconstructions. With finer spatial resolution, real-time images degraded, and cardiac structures were less conspicuous. NRMSD in cines decreased with increasing scan times across all resolutions (NRMSD = 10 ± 2% for 7 s scan duration). Good consistency (NRMSD = 11 ± 3%) was achieved between independent reconstruction windows. While this study was performed on an experimental scanner (derated; not commercially available), we have shown that fetal cine CMR is feasible at 0.55T and provides high-quality fetal cardiac images at high spatiotemporal resolutions. [Display omitted]