Sex differences in blood pressure regulation and hypertension: renal, hemodynamic, and hormonal mechanisms.

The teleology of sex differences has been argued since at least as early as Aristotle's controversial Generation of Animals more than 300 years BC, which reflects the sex bias of the time to contemporary readers. Although the question "why are the sexes different" remains a topic of debate in the present day in metaphysics, the recent emphasis on sex comparison in research studies has led to the question "how are the sexes different" being addressed in health science through numerous observational studies in both health and disease susceptibility, including blood pressure regulation and hypertension. These efforts have resulted in better understanding of differences in males and females at the molecular level that partially explain their differences in vascular function and renal sodium handling and hence blood pressure and the consequential cardiovascular and kidney disease risks in hypertension. This review focuses on clinical studies comparing differences between men and women in blood pressure over the life span and response to dietary sodium and highlights experimental models investigating sexual dimorphism in the renin-angiotensin-aldosterone, vascular, sympathetic nervous, and immune systems, endothelin, the major renal sodium transporters/exchangers/channels, and the impact of sex hormones on these systems in blood pressure homeostasis. Understanding the mechanisms governing sex differences in blood pressure regulation could guide novel therapeutic approaches in a sex-specific manner to lower cardiovascular risks in hypertension and advance personalized medicine.

Obstructive nephropathy and molecular pathophysiology of renal interstitial fibrosis.

The kidneys play a key role in maintaining total body homeostasis. The complexity of this task is reflected in the unique architecture of the organ. Ureteral obstruction greatly affects renal physiology by altering hemodynamics, changing glomerular filtration and renal metabolism, and inducing architectural malformations of the kidney parenchyma, most importantly renal fibrosis. Persisting pathological changes lead to chronic kidney disease, which currently affects ∼10% of the global population and is one of the major causes of death worldwide. Studies on the consequences of ureteral obstruction date back to the 1800s. Even today, experimental unilateral ureteral obstruction (UUO) remains the standard model for tubulointerstitial fibrosis. However, the model has certain limitations when it comes to studying tubular injury and repair, as well as a limited potential for human translation. Nevertheless, ureteral obstruction has provided the scientific community with a wealth of knowledge on renal (patho)physiology. With the introduction of advanced omics techniques, the classical UUO model has remained relevant to this day and has been instrumental in understanding renal fibrosis at the molecular, genomic, and cellular levels. This review details key concepts and recent advances in the understanding of obstructive nephropathy, highlighting the pathophysiological hallmarks responsible for the functional and architectural changes induced by ureteral obstruction, with a special emphasis on renal fibrosis.

Hemodynamic Control of Endothelial Cell Fates in Development.

Biomechanical forces are emerging as critical regulators of embryogenesis, particularly in the developing cardiovascular system. From the onset of blood flow, the embryonic vasculature is continuously exposed to a variety of hemodynamic forces. These biomechanical stimuli are key determinants of vascular cell specification and remodeling and the establishment of vascular homeostasis. In recent years, major advances have been made in our understanding of mechano-activated signaling networks that control both spatiotemporal and structural aspects of vascular development. It has become apparent that a major site for mechanotransduction is situated at the interface of blood and the vessel wall and that this process is controlled by the vascular endothelium. In this review, we discuss the hemodynamic control of endothelial cell fates, focusing on arterial-venous specification, lymphatic development, and the endothelial-to-hematopoietic transition, and present some recent insights into the mechano-activated pathways driving these cell fate decisions in the developing embryo.

Phylogenic Determinants of Cardiovascular Frailty, Focus on Hemodynamics and Arterial Smooth Muscle Cells.

The evolution of the circulatory system from invertebrates to mammals has involved the passage from an open system to a closed in-parallel system via a closed in-series system, accompanying the increasing complexity and efficiency of life's biological functions. The archaic heart enables pulsatile motion waves of hemolymph in invertebrates, and the in-series circulation in fish occurs with only an endothelium, whereas mural smooth muscle cells appear later. The present review focuses on evolution of the circulatory system. In particular, we address how and why this evolution took place from a closed, flowing, longitudinal conductance at low pressure to a flowing, highly pressurized and bifurcating arterial compartment. However, although arterial pressure was the latest acquired hemodynamic variable, the general teleonomy of the evolution of species is the differentiation of individual organ function, supported by specific fueling allowing and favoring partial metabolic autonomy. This was achieved via the establishment of an active contractile tone in resistance arteries, which permitted the regulation of blood supply to specific organ activities via its localized function-dependent inhibition (active vasodilation). The global resistance to viscous blood flow is the peripheral increase in frictional forces caused by the tonic change in arterial and arteriolar radius, which backscatter as systemic arterial blood pressure. Consequently, the arterial pressure gradient from circulating blood to the adventitial interstitium generates the unidirectional outward radial advective conductance of plasma solutes across the wall of conductance arteries. This hemodynamic evolution was accompanied by important changes in arterial wall structure, supported by smooth muscle cell functional plasticity, including contractility, matrix synthesis and proliferation, endocytosis and phagocytosis, etc. These adaptive phenotypic shifts are due to epigenetic regulation, mainly related to mechanotransduction. These paradigms actively participate in cardio-arterial pathologies such as atheroma, valve disease, heart failure, aneurysms, hypertension, and physiological aging.

Neuroprosthetic baroreflex controls haemodynamics after spinal cord injury.

Spinal cord injury (SCI) induces haemodynamic instability that threatens survival1-3, impairs neurological recovery4,5, increases the risk of cardiovascular disease6,7, and reduces quality of life8,9. Haemodynamic instability in this context is due to the interruption of supraspinal efferent commands to sympathetic circuits located in the spinal cord10, which prevents the natural baroreflex from controlling these circuits to adjust peripheral vascular resistance. Epidural electrical stimulation (EES) of the spinal cord has been shown to compensate for interrupted supraspinal commands to motor circuits below the injury11, and restored walking after paralysis12. Here, we leveraged these concepts to develop EES protocols that restored haemodynamic stability after SCI. We established a preclinical model that enabled us to dissect the topology and dynamics of the sympathetic circuits, and to understand how EES can engage these circuits. We incorporated these spatial and temporal features into stimulation protocols to conceive a clinical-grade biomimetic haemodynamic regulator that operates in a closed loop. This 'neuroprosthetic baroreflex' controlled haemodynamics for extended periods of time in rodents, non-human primates and humans, after both acute and chronic SCI. We will now conduct clinical trials to turn the neuroprosthetic baroreflex into a commonly available therapy for people with SCI.

Identification of KU-55933 as an anti-atherosclerosis compound by using a hemodynamic-based high-throughput drug screening platform.

Several compounds have been used for atherosclerosis treatment, including clinical trials; however, no anti-atherosclerotic drugs based on hemodynamic force-mediated atherogenesis have been discovered. Our previous studies demonstrated that "small mothers against decapentaplegic homolog 1/5" (Smad1/5) is a convergent signaling molecule for chemical [e.g., bone morphogenetic proteins (BMPs)] and mechanical (e.g., disturbed flow) stimulations and hence may serve as a promising hemodynamic-based target for anti-atherosclerosis drug development. The goal of this study was to develop a high-throughput screening (HTS) platform to identify potential compounds that can inhibit disturbed flow- and BMP-induced Smad1/5 activation and atherosclerosis. Through HTS using a Smad1/5 downstream target inhibitor of DNA binding 1 (Id-1) as a luciferase reporter, we demonstrated that KU-55933 and Apicidin suppressed Id-1 expression in AD-293 cells. KU-55933 (10 µM), Apicidin (10 µM), and the combination of half doses of each [1/2(K + A)] inhibited disturbed flow- and BMP4-induced Smad1/5 activation in human vascular endothelial cells (ECs). KU-55933, Apicidin, and 1/2(K + A) treatments caused 50.6%, 47.4%, and 73.3% inhibitions of EC proliferation induced by disturbed flow, respectively, whereas EC inflammation was only suppressed by KU-55933 and 1/2(K + A), but not Apicidin alone. Administrations of KU-55933 and 1/2(K + A) to apolipoprotein E-deficient mice inhibited Smad1/5 activation in ECs in athero-susceptible regions, thereby suppressing endothelial proliferation and inflammation, with the attenuation of atherosclerotic lesions in these mice. A unique drug screening platform has been developed to demonstrate that KU-55933 and its combination with Apicidin are promising therapeutic compounds for atherosclerosis based on hemodynamic considerations.

Pia-FLOW: Deciphering hemodynamic maps of the pial vascular connectome and its response to arterial occlusion.

The pial vasculature is the sole source of blood supply to the neocortex. The brain is contained within the skull, a vascularized bone marrow with a unique anatomical connection to the brain meninges. Recent developments in tissue clearing have enabled detailed mapping of the entire pial and calvarial vasculature. However, what are the absolute flow rate values of those vascular networks? This information cannot accurately be retrieved with the commonly used bioimaging methods. Here, we introduce Pia-FLOW, a unique approach based on large-scale transcranial fluorescence localization microscopy, to attain hemodynamic imaging of the whole murine pial and calvarial vasculature at frame rates up to 1,000 Hz and spatial resolution reaching 5.4 µm. Using Pia-FLOW, we provide detailed maps of flow velocity, direction, and vascular diameters which can serve as ground-truth data for further studies, advancing our understanding of brain fluid dynamics. Furthermore, Pia-FLOW revealed that the pial vascular network functions as one unit for robust allocation of blood after stroke.

Lower Body Negative Pressure: Physiological Effects, Applications, and Implementation.

This review presents lower body negative pressure (LBNP) as a unique tool to investigate the physiology of integrated systemic compensatory responses to altered hemodynamic patterns during conditions of central hypovolemia in humans. An early review published in Physiological Reviews over 40 yr ago (Wolthuis et al. Physiol Rev 54: 566-595, 1974) focused on the use of LBNP as a tool to study effects of central hypovolemia, while more than a decade ago a review appeared that focused on LBNP as a model of hemorrhagic shock (Cooke et al. J Appl Physiol (1985) 96: 1249-1261, 2004). Since then there has been a great deal of new research that has applied LBNP to investigate complex physiological responses to a variety of challenges including orthostasis, hemorrhage, and other important stressors seen in humans such as microgravity encountered during spaceflight. The LBNP stimulus has provided novel insights into the physiology underlying areas such as intolerance to reduced central blood volume, sex differences concerning blood pressure regulation, autonomic dysfunctions, adaptations to exercise training, and effects of space flight. Furthermore, approaching cardiovascular assessment using prediction models for orthostatic capacity in healthy populations, derived from LBNP tolerance protocols, has provided important insights into the mechanisms of orthostatic hypotension and central hypovolemia, especially in some patient populations as well as in healthy subjects. This review also presents a concise discussion of mathematical modeling regarding compensatory responses induced by LBNP. Given the diverse applications of LBNP, it is to be expected that new and innovative applications of LBNP will be developed to explore the complex physiological mechanisms that underline health and disease.

Intravenous Levothyroxine for Unstable Brain-Dead Heart Donors.

BACKGROUND: Hemodynamic instability and myocardial dysfunction are major factors preventing the transplantation of hearts from organ donors after brain death. Intravenous levothyroxine is widely used in donor care, on the basis of observational data suggesting that more organs may be transplanted from donors who receive hormonal supplementation. METHODS: In this trial involving 15 organ-procurement organizations in the United States, we randomly assigned hemodynamically unstable potential heart donors within 24 hours after declaration of death according to neurologic criteria to open-label infusion of intravenous levothyroxine (30 µg per hour for a minimum of 12 hours) or saline placebo. The primary outcome was transplantation of the donor heart; graft survival at 30 days after transplantation was a prespecified recipient safety outcome. Secondary outcomes included weaning from vasopressor therapy, donor ejection fraction, and number of organs transplanted per donor. RESULTS: Of the 852 brain-dead donors who underwent randomization, 838 were included in the primary analysis: 419 in the levothyroxine group and 419 in the saline group. Hearts were transplanted from 230 donors (54.9%) in the levothyroxine group and 223 (53.2%) in the saline group (adjusted risk ratio, 1.01; 95% confidence interval [CI], 0.97 to 1.07; P = 0.57). Graft survival at 30 days occurred in 224 hearts (97.4%) transplanted from donors assigned to receive levothyroxine and 213 hearts (95.5%) transplanted from donors assigned to receive saline (difference, 1.9 percentage points; 95% CI, -2.3 to 6.0; P<0.001 for noninferiority at a margin of 6 percentage points). There were no substantial between-group differences in weaning from vasopressor therapy, ejection fraction on echocardiography, or organs transplanted per donor, but more cases of severe hypertension and tachycardia occurred in the levothyroxine group than in the saline group. CONCLUSIONS: In hemodynamically unstable brain-dead potential heart donors, intravenous levothyroxine infusion did not result in significantly more hearts being transplanted than saline infusion. (Funded by Mid-America Transplant and others; ClinicalTrials.gov number, NCT04415658.).

Neural activity induced by sensory stimulation can drive large-scale cerebrospinal fluid flow during wakefulness in humans.

Cerebrospinal fluid (CSF) flow maintains healthy brain homeostasis, facilitating solute transport and the exchange of brain waste products. CSF flow is thus important for brain health, but the mechanisms that control its large-scale movement through the ventricles are not well understood. While it is well established that CSF flow is modulated by respiratory and cardiovascular dynamics, recent work has also demonstrated that neural activity is coupled to large waves of CSF flow in the ventricles during sleep. To test whether the temporal coupling between neural activity and CSF flow is in part due to a causal relationship, we investigated whether CSF flow could be induced by driving neural activity with intense visual stimulation. We manipulated neural activity with a flickering checkerboard visual stimulus and found that we could drive macroscopic CSF flow in the human brain. The timing and amplitude of CSF flow was matched to the visually evoked hemodynamic responses, suggesting neural activity can modulate CSF flow via neurovascular coupling. These results demonstrate that neural activity can contribute to driving CSF flow in the human brain and that the temporal dynamics of neurovascular coupling can explain this effect.

Circadian and Diurnal Regulation of Cerebral Blood Flow.

Circadian and diurnal variation in cerebral blood flow directly contributes to the diurnal variation in the risk of stroke, either through factors that trigger stroke or due to impaired compensatory mechanisms. Cerebral blood flow results from the integration of systemic hemodynamics, including heart rate, cardiac output, and blood pressure, with cerebrovascular regulatory mechanisms, including cerebrovascular reactivity, autoregulation, and neurovascular coupling. We review the evidence for the circadian and diurnal variation in each of these mechanisms and their integration, from the detailed evidence for mechanisms underlying the nocturnal nadir and morning surge in blood pressure to identifying limited available evidence for circadian and diurnal variation in cerebrovascular compensatory mechanisms. We, thus, identify key systemic hemodynamic factors related to the diurnal variation in the risk of stroke but particularly identify the need for further research focused on cerebrovascular regulatory mechanisms.

Antiarrhythmic Mechanisms of Epidural Blockade After Myocardial Infarction.

BACKGROUND: Thoracic epidural anesthesia (TEA) has been shown to reduce the burden of ventricular tachycardia in small case series of patients with refractory ventricular tachyarrhythmias and cardiomyopathy. However, its electrophysiological and autonomic effects in diseased hearts remain unclear, and its use after myocardial infarction is limited by concerns for potential right ventricular dysfunction. METHODS: Myocardial infarction was created in Yorkshire pigs (N=22) by left anterior descending coronary artery occlusion. Approximately, six weeks after myocardial infarction, an epidural catheter was placed at the C7-T1 vertebral level for injection of 2% lidocaine. Right and left ventricular hemodynamics were recorded using Millar pressure-conductance catheters, and ventricular activation recovery intervals (ARIs), a surrogate of action potential durations, by a 56-electrode sock and 64-electrode basket catheter. Hemodynamics and ARIs, baroreflex sensitivity and intrinsic cardiac neural activity, and ventricular effective refractory periods and slope of restitution (Smax) were assessed before and after TEA. Ventricular tachyarrhythmia inducibility was assessed by programmed electrical stimulation. RESULTS: TEA reduced inducibility of ventricular tachyarrhythmias by 70%. TEA did not affect right ventricular-systolic pressure or contractility, although left ventricular-systolic pressure and contractility decreased modestly. Global and regional ventricular ARIs increased, including in scar and border zone regions post-TEA. TEA reduced ARI dispersion specifically in border zone regions. Ventricular effective refractory periods prolonged significantly at critical sites of arrhythmogenesis, and Smax was reduced. Interestingly, TEA significantly improved cardiac vagal function, as measured by both baroreflex sensitivity and intrinsic cardiac neural activity. CONCLUSIONS: TEA does not compromise right ventricular function in infarcted hearts. Its antiarrhythmic mechanisms are mediated by increases in ventricular effective refractory period and ARIs, decreases in Smax, and reductions in border zone electrophysiological heterogeneities. TEA improves parasympathetic function, which may independently underlie some of its observed antiarrhythmic mechanisms. This study provides novel insights into the antiarrhythmic mechanisms of TEA while highlighting its applicability to the clinical setting.

Genetic and functional insights into the fractal structure of the heart.

The inner surfaces of the human heart are covered by a complex network of muscular strands that is thought to be a remnant of embryonic development1,2. The function of these trabeculae in adults and their genetic architecture are unknown. Here we performed a genome-wide association study to investigate image-derived phenotypes of trabeculae using the fractal analysis of trabecular morphology in 18,096 participants of the UK Biobank. We identified 16 significant loci that contain genes associated with haemodynamic phenotypes and regulation of cytoskeletal arborization3,4. Using biomechanical simulations and observational data from human participants, we demonstrate that trabecular morphology is an important determinant of cardiac performance. Through genetic association studies with cardiac disease phenotypes and Mendelian randomization, we find a causal relationship between trabecular morphology and risk of cardiovascular disease. These findings suggest a previously unknown role for myocardial trabeculae in the function of the adult heart, identify conserved pathways that regulate structural complexity and reveal the influence of the myocardial trabeculae on susceptibility to cardiovascular disease.

Adaptable haemodynamic endothelial cells for organogenesis and tumorigenesis.

Endothelial cells adopt tissue-specific characteristics to instruct organ development and regeneration1,2. This adaptability is lost in cultured adult endothelial cells, which do not vascularize tissues in an organotypic manner. Here, we show that transient reactivation of the embryonic-restricted ETS variant transcription factor 2 (ETV2)3 in mature human endothelial cells cultured in a serum-free three-dimensional matrix composed of a mixture of laminin, entactin and type-IV collagen (LEC matrix) 'resets' these endothelial cells to adaptable, vasculogenic cells, which form perfusable and plastic vascular plexi. Through chromatin remodelling, ETV2 induces tubulogenic pathways, including the activation of RAP1, which promotes the formation of durable lumens4,5. In three-dimensional matrices-which do not have the constraints of bioprinted scaffolds-the 'reset' vascular endothelial cells (R-VECs) self-assemble into stable, multilayered and branching vascular networks within scalable microfluidic chambers, which are capable of transporting human blood. In vivo, R-VECs implanted subcutaneously in mice self-organize into durable pericyte-coated vessels that functionally anastomose to the host circulation and exhibit long-lasting patterning, with no evidence of malformations or angiomas. R-VECs directly interact with cells within three-dimensional co-cultured organoids, removing the need for the restrictive synthetic semipermeable membranes that are required for organ-on-chip systems, therefore providing a physiological platform for vascularization, which we call 'Organ-On-VascularNet'. R-VECs enable perfusion of glucose-responsive insulin-secreting human pancreatic islets, vascularize decellularized rat intestines and arborize healthy or cancerous human colon organoids. Using single-cell RNA sequencing and epigenetic profiling, we demonstrate that R-VECs establish an adaptive vascular niche that differentially adjusts and conforms to organoids and tumoroids in a tissue-specific manner. Our Organ-On-VascularNet model will permit metabolic, immunological and physiochemical studies and screens to decipher the crosstalk between organotypic endothelial cells and parenchymal cells for identification of determinants of endothelial cell heterogeneity, and could lead to advances in therapeutic organ repair and tumour targeting.

Interpericyte tunnelling nanotubes regulate neurovascular coupling.

Signalling between cells of the neurovascular unit, or neurovascular coupling, is essential to match local blood flow with neuronal activity. Pericytes interact with endothelial cells and extend processes that wrap capillaries, covering up to 90% of their surface area1,2. Pericytes are candidates to regulate microcirculatory blood flow because they are strategically positioned along capillaries, contain contractile proteins and respond rapidly to neuronal stimulation3,4, but whether they synchronize microvascular dynamics and neurovascular coupling within a capillary network was unknown. Here we identify nanotube-like processes that connect two bona fide pericytes on separate capillary systems, forming a functional network in the mouse retina, which we named interpericyte tunnelling nanotubes (IP-TNTs). We provide evidence that these (i) have an open-ended proximal side and a closed-ended terminal (end-foot) that connects with distal pericyte processes via gap junctions, (ii) carry organelles including mitochondria, which can travel along these processes, and (iii) serve as a conduit for intercellular Ca2+ waves, thus mediating communication between pericytes. Using two-photon microscope live imaging, we demonstrate that retinal pericytes rely on IP-TNTs to control local neurovascular coupling and coordinate light-evoked responses between adjacent capillaries. IP-TNT damage following ablation or ischaemia disrupts intercellular Ca2+ waves, impairing blood flow regulation and neurovascular coupling. Notably, pharmacological blockade of Ca2+ influx preserves IP-TNTs, rescues light-evoked capillary responses and restores blood flow after reperfusion. Our study thus defines IP-TNTs and characterizes their critical role in regulating neurovascular coupling in the living retina under both physiological and pathological conditions.

Hemodynamic transient and functional connectivity follow structural connectivity and cell type over the brain hierarchy.

The neural circuit of the brain is organized as a hierarchy of functional units with wide-ranging connections that support information flow and functional connectivity. Studies using MRI indicate a moderate coupling between structural and functional connectivity at the system level. However, how do connections of different directions (feedforward and feedback) and regions with different excitatory and inhibitory (E/I) neurons shape the hemodynamic activity and functional connectivity over the hierarchy are unknown. Here, we used functional MRI to detect optogenetic-evoked and resting-state activities over a somatosensory pathway in the mouse brain in relation to axonal projection and E/I distribution. Using a highly sensitive ultrafast imaging, we identified extensive activation in regions up to the third order of axonal projections following optogenetic excitation of the ventral posteriomedial nucleus of the thalamus. The evoked response and functional connectivity correlated with feedforward projections more than feedback projections and weakened with the hierarchy. The hemodynamic response exhibited regional and hierarchical differences, with slower and more variable responses in high-order areas and bipolar response predominantly in the contralateral cortex. Electrophysiological recordings suggest that these reflect differences in neural activity rather than neurovascular coupling. Importantly, the positive and negative parts of the hemodynamic response correlated with E/I neuronal densities, respectively. Furthermore, resting-state functional connectivity was more associated with E/I distribution, whereas stimulus-evoked effective connectivity followed structural wiring. These findings indicate that the structure-function relationship is projection-, cell-type- and hierarchy-dependent. Hemodynamic transients could reflect E/I activity and the increased complexity of hierarchical processing.

Cortical Networks Relating to Arousal Are Differentially Coupled to Neural Activity and Hemodynamics.

Even in the absence of specific sensory input or a behavioral task, the brain produces structured patterns of activity. This organized activity is modulated by changes in arousal. Here, we use wide-field voltage imaging to establish how arousal relates to cortical network voltage and hemodynamic activity in spontaneously behaving head-fixed male and female mice expressing the voltage-sensitive fluorescent FRET sensor Butterfly 1.2. We find that global voltage and hemodynamic signals are both positively correlated with changes in arousal with a maximum correlation of 0.5 and 0.25, respectively, at a time lag of 0 s. We next show that arousal influences distinct cortical regions for both voltage and hemodynamic signals. These include a broad positive correlation across most sensory-motor cortices extending posteriorly to the primary visual cortex observed in both signals. In contrast, activity in the prefrontal cortex is positively correlated to changes in arousal for the voltage signal while it is a slight net negative correlation observed in the hemodynamic signal. Additionally, we show that coherence between voltage and hemodynamic signals relative to arousal is strongest for slow frequencies below 0.15 Hz and is near zero for frequencies >1 Hz. We finally show that coupling patterns are dependent on the behavioral state of the animal with correlations being driven by periods of increased orofacial movement. Our results indicate that while hemodynamic signals show strong relations to behavior and arousal, these relations are distinct from those observed by voltage activity.

The Elusive Hypertrophy of the Python Heart.

The Burmese python, one of the world's largest snakes, has reached celebrity status for its dramatic physiological responses associated with digestion of enormous meals. The meals elicit a rapid gain of mass and function of most visceral organs, particularly the small intestine. There is also a manyfold elevation of oxygen consumption that demands the heart to deliver more oxygen. It therefore made intuitive sense when it was reported that the postprandial response entailed a 40% growth of heart mass that could accommodate a rise in stroke volume. Many studies, however, have not been able to reproduce the 40% growth of the heart. We collated published values on postprandial heart mass in pythons, which include several instances of no change in heart mass. On average, the heart mass is only 15% greater. The changes in heart mass did not correlate to the mass gain of the small intestine or peak oxygen consumption. Hemodynamic studies show that the rise in cardiac output does not require increased heart mass but can be fully explained by augmented cardiac filling and postprandial tachycardia. Under the assumption that hypertrophy is a contingent phenomenon, more recent experiments have employed two interventions such as feeding with a concomitant reduction in hematocrit. The results suggest that the postprandial response of the heart can be enhanced, but the 40% hypertrophy of the python heart remains elusive.

VascuViz: a multimodality and multiscale imaging and visualization pipeline for vascular systems biology.

Despite advances in imaging, image-based vascular systems biology has remained challenging because blood vessel data are often available only from a single modality or at a given spatial scale, and cross-modality data are difficult to integrate. Therefore, there is an exigent need for a multimodality pipeline that enables ex vivo vascular imaging with magnetic resonance imaging, computed tomography and optical microscopy of the same sample, while permitting imaging with complementary contrast mechanisms from the whole-organ to endothelial cell spatial scales. To achieve this, we developed 'VascuViz'-an easy-to-use method for simultaneous three-dimensional imaging and visualization of the vascular microenvironment using magnetic resonance imaging, computed tomography and optical microscopy in the same intact, unsectioned tissue. The VascuViz workflow permits multimodal imaging with a single labeling step using commercial reagents and is compatible with diverse tissue types and protocols. VascuViz's interdisciplinary utility in conjunction with new data visualization approaches opens up new vistas in image-based vascular systems biology.

Normalization of cerebral hemodynamics after hematopoietic stem cell transplant in children with sickle cell disease.

Children with sickle cell disease (SCD) demonstrate cerebral hemodynamic stress and are at high risk of strokes. We hypothesized that curative hematopoietic stem cell transplant (HSCT) normalizes cerebral hemodynamics in children with SCD compared with pre-transplant baseline. Whole-brain cerebral blood flow (CBF) and oxygen extraction fraction (OEF) were measured by magnetic resonance imaging 1 to 3 months before and 12 to 24 months after HSCT in 10 children with SCD. Three children had prior overt strokes, 5 children had prior silent strokes, and 1 child had abnormal transcranial Doppler ultrasound velocities. CBF and OEF of HSCT recipients were compared with non-SCD control participants and with SCD participants receiving chronic red blood cell transfusion therapy (CRTT) before and after a scheduled transfusion. Seven participants received matched sibling donor HSCT, and 3 participants received 8 out of 8 matched unrelated donor HSCT. All received reduced-intensity preparation and maintained engraftment, free of hemolytic anemia and SCD symptoms. Pre-transplant, CBF (93.5 mL/100 g/min) and OEF (36.8%) were elevated compared with non-SCD control participants, declining significantly 1 to 2 years after HSCT (CBF, 72.7 mL/100 g per minute; P = .004; OEF, 27.0%; P = .002), with post-HSCT CBF and OEF similar to non-SCD control participants. Furthermore, HSCT recipients demonstrated greater reduction in CBF (-19.4 mL/100 g/min) and OEF (-8.1%) after HSCT than children with SCD receiving CRTT after a scheduled transfusion (CBF, -0.9 mL/100 g/min; P = .024; OEF, -3.3%; P = .001). Curative HSCT normalizes whole-brain hemodynamics in children with SCD. This restoration of cerebral oxygen reserve may explain stroke protection after HSCT in this high-risk patient population.