Influence of contrast agent dispersion on bolus-based MRI myocardial perfusion measurements: A computational fluid dynamics study.

PURPOSE: Bolus-based dynamic contrast agent (CA) perfusion measurements of the heart are subject to systematic errors due to CA bolus dispersion in the coronary arteries. To better understand these effects on quantification of myocardial blood flow and myocardial perfusion reserve (MPR), an in-silico model of the coronary arteries down to the pre-arteriolar vessels has been developed. METHODS: In this work, a computational fluid dynamics analysis is performed to investigate these errors on the basis of realistic 3D models of the left and right porcine coronary artery trees, including vessels at the pre-arteriolar level. Using advanced boundary conditions, simulations of blood flow and CA transport are conducted at rest and under stress. These are evaluated with regard to dispersion (assessed by the width of CA concentration time curves and associated vascular transport functions) and errors of myocardial blood flow and myocardial perfusion reserve quantification. RESULTS: Contrast agent dispersion increases with traveled distance as well as vessel diameter, and decreases with higher flow velocities. Overall, the average myocardial blood flow errors are -28% ± 16% and -8.5% ± 3.3% at rest and stress, respectively, and the average myocardial perfusion reserve error is 26% ± 22%. The calculated values are different in the left and right coronary tree. CONCLUSION: Contrast agent dispersion is dependent on a complex interplay of several different factors characterizing the cardiovascular bed, including vessel size and integrated vascular length. Quantification errors evoked by the observed CA dispersion show nonnegligible distortion in dynamic CA bolus-based perfusion measurements. We expect future improvements of quantitative perfusion measurements to make the systematic errors described here more apparent.

Clinical Monitoring of Sacrococcygeal Teratoma.

BACKGROUND: Sacrococcygeal teratomas (SCT) are often highly vascularized and may result in high-output cardiac failure, polyhydramnios, fetal hydrops, and demise. Delivery is guided by the SCT to fetus volume ratio (SCTratio), SCT growth rate, and cardiac output indexed for weight (CCOi). METHODS: We compared measurements and outcome in 12 consecutive fetuses referred with SCT. Adverse outcomes were: fetal surgery, delivery < 32 gestational weeks or neonatal demise. Only SCTratio and CCOi were used to manage the cases. SCT vascularization index (VI%) was derived from the 3D virtual organ computer-aided analysis (VOCAL) software. The SCTModel (modified from acardiac twins) calculated a hypothetical SCT draining vein size and derived a risk line, using diameters of the superior and inferior vena cava, the azygous and umbilical veins. VI% and a model of systemic and umbilical venous volumes (SCTModel) were tested as indicators for outcome in SCT. RESULTS: Fetuses were monitored from 20.1 to 36.4 gestational weeks and 5/12 had adverse outcomes: 1 had successful open fetal surgery at 23.8 weeks and delivered at term, 4 delivered at < 32 weeks with 3/4 having neonatal demise between 25 and 29 weeks. VI% was significantly higher in cases with adverse outcomes (mean 10.3 [8.9-11.6] vs. 4.4 [3.4-5.3], p < 0.0001). The additional fraction of the fetal cardiac output required to perfuse the SCT-draining vein (XSCO%) (p = 0.46), SCTratio (p = 0.08), and CCOi (p = 0.64) were not significant. All cases with adverse outcome had VI% > 8%. The SCTModel risk line predicted nonadverse outcomes well but lacked data in 2/5 cases with adverse outcomes. CONCLUSIONS: VI% is a significant indicator of SCT cases with adverse outcomes and combined with SCTratio may guide timing of delivery better than current measures.

Impact of coronary bifurcation morphology on wave propagation.

The branching pattern of the coronary vasculature is a key determinant of its function and plays a crucial role in shaping the pressure and velocity wave forms measured for clinical diagnosis. However, although multiple scaling laws have been proposed to characterize the branching pattern, the implications they have on wave propagation remain unassessed to date. To bridge this gap, we have developed a new theoretical framework by combining the mathematical formulation of scaling laws with the wave propagation theory in the pulsatile flow regime. This framework was then validated in multiple species using high-resolution cryomicrotome images of porcine, canine, and human coronary networks. Results demonstrate that the forward well-matchedness (no reflection for pressure/flow waves traveling from the coronary stem toward the microcirculation) is a salient feature in the coronary vasculature, and this result remains robust under many scenarios of the underlying pulse wave speed distribution assumed in the network. This result also implies a significant damping of the backward traveling waves, especially for smaller vessels (radius, <0.3 mm). Furthermore, the theoretical prediction of increasing area ratios (ratio between the area of the mother and daughter vessels) in more symmetric bifurcations found in the distal circulation was confirmed by experimental measurements. No differences were observed by clustering the vessel segments in terms of transmurality (from epicardium to endocardium) or perfusion territories (left anterior descending, left circumflex, and right coronary artery).

Acardiac twin pregnancies part II: Fetal risk of chorangioma and sacrococcygeal teratoma predicted by pump/acardiac umbilical vein diameters.

BACKGROUND: We recently published pump/acardiac umbilical venous diameter (UVD) ratios, representing the pump twin's excess cardiac output fraction, of 27 acardiac twin pregnancies. There was a clear separation between the 17 pump twins that had life-threatening complications and the 10 that did not. The hypothesis of this study is that placental chorangioma and sacrococcygeal teratoma (SCT), tumors whose perfusion also causes high-output complications, have the same fetal outcome as pump twins when perfusion of the tumor requires the same excess cardiac output fraction. METHODS: We compared the three fetoplacental circulations. Fetuses with a placental chorangioma and acardiac twin pregnancies both have their feeding artery and draining vein located at the placental cord insertion. In contrast, SCT lacks a prescribed feeding artery and draining vein. We, therefore, had to modify our model to assume that the diameter of the hypothetical draining vein is related to the flow difference between inferior vena cava and superior vena cava. The latter flow has been estimated sonographically and is the same as the inferior vena cava flow in the absence of an SCT. Furthermore, a simple modification accounts for the different location of the tumor with respect to the placental cord insertion. RESULTS: We propose to apply the clinical pump/acardiac UVD ratios to pregnancies complicated by placental chorangiomas and the modified pump/acardiac UVD ratios for SCT. CONCLUSION: Risk prediction of these rare fetal tumors may be possible based on application of data on excess cardiac output fractions from pump/acardiac UVD ratios and will require future clinical validation. Birth Defects Research (Part A) 106:733-738, 2016. © 2016 Wiley Periodicals, Inc.

Hypothesis acardiac twin pregnancies: Pathophysiology-based hypotheses suggest risk prediction by pump/acardiac umbilical venous diameter ratios.

BACKGROUND: A total of 75% of monozygotic twins share 1 monochorionic placenta where placental anastomoses cause several serious complications, for example, acardiac twinning. Acardiac twins lack cardiac function but grow by perfusion of arterial blood from the pump twin. This rare pregnancy has 50% natural pump twin mortality but accurate risk prediction is currently impossible. Recent guidelines suggest prophylactic surgery before 18 weeks, suggesting 50% unnecessary interventions. We hypothesize that (1) adverse pump twin outcome relates to easy-to-measure pump/acardiac umbilical venous diameter (UVD) ratios, representing acardiac perfusion by the pump's excess cardiac output. This hypothesis suggests that (2) UVD-ratios are large, mildly varying in cases without complications but small and decreasing when complications develop, thus predicting that (3) UVD-ratios may allow risk prediction of pump twins. In this exploratory clinical pilot, we tested whether UVD-ratio measurements support these predictions. METHODS: We included 7 uncomplicated (expectant management), 3 elective surgical, and 17 complicated cases (pump decompensation, emergency intervention/delivery or demise). Nine UVD-ratios were measured sonographycally and 18 by pathology. RESULTS: Uncomplicated cases have larger, two serial measurements showing mildly varying UVD-ratios; elective surgical cases show larger UVD-ratios; complicated cases have smaller, two serial measurements showing decreasing UVD-ratios. There were no false-positives, no false-negatives and noncrossing linear trendlines of uncomplicated and complicated cohorts. CONCLUSION: Our data provide first evidence that UVD-ratios allow risk prediction of pump twins. More early uncomplicated and late complicated cases are needed, for example, in a prospective trial, before the separation between uncomplicated and complicated cohorts is accurate enough to support a well-founded decision on (early) intervention.

Acardiac twinning: High resolution three-dimensional reconstruction of a low resistance case.

BACKGROUND: Acardiac twinning is a rare anomaly of monochorionic twin pregnancies. Acardiac fetuses lack a functional heart but are passively perfused by arterial blood from their pump co-twin. Although four acardiac morphological types have been classified, the various paths of anatomical and circulatory acardiac twin development, and the potential influence of acardiac size and perfusion flow as possible predictors of pump twin morbidity and mortality are poorly understood. This report presents the first high resolution three-dimensional reconstruction of the vasculature of an acardiac twin by cryomicrotome imaging. CASE: A small, approximately 7.5-cm-diameter ball-shaped acardius amorphous of 30 5/7 weeks had caused pump twin cardiac decompensation that necessitated an emergency cesarian section. The pump twin survived well. The acardiac body had a partially intact vascular system with large diameter arteries and veins and multiple zones that appeared devoid of perfusion. The three-dimensional reconstruction showed neither recognizable organ structures nor identifiable blood vessels except for the umbilical artery and vein. CONCLUSION: Our case showed a small acardiac mass with large diameter vessels and consequential low outflow resistance that caused pump twin complications. This indicates that the development of a method that allows pump twin prognosis is likely more successful if based on the use of acardiac versus pump twin perfusion flows than on body volume ratios.

Microsphere skimming in the porcine coronary arteries: Implications for flow quantification.

Particle skimming is a phenomenon where particles suspended in fluid flowing through vessels distribute disproportionately to bulk fluid volume at junctions. Microspheres are considered a gold standard of intra-organ perfusion measurements and are used widely in studies of flow distribution and quantification. It has previously been hypothesised that skimming at arterial junctions is responsible for a systematic over-estimation of myocardial perfusion from microspheres at the subendocardium. Our objective is to integrate coronary arterial structure and microsphere distribution, imaged at high resolution, to test the hypothesis of microsphere skimming in a porcine left coronary arterial (LCA) network. A detailed network was reconstructed from cryomicrotome imaging data and a Poiseuille flow model was used to simulate flow. A statistical approach using Clopper-Pearson confidence intervals was applied to determine the prevalence of skimming at bifurcations in the LCA. Results reveal that microsphere skimming is most prevalent at bifurcations in the larger coronary arteries, namely the epicardial and transmural arteries. Bifurcations at which skimming was identified have significantly more asymmetric branching parameters. This finding suggests that when using thin transmural segments to quantify flow from microspheres, a skimming-related deposition bias may result in underestimation of perfusion in the subepicardium, and overestimation in the subendocardium.

Twin reversed arterial perfusion sequence is more common than generally accepted.

BACKGROUND: Approximately 75% of monozygotic twin pregnancies share one monochorionic placenta where placental anastomoses are virtually always present to connect the two fetoplacental circulations. These anastomoses cause several serious complications such as acardiac twinning. Acardiac twins lack a functional heart but nevertheless show fetal growth because the normal pump twin perfuses the acardiac body through arterioarterial (AA) and venovenous (VV) anastomoses. The widely accepted 1% monochorionic acardiac incidence dates back to 1944 and the associated 1:35,000 pregnancies to 1953. Our aim was to update this analysis. METHODS: We accepted the 1% (actually 1.1%) monochorionic acardiac incidence due to lack of more precise data, included the recently observed 58% early cessation of acardiac development as well as consequences of assisted reproductive technology, and assessed the incidence of acardiac twinning under conditions of AA-VV anastomoses. RESULTS: Early acardiac monochorionic twinning increased from 1.1% to 1.1/(1-0.58) = 2.6%, from 1:35,000 to 1:9,500 to 11,000 pregnancies, depending on number and method of assisted reproductive technology, and occurs in approximately 1:8 AA-VV anastomoses-containing monochorionic placentas. CONCLUSION: Early acardiac twinning is not a rare event. The 1944-based 1% acardiac monochorionic incidence has a weak basis and could therefore be (much) larger. Knowing this incidence more precisely may contribute to our knowledge of embryonic splitting in unequal cell masses.

Detection and quantification methods of monocyte homing in coronary vasculature with an imaging cryomicrotome.

Cellular imaging modalities are important for revealing the behavior and role of monocytes in response to neovascularization progression in coronary artery disease. In this study we aimed to develop methods for high-resolution three-dimensional (3D) imaging and quantification of monocytes relative to the entire coronary artery network using a novel episcopic imaging modality. In a series of ex vivo experiments, human umbilical vein endothelial cells and CD14+ monocytes were labeled with fluorescent live cell tracker probes and infused into the coronary artery network of excised rat hearts by a Langendorff perfusion method. Coronary arteries were subsequently infused with fluorescent vascular cast material and processed with an imaging cryomicrotome, whereby each heart was consecutively cut (5 µm slice thickness) and block face imaged at appropriate excitation and emission wavelengths. The resulting image stacks yielded 3D reconstructions of the vascular network and the location of cells administered. Successful detection and quantification of single cells and cell clusters were achieved relative to the coronary network using customized particle detection software. These methods were then applied to an in vivo rabbit model of chronic myocardial ischemia in which autologous monocytes were isolated from peripheral blood, labeled with a fluorescent live cell tracker probe and re-infused into the host animal. The processed 3D image stacks revealed homing of monocytes to the ischemic myocardial tissue. Monocytes detected in the ischemic tissue were predominantly concentrated in the mid-myocardium. Vessel segmentation identified coronary collateral connections relative to monocyte localization. This study established a novel imaging platform to efficiently determine the localization of monocytes in relation to the coronary microvascular network. These techniques are invaluable for investigating the role of monocyte populations in the progression of coronary neovascularization in animal models of chronic and sub-acute myocardial ischemia.

Innate collateral segments are predominantly present in the subendocardium without preferential connectivity within the left ventricular wall.

Functional collateral vessels often stem from outward remodelling of pre-existing connections between perfusion territories. Knowledge of the distribution and morphology of innate collateral connections may help in identifying myocardial areas with protection against risk for ischaemia. The coronary network of six healthy canine hearts was investigated with an imaging cryomicrotome. Innate collateral connections ranged from 286 to 1015 µm in diameter. Left ventricular collateral density (number per gram of tissue) was about five in the subendocardium vs. 2.5 in the mid-myocardium (P < 0.01) and 1.3 in the epicardium (P < 0.01). Subendocardial collateral connections were oriented parallel to the long axis of the heart. For the major coronary arteries, five times more intracoronary than intercoronary connections were found, while their median diameter and interquartile range were not significantly different, at 96.1 (16.9) vs. 94.7 (18.9) µm. Collateral vessels connecting crowns from sister branches from a stem are denoted intercrown connections and those within crowns intracrown connections. The number of intercrown connections was related to the mean tissue weight of the crowns (y = 0.73x - 0.33, r2 = 0.85, P < 0.0001). This relation was likewise found to describe intercoronary connections. The median collateral diameter and length were independent of the tissue volumes bridged. We conclude that connectivity and morphology of the innate collateral network are distributed with no preference for intra- or intercrown connections, independent of stem diameter, including epicardial arteries. This renders all sites of the myocardium equally protected in case of coronary artery disease. The orientation of subendocardial collateral vessels indicates the longitudinal direction of subendocardial collateral flow.

Quantitative assessment of magnetic resonance derived myocardial perfusion measurements using advanced techniques: microsphere validation in an explanted pig heart system.

BACKGROUND: Cardiovascular Magnetic Resonance (CMR) myocardial perfusion imaging has the potential to evolve into a method allowing full quantification of myocardial blood flow (MBF) in clinical routine. Multiple quantification pathways have been proposed. However at present it remains unclear which algorithm is the most accurate. An isolated perfused, magnetic resonance (MR) compatible pig heart model allows very accurate titration of MBF and in combination with high-resolution assessment of fluorescently-labeled microspheres represents a near optimal platform for validation. We sought to investigate which algorithm is most suited to quantify myocardial perfusion by CMR at 1.5 and 3 Tesla using state of the art CMR perfusion techniques and quantification algorithms. METHODS: First-pass perfusion CMR was performed in an MR compatible blood perfused pig heart model. We acquired perfusion images at physiological flow ("rest"), reduced flow ("ischaemia") and during adenosine-induced hyperaemia ("hyperaemia") as well as during coronary occlusion. Perfusion CMR was performed at 1.5 Tesla (n = 4 animals) and at 3 Tesla (n = 4 animals). Fluorescently-labeled microspheres and externally controlled coronary blood flow served as reference standards for comparison of different quantification strategies, namely Fermi function deconvolution (Fermi), autoregressive moving average modelling (ARMA), exponential basis deconvolution (Exponential) and B-spline basis deconvolution (B-spline). RESULTS: All CMR derived MBF estimates significantly correlated with microsphere results. The best correlation was achieved with Fermi function deconvolution both at 1.5 Tesla (r = 0.93, p < 0.001) and at 3 Tesla (r = 0.9, p < 0.001). Fermi correlated significantly better with the microspheres than all other methods at 3 Tesla (p < 0.002). B-spline performed worse than Fermi and Exponential at 1.5 Tesla and showed the weakest correlation to microspheres (r = 0.74, p < 0.001). All other comparisons were not significant. At 3 Tesla exponential deconvolution performed worst (r = 0.49, p < 0.001). CONCLUSIONS: CMR derived quantitative blood flow estimates correlate with true myocardial blood flow in a controlled animal model. Amongst the different techniques, Fermi function deconvolution was the most accurate technique at both field strengths. Perfusion CMR based on Fermi function deconvolution may therefore emerge as a useful clinical tool providing accurate quantitative blood flow assessment.

Disruption of hexokinase II-mitochondrial binding blocks ischemic preconditioning and causes rapid cardiac necrosis.

RATIONALE: Isoforms I and II of the glycolytic enzyme hexokinase (HKI and HKII) are known to associate with mitochondria. It is unknown whether mitochondria-bound hexokinase is mandatory for ischemic preconditioning and normal functioning of the intact, beating heart. OBJECTIVE: We hypothesized that reducing mitochondrial hexokinase would abrogate ischemic preconditioning and disrupt myocardial function. METHODS AND RESULTS: Ex vivo perfused HKII(+/-) hearts exhibited increased cell death after ischemia and reperfusion injury compared with wild-type hearts; however, ischemic preconditioning was unaffected. To investigate acute reductions in mitochondrial HKII levels, wild-type hearts were treated with a TAT control peptide or a TAT-HK peptide that contained the binding motif of HKII to mitochondria, thereby disrupting the mitochondrial HKII association. Mitochondrial hexokinase was determined by HKI and HKII immunogold labeling and electron microscopy analysis. Low-dose (200 nmol/L) TAT-HK treatment significantly decreased mitochondrial HKII levels without affecting baseline cardiac function but dramatically increased ischemia-reperfusion injury and prevented the protective effects of ischemic preconditioning. Treatment for 15 minutes with high-dose (10 µmol/L) TAT-HK resulted in acute mitochondrial depolarization, mitochondrial swelling, profound contractile impairment, and severe cardiac disintegration. The detrimental effects of TAT-HK treatment were mimicked by mitochondrial membrane depolarization after mild mitochondrial uncoupling that did not cause direct mitochondrial permeability transition opening. CONCLUSIONS: Acute low-dose dissociation of HKII from mitochondria in heart prevented ischemic preconditioning, whereas high-dose HKII dissociation caused cessation of cardiac contraction and tissue disruption, likely through an acute mitochondrial membrane depolarization mechanism. The results suggest that the association of HKII with mitochondria is essential for the protective effects of ischemic preconditioning and normal cardiac function through maintenance of mitochondrial potential.

Coronary pressure-flow relations as basis for the understanding of coronary physiology.

Recent technological advancements in the area of intracoronary physiology, as well as non-invasive contrast perfusion imaging, allow to make clinical decisions with respect to percutaneous coronary interventions and to identify microcirculatory coronary pathophysiology. The basic characteristics of coronary hemodynamics, as described by pressure-flow relations in the normal and diseased heart, need to be understood for a proper interpretation of these physiological measurements. Especially the hyperemic coronary pressure-flow relation, as well as the influence of cardiac function on it, bears great clinical significance. The interaction of a coronary stenosis with the coronary pressure-flow relation can be understood from the stenosis pressure drop-flow velocity relationship. Based on these relationships the clinically applied concepts of coronary flow velocity reserve, fractional flow reserve, stenosis resistance and microvascular resistance are discussed. Attention is further paid to the heterogeneous nature of myocardial perfusion, the vulnerability of the subendocardium and the role of collateral flow on hyperemic coronary pressure-flow relations. This article is part of a Special Issue entitled "Coronary Blood Flow".

Hypothesized pathogenesis of acardius acephalus, acormus, amorphus, anceps, acardiac edema, single umbilical artery, and pump twin risk prediction.

BACKGROUND: Acardiac twinning complicates monochorionic twin pregnancies in ≈2.6%, in which arterioarterial (AA) and venovenous placental anastomoses cause a reverse circulation between prepump and preacardiac embryos and cessation of cardiac function in the preacardiac. Literature suggested four acardiac body morphologies in which select (groups of) organs fail to develop, deteriorate, or become abnormal: acephalus (≈64%, [almost] no head, part of body, legs), amorphus (≈22%, amorphous tissue lump), anceps (≈10%, cranial bones, well-developed), and acormus (≈4%, head only). We sought to develop hypotheses that could explain acardiac pathogenesis, its progression, and develop methods for clinical testing. METHODS: We used qualitatively described pathophysiology during development, including twin-specific AA and Hyrtl's anastomoses, the short umbilical cord syndrome, high capillary permeability, properties of spontaneous aborted embryos, and Pump/Acardiac umbilical venous diameter (UVD) ratios. RESULTS: We propose that each body morphology has a specific pathophysiologic pathway. An acephalus acardius may be larger than an anceps, verifiable from UVD ratio measurements. A single umbilical artery develops when one artery, unconnected to the AA, vanishes due to flow reduction by Hyrtl's anastomotic resistance. Acardiac edema may result from acardiac body hypoxemia combined with physiological high fetal capillary permeability, high interstitial compliance and low albumin synthesis. Morphological changes may occur after acardiac onset. Pump twin risk follows from UVD ratios. CONCLUSION: Our suggested outcomes agree reasonably well with reported onset, incidence, and progression of acardiac morphologies. Guidance for clinical prediction and testing requires ultrasound anatomy/circulation study, from the first trimester onward.

Porcine coronary collateral formation in the absence of a pressure gradient remote of the ischemic border zone.

In the current paradigm on coronary collateral development, it is assumed that these vessels develop consequentially from increased fluid shear stress (FSS) through preexisting collateral arteries. The increased FSS follows from an increase in pressure gradient between the region at risk and well-perfused surroundings. The objective of this study was to test the hypothesis that, in the heart, collateral connections can form in the absence of an increased FFS and consequentially at any depth and region within the ventricular wall. In Yorkshire pigs, gradual left circumflex coronary artery occlusion was obtained over 6 wk by an ameroid constrictor, whereas the control group underwent a sham operation. Hearts were harvested and subsequently processed in an imaging cryomicrotome, resulting in 40-µm voxel resolution three-dimensional reconstructions of the intramural vascular vessels. Dedicated software segmented the intramural vessels and all continuous vascular pathways containing a collateral connection. In the ameroid group, 192 collaterals, 22-1,049 µm in diameter, were detected with 62% within the subendocardium. Sixty percent of collaterals bridged from the left anterior descending artery to left circumflex coronary artery. A novel result is that 25% (n = 48) of smaller-radius collaterals (P = 0.047) connected with both origin and terminus in the nontarget area where perfusion was assumed uncompromised. In the porcine heart, collateral vessels develop not only in ischemic border zones with increased FSS but also away from such border zones where increased FSS is unlikely. The majority of collaterals were located at the subendocardium, corresponding to the region with highest prevalence for ischemia.

Gradient changes in porcine renal arterial vascular anatomy and blood flow after cryoablation.

PURPOSE: We quantified temporal changes in vascular structure and blood flow after cryosurgery of the porcine kidney in vivo. MATERIALS AND METHODS: We studied 5 groups of 4 kidneys each with a survival time of 20 minutes, 4 hours, 2 days, and 1 and 2 weeks after cryoablation, respectively. Before harvesting the kidneys, fluorescently labeled microspheres were administrated in the descending aorta. After harvest the kidney and its vasculature were casted with fluorescently dyed elastomer, frozen and processed in an imaging cryomicrotome to reveal the 3-dimensional arterial branching structure and microsphere distribution. In regions of interest vessels were segmented by image analysis software and histograms were constructed to reveal the total summed vessel length as a function of diameter. A characteristic diameter of the ablated area was measured. RESULTS: The 20-minute survival group histograms showed a significant shift of the peak to larger diameters (p<0.002), indicating that smaller vessels were destroyed. Microsphere density was decreased to 2% in the ablated region but not in the nonablated border zone, depending on the remaining crater crossing larger vessels. After 2 weeks neither vessels nor microspheres were left in the ablated area, which had shrunk by about 40% in diameter. Study limitations are the lack of histological confirmation and the use of normal rather than cancerous tissue. CONCLUSIONS: Larger vessels remain patent just after ablation and transport blood to the border of the ablation crater but perfusion within the crater is halted instantly. Characteristic crater diameter increases initially but decreases thereafter. Destruction of vessels and tissue is complete 2 weeks after cryoablation.

Acardiac twin pregnancies part VI: Why does acardiac twinning occur only in the first trimester?

BACKGROUND: Clinical observation suggests that acardiac twinning occurs only in the first trimester. In part, this contradicts our previous analysis (part IV) of Benirschke's concept that unequal embryonic splitting causes unequal embryo/fetal blood volumes and pressures. Our aim is to explain why acardiac onset is restricted to the first trimester. METHODS: We applied the vascular resistance scheme of two fetuses connected by arterio-arterial (AA) and veno-venous (VV) anastomoses, the small VV resistance approximated as zero. The smaller twin has volume fraction α < 1 of the assumed normal larger twin, and has only access to fraction X < 1 of its placenta; the larger twin's larger mean arterial pressure accesses the remaining fraction. Before 13 weeks, embryos have a much smaller vascular resistance than placentas. After 13 weeks, when maternal blood provides oxygen, smaller twins can increase their vascular volume by hypoxemia-mediated neovascularization. Estimated AA radii at 40 weeks, rAA (40), are 0.5-1.3 mm. RESULTS: Embryos with α < 0.33 unlikely survive 13 weeks and acardiac twinning occurs under appropriate conditions (AA-VV, small placenta). Acardiac body perfusion occurs because of a much smaller vascular resistance than the placenta. When α > 0.33 and rAA (40)=1.3 mm, modeled survival is >32 weeks. CONCLUSION: Before 13 weeks, embryos with α < 0.33 cannot survive and may result in the onset of acardia. Beyond 13 weeks, fetuses with α ≥ 0.33 survive because rAA (40) is too small for acardiac onset. Following fetal demise, exsanguination from the live twin increases its blood volume and, we assumed also, its vascular resistance. Perfusion then occurs through the lower resistance placenta.

Acardiac twin pregnancies part V: Why does an acardiac twin with renal tissue produce polyhydramnios?

BACKGROUND: Acardiac twinning is a complication of monochorionic twin pregnancies. From literature reports, 30 of 41 relatively large acardiac twins with renal tissue produced polyhydramnios within their amniotic compartment. We aim to investigate the underlying mechanisms that cause excess amniotic fluid using an established model of fetal fluid dynamics. METHODS: We assumed that acardiac onset is before 13 weeks, acardiacs with renal tissue have normal kidney function and produce urine flow from 11 weeks on, and acardiac urine production requires a pressure of half the pump twin's mean arterial pressure. We apply a resistance network with the pump twin's arterio-venous pressure as source, pump umbilical arteries, placenta, placental arterio-arterial (AA) anastomoses and acardiac resistances. Acardiac amniotic fluid dynamics excluded acardiac lung fluid secretion, swallowing and the relatively small intramembranous flow. RESULTS: In small acardiacs with sufficient urine production, polyhydramnios will occur due to the lack of amniotic fluid resorption. Urine production is dependent upon having sufficient mean arterial pressure, which requires nearly a two-fold larger resistance within the acardiac as compared to the placental AA resistance. Subphysiologic arterial pressure may result in renal dysgenesis. CONCLUSION: Our findings suggest the potential for prediction of which clinical acardiac cases may or may not develop polyhydramnios based upon noninvasive assessments of renal tissue, blood flow and urine production. This information would be of great value in determining early obstetric interventions as opposed to conservative management. These findings may also contribute to an improved knowledge of the fascinating pathophysiology that surrounds acardiac twinning.

Why does second trimester demise of a monochorionic twin not result in acardiac twinning?

BACKGROUND: We previously explained why acardiac twinning occurs in the first trimester. We raised the question why a sudden demised monochorionic twin beyond the first trimester does not lead to acardiac twinning. We argued that exsanguinated blood from the live twin would strongly increase the demised twins' vascular resistance, preventing its perfusion and acardiac onset. However, our current hypothesis is that perfusion of the demised twin does occur but that it is insufficient for onset of acardiac twinning. METHODS: We analyzed blood pressures and flows in a vascular resistance model of a monochorionic twin pregnancy where one of the fetuses demised. The resistance model consists of a demised twin with a (former) placenta, a live twin and its placenta, and arterioarterial (AA) and venovenous placental anastomoses. We assumed that only twins with a weight of at least 33% of normal survived the first trimester and that exsanguination of more than 50% of its blood volume is fatal for the live twin. RESULTS: At 20 weeks, only AA anastomoses with radii ≲1 mm keep the exsanguinated blood volume below 50%. Then, perfusion of the deceased body with arterial blood from the live fetus is about 5-40 times smaller than when that body was alive. Beyond 20 weeks, this factor is even smaller. At 14 weeks, this factor is at most 2. CONCLUSION: We hypothesize that this small perfusion flow of arterial blood prevents further growth of the deceased body and hence precludes onset of acardiac twinning.