Assessment of liver function by gadoxetic acid avidity in MRI in a model of rapid liver regeneration in rats.

BACKGROUND: This animal study investigates the hypothesis of an immature liver growth following ALPPS (associating liver partition and portal vein ligation for staged hepatectomy) by measuring liver volume and function using gadoxetic acid avidity in magnetic resonance imaging (MRI) in models of ALPPS, major liver resection (LR) and portal vein ligation (PVL). METHODS: Wistar rats were randomly allocated to ALPPS, LR or PVL. In contrast-enhanced MRI scans with gadoxetic acid (Primovist®), liver volume and function of the right median lobe (=future liver remnant, FLR) and the deportalized lobes (DPL) were assessed until post-operative day (POD) 5. Liver functionFLR/DPL was defined as the inverse value of time from injection of gadoxetic acid to the blood pool-corrected maximum signal intensityFLR/DPL multiplied by the volumeFLR/DPL. RESULTS: In ALPPS (n = 6), LR (n = 6) and PVL (n = 6), volumeFLR and functionFLR increased proportionally, except on POD 1. Thereafter, functionFLR exceeded volumeFLR increase in LR and ALPPS, but not in PVL. Total liver function was significantly reduced after LR until POD 3, but never undercuts 60% of its pre-operative value following ALPPS and PVL. DISCUSSION: This study shows for the first time that functional increase is proportional to volume increase in ALPPS using gadoxetic acid avidity in MRI.

Cerebrospinal Fluid Pressure Dynamics as a Bedside Test in Traumatic Spinal Cord Injury to Assess Surgical Spinal Cord Decompression: Safety, Feasibility, and Proof-of-Concept.

BACKGROUND: Sufficient and timely spinal cord decompression is a critical surgical objective for neurological recovery in spinal cord injury (SCI). Residual cord compression may be associated with disturbed cerebrospinal fluid pressure (CSFP) dynamics. OBJECTIVES: This study aims to assess whether intrathecal CSFP dynamics in SCI following surgical decompression are feasible and safe, and to explore the diagnostic utility. METHODS: Prospective cohort study. Bedside lumbar CSFP dynamics and cervical MRI were obtained following surgical decompression in N = 9 with mostly cervical acute-subacute SCI and N = 2 patients with non-traumatic SCI. CSFP measurements included mean CSFP, cardiac-driven CSFP peak-to-valley amplitudes (CSFPp), Valsalva maneuver, and Queckenstedt's test (firm pressure on jugular veins, QT). From QT, proxies for cerebrospinal fluid pulsatility curve were calculated (ie, relative pulse pressure coefficient; RPPC-Q). CSFP metrics were compared to spine-healthy patients. computer tomography (CT)-myelography was done in 3/8 simultaneous to CSFP measurements. RESULTS: Mean age was 45 ± 9 years (range 17-67; 3F), SCI was complete (AIS A, N = 5) or incomplete (AIS B-D, N = 6). No adverse events related to CSFP assessments. CSFP rise during QT was induced in all patients [range 9.6-26.6 mmHg]. However, CSFPp was reduced in 3/11 (0.1-0.3 mmHg), and in 3/11 RPPC-Q was abnormal (0.01-0.05). Valsalva response was reduced in 8/11 (2.6-23.4 mmHg). CSFP dynamics corresponded to CT-myelography. CONCLUSIONS: Comprehensive bedside lumbar CSFP dynamics in SCI following decompression are safe, feasible, and can reveal distinct patterns of residual spinal cord compression. Longitudinal studies are required to define critical thresholds of impaired CSFP dynamics that may impact neurological recovery and requiring surgical revisions.

Characterising spinal cerebrospinal fluid flow in the pig with phase-contrast magnetic resonance imaging.

BACKGROUND: Detecting changes in pulsatile cerebrospinal fluid (CSF) flow may assist clinical management decisions, but spinal CSF flow is relatively understudied. Traumatic spinal cord injuries (SCI) often cause spinal cord swelling and subarachnoid space (SAS) obstruction, potentially causing pulsatile CSF flow changes. Pigs are emerging as a favoured large animal SCI model; therefore, the aim of this study was to characterise CSF flow along the healthy pig spine. METHODS: Phase-contrast magnetic resonance images (PC-MRI), retrospectively cardiac gated, were acquired for fourteen laterally recumbent, anaesthetised and ventilated, female domestic pigs (22-29 kg). Axial images were obtained at C2/C3, T8/T9, T11/T12 and L1/L2. Dorsal and ventral SAS regions of interest (ROI) were manually segmented. CSF flow and velocity were determined throughout a cardiac cycle. Linear mixed-effects models, with post-hoc comparisons, were used to identify differences in peak systolic/diastolic flow, and maximum velocity (cranial/caudal), across spinal levels and dorsal/ventral SAS. Velocity wave speed from C2/C3 to L1/L2 was calculated. RESULTS: PC-MRI data were obtained for 11/14 animals. Pulsatile CSF flow was observed at all spinal levels. Peak systolic flow was greater at C2/C3 (dorsal: - 0.32 ± 0.14 mL/s, ventral: - 0.15 ± 0.13 mL/s) than T8/T9 dorsally (- 0.04 ± 0.03 mL/s; p < 0.001), but not different ventrally (- 0.08 ± 0.08 mL/s; p = 0.275), and no difference between thoracolumbar levels (p > 0.05). Peak diastolic flow was greater at C2/C3 (0.29 ± 0.08 mL/s) compared to T8/T9 (0.03 ± 0.03 mL/s, p < 0.001) dorsally, but not different ventrally (p = 1.000). Cranial and caudal maximum velocity at C2/C3 were greater than thoracolumbar levels dorsally (p < 0.001), and T8/T9 and L1/L2 ventrally (p = 0.022). Diastolic velocity wave speed was 1.41 ± 0.39 m/s dorsally and 1.22 ± 0.21 m/s ventrally, and systolic velocity wave speed was 1.02 ± 0.25 m/s dorsally and 0.91 ± 0.22 m/s ventrally. CONCLUSIONS: In anaesthetised and ventilated domestic pigs, spinal CSF has lower pulsatile flow and slower velocity wave propagation, compared to humans. This study provides baseline CSF flow at spinal levels relevant for future SCI research in this animal model.

Cerebrospinal fluid pressure dynamics reveal signs of effective spinal canal narrowing in ambiguous spine conditions.

Spinal canal narrowing with consecutive spinal cord compression is considered a key mechanism in degenerative cervical myelopathy (DCM). DCM is a common spine condition associated with progressive neurological disability, and timely decompressive surgery is recommended. However, the clinical and radiological diagnostic workup is often ambiguous, challenging confident proactive treatment recommendations. Cerebrospinal fluid pressure dynamics (CSFP) are altered by spinal canal narrowing. Therefore, we aim to explore the potential value of bedside CSFP assessments for qualitative and quantitative assessment of spinal canal narrowing in DCM. In this prospective case series, seven patients with DCM underwent bedside lumbar puncture with measurement of CSFP dynamics and routine CSF analysis (NCT02170155). The patients were enrolled when standard diagnostic algorithms did not permit a clear treatment decision. Measurements include baseline CSFP, cardiac-driven CSFP peak-to-trough amplitude (CSFPp), and the Queckenstedt's test (firm pressure on jugular veins) in neutral and reclined head position. From the Queckenstedt's test, proxies for craniospinal elastance (i.e., relative pulse pressure coefficient; RPPC-Q) were calculated analogously to infusion testing. CSFP metrics were deemed suspicious of canal narrowing when numbers were lower than the minimum value from a previously tested elderly spine-healthy cohort (N = 14). Mean age was 56 ± 13 years (range, 38-75; 2F); symptom severity was mostly mild to moderate (mean mJOA, 13.5 ± 2.6; range, 9-17). All the patients showed some extent of cervical stenosis in the MRI of unclear significance (5/7 following decompressive cervical spine surgery with an adjacent level or residual stenosis). Baseline CSFP was normal except for one patient (range, 4.7-17.4 mmHg). Normal values were found for CSFPp (0.4-1.3 mmHg) and the Queckenstedt's test in normal head positioning (9.-25.3 mmHg). During reclination, the Queckenstedt's test significantly decreased in one, and CSFPp in another case (>50% compared to normal position). RPPC-Q (0.07-0.19) aligned with lower values from spine-healthy (0.10-0.44). Routine CSF examinations showed mild total protein elevation (mean, 522 ± 108 mg/ml) without further evidence for the disturbed blood brain barrier. Intrathecal CSFP measurements allow discerning disturbed from normal CSFP dynamics in this population. Prospective longitudinal studies should further evaluate the diagnostic utility of CSFP assessments in DCM.

Intraoperative Monitoring of CSF Pressure in Patients with Degenerative Cervical Myelopathy (COMP-CORD Study): A Prospective Cohort Study.

Degenerative cervical myelopathy (DCM) is hallmarked by spinal canal narrowing and related cord compression and myelopathy. Cerebrospinal fluid (CSF) pressure dynamics are likely disturbed due to spinal canal stenosis. The study aimed to investigate the diagnostic value of continuous intraoperative CSF pressure monitoring during surgical decompression. This prospective single center study (NCT02170155) enrolled DCM patients who underwent surgical decompression between December 2019 and May 2021. Data from n = 17 patients were analyzed and symptom severity graded with the modified Japanese Orthopedic Score (mJOA). CSF pulsations were continuously monitored with a lumbar intrathecal catheter during surgical decompression. Mean patient age was 62 ± 9 years (range 38-73; 8 female), symptoms were mild-moderate in most patients (mean mJOA 14 ± 2, range 10-18). Measurements were well tolerated without safety concerns. In 15/16 patients (94%), CSF pulsations increased at the time of surgical decompression. In one case, responsiveness could not be evaluated for technical reasons. Unexpected CSF pulsation decrease was related to adverse events (i.e., CSF leakage). Median CSF pulsation amplitudes increased from pre-decompression (0.52 mm Hg, interquartile range [IQR] 0.71) to post-decompression (0.72 mm Hg, IQR 0.96; p = 0.001). Mean baseline CSF pressure increased with lower magnitude than pulsations, from 9.5 ± 3.5 to 10.3 ± 3.8 mm Hg (p = 0.003). Systematic relations of CSF pulsations were confined to surgical decompression, independent of arterial blood pressure (p = 0.927) or heart rate (p = 0.102). Intraoperative CSF pulsation monitoring was related to surgical decompression while in addition adverse events could be discerned. Further investigation of the clinical value of intraoperative guidance for decompression in complex DCM surgery is promising.

Shape irregularity of the intracranial aneurysm lumen exhibits diagnostic value.

BACKGROUND: Morphological irregularity is linked to intracranial aneurysm wall instability and manifests in the lumen shape. Yet there is currently no consent on how to assess shape irregularity. The aims of this work are to quantify irregularity as perceived by clinicians, to break down irregularity into morphological attributes, and to relate these to clinically relevant factors such as rupture status, aneurysm location, and patient age or sex. METHODS: Thirteen clinicians and 26 laypersons assessed 134 aneurysm lumen segmentations in terms of overall perceived irregularity and five different morphological attributes (presence/absence of a rough surface, blebs, lobules, asymmetry, complex geometry of the parent vasculature). We examined rater agreement and compared the ratings with clinical factors by means of regression analysis or binary classification. RESULTS: Using rank-based aggregation, the irregularity ratings of clinicians and laypersons did not differ statistically. Perceived irregularity showed good agreement with curvature (coefficient of determination R2 = 0.68 ± 0.08) and was modeled very accurately using the five morphological rating attributes plus shape elongation (R2 = 0.95 ± 0.02). In agreement with previous studies, irregularity was associated with aneurysm rupture status (AUC = 0.81 ± 0.08); adding aneurysm location as an explanatory variable increased the AUC to 0.87 ± 0.09. Besides irregularity, perceived asymmetry, presence of blebs or lobules, aneurysm size, non-sphericity, and curvature were linked to rupture. No association was found between morphology and any of patient sex, age, and history of smoking or hypertension. Aneurysm size was linked to morphology. CONCLUSIONS: Irregular lumen shape carries significant information on the aneurysm's disease status. Irregularity constitutes a continuous parameter that shows a strong association with the rupture status. To improve the objectivity of morphological assessment, we suggest examining shape through six different morphological attributes, which can characterize irregularity accurately.

Hypoxia sensing by hepatic stellate cells leads to VEGF-dependent angiogenesis and may contribute to accelerated liver regeneration.

Portal vein ligation (PVL) induces liver growth prior to resection. Associating liver partition and portal vein ligation (PVL plus transection=ALPPS) or the addition of the prolyl-hydroxylase inhibitor dimethyloxalylglycine (DMOG) to PVL both accelerate growth via stabilization of HIF-α subunits. This study aims at clarifying the crosstalk of hepatocytes (HC), hepatic stellate cells (HSC) and liver sinusoidal endothelial cells (LSEC) in accelerated liver growth. In vivo, liver volume, HC proliferation, vascular density and HSC activation were assessed in PVL, ALPPS, PVL+DMOG and DMOG alone. Proliferation of HC, HSC and LSEC was determined under DMOG in vitro. Conditioned media experiments of DMOG-exposed cells were performed. ALPPS and PVL+DMOG accelerated liver growth and HC proliferation in comparison to PVL. DMOG alone did not induce HC proliferation, but led to increased vascular density, which was also observed in ALPPS and PVL+DMOG. Activated HSC were detected in ALPPS, PVL+DMOG and DMOG, again not in PVL. In vitro, DMOG had no proliferative effect on HC, but conditioned supernatant of DMOG-treated HSC induced VEGF-dependent proliferation of LSEC. Transcriptome analysis confirmed activation of proangiogenic factors in hypoxic HSC. Hypoxia signaling in HSC induces VEGF-dependent angiogenesis. HSC play a crucial role in the cellular crosstalk of rapid liver regeneration.

Generation of renal Epo-producing cell lines by conditional gene tagging reveals rapid HIF-2 driven Epo kinetics, cell autonomous feedback regulation, and a telocyte phenotype.

Erythropoietin (Epo) is essential for erythropoiesis and is mainly produced by the fetal liver and the adult kidney following hypoxic stimulation. Epo regulation is commonly studied in hepatoma cell lines, but differences in Epo regulation between kidney and liver limit the understanding of Epo dysregulation in polycythaemia and anaemia. To overcome this limitation, we have generated a novel transgenic mouse model expressing Cre recombinase specifically in the active fraction of renal Epo-producing (REP) cells. Crossing with reporter mice confirmed the inducible and highly specific tagging of REP cells, located in the corticomedullary border region where there is a steep drop in oxygen bioavailability. A novel method was developed to selectively grow primary REP cells in culture and to generate immortalized clonal cell lines, called fibroblastoid atypical interstitial kidney (FAIK) cells. FAIK cells show very early hypoxia-inducible factor (HIF)-2α induction, which precedes Epo transcription. Epo induction in FAIK cells reverses rapidly despite ongoing hypoxia, suggesting a cell autonomous feedback mechanism. In contrast, HIF stabilizing drugs resulted in chronic Epo induction in FAIK cells. RNA sequencing of three FAIK cell lines derived from independent kidneys revealed a high degree of overlap and suggests that REP cells represent a unique cell type with properties of pericytes, fibroblasts, and neurons, known as telocytes. These novel cell lines may be helpful to investigate myofibroblast differentiation in chronic kidney disease and to elucidate the molecular mechanisms of HIF stabilizing drugs currently in phase III studies to treat anemia in end-stage kidney disease.

Virtual surgical planning, flow simulation, and 3-dimensional electrospinning of patient-specific grafts to optimize Fontan hemodynamics.

BACKGROUND: Despite advances in the Fontan procedure, there is an unmet clinical need for patient-specific graft designs that are optimized for variations in patient anatomy. The objective of this study is to design and produce patient-specific Fontan geometries, with the goal of improving hepatic flow distribution (HFD) and reducing power loss (Ploss), and manufacturing these designs by electrospinning. METHODS: Cardiac magnetic resonance imaging data from patients who previously underwent a Fontan procedure (n = 2) was used to create 3-dimensional models of their native Fontan geometry using standard image segmentation and geometry reconstruction software. For each patient, alternative designs were explored in silico, including tube-shaped and bifurcated conduits, and their performance in terms of Ploss and HFD probed by computational fluid dynamic (CFD) simulations. The best-performing options were then fabricated using electrospinning. RESULTS: CFD simulations showed that the bifurcated conduit improved HFD between the left and right pulmonary arteries, whereas both types of conduits reduced Ploss. In vitro testing with a flow-loop chamber supported the CFD results. The proposed designs were then successfully electrospun into tissue-engineered vascular grafts. CONCLUSIONS: Our unique virtual cardiac surgery approach has the potential to improve the quality of surgery by manufacturing patient-specific designs before surgery, that are also optimized with balanced HFD and minimal Ploss, based on refinement of commercially available options for image segmentation, computer-aided design, and flow simulations.

In vivo characterization of the integration and vascularization of a silk-derived surgical scaffold.

BACKGROUND: The application of acellular matrices, biomaterials, and polymeric scaffolds in reconstructive surgery facilitates postsurgical tissue remodeling and is increasingly used clinically in order to improve tissue healing and implant coverage. This study presents an in vivo investigation of the integration of the knitted, silk-derived surgical scaffold, SERI(®) with regard to angiogenesis and wound healing. METHODS: SERI(®) Surgical Scaffold was implanted into a full-thickness skin defect in male C57BL/6J mice (n = 45) via the dorsal skinfold chamber (DSC). Skin tissue samples were collected for histology on days 2, 5, 7, 10, 14, and 21 (n = 5 per time point) post implantation. Immunohistochemistry was performed for various angiogenic and inflammatory markers, as well as collagen deposition (CD31, VEGF, CD3, CD45, Desmin, and Sirius red). Vascular corrosion casting was used to assess the neovasculature within the silk and was visualized with scanning electron microscopy. RESULTS: We observed both early and late stages of inflammation during the healing process characterized by the infiltration of regenerating tissue by different subsets of leukocytes. Histological analysis displayed capillary-containing granulation tissue with full scaffold integration. In addition, collagen deposition within the scaffold and full skin defect was significantly increased over time. Qualitative analysis of the regenerated vasculature through corrosion casting and scanning electron microscopy revealed a complex, angiogenic network of capillaries originating from the wound bed. CONCLUSIONS: Based on these findings, SERI(®) displays the potential to be a promising resorbable bioengineered material for use in reconstructive surgery.

Patient-Specific Surgical Planning, Where Do We Stand? The Example of the Fontan Procedure.

The Fontan surgery for single ventricle heart defects is a typical example of a clinical intervention in which patient-specific computational modeling can improve patient outcome: with the functional heterogeneity of the presenting patients, which precludes generic solutions, and the clear influence of the surgically-created Fontan connection on hemodynamics, it is acknowledged that individualized computational optimization of the post-operative hemodynamics can be of clinical value. A large body of literature has thus emerged seeking to provide clinically relevant answers and innovative solutions, with an increasing emphasis on patient-specific approaches. In this review we discuss the benefits and challenges of patient-specific simulations for the Fontan surgery, reviewing state of the art solutions and avenues for future development. We first discuss the clinical impact of patient-specific simulations, notably how they have contributed to our understanding of the link between Fontan hemodynamics and patient outcome. This is followed by a survey of methodologies for capturing patient-specific hemodynamics, with an emphasis on the challenges of defining patient-specific boundary conditions and their extension for prediction of post-operative outcome. We conclude with insights into potential future directions, noting that one of the most pressing issues might be the validation of the predictive capabilities of the developed framework.

Phantom model of physiologic intracranial pressure and cerebrospinal fluid dynamics.

We describe herein a novel life-size phantom model of the intracranial cavity and its validation. The cerebrospinal fluid (CSF) domains including ventricular, cysternal, and subarachnoid spaces were derived via magnetic resonance imaging. Brain mechanical properties and cranio-spinal compliance were set based on published data. Both bulk and pulsatile physiologic CSF flow were modeled. Model validation was carried out by comparisons of flow and pressure measurements in the phantom with published in vivo data of healthy subjects. Physiologic intracranial pressure with 10 mmHg mean and 0.4 mmHg peak pulse amplitude was recorded in the ventricles. Peak CSF flow rates of 0.2 and 2 ml/s were measured in the cerebral aqueduct and subarachnoid space, respectively. The phantom constitutes a first-of-its-kind approach to modeling physiologic intracranial dynamics in vitro. Herein, we describe the phantom design and manufacturing, definition and implementation of its operating parameters, as well as the validation of the modeled dynamics.

A mathematical method for the 3D analysis of rotating deformable systems applied on lumen-forming MDCK cell aggregates.

Cell motility contributes to the formation of organs and tissues, into which multiple cells self-organize. However such mammalian cellular motilities are not characterized in a quantitative manner and the systemic consequences are thus unknown. A mathematical tool to decipher cell motility, accounting for changes in cell shape, within a three-dimensional (3D) cell system was missing. We report here such a tool, usable on segmented images reporting the outline of clusters (cells) and allowing the time-resolved 3D analysis of circular motility of these as parts of a system (cell aggregate). Our method can analyze circular motility in sub-cellular, cellular, multi-cellular, and also non-cellular systems for which time-resolved segmented cluster outlines are available. To exemplify, we characterized the circular motility of lumen-initiating MDCK cell aggregates, embedded in extracellular matrix. We show that the organization of the major surrounding matrix fibers was not significantly affected during this cohort rotation. Using our developed tool, we discovered two classes of circular motion, rotation and random walk, organized in three behavior patterns during lumen initiation. As rotational movements were more rapid than random walk and as both could continue during lumen initiation, we conclude that neither the class nor the rate of motion regulates lumen initiation. We thus reveal a high degree of plasticity during a developmentally critical cell polarization step, indicating that lumen initiation is a robust process. However, motility rates decreased with increasing cell number, previously shown to correlate with epithelial polarization, suggesting that migratory polarization is converted into epithelial polarization during aggregate development.

Long-term follow-up, computed tomography, and computational fluid dynamics of the Cabrol procedure.

OBJECTIVES: The Cabrol procedure is characterized by insertion of an ascending aortic composite graft with reimplantation of the coronary arteries by the interposition of a graft tube. Our purpose is to report the clinical long-term follow-up and computed tomographic findings in patients having undergone the Cabrol procedure and to determine blood flow in the Cabrol graft using computational fluid dynamics. METHODS: Clinical follow-up (76.6 +/- 16.6 months) and dual-source computed tomographic angiography data of 7 patients (all men, mean age 54.9 +/- 9.6 years) with 12 Cabrol grafts (left main coronary artery, n = 7; right coronary artery, n = 5) were reviewed. In 2 patients, the right coronary artery was directly reattached to the aortic graft. Computational fluid dynamics were calculated using computed tomographic data of a patient with the Cabrol procedure and compared with those in a Valsalva graft and a healthy aortic root. RESULTS: Computed tomography showed Cabrol graft occlusions to 1 of 7 (14%) left main and of 2 of 5 (40%) right coronary arteries. Six grafts to the left main and 3 to the right coronary artery were fully patent, similar to the 2 directly reattached right coronary arteries to the aortic graft. Computational fluid dynamics results show similar blood flow parameters into the coronaries for the healthy aortic root and Valsalva graft. In the Cabrol graft, a spiraling flow pattern with low flow into the right coronary artery was found (right coronary artery = 1 mL/min at both systole and diastole). CONCLUSIONS: Our study indicates low flow rates particularly in the right Cabrol graft correlating with a higher incidence of occlusions of the right as compared with the left Cabrol graft at long-term follow-up.

Ex vivo and in vivo coronary ostial locations in humans.

PURPOSE: Knowledge of the normal in vivo distribution and variation of coronary ostial locations is essential in the planning of various interventional and surgical procedures. However, all studies to date have reported the distribution of coronary ostia locations only in cadaver hearts. In this study, we sought to assess the distribution of coronary ostial locations in patients using cardiac dual-source computed tomography (CT) and compare these values to those of human cadaveric specimens. METHODS: Measurements of the coronary ostia location were performed in 150 patients undergoing dual-source CT and in 75 cadavers using open measurement techniques. All 150 patients had a normal aortic valve function and no previous cardiac intervention or surgery. The location of the right and left coronary origin in relation to the aortic annulus and the height of the sinus of Valsalva were measured. RESULTS: Mean ostial locations at CT were 17.0 (+/-3.6) mm and 15.3 (+/-3.1) mm for the right and left coronary ostia, with large variations of both sides (right: 10.4-28.5 mm; left: 9.8-29.3 mm). In cadavers, mean locations were 14.9 (+/-4.3) mm [5-24 mm] for right and 16.0 (+/-3.6) mm [9-24 mm] for left coronary ostia. Comparison of CT and cadaver data showed statistically significant differences for right (P < 0.0001) but not left (P = 0.1675) coronary ostia. CONCLUSIONS: This study provides data of normal coronary ostial origins and demonstrates significant differences between in vivo and ex vivo measurements regarding the right coronary ostium. The observed large variations of coronary ostia origins emphasize the importance of considering such anatomic variations in the development of treatments.