Performance and failure of right ventricle to pulmonary artery conduit in congenital heart disease.

INTRODUCTION: Surgical implantation of a right ventricle to pulmonary artery (RV-PA) conduit is an important component of congenital heart disease (CHD) surgery but with limited durability leading to re-intervention. Current single-center, retrospective, cohort study is reporting results of surgically implanted RV-PA conduits in a consecutive series of children and adults with CHD. METHODS: Patients with CHD referred for RV-PA conduits surgical implantation (October 1997 and January 2022) have been included. Primary outcome was conduit failure defined as peak gradient above 64mmHg/severe regurgitation/need for conduit-related interventions. Longitudinal echocardiographic studies were available for mixed-effect linear regression analysis. RESULTS: Two-hundred and fifty-two patients were initially included. One hundred and forty-nine patients were elegible for follow-up data collection. After a median follow-up time of 49 months the primary study endpoint occurred in 44 (29%) patients. Multivariable Cox regression model identified adult age (>18 years) at implantation and pulmonary homograft as protective factors (HR 0.11, 95% CI 0.02-0.47 and HR 0.34, 95% CI 0.16-0.74, respectively). Fever within 7 days of surgical conduit implantation was a risk factor for early (within 24 months) failure (OR 4.29, 95% CI 1.41-13.01). Longterm use of oral anticoagulant was independently associated with slower progression of peak echocardiographic gradient across conduits (mixed effect linear regression p-value 0.027). CONCLUSION: In patients with CHD, surgically implanted RV-PA conduit failure is faster in children and after non-homograft conduit implantation. Early fever after surgery is a strong risk factor for early failure. Longterm anticoagulation seems to exert a protective effect.

The functional lumen imaging probe contractile response pattern is the best predictor of botulinum toxin response in esophagogastric junction outflow obstruction.

BACKGROUND: Esophagogastric junction outflow obstruction (EGJOO) is a heterogenous disorder in which the correct management strategy is unclear. We assessed whether functional lumen imaging probe (FLIP) topography data could select EGJOO, which would benefit from lower esophageal sphincter Botulinum toxin (Botox) injection. METHODS: This was a single-center prospective study of adult patients meeting Chicago Classification (CC) v3.0 criteria for EGJOO. We assessed differences in pretreatment physiologic measurements on high-resolution manometry (HRM) and FLIP and other relevant clinical variables in predicting Botox response (>50% in BEDQ at 2 months). KEY RESULTS: Sixty-nine patients were included (ages 33-90, 73.9% female). Of these, 42 (61%) were Botox responders. Majority of physiologic measures on HRM and FLIP and esophageal emptying were not different based on Botox response. However, a spastic-reactive (SR) FLIP contractile response (CR) pattern predicted a Botox response with OR 25.6 (CI 2.9-229.6) when compared to antegrade FLIP CR; and OR for impaired-disordered/absent CR was 22.5 (CI 2.5-206.7). Logistic regression model using backward elimination (p value = 0.0001, AUC 0.79) showed that a SRCR or IDCR/absent response and the upright IRP predicted Botox response. Response rates in tiered diagnostic groups were: (i) CCv3.0 EGJOO (60.9%), (ii) CCv4.0 EGJOO (73.1%), (iii) CCv4.0 + FLIP REO (80%), (iv) CCv4.0, FLIP REO, and abnormal FLIP CR (84.2%), and (v) CCv4.0, FLIP REO, and SR FLIP CR (90%). CONCLUSIONS AND INFERENCES: FLIP helps identify patients with EGJOO who are likely to response to LES Botox therapy. An abnormal FLIP contractile response pattern is the single-most important predictor of a Botox response.

Flow Analysis of Central Venous Outflow Tract: A New Approach to Understanding Pulse-Synchronous Tinnitus.

OBJECTIVE: Pulse-synchronous tinnitus (PST) has been linked to multiple anatomical variants of the central venous outflow tract (CVOT) including sigmoid sinus (SS) dehiscence and diverticulum. This study investigates flow turbulence, pressure, and wall shear stress along the CVOT and proposes a mechanism that results in SS dehiscence and PST. STUDY DESIGN: Case series. SETTING: Tertiary Academic Center. METHODS: Venous models were reconstructed from computed tomography scans of 3 patients with unilateral PST. Two models for each patient are obtained: a symptomatic and contralateral asymptomatic side. A turbulent model-enabled commercial flow solver was used to simulate the pulsatile blood flow over the cardiac cycle through the models. Fluid flow through the transverse and SS junction was analyzed to observe the velocity, pressure, turbulent kinetic energy (TKE), and shear stress over a simulated cardiac cycle. RESULTS: Fluid flow on the symptomatic side showed increased vorticity in the presence of an SS diverticulum. Higher TKE with periodicity following the cardiac cycle was observed on the symptomatic side, and a sharp increase was observed if SS diverticulum was present. Shear stress was highest near the narrowest segments of the vessel. Pressure was observed to be lower on the symptomatic side at the transverse-SS junction for all 3 patients. CONCLUSION: Computational fluid dynamics modeling of blood flow through the CVOT in PST suggests that low pressure may be the cause of dehiscence, and tinnitus may result from periodic increases in TKE.

A Re-do Repair of Tetralogy of Fallot With an Anomalous Coronary Artery Using a Valved Conduit for the Right Ventricular Outflow Tract Reconstruction.

Several techniques can be used for the repair of right ventricular outflow tract (RVOT) stenosis in patients with an anomalous coronary artery. Here, we report a case of conduit obstruction after re-operation following double-tract reconstruction and release of stenosis by main pulmonary artery transection and conduit replacement. The patient is a female child diagnosed with tetralogy of Fallot with an anomalous coronary artery (right coronary across right ventricle outflow) who underwent correction with a double-tract RVOT repair at the age of 10 months (weight: 8 kg). At the age of eight years (weight: 24 kg), a conduit re-implantation procedure was required because of an increase in body weight. Designing smooth conduits proved challenging due to the anomalous coronary artery and a short main pulmonary arterial trunk. RVOT stenosis was documented early postoperatively, and further intervention was deemed necessary. At 13 years of age (weight: 45 kg), the patient underwent implantation of an adult-size valved conduit. Transection of the main pulmonary artery and extensive mobilization of the bilateral pulmonary arteries were effective in creating a relative laminar blood flow. Postoperative evaluations confirmed that the conduit was well-shaped and had satisfactory valve functionality. This case highlights the potential difficulties involved with replacing an additional conduit after double-tract cardiac repair procedures, particularly due to anatomical constraints posed by a coronary artery and a short pulmonary arterial trunk. Main pulmonary artery transection and comprehensive mobilization of branch pulmonary arteries can be a solution to conduit design difficulties in RVOT reconstruction after double-tract cardiac repair procedures.

Rescue of outflow block of the remnant left liver after extended right hemihepatectomy for resection of a tumor in the caudate lobe.

Outflow block of the liver is a life-threatening event after living donor liver transplantation. Herein, we rescued a patient suffering from the outflow block of the remnant left hemiliver caused by bending of the left hepatic vein (LHV) after right hemihepatectomy plus caudate lobectomy combined with resection of the middle hepatic vein (MHV). A metastatic tumor sized 6 cm in the caudate lobe of the liver involving the root of the MHV was found in a 50's year old patient after resection of a right breast cancer eight years ago. Right hemihepatectomy and caudate lobectomy combined with resection of the MHV was performed using a two-stage hepatectomy (partial TIPE ALPPS). On day 1, the total bilirubin value increased to 4.5 mg/dL, and a dynamic computed tomography (CT) scan showed the bent LHV. On the diagnosis of outflow block of the left liver, a self-expandable metallic stent was placed in the LHV using an interventional approach, and the pressure in the LHV decreased from 27 cmH2O to 12 cmH2O. The bilirubin value decreased to 1.2 mg/dL on day 3. Outflow block of the LHV can happen after extended right hemihepatectomy with resection of the MHV. Early diagnosis and interventional stenting treatment can rescue the patient from congestive liver failure.

Unmasking obstruction in hypertrophic cardiomyopathy with postprandial resting and treadmill stress echocardiography.

BACKGROUND: Latent left ventricular outflow tract obstruction (LVOTO) is an important cause of symptoms in patients with hypertrophic cardiomyopathy (HCM) but can be challenging to provoke. OBJECTIVES AND METHODS: To examine the value of postprandial resting and stress echocardiography and utilization of invasive or enhanced drug therapies (surgical myectomy, alcohol septal ablation, disopyramide and mavacamten) in patients with postprandial LVOTO. Consecutive HCM patients without LVOTO underwent routine and postprandial echocardiography at rest, with provocation (Valsalva and standing) and after symptom-limited treadmill stress. RESULTS: Among 252 patients (mean age 58 years, 39% women), postprandial LVOT gradients were higher compared with routine echocardiography at rest (median 9.0 [0-38.0] vs 0 [0-14.0] mmHg, p<0.0001) and with provocation (18.5 [0-70.3] vs 1.5 [0-41.0] mmHg, p<0.0001). Postprandial exercise (PPXSE) gradients were higher in a subset of 44 patients who underwent both postprandial and fasting stress echocardiography, (47.0 [5.3-81.0] vs 17.5 [0-46.0] mmHg, p<0.0001). In total, 49 (19.5%) patients achieved the ≥50 mmHg threshold under routine conditions (rest/provocation); 90 (35.7%) additional patients achieved postprandial gradients ≥50 mmHg (rest/provocation/exercise), 38 (15.1%) with PPXSE alone. A total of 71 patients were treated with 91 invasive or enhanced drug therapies, 32 (45.1%) of whom had gradients ≥50 mmHg only after eating (rest/provocation) and 8 (11.3%) only with PPXSE, with symptom relief in the majority. CONCLUSIONS: Postprandial echocardiography was useful at unmasking LVOTO in more than one third of patients who did not have high gradients otherwise. Eating before echocardiography is a powerful provocative tool in the evaluation of patients with HCM.

Fluid Responsiveness and Management in Obstetrics using Point-of-Care Ultrasound.

Fluid management in obstetric care is crucial due to the complex physiological conditions of pregnancy, which complicate clinical manifestations and fluid balance management. This expert review examines the use of point-of-care ultrasound (POCUS) to evaluate and monitor the response to fluid therapy in pregnant patients. Pregnancy induces significant physiological changes, including increased cardiac output and glomerular filtration rate, decreased systemic vascular resistance, and plasma oncotic pressure. Conditions like preeclampsia further complicate fluid management due to decreased intravascular volume and increased capillary permeability. Traditional methods of assessing fluid volume status, such as physical examination and invasive monitoring, are often unreliable or inappropriate. POCUS provides a non-invasive, rapid, and reliable means to assess fluid responsiveness, which is essential in managing fluid therapy in pregnant patients. This review details various POCUS modalities used to measure dynamic changes in fluid status, focusing on the evaluation of the inferior vena cava (IVC), lung ultrasound (Lung US), and the left ventricular outflow tract (LVOT). IVC ultrasound in spontaneously breathing patients determines diameter variability, predicting fluid responsiveness and being feasible even late in pregnancy. Lung ultrasound is critical for detecting early signs of pulmonary edema before clinical symptoms arise and is more accurate than traditional radiography. The LVOT velocity-time integral (VTI) assesses stroke volume response to fluid challenges, providing a quantifiable measure of cardiac function, especially beneficial in critical care settings where rapid and accurate fluid management is essential. The expert review synthesizes current evidence and practice guidelines, suggesting integrating POCUS as a fundamental aspect of fluid management in obstetrics. It calls for ongoing research to enhance techniques and validate their use in broader clinical settings, aiming to improve outcomes for pregnant patients and their babies by preventing complications associated with both under- and over-resuscitation.

Validation of the area under the Watts factor curve during the voiding cycle as a novel parameter for diagnosing detrusor underactivity in females.

OBJECTIVE: Detrusor underactivity (DU) is a common cause of lower urinary tract symptoms (LUTS). To date, no consensus has been reached on the urodynamic criteria for defining DU. We previously proposed the area under the curve of the Watts factor (WF-AUC) as a new parameter for diagnosing DU. By comparing previously reported five criteria for DU and WF-AUC, we analyzed whether the WF-AUC could assess detrusor contraction in women with LUTS. METHODS: Using urodynamic data of consecutive 77 women with LUTS, first, we classified DU based on previously reported five criteria. Second, we assessed the potential correlation between multiple parameters and WF-AUC. Third, receiver operating characteristic curve analysis was performed to determine the cutoff value of WF-AUC for diagnosing DU based on previously reported five criteria. Fourth, a linear regression analysis was conducted and compared using multiple criteria and female bladder outlet obstruction index (BOOIf). RESULTS: WF-AUC was positively correlated with the maximum values of WF, bladder contractility index (BCI), and projected isovolumetric pressure 1 (PIP1) with correlation coefficients of 0.63, 0.57, and 0.34, respectively. AUC for diagnosing DU based on previously reported five criteria ranging from 0.773 to 0.896 with different cutoff values of AUC-WF. The Spearman's correlation test revealed that BOOIf was significantly correlated with BCI, but not Wmax, PIP1 and WF-AUC. CONCLUSIONS: This study demonstrated the non-inferiority of the WF-AUC compared to previously reported criteria for defining DU. Depending on the cutoff value, the WF-AUC could appropriately evaluate women with DU, regardless of the presence of BOO.

The prognostic value of right ventricular outflow tract velocity time integral in patients with pulmonary hypertension.

AIMS: Right ventricular (RV) failure is one of the leading causes of death in patients with pulmonary hypertension (PH). Conventional echocardiographic parameters are not included in risk stratification and follow-up for prognostic assessment due to PH's diverse nature and the RV's complex geometry. RV outflow tract velocity time integral (RVOT VTI) is a simple, non-invasive estimate of pulmonary flow and an echocardiographic surrogate of RV stroke volume. In this study, we aimed to define the prognostic value of RVOT VTI in PH patients. METHODS: Sixty-three subjects with idiopathic PAH (IPAH) (n = 23), connective tissue disease-associated PAH (CTD-associated PAH) (n = 19) and chronic thromboembolic pulmonary hypertension (CTEPH) (n = 21) were retrospectively included. A comprehensive two-dimensional echocardiographic evaluation, including RVOT-VTI measurement, was performed during the follow-up and the New York Heart Association functional class (NYHA FC), 6 min walk distance (6MWD) and brain natriuretic peptide (BNP) levels were recorded. RESULTS: The median age of the whole cohort was 63 years (52-68), and 47 (74.6%) of the patients were women. The median follow-up period was 20 months (11-33), and 20 (31.7%) patients died in this period. BNP values were higher [317 (210-641) vs 161 (47-466), P = 0.02], and 6MWD values were lower [197.5 ± 89.5 vs 339 ± 146.3, P < 0.0001] in the non-survivor group, and the non-survivor group had a worse NYHA-FC (P = 0.02). Among echocardiographic data, tricuspid annular plane systolic excursion (TAPSE) (15.4 ± 4.8 vs 18.6 ± 4.2, P = 0.01) and RVOT VTI (11.9 ± 4.1 vs 17.2 ± 4.3, P < 0.0001) values were lower whereas right atrial area (RAA) (26.9 ± 10.1 vs 22.2 ± 7.1, P = 0.04) values were higher in the non-survivor group. The area under curve of the RVOT VTI for predicting mortality was 0.82 [95% confidence interval (CI) 0.715-0.940, P < 0.0001], and the best cut-off value was 14.7 cm with a sensitivity of 80% and specificity of 77%. Survival was significantly lower in subjects with RVOT VTI ≤ 14.7 cm (log-rank P < 0.0001). Survival rates for patients with RVOT VTI ≤ 14.7 cm were 70% at 1 year, 50% at 2 years, %29 at 3 years and 21% at 5 years. The univariate determinants of all-cause mortality were BNP [hazard ratio (HR) 1.001 (1.001-1.002), P = 0.001], 6MWD [HR 0.994 (0.990-0.999), P = 0.012] and NYHA-FC III-IV [HR 3.335 (1.103-10.083), P = 0.03], TAPSE [HR 0.838 (0.775-0.929), P = 0.001], RAA [HR 1.072 (1.013-1.135), P = 0.016] and RVOT VTI [HR 0.819 (0.740-0.906), P < 0.0001]. RVOT VTI was found to be the only independent determinant of mortality [HR 0.857 (0.766-0.960), P = 0.008]. CONCLUSIONS: The decreased RVOT VTI predicts mortality in patients with PH and each 1 mm decrease in RVOT VTI increases the risk of mortality by 14.3%. This parameter might serve as an additional parameter in the follow-up of these patients especially when 6MWD and NYHA-FC could not be determined.

[Comparative evaluation of transscleral laser exposure in anatomical experiment]. / Sravnitel'naya otsenka lazernogo transskleral'nogo vozdeistviya v usloviyakh anatomicheskogo eksperimenta.

PURPOSE: This study comparatively analyzed the morphology of eye tissues after laser exposure using the latest generation of transscleral laser techniques - micropulse transscleral cyclophotocoagulation (MP-TSCPC) and laser activation of scleral hydropermeability (LASH) - in an anatomical experiment. MATERIAL AND METHODS: The study used pulsed-periodic radiation of an Er-glass fiber laser (λ=1.56 µm) and radiation of a diode laser (λ=0.81 µm) in the micropulse mode. A comparative morphological evaluation of histological preparations of target scleral and ciliary body (CB) tissues was performed with the study of laser-induced changes occurring after LASH and MP-TSCPC. RESULTS: The study of histological preparations obtained after MP-TSCPC and LASH did not reveal any noticeable signs of an inflammatory reaction or significant destructive changes. There were no signs of pronounced coagulative changes in the form of disorganization of connective and muscle tissue in the exposure area. At the same time, MP-TSCPC was accompanied by thinning and discontinuity of the CB pigment epithelium in the projection of its flat part and expansion of the gaps between the anterior connective tissue fibers fixing the CB to the sclera, which is likely a factor contributing to uveoscleral outflow. After LASH, in the irradiated areas at the level of the outer layers of the sclera (¾ of its thickness) located in the projection of the flat part of the ciliary body, multiple slit-like cavities and enlargements (stretching) of interfiber spaces were revealed with simultaneous compaction of the inner part of the sclera (» of its thickness). CONCLUSION: The identified morphological changes may indicate certain differences in the mechanisms of intraocular pressure (IOP) reduction after MP-TSCPC and LASH. The results of this study suggest that the enhancement of uveoscleral outflow of intraocular fluid and the hypotensive effect after MP-TSCPC may be associated with laser-induced expansion of the interspaces between the anterior connective tissue fibers of the CB in the suprachoroidal space. With LASH, the possible mechanism of lowering IOP may be related rather to an increase in transscleral filtration due to the appearance of slit-like interfiber spaces in the sclera, caused by local contraction of scleral fibers in the area of laser exposure. The absence of pronounced destructive changes at the histological level indicates the gentle nature of both laser techniques and the possibility of expanding the indications for the use of LASH in the treatment of glaucoma, including at its earlier stages.

Successful management of ischaemic symptoms in a patient with asymmetric septal hypertrophy: a grand round case report.

Background: Hypertrophic cardiomyopathy (HCM) is a genetic heart disease that can lead to heart failure, atrial fibrillation, and ischaemic symptoms. Managing patients with HCM and ischaemic symptoms is challenging, and several treatment options have been proposed. Case summary: A 30-year-old male patient presented with severe chest pain that had been ongoing for more than 30 min at rest. He was diagnosed with HCM and had periodic chest pain since the age of 14. He underwent two separate ethyl alcohol ablations of the first septal branches of the left anterior descending and posterior descending arteries, which relieved his symptoms. Discussion: This case report highlights the challenges in managing patients with HCM and ischaemic symptoms. In this patient, the use of ethyl alcohol ablation was effective in reducing left ventricular outflow tract obstruction and improving symptoms. Ethyl alcohol ablation is a minimally invasive procedure that has been shown to be effective in symptomatic patients with HCM. Overall, this case report emphasizes the importance of individualized treatment for patients with HCM and the potential benefits of alcohol ablation in this population.

Uveoscleral Outflow Routes after MicroPulse Laser Therapy for Refractory Glaucoma: An Optical Coherence Tomography Study of the Sclera.

To analyze in vivo scleral changes induced by MicroPulse transscleral laser therapy (MP-TLT) in refractory glaucoma using anterior segment-optical coherence tomography (AS-OCT). Forty-two candidate patients for MP-TLT were consecutively enrolled and underwent AS-OCT at baseline and after six months. MP-TLT success was defined as an intraocular pressure (IOP) reduction by one-third. The main outcome measures were the mean superior (S-), inferior (I-), and total (T-) intra-scleral hypo-reflective space area (MISHA: mm2) and scleral reflectivity (S-SR, I-SR, T-SR; arbitrary scale) as in vivo biomarkers of uveoscleral aqueous humor (AH) outflow. The IOP was the secondary outcome. The relations between the baseline-to-six months differences (D) of DS-MISHA, DI-MISHA, and DT-MISHA and DS-SR, DI-SR, DT-SR, and DIOP, were investigated. At 6 months, the median IOP reduction was 21% in the failures and 38% in the successes. The baseline S-MISHA, I-MISHA, and T-MISHA did not differ between the groups, while S-SR and T-SR were higher in the successes (p < 0.05). At six months, successful and failed MP-TLTs showed a 50% increase in S-MISHA (p < 0.001; p = 0.037), whereas I-SR and T-SR reduced only in the successes (p = 0.002; p = 0.001). When comparing DS-MISHA, DI-MISHA, and DT-MISHA and DS-SR, DI-SR, and DT-SR, there were no significant differences between the groups. In the successful procedures, DIOP was positively correlated with DT-MISHA and DI-MISHA (ρ = 0.438 and ρ = 0.490; p < 0.05). MP-TLT produced potentially advantageous modifications of the sclera in refractory glaucoma. Given the partial correlation between these modifications and post-treatment IOP reduction, our study confirmed that the activation of the uveoscleral AH outflow route could significantly contribute to the IOP lowering after MP-TLT.

Histologic Findings of Sinusoidal Dilatation and Congestion in Liver Grafts Do Not Correlate with Hepatic Venous Anastomotic Gradients.

PURPOSE: Hepatic venous transplant anastomotic pressure gradient measurement and transjugular liver biopsy are commonly used in clinical decision-making in patients with suspected anastomotic hepatic venous outflow obstruction. This investigation aimed to determine if sinusoidal dilatation and congestion on histology are predictive of hepatic venous anastomotic outflow obstruction, and if it can help select patients for hepatic vein anastomosis stenting. MATERIALS AND METHODS: This is a single-center retrospective study of 166 transjugular liver biopsies in 139 patients obtained concurrently with transplant venous anastomotic pressure gradient measurement. Demographic characteristics, laboratory parameters, procedure and clinical data, and histology of time-zero allograft biopsies were analyzed. RESULTS: No relationship was found between transplant venous anastomotic pressure gradient and sinusoidal dilatation and congestion (P = 0.92). Logistic regression analysis for sinusoidal dilatation and congestion confirmed a significant relationship with reperfusion/preservation injury and/or necrosis of the allograft at time-zero biopsy (OR 6.6 [1.3-33.1], P = 0.02). CONCLUSION: There is no relationship between histologic sinusoidal dilatation and congestion and liver transplant hepatic vein anastomotic gradient. In this study group, sinusoidal dilatation and congestion is a nonspecific histopathologic finding that is not a reliable criterion to select patients for venous anastomosis stenting.

Constrictive versus compressive bladder outflow obstruction in men: Does it matter?

INTRODUCTION: Bladder outflow obstruction (BOO) is a urethral resistance (UR) at a level above a clinically relevant threshold. UR is currently graded in terms of the existence and severity of the BOO based on maximum flowrate and associated detrusor pressure only. However, the pressure-flow relation throughout the course of voiding includes additional information that may be relevant to identify the type of BOO. This study introduces a new method for the distinction between the provisionally called compressive and constrictive types of BOO and relates this classification to underlying patient and urodynamic differences between those BOO types. METHODS: In total, 593 high-quality urodynamic pressure-flow studies in men were included in this study. Constrictive BOO was identified if the difference Δp between the actual minimal urethral opening pressure (pmuo) and the expected pmuo according to the linearized passive urethral resistance relation (linPURR) nomogram was >25 cmH2O. Compressive BOO is identified in the complementary case where the pressure difference Δp ≤ 25 cmH2O. Differences in urodynamic parameters, patient age, and prostate size were explored. RESULTS: In 81 (13.7%) of the cases, constrictive BOO was found. In these patients, the prostate size was significantly smaller when compared to patients diagnosed with compressive BOO, while displaying a significantly lower maximum flowrate, higher detrusor pressure at maximal flowrate and more postvoid residual (PVR). CONCLUSION: This study is an initial step in the validation of additional subtyping of BOO. We found significant differences in prostate size, severity of BOO, and PVR, between patients with compressive and constrictive BOO. Subtyping of voiding-outflow dynamics may lead to more individualized management in patients with BOO.

Development and characterization of a chronic high intraocular pressure model in New Zealand white rabbits for glaucoma research.

Glaucoma is a neurodegenerative disease characterized by visual field loss associated with optic nerve damage and ocular hypertension. The biological basis for the elevated intraocular pressure (IOP) is largely unknown, such that lowering the IOP is currently the only established treatment. Several animal models have been developed to elucidate the mechanism underlying the increased IOP and for use in drug discovery research, but their utility is often limited by the occurrence of severe intraocular inflammation and by technical challenges. In this study, we developed a rabbit glaucoma model that does not require experimental disease induction. Rabbits were chosen as the model because their eyeballs are similar in size to those of humans, and they are easy to breed. By crossing rabbit strains with inherited glaucoma, as indicated by obvious buphthalmos, we produced a strain that exhibits ocular hypertension. The IOP of the Ocular Hypertension (OH) rabbits was significantly higher than that of the wild type (WT; normal New Zealand white rabbits) from the age of 3 weeks to at least 22 weeks. The significantly larger corneal diameter of the OH rabbits indicated ocular enlargement, whereas there was no significant difference in corneal thickness compared with WT rabbits. Anterior segment ocular coherence tomography and gonioscopic observations revealed an open angle in the OH rabbits. Hematoxylin and eosin (HE) staining together with Masson's trichrome staining showed abnormal collagen accumulation in the angle of the OH rabbit's eyes. Furthermore, aqueous humor (AH) outflow imaging following an intravitreal injection of a fluorescent probe into the anterior chamber for tissue-section analysis revealed retention of the probe in the area of collagen deposition in the OH eyes. The OH rabbits also had a time-dependent increase in the cup/disc ratio. In conclusion, investigations using our newly developed rabbit model of open-angle ocular hypertension showed that abnormal accumulation of extracellular matrix at the angle increased AH outflow resistance in the conventional outflow pathway, leading to a high IOP. Furthermore, the OH rabbits exhibited glaucomatous optic disc cupping over time. These findings suggest the utility of the OH rabbits as a model for open-angle glaucoma (OAG).

A new Prdm1-Cre line is suitable for studying the second heart field development.

The second heart field (SHF) plays a pivotal role in heart development, particularly in outflow tract (OFT) morphogenesis and septation, as well as in the expansion of the right ventricle (RV). Two mouse Cre lines, the Mef2c-AHF-Cre (Mef2c-Cre) and Isl1-Cre, have been widely used to study the SHF development. However, Cre activity is triggered not only in the SHF but also in the RV in the Mef2c-Cre mice, and in the Isl1-Cre mice, Cre activation is not SHF-specific. Therefore, a more suitable SHF-Cre line is desirable for better understanding SHF development. Here, we generated and characterized the Prdm1-Cre knock-in mice. In comparison with Mef2c-Cre mice, the Cre activity is similar in the pharyngeal and splanchnic mesoderm, and in the OFT of the Prdm1-Cre mice. Nonetheless, it was noticed that Cre expression is largely reduced in the RV of Prdm1-Cre mice compared to the Mef2c-Cre mice. Furthermore, we deleted Hand2, Nkx2-5, Pdk1 and Tbx20 using both Mef2c-Cre and Prdm1-Cre mice to study OFT morphogenesis and septation, making a comparison between these two Cre lines. New insights were obtained in understanding SHF development including differentiation into cardiomyocytes in the OFT using Prdm1-Cre mice. In conclusion, we found that Prdm1-Cre mouse line is a more appropriate tool to monitor SHF development, while the Mef2c-Cre mice are excellent in studying the role and function of the SHF in OFT morphogenesis and septation.