Quantitative Evaluation of Right Ventricular Workload Based on the Stroke Work Index in Patients after Right Ventricular Outflow Tract Reconstruction.

The evaluation of right ventricular workload is sometimes complicated in patients after right ventricular outflow tract reconstruction (RVOTR) because both stenotic and regurgitation lesions are involved. In this study, we modified the right ventricular stroke work index (RVSWI) and evaluated the relationship between the modified RVSWI (mRVSWI) and patient prognosis after RVOTR.We enrolled 69 patients who underwent RVOTR (the RVOTR group), including those who needed early reoperation (early reoperation subgroup) and those who did not (follow-up subgroup), and 13 age-matched control participants (control group). Based on the catheterization results 1 year after RVOTR, we compared the mRVSWI between these groups. Additionally, we evaluated the influence of the mRVSWI on the reoperation avoidance rate and survival.The mRVSWI in the RVOTR group was significantly greater than that in the control group (17.7 ± 8.6 vs. 11.0 ± 2.7 g·m/m2, p = 0.008). The mRVSWI in the early reoperation subgroup was significantly greater than that in the follow-up subgroup (32.5 ± 11.1 vs. 15.8 ± 6.0 g·m/m2, p < 0.0001). In the follow-up subgroup, patients with an mRVSWI higher than the upper limit of normal (16.4 g·m/m2) had a greater rate of reoperation than did the other patients (p = 0.0013). One patient died suddenly, and her mRVSWI was consistently high throughout her life.We established the mRVSWI as an index that integrates the pressure and volume load on the right ventricle. Our results indicate the utility of the mRVSWI for predicting patient prognosis after RVOTR.

Mediterranean G6PD variant mitigates expression of DNA methyltransferases and right heart pressure in experimental model of pulmonary hypertension.

DNA methylation potentially contributes to the pathogenesis of pulmonary hypertension (PH). However, the role of DNA methyltransferases (DNMTs: 1, 3a, and 3b), the epigenetic writers, in modulating DNA methylation observed in PH remains elusive. Our objective was to determine DNMT activity and expression in the lungs of experimental rat models of PH. Because the activity of DNMTs is metabolically driven, another objective was to determine the role of glucose-6-phosphate dehydrogenase (G6PD) in regulating DNMT expression and activity in the lungs of novel loss-of-function Mediterranean G6PD variant (G6PDS188F) rats. As outlined for modeling PH, rats injected with sugen5416 (SU) were placed in a hypoxia (Hx) chamber set at 10% oxygen for 3 weeks and then returned to normoxia (Nx) for 5 weeks (SU/Hx/Nx). Rats kept in atmospheric oxygen and treated with SU were used as controls. We assessed the activity and expression of DNMTs in the lungs of rats exposed to SU/Hx/Nx. WT rats exposed to SU/Hx/Nx developed hypertension and exhibited increased DNMT activity and Dnmt1 and Dnmt3b expression. In G6PDS188F rats, which developed less of a SU/Hx/Nx-induced increase in right ventricle pressure and hypertrophy than WT rats, we observed a diminished increase in expression and activity of DNMTs, DNA hypomethylation, increased histone acetylation and methylation, and increased expression of genes encoding NOS3 and SOD2-vascular-protective proteins. Collectively, increased DNMTs contribute to reduced expression of protective genes and to the pathogenesis of SU/Hx/Nx-induced experimental PH. Notably, G6PD regulates the expression of DNMTs and protective proteins in the lungs of hypertensive rats.

G6PD activity contributes to the regulation of histone acetylation and gene expression in smooth muscle cells and to the pathogenesis of vascular diseases.

We aimed to determine 1) the mechanism(s) that enables glucose-6-phosphate dehydrogenase (G6PD) to regulate serum response factor (SRF)- and myocardin (MYOCD)-driven smooth muscle cell (SMC)-restricted gene expression, a process that aids in the differentiation of SMCs, and 2) whether G6PD-mediated metabolic reprogramming contributes to the pathogenesis of vascular diseases in metabolic syndrome (MetS). Inhibition of G6PD activity increased (>30%) expression of SMC-restricted genes and concurrently decreased (40%) the growth of human and rat SMCs ex vivo. Expression of SMC-restricted genes decreased (>100-fold) across successive passages in primary cultures of SMCs isolated from mouse aorta. G6PD inhibition increased Myh11 (47%) while decreasing (>50%) Sca-1, a stem cell marker, in cells passaged seven times. Similarly, CRISPR-Cas9-mediated expression of the loss-of-function Mediterranean variant of G6PD (S188F; G6PDS188F) in rats promoted transcription of SMC-restricted genes. G6PD knockdown or inhibition decreased (48.5%) histone deacetylase (HDAC) activity, enriched (by 3-fold) H3K27ac on the Myocd promoter, and increased Myocd and Myh11 expression. Interestingly, G6PD activity was significantly higher in aortas from JCR rats with MetS than control Sprague-Dawley (SD) rats. Treating JCR rats with epiandrosterone (30 mg/kg/day), a G6PD inhibitor, increased expression of SMC-restricted genes, suppressed Serpine1 and Epha4, and reduced blood pressure. Moreover, feeding SD control (littermates) and G6PDS188F rats a high-fat diet for 4 mo increased Serpine1 and Epha4 expression and mean arterial pressure in SD but not G6PDS188F rats. Our findings demonstrate that G6PD downregulates transcription of SMC-restricted genes through HDAC-dependent deacetylation and potentially augments the severity of vascular diseases associated with MetS.NEW & NOTEWORTHY This study gives detailed mechanistic insight about the regulation of smooth muscle cell (SMC) phenotype by metabolic reprogramming and glucose-6-phosphate dehydrogenase (G6PD) in diabetes and metabolic syndrome. We demonstrate that G6PD controls the chromatin modifications by regulating histone deacetylase (HDAC) activity, which deacetylates histone 3-lysine 9 and 27. Notably, inhibition of G6PD decreases HDAC activity and enriches H3K27ac on myocardin gene promoter to enhance the expression of SMC-restricted genes. Also, we demonstrate for the first time that G6PD inhibitor treatment accentuates metabolic and transcriptomic reprogramming to reduce neointimal formation in coronary artery and large artery elastance in metabolic syndrome rats.

Inhibition of Glucose-6-Phosphate Dehydrogenase Activity Attenuates Right Ventricle Pressure and Hypertrophy Elicited by VEGFR Inhibitor + Hypoxia.

Pulmonary hypertension (PH) is a disease of hyperplasia of pulmonary vascular cells. The pentose phosphate pathway (PPP)-a fundamental glucose metabolism pathway-is vital for cell growth. Because treatment of PH is inadequate, our goal was to determine whether inhibition of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the PPP, prevents maladaptive gene expression that promotes smooth muscle cell (SMC) growth, reduces pulmonary artery remodeling, and normalizes hemodynamics in experimental models of PH. PH was induced in mice by exposure to 10% oxygen (Hx) or weekly injection of vascular endothelial growth factor receptor blocker [Sugen5416 (SU); 20 mg kg-1] during exposure to hypoxia (Hx + SU). A novel G6PD inhibitor (N-[(3ß,5α)-17-oxoandrostan-3-yl]sulfamide; 1.5 mg kg-1) was injected daily during exposure to Hx. We measured right ventricle (RV) pressure and left ventricle pressure-volume relationships and gene expression in lungs of normoxic, Hx, and Hx + SU and G6PD inhibitor-treated mice. RV systolic and end-diastolic pressures were higher in Hx and Hx + SU than normoxic control mice. Hx and Hx + SU decreased expression of epigenetic modifiers (writers and erasers), increased hypomethylation of the DNA, and induced aberrant gene expression in lungs. G6PD inhibition decreased maladaptive expression of genes and SMC growth, reduced pulmonary vascular remodeling, and decreased right ventricle pressures compared with untreated PH groups. Pharmacologic inhibition of G6PD activity, by normalizing activity of epigenetic modifiers and DNA methylation, efficaciously reduces RV pressure overload in Hx and Hx + SU mice and preclinical models of PH and appears to be a safe pharmacotherapeutic strategy. SIGNIFICANCE STATEMENT: The results of this study demonstrated that inhibition of a metabolic enzyme efficaciously reduces pulmonary hypertension. For the first time, this study shows that a novel inhibitor of glucose-6-phosphate dehydrogenase, the rate-limiting enzyme in the fundamental pentose phosphate pathway, modulates DNA methylation and alleviates pulmonary artery remodeling and dilates pulmonary artery to reduce pulmonary hypertension.

Hypoxic activation of glucose-6-phosphate dehydrogenase controls the expression of genes involved in the pathogenesis of pulmonary hypertension through the regulation of DNA methylation.

Metabolic reprogramming is considered important in the pathogenesis of the occlusive vasculopathy observed in pulmonary hypertension (PH). However, the mechanisms that link reprogrammed metabolism to aberrant expression of genes, which modulate functional phenotypes of cells in PH, remain enigmatic. Herein, we demonstrate that, in mice, hypoxia-induced PH was prevented by glucose-6-phosphate dehydrogenase deficiency (G6PDDef), and further show that established severe PH in Cyp2c44-/- mice was attenuated by knockdown with G6PD shRNA or by G6PD inhibition with an inhibitor (N-ethyl-N'-[(3ß,5α)-17-oxoandrostan-3-yl]urea, NEOU). Mechanistically, G6PDDef, knockdown and inhibition in lungs: 1) reduced hypoxia-induced changes in cytoplasmic and mitochondrial metabolism, 2) increased expression of Tet methylcytosine dioxygenase 2 (Tet2) gene, and 3) upregulated expression of the coding genes and long noncoding (lnc) RNA Pint, which inhibits cell growth, by hypomethylating the promoter flanking region downstream of the transcription start site. These results suggest functional TET2 is required for G6PD inhibition to increase gene expression and to reverse hypoxia-induced PH in mice. Furthermore, the inhibitor of G6PD activity (NEOU) decreased metabolic reprogramming, upregulated TET2 and lncPINT, and inhibited growth of control and diseased smooth muscle cells isolated from pulmonary arteries of normal individuals and idiopathic-PAH patients, respectively. Collectively, these findings demonstrate a previously unrecognized function for G6PD as a regulator of DNA methylation. These findings further suggest that G6PD acts as a link between reprogrammed metabolism and aberrant gene regulation and plays a crucial role in regulating the phenotype of cells implicated in the pathogenesis of PH, a debilitating disorder with a high mortality rate.

Improved design of peptides exhibiting angiogenic activities for clinical applications.

Vascularization is one of the key steps for engraftment in regenerative medicine. Previously one of the authors had discovered peptides exhibiting significant angiogenic activities designated AGP and elucidated the active core. For neovascularization basic fibroblast growth factor is used although permeation can be envisaged. The original AGPs did not suffer from this although their half-life times are short because of decomposition by endogenous enzymes. Several new AGP-libraries have been constructed and their enzymatic resistance has been investigated by the use of human umbilical vein endothelial cells to find candidates for clinical applications.

Flow Energy Loss as a Predictive Parameter for Right Ventricular Deterioration Caused by Pulmonary Regurgitation After Tetralogy of Fallot Repair.

The optimal timing for pulmonary valve replacement after Tetralogy of Fallot (TOF) repair remains controversial. In this study, we estimated the feasibility of using flow energy loss (FEL) to predict right ventricular (RV) deterioration due to pulmonary regurgitation after TOF repair. We examined RV outflow tract (RVOT) flow in nine patients who underwent TOF or double-outlet right ventricle repair in the intervention group (Group I) and compared them with three healthy children in the control group (Group C). We evaluated flow across the RVOT and pulmonary valve by vector flow mapping (VFM) on echocardiography and by phase contrast-magnetic resonance imaging (PC-MRI). Next, we calculated FEL and analyzed the relationship between FEL and clinical parameters of RV function. The mean FEL was significantly greater in Group I than in Group C (p = 0.002). Flow pattern and FEL were comparable by VFM and PC-MRI at the same phase 14.6 years after TOF repair. There was a significant positive correlation for the cardiothoracic ratio with both the mean FEL [correlation coefficient (r) = 0.78; p = 0.012] and the diastolic peak FEL (r = 0.75; p = 0.021) in Group I. There was also a significant positive correlation between the serial change in QRS duration with both the mean FEL (r = 0.82; p = 0.014) and the diastolic FEL (r = 0.70; p = 0.052) in Group I. FEL by VFM is an effective tool for evaluating ventricular deterioration caused by RV workload.

The Clinical Utility and Safety of a New Strategy for the Treatment of Refractory Kawasaki Disease.

OBJECTIVE: To assess the clinical utility and safety of a strategy for refractory Kawasaki disease, defined by Egami score ≥3. STUDY DESIGN: First-line treatment was with intravenous methylprednisolone (30 mg/kg, 2 hours, 1 dose) plus intravenous immunoglobulin (2 g/kg, 24 hours) treatment. Patients resistant to first-line treatment received additional intravenous immunoglobulin as a second-line treatment. Patients resistant to second-line treatment who had received Bacillus Calmette-Guérin vaccination 6 months earlier were treated with infliximab; otherwise, plasma exchange was performed. A total of 71 refractory patients with Kawasaki disease (median age: 2.4 years) of 365 patients with Kawasaki disease were treated according to our strategy from April 2007 to April 2016. Treatment resistance was defined as a persistent fever at 36 hours after treatment. We evaluated coronary artery lesions at the time of the diagnosis, at 1 month, and at 1 year after the diagnosis in accordance with the American Heart Association guidelines and the criteria of the Japanese Ministry of Health, Labour, and Welfare. RESULTS: First-line therapy was effective for 58 of 71 patients (81.6%), and second-line therapy was effective for 9 of 13 patients (69.2%). At third line, 3 patients were treated by infliximab, and 1 was treated with plasma exchange. Of the 18 patients with coronary artery abnormalities at diagnosis, 13 patients at 1 month and 6 patients at 1 year had coronary artery dilatation (median z score 3.0, 2.6, and 1.4, respectively). There were no patients with coronary artery aneurysm (CAA). CONCLUSIONS: Our strategy for refractory Kawasaki disease was safe and effective in preventing CAA.

High throughput sequencing of cyclic peptide immobilized on a gel-type single bead.

Relatively larger scale peptide libraries immobilized on a gel-type solid support consisting of 24 natural and non-natural amino acids by the "split and combine method" have been constructed to find interacting molecules. The diversity was ca. 200 millions of hexapeptides with cysteinyl residues forming cyclotide. Selected beads after screening can be sequenced by the conventional Edman degradation, although several restrictions and the problems are known. To resolve these, a novel combinatorial method involving partial acid hydrolysis followed by liquid chromatography with on-line mass spectrometric analyses has been established. Problems were uncovered in an early stage of the process. Uncertain assignment caused by byproducts derived from a cystine residue and other materials could be resolved by optimal hydrolysis conditions and derivatization before mass spectrometric analysis. Discrimination between Leu and Ile could be performed using high energy collision induced dissociation in the high resolution MALDI-TOF-MS/MS. The present optimized protocol is useful for discovery of sequences of interacting molecules and a second library construction.

Timing of Haemophilus influenzae type b vaccination after cardiac surgery.

BACKGROUND: The best time for vaccination in infants with congenital heart disease (CHD) after cardiopulmonary bypass (CPB) surgery is unclear, but it is important to prevent Haemophilus influenzae type b (Hib) infection in infants with CHD after CPB surgery. To identify the best time for Hib vaccination in infants with CHD after CPB surgery, we investigated the immunological status, and the efficacy and safety of Hib vaccination after CPB surgery. METHODS: Sixteen subjects who underwent surgical correction of ventricular septal defect with CPB were investigated. Immunological status and cytokines were analyzed before surgery, 2 months after surgery, and before Hib booster vaccination. Hib-specific IgG was also measured to evaluate the effectiveness of vaccination. RESULTS: Immunological status before and 2 months after surgery (e.g. whole blood cells and lymphocyte subset profile) was within the normal range and no subjects had hypercytokinemia. Additionally, all subjects who received Hib vaccination at 2-3 months after CPB surgery had effective serum Hib-specific IgG level for protection against Hib infection without any side-effects. CONCLUSIONS: CPB surgery does not influence acquired immunity and Hib vaccination may be immunologically safe to perform at 2 months after CPB surgery. Hib vaccination at 2-3 months after CPB surgery was effective in achieving immunization for infants with simple left-right shunt-type CHD.

Clinical utility of the plasma brain natriuretic peptide level in monitoring tetralogy of fallot patients over the long term after initial intracardiac repair: considerations for pulmonary valve replacement.

Clinicians are currently encountering an increasing number of patients in the long-term period after tetralogy of Fallot (TOF) repair presenting with pulmonary valve regurgitation (PR) or right ventricular (RV) dysfunction. The purpose of this study was to evaluate the clinical utility of the plasma brain natriuretic peptide (BNP) level and consider surgical indications and timing of pulmonary valve replacement (PVR). We examined 33 patients (21 males, 12 females, mean age 14.5 ± 2.8 years) who underwent TOF repair at Kitasato University Hospital. All patients were evaluated using echocardiography and blood sampling. The mean age at the time of initial repair was 1.3 ± 0.7 years. The patients with moderate-severe PR exhibited significantly higher plasma BNP levels than the patients with trivial-mild PR (mean 37.5 ± 33.1 vs. 17.3 ± 6.6 pg/ml, p = 0.013). The mean plasma BNP level with cardiac symptoms was higher than that observed in the patients without any symptoms (71.4 ± 46.1 vs. 25.0 ± 14.0 pg/ml, p = 0.005). The mean BNP level was significantly decreased after PVR (71.3 ± 46.1-26.1 ± 13.2 pg/ml, p = 0.009), and the plasma BNP level was found to be positively correlated with the RV end-diastolic pressure (r = 0.851; p = 0.008). The optimal BNP cut-off value for considering PVR was 32.15 pg/ml (sensitivity, 85.7 %; specificity, 83.3 %). The plasma BNP level may become a useful diagnostic tool for considering the indications and optimal timing of PVR over the long term after TOF repair.

Quantitative evaluation of hemodynamics in the Fontan circulation: a cross-sectional study measuring energy loss in vivo.

Flow energy loss (EL) at the Fontan anastomosis has been thought to reflect flow efficiencies and to influence on hemodynamics in the Fontan circulation and has been often discussed in numerical studies. However, in vivo EL measurements have to date not been reported. We directly measured EL in the Fontan circulation and examined the relationship between the structural configuration and EL, as well as the influence of EL, on the hemodynamics in the Fontan circulation. We performed a catheterization study measuring simultaneous pressure and flow velocity to calculate EL in nine patients (mean age 2.3 ± 0.3 years) 1 year after the Fontan procedure. The measured EL was 9.66 ± 8.50 mW. One patient with left pulmonary artery stenosis recorded the highest EL (17.78 mW), and one patient with bilateral superior vena cava and left phrenic nerve palsy recorded the second highest EL (14.62 mW). EL significantly correlated with time constant tau and weakly with max-dp/dt during the isovolumic diastolic phase (r = 0.795 and -0.574, respectively). EL also correlated with max-dp/dt during the isovolumic systolic phase (r = 0.842) but not with ejection fraction or systemic blood flow (r = 0.384 and -0.034, respectively). In conclusion, inefficient structural configuration and phrenic nerve palsy seem to be related with increased in EL at the Fontan anastomosis. Although these preliminary findings also suggest that EL is associated with an impaired relaxation of the ventricle, a long-term study with a large population is warranted to reach such a definitive conclusion.

Partial restoration of knee kinematics in severe valgus deformity using the medial-pivot total knee arthroplasty.

PURPOSE: The objectives of the study were to examine knee kinematics in knees with severe valgus deformities and to compare pre- and post-operative knee kinematics for the same subjects implanted with medial-pivot total knee arthroplasty (TKA). METHODS: Seven subjects with severe valgus deformities due to osteoarthritis (OA) or rheumatoid arthritis (RA) were enrolled in the prospective study. Prior to TKA, three-dimensional (3D) kinematics were assessed by 3D to 2D registration technique using the image matching software 'Knee Motion', under in vivo, weight-bearing conditions. Postoperatively, each subject again performed the same motion under fluoroscopic surveillance. RESULTS: Preoperative kinematics demonstrated external rotation of tibias from extension to flexion, and small posterior femoral translations dominated in the medial condyle associated with anterior slides during partial range of motion. Postoperatively, these non-physiological tibial rotations were restored, and most subjects exhibited small internal rotations of tibias. On average, preoperative tibial internal rotation was -4.7° ± 7.6° from full extension to maximum flexion, and the angle was 4.8° ± 3.1° postoperatively (p = 0.01). In addition, small amounts of posterior translation of the lateral condyle and anterior translation of the medial condyle were confirmed in most subjects postoperatively. CONCLUSIONS: The study showed that the preoperative kinematic pattern established in severe valgus deformity was different from the physiological knee pattern. In addition, post-operative results suggest that the non-physiological kinematics were partially restored after TKA by using the prosthesis design even in the absence of the posterior cruciate ligament (PCL) and the cam-post mechanism.

Evaluation of patellofemoral joint in ADVANCE Medial-pivot total knee arthroplasty.

PURPOSE: ADVANCE Medial Pivot (MP) (Wright Medical) total knee arthroplasty (TKA) was established to replicate normal tibio-femoral knee joint kinematics, however, its influence on the patello-femoral (PF) joint is unclear. The purpose in this study was to assess the PF joint conditions in Advance MP TKA, via radiography and three-dimensional image-matching software. METHODS: Ten subjects with osteoarthritis were treated with the ADVANCE MP TKA. Pre-operatively and one month after surgery, skyline views at 30, 60, and 90° of flexion were taken, and patella shift and tilt were measured. With 2D-3D registration techniques using software, implant orientations were matched with the pre-operative CT and changes in the anterior part of the femoral prosthesis, condylar twist angle (CTA) for femoral rotation, and tibial rotation were evaluated. The relationships between morphological and rotational changes were evaluated. RESULTS: There were significant differences in patella tilt at 60° and patella shift at all angles between pre- and post-operation (p < 0.05). No correlation was found between morphological changes in the anterior femur with patella tilt and shift. A positive correlation between postoperative CTA and patella shift at 90° was found (p < 0.05); however, no correlation was found between rotational alignment of the tibial component and patella tilt and shift. CONCLUSIONS: ADVANCE MP TKA changed patello-femoral joint kinematics, compared to that found before surgery. The kinematic features were mainly due to the design concepts for tibio-femoral joint motion, indicating the difficulty to reproduce normal patello-femoral joint kinematics after TKA.

Prenatal aortic arch development in double aortic arch: Understanding postnatal closure of left aortic arch: A case report.

Double aortic arch (DAA) is a rare congenital abnormality characterized by a vascular ring that often requires surgical intervention due to respiratory complications. The DAA and right aortic arch with mirror-image branches (RAA-MB) represent abnormalities in development of the aortic arch. However, prognosis differs significantly, as the DAA forms vascular rings, whereas the RAA-MB typically does not. Distinguishing between the conditions becomes particularly challenging in cases of DAA with closure of the posterior portion of the left aortic arch (LAA) because the postnatal manifestations closely resemble those of RAA-MB. Herein, we present a case of DAA in which longitudinal observation of the LAA and RAA diameters during pregnancy aimed in predicting postnatal closure of the LAA. A 37-year-old female with suspected DAA was referred to our hospital at 26 weeks of gestation. Initial measurements revealed comparable diameters for the LAA and RAA; however, the LAA diameter decreased to approximately half that of the RAA by term owing to growth restrictions. Postnatal contrast computed tomography confirmed the closure of the posterior portion of the LAA and RAA with Kommerell diverticulum. Our findings suggest that careful monitoring of DAA throughout fetal development, especially during the third trimester, may aid in predicting atretic changes in the nondominant arch after birth, allowing an easy distinction between the DAA and RAA-MB after birth.

The role of diameter versus volume as the best prognostic measurement of abdominal aortic aneurysms.

Accurate measurement of abdominal aortic aneurysms is necessary to predict rupture risk and, more recently, to follow aneurysm sac behavior following endovascular repair. Up until this point, aneurysm diameter has been the most common measurement utilized for these purposes. Although aneurysm diameter is predictive of rupture, accurate measurement is hindered by such factors as aortic tortuosity and interobserver variability, and it does not account for variations in morphology such as saccular aneurysms. Additionally, decreases in aneurysm diameter do not completely describe the somewhat complex remodeling seen following endovascular repair of aortic aneurysms. Measurement of aneurysm volume has the advantage of describing aneurysm morphology in a multidimensional fashion, but it has not been readily available or easily measured until recently. This has changed with the introduction of commercially available software tools that permit quicker and easier to perform volume measurements. Whether it is time for volume to replace, or compliment, diameter is the subject of the current debate.

Zenith p-branch standard fenestrated endovascular graft for juxtarenal abdominal aortic aneurysms.

OBJECTIVE: This article reports the early clinical outcomes and experiences of Zenith pivot branch device (p-branch) standard fenestrated endovascular graft (Cook, Bloomington, Ind) for treating juxtarenal abdominal aortic aneurysm (AAA) originating below the superior mesenteric artery (SMA). METHODS: A physician-sponsored investigational device exemption study was used to assess enrolled elective and emergency patients from August 2011 to September 2012 for treatment with an off-the-shelf Zenith p-branch device. Patients were included provided an anatomic seal could be established 4 mm below the SMA and the renal geometry fit the protocol based on reconstructed computed tomography data. The celiac artery was addressed with a scallop and the SMA with an 8-mm fenestration. The renal fenestrations were constructed as a modified design to allow a range of renal locations (7.5 mm radially from the center of the fenestration) to be acceptably treated with a single configuration. Two anatomic configurations were created for renal arteries (origins at the same level, or disparate renal arteries with left lower than right). Outcomes are reported in coherence with endovascular reporting standards documents. RESULTS: The study enrolled 16 patients (94% men; median age, 75 years [range, 59-87 years]) with a mean aneurysm size of 61 mm (range, 52-82 mm). Two were treated for aneurysm rupture. Technical success was achieved in all patients. The median fluoroscopy time was 62 minutes (range, 38-105 minutes), and the amount of contrast media was 69 mL (range, 31-121 mL). There were no aortic-related deaths, aneurysm ruptures, open surgical conversion, or type I/III endoleaks. One right renal artery occluded during follow-up in the setting of a conically shaped visceral aortic segment and was successfully treated with endovascular recanalization. CONCLUSIONS: The use of the p-branch device for aneurysms originating infra-SMA is associated with a high rate of technical success and minimal problems during the short follow-up duration. The off-the-shelf design allows for the treatment of ruptures and other urgent situations. Additional patients and more follow-up will be required to further define the risks and benefits of such a treatment strategy.

Fenestrated and branched endovascular aortic repair for chronic type B aortic dissection with thoracoabdominal aneurysms.

OBJECTIVE: The treatment of patients with arch and thoracoabdominal aortic aneurysms (TAAAs) and chronic dissections is challenging. We report the results of fenestrated and branched endovascular aortic repair (FEVAR) of such aneurysms. METHODS: A single-center prospective FEVAR trial enrolled 356 patients (2006 to 2011), of whom 30 had chronic dissections with arch aneurysm or TAAAs, or both. Patients were divided into group A, 15 patients (mean age, 58 years) with extensive dissections extending from the arch through the visceral segment, and group B, 15 patients (mean age, 74 years old) with focal dissections and no extension into the thoracic aorta. Inclusion criterion was aneurysm size >5.5 cm in diameter. Customized grafts were implanted into the true lumen, and branches were extended into the true lumen of the supra-aortic trunk (arch branch devices) and visceral vessels. Patients were monitored annually with clinical, imaging, and laboratory studies. Outcome analyses included survival, rupture, spinal cord ischemia, endoleak, morbidity (cardiac, renal or pulmonary), reinterventions, dissection, and aneurysm growth. RESULTS: The mean time from the onset of dissection to the FEVAR performed in group A was 10.4 years. The mean maximum aneurysm diameter was 60 mm. Follow-up averaged 1.7 years. There were no perioperative deaths. One aortic-related death occurred at 87 days due to progression of a pre-existing untreated arch dissection. No ruptures, cardiac, renal, pulmonary, or spinal cord ischemia complications occurred. Despite the initially narrow true lumen dimensions, stent grafts expanded to their nominal diameters after implantation without any blood flow disturbance of branched visceral vessels and distal aorta. No graft compression occurred. Post-FEVAR growth was noted in two patients, related to type II endoleaks. Sac regression was similar (-6.8 vs -11.4 mm; P = .43), but early endovascular reinterventions were more common in group A (8 patients). Patients with extensive dissection were younger, and the dissection more likely to be associated with a defined connective tissue disease (Marfan syndrome or Loeys-Dietz mutations, 40% vs 0%; P = .006). CONCLUSIONS: FEVAR is feasible for patients with chronic dissections and TAAA. Concerns regarding visceral vessel access and graft compression resulting from narrow true lumen diameters were not relevant in our experience. Favorable sac and lumen morphologic changes, coupled with a low mortality and complication risk, makes this an attractive means of handling this clinical problem.

Successful treatment of fulminant myocarditis due to COVID-19 in a 5-year-old girl.

Reports of acute myocarditis are increasing due to the worldwide spread of coronavirus disease 2019 (COVID-19). We report a case of a 5-year-old girl with fulminant myocarditis caused by COVID-19, who was successfully treated with veno-arterial extracorporeal membrane oxygenation (VA-ECMO). The unvaccinated patient had developed fever 1 week before attending our hospital and was "presumptive positive" for COVID-19 based on the surrounding infectious situation. The fever resolved, but the day before the visit, abdominal pain appeared. The patient visited her previous physician with vomiting as the main complaint. She was transferred to our hospital due to impaired consciousness and bradycardia, with a heart rate of 40 beats/min. Immediately after transfer, she was diagnosed with complete atrioventricular (AV) block and was scheduled to undergo percutaneous pacing lead insertion. However, the patient had ventricular tachycardia, AV block and hypotension intraoperatively and required cardiopulmonary resuscitation. The patient was in an extremely unstable circulatory state, and VA-ECMO was urgently introduced. After multidisciplinary treatment for acute myocarditis, waiting for an improvement in AV block, and recovery of cardiac function, the patient was weaned from VA-ECMO on the eighth day after admission. The patient was discharged with no cardiac or neurologic sequelae. Learning objective: The rapid introduction of veno-arterial extracorporeal membrane oxygenation for fulminant myocarditis caused by coronavirus disease 2019 (COVID-19) in young children is extremely effective. Vaccination may be important for preventing infection with COVID-19 and avoiding severe complications.

Global and endothelial G-protein coupled receptor 75 (GPR75) knockout relaxes pulmonary artery and mitigates hypoxia-induced pulmonary hypertension.

RATIONALE: Pulmonary hypertension (PH) is a multifactorial disease with a poor prognosis and inadequate treatment options. We found two-fold higher expression of the orphan G-Protein Coupled Receptor 75 (GPR75) in leukocytes and pulmonary arterial smooth muscle cells from idiopathic PH patients and from lungs of C57BL/6 mice exposed to hypoxia. We therefore postulated that GPR75 signaling is critical to the pathogenesis of PH. METHODS: To test this hypothesis, we exposed global (Gpr75-/-) and endothelial cell (EC) GPR75 knockout (EC-Gpr75-/-) mice and wild-type (control) mice to hypoxia (10% oxygen) or normal atmospheric oxygen for 5 weeks. We then recorded echocardiograms and performed right heart catheterizations. RESULTS: Chronic hypoxia increased right ventricular systolic and diastolic pressures in wild-type mice but not Gpr75-/- or EC-Gpr75-/- mice. In situ hybridization and qPCR results revealed that Gpr75 expression was increased in the alveoli, airways and pulmonary arteries of mice exposed to hypoxia. In addition, levels of chemokine (CC motif) ligand 5 (CCL5), a low affinity ligand of GPR75, were increased in the lungs of wild-type, but not Gpr75-/-, mice exposed to hypoxia, and CCL5 enhanced hypoxia-induced contraction of intra-lobar pulmonary arteries in a GPR75-dependent manner. Gpr75 knockout also increased pulmonary cAMP levels and decreased contraction of intra-lobar pulmonary arteries evoked by endothelin-1 or U46619 in cAMP-protein kinase A-dependent manner. CONCLUSION: These results suggest GPR75 has a significant role in the development of hypoxia-induced PH.