Search Results (44)

Pulmonary arterial hypertension (PAH) is a rare, progressive, and incurable disease characterized by an elevated pulmonary blood pressure, extensive remodeling of the pulmonary vasculature, increased pulmonary vascular resistance, and culminating in right ventricular failure. Mitochondrial dysfunction has a major role in the pathogenesis of PAH and secondary right ventricular failure, and its targeting may offer therapeutic benefit. In this study, we provide proof-of-concept for the use of the mitochondrially active drug SUL-150 to treat PAH. PAH was induced in rats by monocrotaline, followed by the placement of an aortocaval shunt one week later. The mitoprotective compound SUL-150 (~6 mg·kg⁻¹·day⁻¹) or vehicle was administered intraperitoneally via osmotic minipump for 28 days, implanted at the time of aortocaval shunt placement. Vehicle-treated PAH rats had dyspnea and showed pulmonary artery remodeling with increased responsiveness to phenylephrine, in addition to remodeling of the intrapulmonary arterioles. SUL-150 administration mitigated the dyspnea and the remodeling responses. Vehicle-treated PAH rats developed right ventricular hypertrophy, fibrosis, and failure. SUL-150 administration precluded cardiomyocyte hypertrophy and inhibited ventricular fibrogenesis. Right ventricular failure in vehicle-treated PAH rats induced mitochondrial loss and dysfunction associated with a decrease in mitophagy. SUL-150 was unable to prevent the mitochondrial loss but improved mitochondrial health in the right ventricle, which culminated in the preservation of right ventricular function. We conclude that SUL-150 improves PAH-associated morbidity by the amelioration of pulmonary vascular remodeling and right ventricular failure and may be considered a promising therapeutic candidate to slow disease progression in pulmonary arterial hypertension and secondary right ventricular failure. Full article

It is well-established that mitochondrial dysfunction plays a critical role in the development of pulmonary hypertension (PH). However, the molecular mechanisms and how the individual electron transport complexes (ETC) may be affected are poorly understood. In this study, we identified decreased ETC Complex I activity and assembly and linked these changes to disrupted mitochondrial bioenergetics in pulmonary arterial endothelial cells (PAECs) isolated from a lamb model of PH with increased pulmonary blood flow (Shunt). These derangements were associated with decreased mitochondrial activity of the protein tyrosine kinase, pp60^Src. Treating Control PAECs with either the Src family kinase inhibitor, PP2, or the siRNA-mediated knockdown of pp60^Src was able to recapitulate the adverse effects on ETC Complex I activity and assembly and mitochondrial bioenergetics. Conversely, restoring pp60^Src activity in lamb PH PAECs re-established ETC Complex I activity, improved ETC Complex I assembly and enhanced mitochondrial bioenergetics. Phosphoprotein enrichment followed by two-dimensional gel electrophoresis and tandem mass spectrometry was used to identify three ETC Complex I subunits (NDUFS1, NDUFAF5, and NDUFV2) as pp60^Src substrates. Finally, we demonstrated that the pY levels of NDUFS1, NDUFAF5, and NDUFV2 are decreased in lamb PH PAECs. Enhancing mitochondrial pp60^Src activity could be a therapeutic strategy to reverse PH-related mitochondrial dysfunction. Full article

Pulmonary hypertension (PH) is a progressive disorder characterized by obstructive changes in the pulmonary vasculature, leading to increased pulmonary vascular resistance (PVR), right ventricular (RV) strain, and eventual RV failure (RVF). Despite advancements in medical therapy, PH remains associated with significant morbidity and mortality, particularly in children. RVF is a clinical syndrome resulting from complex structural and functional remodeling of the right heart, leading to inadequate pulmonary circulation, reduced cardiac output, and elevated venous pressure. Management paradigms for pediatric PH diverge significantly from those in adults, particularly due to the predominance of congenital heart disease (CHD) and the dynamic nature of pediatric cardiovascular and pulmonary development. CHD remains a principal driver of PH in children, and its associated pathophysiology demands a nuanced approach. In patients with unrepaired left-to-right shunts, elevated pulmonary blood flow can lead to progressive pulmonary vascular remodeling and increased PVR. The postoperative persistence or progression of PH may occur if irreversible vascular changes have already developed. Current PH treatments primarily focus on reducing PVR, yet distinguishing between therapeutic approaches that target the pulmonary vasculature and those aimed at improving RV function remain challenging. In pediatric patients with progressive PH despite optimal therapy, additional targeted interventions may be necessary to mitigate RV dysfunction and disease progression. This review provides a comprehensive analysis of the mechanisms underlying RVF in PH, incorporating insights from clinical studies in adults and experimental models, while highlighting the unique considerations in children. Furthermore, it explores current pharmacological and interventional treatment strategies, emphasizing the need for novel therapeutic approaches aimed at directly reversing RV remodeling. Given the complexities of RV adaptation in pediatric PH, further research into disease-modifying treatments and innovative interventions is crucial to improving long-term outcomes in affected children. Full article

Background: Chronic liver disease (CLD) and cirrhosis contribute to approximately 2 million deaths annually, with primary causes including alcohol-related liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), and chronic hepatitis B and C infections. Among these, MASLD has emerged as a significant global health concern, closely linked to metabolic disorders and a leading cause of liver failure and transplantation. Objective: This review aims to highlight the interplay between cirrhosis and cardiac dysfunction, emphasizing the pathophysiology, diagnostic criteria, and management of cirrhotic cardiomyopathy (CCM). Methods: A comprehensive literature review was conducted to evaluate the hemodynamic and structural cardiac alterations in cirrhosis. Results: Cirrhosis leads to portal hypertension and systemic inflammation, contributing to CCM, which manifests as subclinical cardiac dysfunction, impaired contractility, and electrophysiological abnormalities. Structural changes, such as increased left ventricular mass, myocardial fibrosis, and ion channel dysfunction, further impair cardiac function. Vasodilation in the splanchnic circulation reduces peripheral resistance, triggering compensatory tachycardia, while the activation of the renin–angiotensin–aldosterone system (RAAS) promotes fluid retention and increases cardiac preload. Chronic inflammation and endotoxemia exacerbate myocardial dysfunction. The 2005 World Congress of Gastroenterology (WCG) and the 2019 Cirrhotic Cardiomyopathy Consortium (CCC) criteria provide updated diagnostic frameworks that incorporate global longitudinal strain (GLS) and tissue Doppler imaging (TDI). Prolonged QT intervals and arrhythmias are frequently observed. Managing heart failure in cirrhotic patients remains complex due to intolerance to afterload-reducing agents, and beta-blockers require careful use due to potential systemic hypotension. The interaction between CCM and major interventions, such as transjugular intrahepatic portosystemic shunt (TIPS) and orthotopic liver transplantation (OLT), highlights the critical need for thorough preoperative cardiac evaluation and vigilant postoperative monitoring. Conclusions: CCM is a frequently underdiagnosed yet significant complication of cirrhosis, impacting prognosis, particularly post-liver transplantation. Early identification using echocardiography and thorough evaluations of arrhythmia risk in cirrhotic patients are critical for optimizing management strategies. Future research should focus on targeted therapeutic approaches to mitigate the cardiac burden in cirrhotic patients and improve clinical outcomes. Full article

Purpose: Porto-systemic shunting (PSS) in patients with Abernethy malformation (AM) or obstruction of the portal vein (OVP) is often associated with normal liver parenchyma and hepatic function. This association provides an interesting natural model for studying the brain functional connectivity changes secondary to PSS but independently from hepatic (dys)function. Because PSS can be eliminated with appropriate interventions, these particular conditions offer a unique physio-pathological model where the same patient can be studied in both “active PSS” and “absent PSS” conditions (pre- and post-cure analyses). Methods: Four children (<18 years) who were evaluated for Abernethy malformation (n = 2) or portal cavernoma (n = 2) and underwent corrective surgery (living-donor liver transplantation for AM, or Meso-Rex bypass for OPV, respectively) were included in the study. Brain magnetic resonance imaging and resting-state functional magnetic resonance imaging (rest-fMRI) were acquired in all patients before and after the corrective surgery. A functional connectome analysis was performed before (“active PSS” condition) and after (“absent PSS”—physiological condition) the cure of PSS. Results: As a result of the cancelation of PSS, rest-fMRI connectomics revealed a statistically significant (p < 0.05 family-wise error) improvement in global brain functional connectivity in both groups following each surgical procedure. Conclusions: In this clinical model of isolated PSS (with absence of hepatic dysfunction), brain functional connectivity was altered even in young patients and in the absence of hyperammonemia; moreover, specific interventions to cancel out PSS consequently significantly improved brain functional connectivity. Full article

Background and Clinical Significance: Pulmonary hypertension (PH) is characterized by an increase in mean pulmonary arterial pressure and pulmonary vascular resistance. It is frequently encountered in patients with significant intracardiac shunts, often necessitating the implementation of a closure device or surgical correction. Nevertheless, the occurrence of a concomitant atrial septal defect (ASD) with a right-to-left shunt inducing left ventricular dysfunction is a rare phenomenon. Case Presentation: A 69-year-old female patient with a history of heart failure (with preserved ejection fraction) and end-stage renal disease on hemodialysis presented to an outside facility, with syncope and hypoxia. She was recently diagnosed with severe pulmonary hypertension (measuring 86 mmHg). Right heart catheterization (RHC) revealed precapillary pulmonary hypertension (88/37/54 mmHg), prompting the initiation of intravenous epoprostenol. Nevertheless, the patient was persistently hypoxic, raising the possibility of a concomitant diagnosis. Upon review of the prior echocardiogram, which included a bubble study, an intracardiac shunt was identified. It was hypothesized that a combination of right ventricular failure and the right-to-left shunt resulting from the ASD contributed to the persistent hypoxemia. In light of this, prostacyclin therapy was continued alongside adjunctive vasopressors, resulting in clinical stabilization. The patient was eventually discharged with a treatment regimen that included subcutaneous Treprostinil. Conclusions: It is important to recognize that the consequences of PH are extensive, and that a rare yet significant etiology for persistent hypoxemia may be attributed to right-to-left shunting. Full article

Hepatic encephalopathy (HE) in dogs is a metabolic disorder of the central nervous system that occurs secondarily to liver dysfunctions, whether due to acquired or congenital causes. A portosystemic shunt is the presence of abnormal communications between the hepatic vessels (portal and suprahepatic veins). As a result of this, the blood brought from the digestive tract through the portal vein bypasses the liver, and the unmetabolized components of the portal bloodstream enter directly into systemic circulation, causing clinical symptoms of metabolic encephalopathy (HE). A 3-month-old Bichon canine patient with a history of seizures secondarily to a portosystemic shunt (PS), confirmed through color Doppler ultrasound exam and computed tomography, was presented for evaluation. The typical electroencephalographic (EEG) traces recorded were characterized by the presence of bilateral symmetrical triphasic waves, resembling non-convulsive status epilepticus. The presence of this EEG pattern is useful in choosing the best therapeutic option in order to not accentuate the HE sings and, consequently, to decrease the mortality risk due to a prolonged status epilepticus. Full article

Background/Objectives: This study aimed to investigate the surgical treatment and management of hydrocephalus in infants with meningomyelocele and compare the single-center experience with the previous studies. Methods: This retrospective study included 81 infants (47 females and 34 males) who underwent meningomyelocele closure surgery and subsequent ventriculoperitoneal (VP) shunt surgery for hydrocephalus. Clinical and demographic data were retrospectively collected from hospital records, focusing on variables such as the timing of VP shunt placement relative to MMC closure, postoperative complications, and the need for shunt revisions. Patients were followed for a mean duration of 58.11 months to monitor long-term outcomes and identify factors associated with shunt failures and infections. Results: The mean follow-up period since birth was 58.11 (33.72) months. Shunt problems affected 30% (25/81) of patients with mechanical causes (8/25) and infections (6/25). A proximal mechanical malfunction/dysfunction was seen in 32% (8/25) of the shunts. Shunt infections occurred in 23% (19/81) of infants, and the mean time for shunt infection onset following the VP shunt procedure was 0 (0–39) median (min–max) months. Overall, 8 (9.9%) infants had short-term shunt infections, whereas 11 (13.6%) had long-term shunt infections. The mean length of the intensive care unit stay was 35.75 (25.28) days. Significant difference was seen in the number of shunt reoperations for short- and long-term infections (p < 0.001). All infants had at least one operation before the infection of their shunt system. Male gender was significantly associated with long-term shunt infections (p = 0.021). The study revealed methicillin-resistant coagulase-negative staphylococcus to be the most common isolated organism from infected shunts at 72.7% (6/11). Conclusions: This study demonstrates that hydrocephalic infants with meningomyelocele undergoing VP shunt surgery face notable risks of infection and mechanical complications, with methicillin-resistant coagulase-negative staphylococcus identified as the most common pathogen. The findings emphasize the importance of comprehensive postoperative care and targeted infection management to improve outcomes in this vulnerable population. Full article

The pathophysiologic substrate of pediatric hydrocephalus has not been thoroughly elucidated. Valve-based shunt systems have constituted the main therapeutic option since the late 1950s. The initially used systems were concerning the ventricular system and the atrium. In the 1970s, VA shunts were not the main stay of treatment as the preferred option for the terminal end of the drainage system was the peritoneum. Our review analyzes these valve types and attempts a comparison, based on their functional characteristics. Nowadays, the only available surgical alternative for the treatment of hydrocephalus is ETV. This technique is associated with lower infection rates as well as, on average, a lower re-operation rate. Another term that deserves special mention is related to the outcome of ETV in children who had a medical history of previously incorporated shunts and who were subsequently suffering from shunt malfunction. Well-recognized predictive factors associated with secondary ETV failure include age, early onset of hydrocephalus, and prematurity. Although several attempts have been made in order to establish the optimum surgical treatment management in the different subgroups of patientswho are suffering from shunt dysfunction, there is no universal agreement. Therefore, this review attempts to identify the specific subpopulations of patients in whom the insertion of a drainage system as the preferred treatment modality is associated with an optimum long-term prognosis, compared to ETV, and vice versa. The objective of our study is to analyze the safety, efficacy, and outcomes of drainage devices and ETV in pediatric hydrocephalus patients. Full article

Background: Despite several challenges in clinical management, there has been significant progress in understanding the aetiology, natural history and outcomes of Budd–Chiari syndrome (BCS) treatments. This study aims to evaluate the outcomes of transjugular intrahepatic portosystemic shunt (TIPS) using covered stent in management of BCS. Methods: We conducted a retrospective analysis of 70 BCS patients who underwent TIPS using covered stents between January 2010 and December 2022 at a single tertiary liver transplant centre. Patients’ clinical features, laboratory parameters, and imagine findings were collected before and after TIPS. The primary endpoint was overall survival. Results: TIPS was performed on 70 patients with BCS out of a total of 88 patients. The remaining patients (18) underwent liver transplantation. The mean age was 37.7 ± 11.2 years at time of diagnosis and the majority were female (64.35). The most common symptoms and signs at presentation were abdominal pain, jaundice, ascites, and variceal bleeding. Over a median followup of 76 months, the survival rates at 1, 3, and 5 years were 98.8%, 97.9%, and 97.7%, respectively. Patients who underwent TIPS alone had better survival that patients with BCS who required liver transplantation (LTx) (p = 0.003). Conclusions: In our study TIPS provided a highly effective treatment option for BCS patients. The long-term favourability of the outcome was not impacted by the need for repeated TIPS revision. Use of covered stents was instrumental in reducing shunt dysfunction rates. Prospective and larger studies are needed to further optimize therapeutic strategies in this challenging population. Full article

Vein of Galen aneurysmal malformation is a relatively rare disease in which failure of the median prosencephalic vein of Markowski to involute early in gestation leads to a grossly dilated deep cerebral vein with multiple arterial feeders, causing a large arteriovenous shunt which leads to high-output cardiac failure. We describe a case of a term neonate who presented to a tertiary neonatal centre on day one of life with history, symptoms, and signs consistent with perinatal asphyxia; however, in the context of worsening multi-organ dysfunction and cardiomegaly, the infant was found to have a severe vein of Galen aneurysmal dilatation leading to high-output cardiac failure. The patient was transferred to a tertiary paediatric hospital and underwent a total of four coiling procedures to embolise the multiple feeder arteries supplying the aneurysmal malformation. This case highlights the difficulties in diagnosing this relatively uncommon condition, particularly in the context of a possible perinatal insult. Full article

Spinal dural arteriovenous fistula (SDAVF) is among the most common arterial shunt diseases typically found in middle aged or older men. Herein, we aimed to clarify the reasons for misdiagnoses and delayed diagnoses of SDAVF, determine how these affect prognoses, and establish how they can be prevented. We conducted a PubMed/MEDLINE literature search using “spinal dural arteriovenous fistula”, “delayed diagnosis”, “late diagnosis”, and “misdiagnosis” terms. We identified 18 articles, including 965 SDAVF cases. Patients were predominantly males (71.8–100.0%) (mean age: 53.5–71.0 years). Misdiagnoses rates varied (17.5–100.0%) and encompassed many conditions. The mean time between early manifestations and confirmed diagnosis was approximately 10–15 months and from the first radiologic image revealing dural arteriovenous fistula (DAVF) features to diagnosis was 9.2–20.7 months. Posttreatment outcomes showed a significant improvement in motor functions, gait, and micturition, particularly in patients exhibiting preoperative symptoms over a short period. SDAVF is frequently misdiagnosed or subject to delayed diagnosis, causing poor clinical outcomes. SDAVF symptoms including progressive lower-limb weakness, paresthesia, and vesicorectal dysfunction are indications for spinal magnetic resonance imaging with subsequent spinal angiography, wherein DAVF is evidenced by extensive T2 hyperintensity and flow-void abnormalities. We reported a representative case with delayed diagnosis. Full article

Hepatic encephalopathy (HE) is a central nervous system dysfunction syndrome caused by acute and chronic liver failure or various portal systemic shunt disorders. HE arises from metabolic disorder and excludes other known types of encephalopathy. HE is a major cause of death in people with liver disease. Early diagnosis and timely treatment are key to improving HE prognosis. Herein, we established a model of HE and performed metabolomics to identify 50 significantly differential metabolites between the HE group and control group. The main metabolic pathways associated with these differential metabolites were the purine metabolism, pyrimidine metabolism, aminoacyl tRNA biosynthesis, and glucose metabolism. Through proteomics analysis, we identified 226 significantly differential proteins (52 up-regulated and 174 down-regulated). The main (Kyoto Encyclopedia of Genes and Genomes) enrichment pathways were the Staphylococcus aureus infection, vitamin digestion and absorption, and complement and coagulation cascades. Through the conjoint analysis of proteomics and metabolomics, the differentially present proteins and metabolites were found to be involved in vitamin digestion and absorption, and ferroptosis pathways. In HE, malondialdehyde was significantly elevated, but glutathione was significantly diminished, and the redox balance was destroyed, thus leading to changes in proteins’ levels associated with the ferroptosis pathway. In conclusion, this study preliminarily explored the molecular and metabolic mechanisms underlying HE. Full article

Intraocular pressure (IOP) lowering surgery has been shown to alter microvascular density in glaucoma patients. The aim of this study is to report changes in retinal flow density (FD) over the course of treatment with the Preserflo MicroShunt, using optical coherence tomography angiography (OCTA). 34 eyes from 34 patients who underwent Preserflo MicroShunt implantation were prospectively enrolled in this study. OCTA imaging was conducted at the superficial (SCP), deep (DCP) and radial peripapillary plexus (RPC) levels. The progression of FD and IOP was assessed at different time points from baseline to six months postoperatively for the entire patient population, as well as disease severity subgroups. The Preserflo MicroShunt achieved a significant reduction in IOP over the course of six months (median: 8 mmHg; p < 0.01). FD values of the SCP and DCP did not show significant fluctuations, even after adjusting for disease severity. FD of the RPC decreased significantly over the course of six months postoperatively from 42.31 at baseline to 39.59 at six months postoperatively (p < 0.01). The decrease in peripapillary FD was strongest in patients with advanced glaucoma (median: −3.58). These observations hint towards dysfunctional autoregulatory mechanisms in capillaries surrounding the optic nerve head in advanced glaucoma. In comparison, the microvascular structure of the macula appeared more resilient to changes in IOP. Full article

Portal hypertension (PH) constitutes a pivotal factor in the progression of cirrhosis, giving rise to severe complications and a diminished survival rate. The transjugular intrahepatic portosystemic shunt (TIPS) procedure has undergone significant evolution, with advancements in stent technology assuming a central role in managing PH-related complications. This review aims to outline the progression of TIPS and emphasizes the significant influence of stent advancement on its effectiveness. Initially, the use of bare metal stents (BMSs) was limited due to frequent dysfunction. However, the advent of expanding polytetrafluoroethylene-covered stent grafts (ePTFE-SGs) heralded a transformative era, greatly enhancing patency rates. Further innovation culminated in the creation of ePTFE-SGs with controlled expansion, enabling precise adjustment of TIPS diameters. Comparative analyses demonstrated the superiority of ePTFE-SGs over BMSs, resulting in improved patency, fewer complications, and higher survival rates. Additional technical findings highlight the importance of central stent placement and adequate stent length, as well as the use of smaller calibers to reduce the risk of shunt-related complications. However, improving TIPS through technical means alone is inadequate for optimizing patient outcomes. An extensive understanding of hemodynamic, cardiac, and systemic factors is required to predict outcomes and tailor a personalized approach. Looking forward, the ongoing progress in SG technology, paired with the control of clinical factors that can impact outcomes, holds the promise of reshaping the management of PH-related complications in cirrhosis. Full article