Mortality in Adult Congenital Heart Disease: Analysis of Outcomes and Risk Stratification.

Adult congenital heart disease (ACHD) is a rising concern for the current healthcare system, with a prevalence that is anticipated to steadily increase through the year 2050. It is estimated that there are >1.4 million adults in the United States living with a congenital heart defect. Despite significant advances in medical and surgical therapy, most of these patients progress to advanced heart failure due to the unique anatomic, physiological, and hemodynamic abnormalities associated with the disease. Patient awareness of the disease coupled with advances in the diagnosis and treatment has led to a significant increase in the surgical treatment of CHD in adults. The authors aim to summarize and critically appraise the current literature on the morbidity, mortality, and risk scores associated with ACHD.

Implications of Renal Disease in Patients Undergoing Structural Interventions.

Percutaneous structural interventions have a major impact on the morbidity, mortality, and quality of life of patients by providing a lower-risk alternative to cardiac surgery. However, renal disease has a significant impact on outcomes of these interventions. This review explores the incidence, outcomes, pathophysiology, and preventative measures of acute kidney injury and chronic kidney disease on transcatheter aortic valve replacement, transcatheter mitral valve repair, and percutaneous balloon mitral valvuloplasty. Given the expanding indications for percutaneous structural interventions, further research is needed to identify ideal patients with chronic kidney disease or end-stage renal disease who would benefit from intervention.

Study of flow-induced hemolysis using novel Couette-type blood-shearing devices.

To assist the development and application of blood-contacting medical devices, two novel flow-through Couette-type blood-shearing devices have been developed to study the quantitative relationship between blood damage indexes and flow-dependent parameters. One device is an axial flow-through Couette-type device supported by a pair of pin bearings adapted from the adult Jarvik 2000 blood pump. The other is a centrifugal flow-through Couette-type device supported with magnetic bearings adapted from the CentriMag blood pump. In both devices, a rotor spindle was used to replace the original impeller blades so that a small gap was created between the housing and the rotating spindle surface. Computational fluid dynamics simulations have shown that a uniform, high shear stress region can be generated inside the small gap while the shear stresses elsewhere are relatively low. The possibility of secondary blood damage caused by mechanical seals was eliminated due to the use of a magnetic rotor system. Blood flow through the gap was driven by an externally pressurized reservoir. By adjusting the rotational speed and blood flow rate, shear-induced hemolysis was quantified at a matrix of exposure time (0.039 to 1.48 s) and shear stress (50 to 320 Pa). All of the experiments were conducted at room temperature using heparinized ovine blood with a hematocrit value of 30%. The measured hemolysis levels were much lower than those published in the literature, and the overestimation of those earlier studies may be attributable to device-related secondary blood-damaging effects. A new set of coefficients for the power law model was derived from the regression of the experimental data.

Selective Vulnerability of the Foramen Magnum in a Rat Blast Traumatic Brain Injury Model.

Primary blast traumatic brain injury (bTBI) accounts for a significant proportion of wartime trauma. Previous studies have demonstrated direct brain injury by blast waves, but the effect of the location of the blast epicenter on the skull with regard to brain injury remains poorly characterized. In order to investigate the role of the blast epicenter location, we modified a previously established rodent model of cranium-only bTBI to evaluate two specific blast foci: a rostrally focused blast centered on bregma (B-bTBI), which excluded the foramen magnum region, and a caudally focused blast centered on the occipital crest, which included the foramen magnum region (FM-bTBI). At all blast overpressures studied (668-1880 kPa), rats subjected to FM-bTBI demonstrated strikingly higher mortality, increased durations of both apnea and hypoxia, and increased severity of convexity subdural hematomas, than rats subjected to B-bTBI. Together, these data suggest a unique role for the foramen magnum region in mortality and brain injury following blast exposure, and emphasize the importance of the choice of blast focus location in experimental models of bTBI.

Glibenclamide pretreatment protects against chronic memory dysfunction and glial activation in rat cranial blast traumatic brain injury.

Blast traumatic brain injury (bTBI) affects both military and civilian populations, and often results in chronic deficits in cognition and memory. Chronic glial activation after bTBI has been linked with cognitive decline. Pharmacological inhibition of sulfonylurea receptor 1 (SUR1) with glibenclamide was shown previously to reduce glial activation and improve cognition in contusive models of CNS trauma, but has not been examined in bTBI. We postulated that glibenclamide would reduce chronic glial activation and improve long-term memory function after bTBI. Using a rat direct cranial model of bTBI (dc-bTBI), we evaluated the efficacy of two glibenclamide treatment paradigms: glibenclamide prophylaxis (pre-treatment), and treatment with glibenclamide starting after dc-bTBI (post-treatment). Our results show that dc-bTBI caused hippocampal astrocyte and microglial/macrophage activation that was associated with hippocampal memory dysfunction (rapid place learning paradigm) at 28days, and that glibenclamide pre-treatment, but not post-treatment, effectively protected against glial activation and memory dysfunction. We also report that a brief transient time-window of blood-brain barrier (BBB) disruption occurs after dc-bTBI, and we speculate that glibenclamide, which is mostly protein bound and does not normally traverse the intact BBB, can undergo CNS delivery only during this brief transient opening of the BBB. Together, our findings indicate that prophylactic glibenclamide treatment may help to protect against chronic cognitive sequelae of bTBI in warfighters and other at-risk populations.

Changes in Diffusion Kurtosis Imaging and Magnetic Resonance Spectroscopy in a Direct Cranial Blast Traumatic Brain Injury (dc-bTBI) Model.

Explosive blast-related injuries are one of the hallmark injuries of veterans returning from recent wars, but the effects of a blast overpressure on the brain are poorly understood. In this study, we used in vivo diffusion kurtosis imaging (DKI) and proton magnetic resonance spectroscopy (MRS) to investigate tissue microstructure and metabolic changes in a novel, direct cranial blast traumatic brain injury (dc-bTBI) rat model. Imaging was performed on rats before injury and 1, 7, 14 and 28 days after blast exposure (~517 kPa peak overpressure to the dorsum of the head). No brain parenchyma abnormalities were visible on conventional T2-weighted MRI, but microstructural and metabolic changes were observed with DKI and proton MRS, respectively. Increased mean kurtosis, which peaked at 21 days post injury, was observed in the hippocampus and the internal capsule. Concomitant increases in myo-Inositol (Ins) and Taurine (Tau) were also observed in the hippocampus, while early changes at 1 day in the Glutamine (Gln) were observed in the internal capsule, all indicating glial abnormality in these regions. Neurofunctional testing on a separate but similarly treated group of rats showed early disturbances in vestibulomotor functions (days 1-14), which were associated with imaging changes in the internal capsule. Delayed impairments in spatial memory and in rapid learning, as assessed by Morris Water Maze paradigms (days 14-19), were associated with delayed changes in the hippocampus. Significant microglial activation and neurodegeneration were observed at 28 days in the hippocampus. Overall, our findings indicate delayed neurofunctional and pathological abnormalities following dc-bTBI that are silent on conventional T2-weighted imaging, but are detectable using DKI and proton MRS.

Exposure of the thorax to a sublethal blast wave causes a hydrodynamic pulse that leads to perivenular inflammation in the brain.

Traumatic brain injury (TBI) caused by an explosive blast (blast-TBI) is postulated to result, in part, from transvascular transmission to the brain of a hydrodynamic pulse (a.k.a., volumetric blood surge, ballistic pressure wave, hydrostatic shock, or hydraulic shock) induced in major intrathoracic blood vessels. This mechanism of blast-TBI has not been demonstrated directly. We tested the hypothesis that a blast wave impacting the thorax would induce a hydrodynamic pulse that would cause pathological changes in the brain. We constructed a Thorax-Only Blast Injury Apparatus (TOBIA) and a Jugular-Only Blast Injury Apparatus (JOBIA). TOBIA delivered a collimated blast wave to the right lateral thorax of a rat, precluding direct impact on the cranium. JOBIA delivered a blast wave to the fluid-filled port of an extracorporeal intravenous infusion device whose catheter was inserted retrograde into the jugular vein, precluding lung injury. Long Evans rats were subjected to sublethal injury by TOBIA or JOBIA. Blast injury induced by TOBIA was characterized by apnea and diffuse bilateral hemorrhagic injury to the lungs associated with a transient reduction in pulse oximetry signals. Immunolabeling 24 h after injury by TOBIA showed up-regulation of tumor necrosis factor alpha, ED-1, sulfonylurea receptor 1 (Sur1), and glial fibrillary acidic protein in veins or perivenular tissues and microvessels throughout the brain. The perivenular inflammatory effects induced by TOBIA were prevented by ligating the jugular vein and were reproduced using JOBIA. We conclude that blast injury to the thorax leads to perivenular inflammation, Sur1 up-regulation, and reactive astrocytosis resulting from the induction of a hydrodynamic pulse in the vasculature.

Glibenclamide for the treatment of acute CNS injury.

First introduced into clinical practice in 1969, glibenclamide (US adopted name, glyburide) is known best for its use in the treatment of diabetes mellitus type 2, where it is used to promote the release of insulin by blocking pancreatic KATP [sulfonylurea receptor 1 (Sur1)-Kir6.2] channels. During the last decade, glibenclamide has received renewed attention due to its pleiotropic protective effects in acute CNS injury. Acting via inhibition of the recently characterized Sur1-Trpm4 channel (formerly, the Sur1-regulated NCCa-ATP channel) and, in some cases, via brain KATP channels, glibenclamide has been shown to be beneficial in several clinically relevant rodent models of ischemic and hemorrhagic stroke, traumatic brain injury, spinal cord injury, neonatal encephalopathy of prematurity, and metastatic brain tumor. Glibenclamide acts on microvessels to reduce edema formation and secondary hemorrhage, it inhibits necrotic cell death, it exerts potent anti-inflammatory effects and it promotes neurogenesis-all via inhibition of Sur1. Two clinical trials, one in TBI and one in stroke, currently are underway. These recent findings, which implicate Sur1 in a number of acute pathological conditions involving the CNS, present new opportunities to use glibenclamide, a well-known, safe pharmaceutical agent, for medical conditions that heretofore had few or no treatment options.