Ultrasound-Induced Microbubble Cavitation for Targeted Delivery of MiR-29b Mimic to Treat Cardiac Fibrosis.

OBJECTIVE: Cardiac fibrosis contributes to adverse ventricular remodeling and is associated with loss of miR-29b. Overexpression of miR-29b via plasmid or intravenous injection of microRNA mimic has blunted fibrosis, but these are inefficient and non-targeted delivery strategies. In this study, we tested the hypothesis that delivery of microRNA-29b (miR-29b) using ultrasound-targeted microbubble cavitation (UTMC) of miR-29b-loaded microbubbles would attenuate cardiac fibrosis and preserve left ventricular (LV) function. METHODS: Lipid microbubbles were loaded with miR-29b mimic (miR-29b-MB) or negative control (NC) mimic (NC-MB), placed with cardiac fibroblasts (CFs) and treated with pulsed ultrasound. Cells were harvested to measure downstream fibrotic mediators. Mice received angiotensin II (ANG II) infusion causing afterload increase and direct ANG II-induced cardiac fibrosis. UTMC of miRNA-loaded microbubbles was administered to the heart at days 0, 3 and 7. Serial echocardiography was performed, and hearts were harvested on day 10. RESULTS: UTMC treatment of CFs with miR-29b-MB increased miR-29b and decreased fibrotic transcripts compared with NC-MB treatment. In vivo UTMC + NC-MB led to increased LV mass, reduction in cardiac function and increase in fibrotic markers, demonstrating ANGI II-induced adverse cardiac remodeling. Mice treated with UTMC + miR-29b-MB had preservation of cardiac function, downregulation of cardiac fibrillin and trends of lower COL1A1, COL1A2 and COL3 mRNA and decreased cardiac α-smooth muscle protein. CONCLUSION: UTMC-mediated delivery of miR-29b mimic blunts expression of fibrosis markers and preserves LV function in ANG II-induced cardiac fibrosis.

Clinical and Research Tools for the Study of Cardiovascular Effects of Cancer Therapy.

The expansion of cancer therapeutics has paved the way for improved cancer-related outcomes. Cardiotoxicity from cancer therapy occurs in a small but significant subset of patients, is often poorly understood, and contributes to adverse outcomes at all stages of cancer treatment. Given the often-idiopathic occurrence of cardiotoxicity, novel strategies are needed for risk-stratification and early identification of cancer patients experiencing cardiotoxicity. Clinical and research tools extending from imaging to blood-based biomarkers and pluripotent stem cells are being explored as methods to study the cardiovascular impact of various cancer treatments. Here we provide an overview of tools currently available for evaluation of cardiotoxicity and highlight novel techniques in development aimed at understanding underlying pathophysiologic mechanisms.

Estimation of Intraoperative Stimulation Threshold of the Facial Nerve in Patients Undergoing Microvascular Decompression.

Introduction Facial weakness can result from surgical manipulation of the facial nerve. Intraoperative neuromonitoring reduces functional impairment but no clear guidelines exist regarding interpretation of intraoperative electrophysiological results. Most studies describe subjects with facial nerves encumbered by tumors or those with various grades of facial nerve weakness. We sought to obtain the neurophysiological parameters and stimulation threshold following intraoperative facial nerve triggered electromyography (t-EMG) stimulation during microvascular decompression for trigeminal neuralgia to characterize the response of normal facial nerves via t-EMG. Methods Facial nerve t-EMG stimulation was performed in seven patients undergoing microvascular decompression for trigeminal neuralgia. Using constant current stimulation, single stimulation pulses of 0.025 to 0.2 mA intensity were applied to the proximal facial nerve. Compound muscle action potentials, duration to onset, and termination of t-EMG responses were recorded for the orbicularis oculi and mentalis muscles. Patients were evaluated for facial weakness following the surgical procedure. Results Quantifiable t-EMG responses were generated in response to all tested stimulation currents of 0.025, 0.05, 0.1, and 0.2 mA in both muscles, indicating effective nerve conduction. No patients developed facial weakness postoperatively. Conclusions The presence of t-EMG amplitudes in response to 0.025 mA suggests that facial nerve conduction can take place at lower stimulation intensities than previously reported in patients with tumor burden. Proximal facial nerve stimulation that yields responses with thresholds less than 0.05 mA may be a preferred reference baseline for surgical procedures within the cerebellopontine angle to prevent iatrogenic injury.

Cerebral Aneurysm Wall Stress After Coiling Depends on Morphology and Coil Packing Density.

Endovascular coil embolization is now widely used to treat cerebral aneurysms (CA) as an alternative to surgical clipping. It involves filling the aneurysmal sac with metallic coils to reduce flow, induce clotting, and promote the formation of a coil/thrombus mass which protects the aneurysm wall from hemodynamic forces and prevents rupture. However, a significant number of aneurysms are incompletely coiled leading to aneurysm regrowth and/or recanalization. Computational models of aneurysm coiling may provide important new insights into the effects of intrasaccular coil and thrombus on aneurysm wall stresses. Porcine blood and platinum coils were used to construct an in vitro coil thrombus mass (CTM) for mechanical testing. A uniaxial compression test was performed with whole blood clots and CTM, with coil packing densities (CPDs) of 10%, 20%, and 30% to obtain compressive stress/strain responses. A fourth-order polynomial mechanical response function was fit to the experimentally obtained stress/strain responses for each CPD in order to represent their mechanical properties for computational simulations. Patient-specific three-dimensional (3D) geometries of three aneurysms with simple geometry and four with complex geometry were reconstructed from digital subtraction angiography (DSA) images. The CPDs were digitally inserted in the aneurysm geometries and finite element modeling was used to determine transmural peak/mean wall stress (MWS) with and without coil packing. Reproducible stress/strain curves were obtained from compression testing of CTM and the polynomial mechanical response function was found to approximate the experimental stress/strain relationship obtained from mechanical testing to a high degree. An exponential increase in the CTM stiffness was observed with increasing CPD. Elevated wall stresses were found throughout the aneurysm dome, neck, and parent artery in simulations of the CAs with no filling. Complete, 100% filling of the aneurysms with whole blood clot and CPDs of 10%, 20%, and 30% significantly reduced MWS in simple and complex geometry aneurysms. Sequential increases in CPD resulted in significantly greater increases in MWS in simple but not complex geometry aneurysms. This study utilizes finite element analysis to demonstrate the reduction of transmural wall stress following coil embolization in patient-specific computational models of CAs. Our results provide a quantitative measure of the degree to which CPD impacts wall stress and suggest that complex aneurysmal geometries may be more resistant to coil embolization treatment. The computational modeling employed in this study serves as a first step in developing a tool to evaluate the patient-specific efficacy of coil embolization in treating CAs.

Utility of calcium phosphate cement cranioplasty following supraorbital approach for tumor resection.

OBJECTIVE: We have previously documented the utility of calcium phosphate cement cranioplasty following retromastoid craniectomy. In this study, we aimed to demonstrate its efficacy following a supraorbital approach for tumor resection. METHODS: A retrospective analysis of a prospectively maintained database was conducted of eight patients (7 female, 1 male) with anterior cranial fossa meningiomas resected via a supraorbital approach followed by cranioplasty involving adjunctive or sole use of calcium phosphate cement. RESULTS: Cranioplasty was achieved in all patients. No patient developed an incisional leak. The cohort had a mean follow-up of approximately 3.1 months (range: 0.5-7 months) in which time no further complications were noted. No patients developed post-surgical infections. CONCLUSION: In our experience, a low incidence of infection or CSF leaks has been noted after the use of calcium phosphate cement retromastoid cranioplasty. Extending this technique to supraorbital craniotomies may minimize incisional CSF leak.

Successful Manual Aspiration Thrombectomy in a Pediatric Patient.

BACKGROUND: Timely recognition of stroke at major pediatric medical centers is improving, and although treatment guidelines for pediatric stroke exist, no extensive study establishing the efficacy of surgical or thrombolytic treatment has been completed. Extrapolation of adult guidelines to pediatric patients remains the mainstay of treatment in the absence of adequate information regarding safety and efficacy in children. Recent trials have demonstrated revascularization and clinical improvement after endovascular retrieval therapy in adults with acute large vessel occlusive stroke. Furthermore, successful mechanical thrombectomy using a variety of techniques has been documented in numerous children and adolescents. PATIENT DESCRIPTION: We present a 15-year-old boy with altered mental status and left hemiparesis due to acute ischemic stroke secondary to blockage of the right internal carotid artery terminus, most likely precipitated by end-stage heart failure and cardiac embolism. Mechanical aspiration thrombectomy using the Penumbra aspiration catheter without any adjunct surgical equipment or thrombolytic therapy was used to remove thrombus and treat the patient's acute ischemic stroke. He experienced complete artery recanalization with a Thrombolysis in Cerebral Infarction (TICI) score of 2C after the procedure. He also exhibited an 8 point improvement in his pediatric National Institutes of Health Stroke Scale score within 24 hours. CONCLUSIONS: Mechanical aspiration thrombectomy is commonly used in adult hospitals but infrequently employed in pediatric patients with arterial ischemic stroke. Given its efficacy in our patient, we encourage a larger systematic trial to evaluate the use of mechanical thrombectomy in pediatric patients with acute ischemic stroke.