A Novel Epigenetic Drug-Eluting Balloon Angioplasty Device: Evaluation in a Large Animal Model of Neointimal Hyperplasia.

PURPOSE: Drug-eluting balloon catheters (DEBc) coated with paclitaxel (PTX) have been associated with potential safety concerns. An efficacious but less toxic balloon coating may reduce these outcomes. We evaluated a novel DEBc, Epi-Solve, coated with metacept-3 (MCT-3), a member of the histone deacetylase inhibitor (HDACi) class of epigenetic agents, in a large animal model of neointimal hyperplasia (NIH). METHODS: Plain balloon angioplasty (PABA) catheters were ultrasonically coated with MCT-3 to generate Epi-Solve DEBc. An ovine model of NIH formation was established utilising partial left common carotid artery (LCA) ligation. Twenty-eight days post neointima (NI) induction, PABA, Epi-Solve or PTX-coated DEBc were deployed at the site of induced NI formation. Twenty-eight days post-intervention, ligated vessels were evaluated for attenuation of NI formation, gene expression profiles and immunohistochemical analysis. RESULTS: Epi-Solve DEBc demonstrated attenuation of NIH over no intervention and a trend to inhibition of NIH over PABA. Gene expression analysis and immunohistochemical studies identified significant anti-proliferative and anti-inflammatory signatures and reduced vascular endothelial cell activation compared to PABA. CONCLUSIONS: Epi-Solve is a novel HDACi-coated DEBc which demonstrates significant anti-proliferative and anti-inflammatory signatures and reduced vascular endothelial cell activation compared to PABA in an ovine model and may afford endothelial protection.

The use of the AVERT system to limit contrast volume administration during peripheral angiography and intervention.

BACKGROUND: The AVERT(TM) Contrast Modulation System (AVERT) (Osprey Medical, MN) is designed to reduce contrast volume administration during angiography. The AVERT provides an adjustable resistance circuit which decreases the pressure head delivering contrast towards the patient. The AVERT has not been previously studied in patients undergoing peripheral digital subtraction angiography (DSA). The purpose of this study was (1) to evaluate contrast savings with the AVERT and (2) to evaluate the ability to generate clinically acceptable DSA images in the process. To better define the mechanism of action in the peripheral circulation, we also developed a bench model to study the effects of the AVERT on the hydrodynamics of contrast delivery. METHODS: Patients undergoing lower extremity DSA (diagnostic or intervention, sheath or catheter) were studied. The following variables were recorded for each injection: starting control syringe contrast volume, contrast volume injected towards patient, contrast volume returned to AVERT reservoir, net contrast administered to the patient and % savings. The AVERT resistance was adjusted manually based on operator's discretion--balancing image quality and contrast savings. RESULTS: About 408 DSA angiographic sequences were obtained in 22 patients undergoing 29 procedures. Almost 68% of the patients had chronic kidney disease. An 82% presented with critical limb ischemia, 18% had claudication. There was an overall 37% ± 14% savings of contrast (31% for diagnostic DSA, 40% for interventional procedures). Overall 91% of all images were acceptable for clinical decision making. Specifically, 94% of diagnostic and 87% of interventional images were acceptable. Injection through a 4 Fr catheter (77% acceptable) resulted in poorer image quality as compared to a 5 Fr catheter (96% acceptable). Image quality for 5, 6, and 7 Fr sheath injections was 86%, 91%, 98%, respectively. The bench model of peripheral angiography demonstrated a significant reduction in reflux of contrast proximal to the end of the catheter without loss of antegrade image quality - confirming the in vivo findings. CONCLUSIONS: We demonstrate that the use of the AVERT device during peripheral angiography results in significant contrast savings without compromising image quality.

A pilot study of electronic directly observed therapy to improve hydroxyurea adherence in pediatric patients with sickle-cell disease.

BACKGROUND: Poor hydroxyurea (HU) adherence limits effective HU use in patients with sickle cell disease (SCD). Electronic directly observed therapy (DOT) may limit costs and achieve high HU adherence in children with SCD. This study aimed to determine if electronic DOT was feasible, acceptable, and could achieve ≥ 90% HU adherence. PROCEDURE: Children with SCD were recruited for this single institution, 6-month pilot study if they had been prescribed HU for ≥ 6 months and had daily access to a smartphone or computer. Participants submitted HU administration videos daily and received electronic reminder alerts, personalized feedback, and incentives to encourage adherence as part of electronic DOT. Primary outcomes were feasibility, participant satisfaction with electronic DOT, and HU adherence. Secondary outcomes included mean corpuscular volume (MCV), hemoglobin F percentage (HbF), and overall participant satisfaction with HU therapy. RESULTS: Of 15 enrolled participants, 14 completed the study. Satisfaction surveys showed electronic DOT reminded participants to take HU and could be completed in fewer than 5 minutes daily. Participants' median medication possession ratio at study entry improved from 0.75 (0.59-0.82) to 0.91 (0.85-1.00) (P = 0.02) at the end of the study. Overall median observed HU adherence with electronic DOT was 93.3%. Median MCV and HbF increased from 96.0 to 107.2 (P = 0.009) and 10.5 to 11.4 (P = 0.03), respectively. CONCLUSIONS: This study demonstrates electronic DOT is feasible, acceptable, and can achieve high HU adherence. Further study is needed to confirm that electronic DOT can improve HU adherence and impact clinical outcomes in children with SCD.

Comparison of artificial intelligence large language model chatbots in answering frequently asked questions in anaesthesia.

Background: Patients are increasingly using artificial intelligence (AI) chatbots to seek answers to medical queries. Methods: Ten frequently asked questions in anaesthesia were posed to three AI chatbots: ChatGPT4 (OpenAI), Bard (Google), and Bing Chat (Microsoft). Each chatbot's answers were evaluated in a randomised, blinded order by five residency programme directors from 15 medical institutions in the USA. Three medical content quality categories (accuracy, comprehensiveness, safety) and three communication quality categories (understandability, empathy/respect, and ethics) were scored between 1 and 5 (1 representing worst, 5 representing best). Results: ChatGPT4 and Bard outperformed Bing Chat (median [inter-quartile range] scores: 4 [3-4], 4 [3-4], and 3 [2-4], respectively; P<0.001 with all metrics combined). All AI chatbots performed poorly in accuracy (score of ≥4 by 58%, 48%, and 36% of experts for ChatGPT4, Bard, and Bing Chat, respectively), comprehensiveness (score ≥4 by 42%, 30%, and 12% of experts for ChatGPT4, Bard, and Bing Chat, respectively), and safety (score ≥4 by 50%, 40%, and 28% of experts for ChatGPT4, Bard, and Bing Chat, respectively). Notably, answers from ChatGPT4, Bard, and Bing Chat differed statistically in comprehensiveness (ChatGPT4, 3 [2-4] vs Bing Chat, 2 [2-3], P<0.001; and Bard 3 [2-4] vs Bing Chat, 2 [2-3], P=0.002). All large language model chatbots performed well with no statistical difference for understandability (P=0.24), empathy (P=0.032), and ethics (P=0.465). Conclusions: In answering anaesthesia patient frequently asked questions, the chatbots perform well on communication metrics but are suboptimal for medical content metrics. Overall, ChatGPT4 and Bard were comparable to each other, both outperforming Bing Chat.

Extracorporeal membrane oxygenation to support cardiopulmonary resuscitation in a sheep model of refractory ischaemic cardiac arrest.

BACKGROUND: Survival after out-of-hospital cardiac arrest remains limited. It is therefore imperative to develop new resuscitation techniques. We aimed to determine the potential role of extracorporeal membrane oxygenation assisted CPR (ECPR) in an animal model of refractory ischaemic cardiac arrest. METHODS: Twelve sheep were assigned to either ECPR (n=6) or 'conventional' (n=6) resuscitation. All sheep had coronary occlusion, followed by induction of ventricular fibrillation (VF). CPR was than commenced for 10 min in both groups, followed by randomisation to ECPR or CPR for a further 10 min. At 23 min post induction of VF, advanced life support measures were commenced with direct cardioversion, adrenaline and amiodarone. Outcomes measures included rates of return of spontaneous circulation (ROSC), and analysis of VF wave form. RESULTS: Baseline haemodynamics were similar between the two groups. CPR consistently produced coronary perfusion pressures (CPP) greater than 15 mmHg in both groups, with significantly increased CPP post commencement of ECMO in the ECPR group (17.84±2 mmHg vs 22.94±3 mmHg, p=0.04). Number of shocks, pH, lactate and oxygenation were also comparable. Significantly greater rates of ROSC were seen in the ECPR sheep, 3/6 (50%) vs 0/6 (0%) (p=0.032), which was also associated with significantly increased VF amplitude measures (0.51±0.08 mV vs 0.42±0.06 mV, p=0.04). CONCLUSIONS: This study indicates that ECPR increases return of circulation and coronary perfusion pressure in a sheep model of ischaemic VF arrest. Our findings have supported the development of a pilot trial into the effectiveness and feasibility of ECPR in the clinical setting.

Assessment of cardiopulmonary point-of-care ultrasound objective structured clinical examinations in graduating anesthesiology residents across multiple residency programs.

STUDY OBJECTIVE: To implement and assess a cardiopulmonary point-of-care ultrasound (POCUS) objective structured clinical examination (OSCE) in a large cohort of graduating anesthesia residents. DESIGN: Observational cohort study. SETTING: University-affiliated hospitals. SUBJECTS: 150 graduating anesthesia residents in their last nine months of training. INTERVENTIONS: A standardized cardiopulmonary OSCE was administered to each resident. MEASUREMENTS: The cardiac views evaluated were parasternal long axis (PLAX), apical 4 chamber (A4C), and parasternal short axis (PSAX). The pulmonary views evaluated were pleural effusion (PLE) and pneumothorax (PTX). In addition, a pre- and post-exam survey scored on a 5-point Likert scale was administered to each resident. MAIN RESULTS: A4C view (mean 0.7 ± 0.3) scored a lower mean, compared to PSAX (mean 0.8 ± 0.3) and PLAX (mean 0.8 ± 0.4). Residents performed well on the PTX exam (mean 0.9 ± 0.3) but more poorly on the PLE exam (mean 0.6 ± 0.4). Structural identification across cardiac and pulmonary views were mostly high (means >0.7), but advanced interpretive skills and maneuvers had lower mean scores. Pre- and post- OSCE survey results were positive with almost all questions scoring >4 on the Likert scale. CONCLUSION: Our study demonstrates that a cardiopulmonary POCUS OSCE can be successfully implemented across multiple anesthesia training programs. While most residents were able to perform basic ultrasound views and identify structures, advanced interpretive skills and maneuvers performed lower.

Prolonging the life of a patient's IV: an integrative review of intravenous securement devices.

In this integrative review, current research on the effectiveness of intravenous (IV) securement devices is described and practical implications for evidence-based practice in IV care are provided.

Graduate Medical Education Can Be an Impetus for Behavior Changes in Physicians in Practice: Point-Of-Care Ultrasound Faculty Development Intervention in Anesthesiology.

INTRODUCTION: While there is growing evidence to suggest that point-of-care ultrasound (POCUS) may aid in clinical decision-making in the perioperative setting and there are new requirements that anesthesiology residents must be trained in POCUS, few practicing anesthesiologists use POCUS in their practice. The goal of this investigation is to determine whether a multifaceted faculty development program helps a group of faculty members incorporate POCUS into their practice. METHODS: This intervention had five parts: (1) online prework, (2) 2-day workshop, (3) follow-up hands-on sessions, (4) regular communication, and (5) equipment acquisition. This is a pretest/posttest, single group, observational study where the main outcome measure is the number of POCUS examinations documented and the number of providers who performed at least one examination. In addition, presurveys and postsurveys were administered to determine whether there was a change in confidence and self-reported use of POCUS. RESULTS: The number of examinations completed and the number of providers completing examinations by month both seemed to increase over time between May 2017 and October 2018. Between August 2017 and October 2018, the number of examinations completed per month increased by a rate of approximately one examination per month (starting with one examination in May 2017) and the number of providers completing examinations increased by a rate of approximately 0.61 providers per month (staring with one provider in May 2017). DISCUSSION: This study shows that an intervention that targets interested faculty can increase the use of POCUS in practice and residents' perceptions of teaching.

Design, Development, In Vitro and Preliminary In Vivo Evaluation of a Novel Photo-Angioplasty Device: Lumi-Solve.

PURPOSE: Paclitaxel (PTX)-coated drug eluting balloon catheters (DEBc) used in the management of neointimal hyperplasia (NIH) have been associated with safety concerns. Alternative coating agents and targeted delivery systems may improve safety and DEBc efficacy. Utilizing a multi-platform approach we designed, developed and evaluated Lumi-Solve, a novel DEBc, coated with ultraviolet (UV) 365 nm-activated caged metacept-3 (c-MCT-3), an epigenetic agent from the histone deacetylase inhibitor (HDACi) class. METHODS: In vitro catheter and contrast media transmission of UV365nm was evaluated spectroscopically. UV365nm conversion of c-MCT-3 to MCT-3 was evaluated chromatographically. Cellular toxicity and HDACi activity of c-MCT-3 ∓UV365nm was evaluated in vitro. In vivo UV365nm conversion of c-MCT-3 to MCT-3 was evaluated in an ovine carotid artery model. RESULTS: Catheter material and dilute contrast media did not attenuate UV365nm transmission or c-MCT-3 activation. c-MCT-3 demonstrated less cellular toxicity than MCT-3 and PTX. UV365nm-activated c-MCT-3 demonstrated HDACi activity. In vivo activation of c-MCT-3 produced MCT-3. CONCLUSIONS: Lumi-Solve, a novel DEBc device developed utilizing a combination of chemical, fibre-optic and catheter based technology platforms, demonstrated potential for targeted delivery of bioactive HDACi to the blood vessel wall supporting direct application to the management of NIH and warranting additional in vivo studies.

American Society of Regional Anesthesia and Pain Medicine expert panel recommendations on point-of-care ultrasound education and training for regional anesthesiologists and pain physicians-part II: recommendations.

Point-of-care ultrasound (POCUS) is a critical skill for all regional anesthesiologists and pain physicians to help diagnose relevant complications related to routine practice and guide perioperative management. In an effort to inform the regional anesthesia and pain community as well as address a need for structured education and training, the American Society of Regional Anesthesia and Pain Medicine Society (ASRA) commissioned this narrative review to provide recommendations for POCUS. The recommendations were written by content and educational experts and were approved by the guidelines committee and the Board of Directors of the ASRA. In part II of this two-part series, learning goals and objectives were identified and outlined for achieving competency in the use of POCUS, specifically, airway ultrasound, lung ultrasound, gastric ultrasound, the focus assessment with sonography for trauma exam, and focused cardiac ultrasound, in the perioperative and chronic pain setting. It also discusses barriers to POCUS education and training and proposes a list of educational resources. For each POCUS section, learning goals and specific skills were presented in the Indication, Acquisition, Interpretation, and Medical decision-making framework.

American Society of Regional Anesthesia and Pain Medicine expert panel recommendations on point-of-care ultrasound education and training for regional anesthesiologists and pain physicians-part I: clinical indications.

Point-of-care ultrasound (POCUS) is a critical skill for all regional anesthesiologists and pain physicians to help diagnose relevant complications related to routine practice and guide perioperative management. In an effort to inform the regional anesthesia and pain community as well as address a need for structured education and training, the American Society of Regional Anesthesia and Pain Medicine (ASRA) commissioned this narrative review to provide recommendations for POCUS. The guidelines were written by content and educational experts and approved by the Guidelines Committee and the Board of Directors of the ASRA. In part I of this two-part series, clinical indications for POCUS in the perioperative and chronic pain setting are described. The clinical review addresses airway ultrasound, lung ultrasound, gastric ultrasound, the focus assessment with sonography for trauma examination and focused cardiac ultrasound for the regional anesthesiologist and pain physician. It also provides foundational knowledge regarding ultrasound physics, discusses the impact of handheld devices and finally, offers insight into the role of POCUS in the pediatric population.

Recirculating delivery improves myocardial cell engraftment.

INTRODUCTION: Despite pharmacological advances for heart failure, morbidity and mortality remain unacceptably high. As a result, alternative approaches such as cell therapy have been suggested to hold potential promise. However, a major obstacle is the optimization of cell delivery to the heart. Therefore, we investigated the efficacy of a percutaneous recirculation system for the delivery of cells to the heart. METHODS: Ovine fibroblasts were delivered to the ovine heart (3 x 10(7) cells) using the V-Focus system, a "closed" recirculatory system that draws blood from the coronary sinus and returns it to the coronary artery via an oxygenator, or intracoronary (IC) infusion, followed by a 2-hour recovery period. Animals were euthanized and cardiac tissue collected to determine presence of cells. RESULTS: There was a significant difference (P < 0.05) in the number of cells delivered to the heart by the V-Focus compared to direct coronary infusion for left ventricular freewall (V-Focus 1.39 +/- 0.63/mm(2), IC 0.11 +/- 0.06/mm(2)), septum (V-Focus 3.18 +/- 0.88/mm(2), IC 0.38 +/- 0.19/mm(2)), and right ventricle (V-Focus 0.46 +/- 0.23/mm(2), IC 0.05 +/- 0.04/mm(2)). CONCLUSIONS: These results suggest that potential therapeutic cells are optimally delivered to the large animal heart using the V-Focus cardiac delivery system in an ovine heart.

Extended-Release Oral Milrinone for the Treatment of Heart Failure With Preserved Ejection Fraction.

Background Heart failure with preserved ejection fraction (HFpEF) is an increasingly prevalent form of heart failure, representing half of the total burden of heart failure. We hypothesised that modulation of the phosphodiesterase type 3/cyclic AMP using a novel oral formulation of milrinone might exert favorable effects HFpEF via pulmonary and systemic vasodilation and enhancement of ventricular relaxation. We assessed the safety and efficacy of oral milrinone on quality of life and functional outcomes in patients with HFpEF. Methods and Results The MilHFPEF (Extended Release Oral Milrinone for the Treatment of Heart Failure With Preserved Ejection Fraction) study was a randomized, double-blind, placebo-controlled pilot study in 23 patients with symptomatic HFpEF. Efficacy end points included changes from baseline in Kansas City Cardiomyopathy Questionnaire summary score and 6-minute walk distance. The primary safety end point was the development of clinically significant arrhythmia. The Kansas City Cardiomyopathy Questionnaire score improved significantly in milrinone-treated patients compared with placebo (+10±13 versus -3±15; P=0.046). Six-minute walk distance also tended to improve in the treatment group compared with placebo (+22 [-8 to 49] versus -47 [-97 to 12]; P=0.092). Heart rate (-1±5 versus -2±9 bpm; P=0.9) and systolic blood pressure (-3±18 versus +1±12 mm Hg; P=0.57) were unchanged. Early filling velocity/early mitral annular velocity (-0.3±3.0 versus -1.9±4.8; P=0.38) was unchanged. One patient in the placebo arm was hospitalized for heart failure. Holter monitoring did not demonstrate evidence of a proarrhythmic effect of milrinone. Conclusions In this novel pilot study, extended release oral milrinone was well tolerated and associated with improved quality of life in patients with HFpEF. Further longer-term studies are warranted to establish the role of this therapeutic approach in HFpEF. Registration URL: https://www.anzctr.org.au/; Unique identifier: ACTRN12616000619448.

Identification of physiologic treatment targets with favourable haemodynamic consequences in heart failure with preserved ejection fraction.

AIMS: Heart failure with preserved ejection fraction (HFpEF) is characterized by complex pathophysiology including an impaired diastolic reserve. We recently showed that milrinone favourably modifies filling pressures at rest and during exertion in HFpEF patients; however, the responsible mechanism is uncertain. The objective of this study was to develop a clearer understanding of the acutely modifiable physiologic parameters that may be targeted in HFpEF. METHODS AND RESULTS: We conducted computer modelling simulations based on invasive haemodynamic assessments, by right heart catheterization, in HFpEF patients at baseline and in response to milrinone. Our aim was to develop a detailed understanding of the physiologic mechanisms, which accounted for the observed actions. The resultant circulatory model of HFpEF encompassed the left ventricular (LV) end-systolic and end-diastolic pressure-volume relations, together with stressed blood volume, heart rate, and arterial mechanics. To support the modelled action of milrinone, we conducted complementary LV conductance catheter and echocardiography studies in sheep to evaluate LV end-systolic and end-diastolic pressure-volume relations. In HFpEF patients, the acute haemodynamic effects of intravenous milrinone (n = 10) administration compared with placebo (n = 10) included significant reductions in right atrial pressure (7 ± 1 to 3 ± 1 mmHg, P < 0.001) and pulmonary capillary wedge pressure (13 ± 1 to 8 ± 1 mmHg, P < 0.001), while cardiac index increased (2.77 ± 0.19 to 3.15 ± 0.14 L/min/m2 , P < 0.05), and mean arterial pressure remained unchanged (95 ± 2 to 93 ± 3 mmHg, P = not significant). Computer simulations showed that these haemodynamic effects were explained by a concomitant 31% reduction in stressed blood volume together with 44% increase in LV end-systolic elastance (LV Ees ). Individually, changes in these parameters were not sufficient to explain the haemodynamic effects of milrinone. In vivo studies conducted in sheep (n = 5) showed that milrinone reduced LV filling pressure (8.0 ± 0.8 to 2.7 ± 0.6 mmHg, P < 0.01) and increased LV Ees (0.96 ± 0.07 to 2.07 ± 0.49, P < 0.05), while no significant effect on LV stiffness was observed (0.038 ± 0.003 to 0.034 ± 0.008, P = not significant). CONCLUSIONS: These data demonstrate that stressed blood volume in HFpEF represents a relevant physiologic target in HFpEF; however, concomitant modulation of other cardiovascular parameters including LV contractility may be required to achieve desirable haemodynamic effects.

Reversal of global apoptosis and regional stress kinase activation by cardiac resynchronization.

BACKGROUND: Cardiac dyssynchrony in the failing heart worsens global function and efficiency and generates regional loading disparities that may exacerbate stress-response molecular signaling and worsen cell survival. We hypothesized that cardiac resynchronization (CRT) from biventricular stimulation reverses such molecular abnormalities at the regional and global levels. METHODS AND RESULTS: Adult dogs (n=27) underwent left bundle-branch radiofrequency ablation, prolonging the QRS by 100%. Dogs were first subjected to 3 weeks of atrial tachypacing (200 bpm) to induce dyssynchronous heart failure (DHF) and then randomized to either 3 weeks of additional atrial tachypacing (DHF) or biventricular tachypacing (CRT). At 6 weeks, ejection fraction improved in CRT (2.8+/-1.8%) compared with DHF (-4.4+/-2.7; P=0.02 versus CRT) dogs, although both groups remained in failure with similarly elevated diastolic pressures and reduced dP/dtmax. In DHF, mitogen-activated kinase p38 and calcium-calmodulin-dependent kinase were disproportionally expressed/activated (50% to 150%), and tumor necrosis factor-alpha increased in the late-contracting (higher-stress) lateral versus septal wall. These disparities were absent with CRT. Apoptosis assessed by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling staining, caspase-3 activity, and nuclear poly ADP-ribose polymerase cleavage was less in CRT than DHF hearts and was accompanied by increased Akt phosphorylation/activity. Bcl-2 and BAD protein diminished with DHF but were restored by CRT, accompanied by marked BAD phosphorylation, enhanced BAD-14-3-3 interaction, and reduced phosphatase PP1alpha, consistent with antiapoptotic effects. Other Akt-coupled modulators of apoptosis (FOXO-3alpha and GSK3beta) were more phosphorylated in DHF than CRT and thus less involved. CONCLUSIONS: CRT reverses regional and global molecular remodeling, generating more homogeneous activation of stress kinases and reducing apoptosis. Such changes are important benefits from CRT that likely improve cardiac performance and outcome.

Three-dimensional mapping of optimal left ventricular pacing site for cardiac resynchronization.

BACKGROUND: The efficacy of cardiac resynchronization therapy (CRT) depends on placement of the left ventricular lead within the late-activated territory. The geographic extent and 3-dimensional distribution of left ventricular (LV) locations yielding optimal CRT remain unknown. METHODS AND RESULTS: Normal or tachypacing-induced failing canine hearts made dyssynchronous by right ventricular free wall pacing or chronic left bundle-branch ablation were acutely instrumented with a nonconstraining epicardial elastic sock containing 128 electrodes interfaced with a computer-controlled stimulation/recording system. Biventricular CRT was performed using a fixed right ventricular site and randomly selected LV sites covering the entire free wall. For each LV site, global cardiac function (conductance catheter) and mechanical synchrony (magnetic resonance imaging tagging) were determined to yield 3-dimensional maps reflecting CRT impact. Optimal CRT was achieved from LV lateral wall sites, slightly more anterior than posterior and more apical than basal. LV sites yielding > or = 70% of the maximal dP/dtmax increase covered approximately 43% of the LV free wall. This distribution and size were similar in both normal and failing hearts. The region was similar for various systolic and diastolic parameters and correlated with 3-dimensional maps based on mechanical synchrony from magnetic resonance imaging strain analysis. CONCLUSIONS: In hearts with delayed lateral contraction, optimized CRT is achieved over a fairly broad area of LV lateral wall in both nonfailing and failing hearts, with modest anterior or posterior deviation still capable of providing effective CRT. Sites selected to achieve the most mechanical synchrony are generally similar to those that most improve global function, confirming a key assumption underlying the use of wall motion analysis to optimize CRT.

The synergism between atrial fibrillation and heart failure.

BACKGROUND: Atrial fibrillation (AF) is a common comorbidity in heart failure (HF) patients and is classically associated with acceleration in the rate of HF progression. The precise mechanism for this interaction is unclear, but comprises "bidirectional" aspects in which AF promotes HF and HF also increases the likelihood of AF. We therefore studied the relationship between AF in an ovine model of pacing-induced congestive HF, in an attempt to identify the mechanisms that underpin the apparent synergistic relationship between AF and HF. METHODS AND RESULTS: Sixteen adult sheep were paced at 190 beats/min for 21 days (HF). AF was induced in 8 of these animals at 14 days' pacing using programmed extrastimuli (HF + AF). Left ventricular hemodynamics and the pattern of cardiac neurohormonal activation, via coronary sinus (CS) sampling, were determined at rest and during submaximal exercise testing in both groups at 21 days and after AF reversion (by atrial defibrillation) at 21 days. CS norepinephrine (NE), endothelin (ET-1), and brain natriuretic peptide (BNP) levels were significantly increased in HF + AF animals, whereas LV end-diastolic pressure (EDP) and LV dP/dt max were significantly reduced compared with moderate HF alone. Cardioversion significantly reduced CS NE and BNP levels and improved contractility in AF + HF animals. In a further 6 animals, we explored the mechanism by which HF increases susceptibility to AF, with specific emphasis on the influence of functional mitral regurgitation. The elimination of MR in HF animals using a percutaneous mitral annular reduction device significantly decreased the inducibility of AF. CONCLUSIONS: AF induction significantly depresses left ventricular function and causes activation of myocardial neurohormones. In conjunction, the presence of functional MR increases susceptibility to AF and this may be attenuated by MR reduction by percutaneous mitral annular reduction.

An improved murine femur fracture device for bone healing studies.

Murine models are commonly used to investigate bone healing and test new treatments before human trials. Our objective was to design an improved murine femur fracture device and determine optimal mass and velocity settings for maximal likelihood of transverse fracture. Fracture reproducibility was maximized using an adjustable kinetic energy level, a novel mouse positioning system and an electromagnet striker release assembly. Sixty wild-type mice of 8-12-week-old male and female with a weight of 26.4+/-6.1g were subjected to an experimental postmortem fracture in the left and right femur (n=120) using variable kinetic energy inputs. A best-fit prediction equation for transverse fracture was developed using multivariate linear regression. Transverse fracture was shown to correlate most highly with kinetic energy with a maximum likelihood at mv2=292 where m is mass (g) and v is velocity (m/s). Model validation with a group of 134 anesthetized C57BL/6 mice resulted in a favorable transverse fracture rate of 85.8%. Simple modifications to existing fracture devices can improve accuracy and reproducibility. The results may assist researchers studying the effects of genetic modifications and novel treatments on boney healing in murine femur fracture models. Maintaining kinetic energy parameters within suggested ranges may also aid in ensuring accuracy and reproducibility.

Extended Release Oral Milrinone, CRD-102, for Advanced Heart Failure.

Although heart transplantation and mechanical circulatory support are effective therapies for patients with advanced heart failure (HF), many patients are ineligible due to co-morbidities. Continuous home intravenous with positive inotropes such as milrinone are used in these patients to improve quality of life. We hypothesized that, unlike previous studies with oral milrinone, a slow-release formulation that provides stable lower plasma levels may be better tolerated and provide symptomatic benefit. Accordingly, we developed an extended release milrinone formulation (CRD-102) and evaluated its effects in 26 patients with no-option Stage D HF. One month after open-label therapy there were significant improvements in NYHA class, Minnesota Living with Heart Failure score and 6-minute walk distance. There was no evidence of hypotension or increased arrhythmic burden. In conclusion, the present study demonstrates evidence of beneficial actions of extended release milrinone in advanced HF. Longer-term randomized clinical trial data are required.