Electrical Diuretics: Dorsal Root Ganglion Stimulation to Increase Diuresis.

BACKGROUND: Stimulation of diuresis is an essential component of heart failure treatment to reduce fluid overload. Over time, increasing doses of loop diuretics are required to achieve adequate urine output, and approximately 30% to 45% of patients develop diuretic resistance. We investigated the feasibility of affecting renal afferent sensory nerves by dorsal root ganglion neurostimulation as an alternative to medication to increase diuresis. MATERIALS AND METHODS: Acute volume overload with an elevated and stable pulmonary capillary wedge pressure (PCWP) was induced by infusion of isotonic fluid in swine (N = 7). In each experiment, diuresis and blood electrolyte levels were measured during cycles of up to two hours (baseline, stimulation, poststimulation) through bladder catheterization. Efficacy was tested using bilateral dorsal root ganglion (bDRG) stimulation at the T11 and/or T12 vertebral levels. RESULTS: An elevated, stable PCWP (15 ± 4 mm Hg, N = 7) was obtained after uploading. Under these conditions, average diuresis increased 20% to 205% compared with no stimulation. Side effects such as motor stimulation were mitigated by decreasing current or terminated spontaneously without intervention. There was no negative effect on acute kidney function because blood electrolyte concentrations remained stable. When stimulation was deactivated, urine output decreased significantly but did not return to baseline levels, suggesting a carry-over effect of up to two hours. CONCLUSIONS: Electrical stimulation (bDRG) at T11 and/or T12 increased diuresis in an acute volume overload model. Side effects caused by unintended (motor) stimulation could be eliminated by reducing the electrical current while sustaining increased diuresis.

Mapping and Monitoring Zero-Deforestation Commitments.

A growing number of companies have announced zero-deforestation commitments (ZDCs) to eliminate commodities produced at the expense of forests from their supply chains. Translating these aspirational goals into forest conservation requires forest mapping and monitoring (M&M) systems that are technically adequate and therefore credible, salient so that they address the needs of decision makers, legitimate in that they are fair and unbiased, and scalable over space and time. We identify 12 attributes of M&M that contribute to these goals and assess how two prominent ZDC programs, the Amazon Soy Moratorium and the High Carbon Stock Approach, integrate these attributes into their M&M systems. These programs prioritize different attributes, highlighting fundamental trade-offs in M&M design. Rather than prescribe a one-size-fits-all solution, we provide policymakers and practitioners with guidance on the design of ZDC M&M systems that fit their specific use case and that may contribute to more effective implementation of ZDCs.

Right Ventricular Anatomy Can Accommodate Multiple Micra Transcatheter Pacemakers.

BACKGROUND: The introduction of transcatheter pacemaker technology has the potential to significantly reduce if not eliminate a number of complications associated with a traditional leaded pacing system. However, this technology raises new questions regarding how to manage the device at end of service, the number of devices the right ventricle (RV) can accommodate, and what patient age is appropriate for this therapy. In this study, six human cadaver hearts and one reanimated human heart (not deemed viable for transplant) were each implanted with three Micra devices in traditional pacing locations via fluoroscopic imaging. METHODS: A total of six human cadaver hearts were obtained from the University of Minnesota Anatomy Bequest Program; the seventh heart was a heart not deemed viable for transplant obtained from LifeSource and then reanimated using Visible Heart(®) methodologies. Each heart was implanted with multiple Micras using imaging and proper delivery tools; in these, the right ventricular volumes were measured and recorded. The hearts were subsequently dissected to view the right ventricular anatomies and the positions and spacing between devices. RESULTS: Multiple Micra devices could be placed in each heart in traditional, clinically accepted pacing implant locations within the RV and in each case without physical device interactions. This was true even in a human heart considered to be relatively small. CONCLUSIONS: Although this technology is new, it was demonstrated here that within the human heart's RV, three Micra devices could be accommodated within traditional pacing locations: with the potential in some, for even more.

Early Performance and Safety of the Micra Transcatheter Pacemaker in Pigs.

BACKGROUND: The Micra® Transcatheter Pacing System (TPS; Medtronic Inc., Minneapolis, MN, USA) is a miniaturized single-chamber pacemaker system that is delivered via catheter through the femoral vein. In this study, the electrical performance was compared between the TPS and a traditional leaded pacemaker. In addition, the safety profile of the two systems was compared by thorough monitoring for a number of adverse events. METHODS: The TPS was implanted in the right ventricular apex of 10 Yucatan mini pigs and a Medtronic single-lead pacemaker (SLP) was implanted in the right ventricular apex of another 10 pigs and connected to a traditional pacemaker. The electrical performance of all devices was monitored for 12 weeks. The safety profile of each system was characterized using x-ray, computed tomography, ultrasound, blood work, and necropsy to monitor for a variety of adverse events. RESULTS: At implant the mean pacing thresholds were 0.58 ± 0.17 V @0.24 ms and 0.75 ± 0.29 V @0.21 ms for the TPS and the SLP respectively. After 12 weeks, mean thresholds were 0.94 ± 0.46 V and 1.85 ± 0.75 V (P < 0.0001). There were two pulmonary emboli that were small and past the tertiary branch, and one occurred in each arm. There were also two infections with one in each arm. There were no dislodgements (macro or micro), tissue injury, tamponade, or valve injury. CONCLUSIONS: Overall, despite the 10-fold size reduction of the Micra TPS, it appears to perform similarly and have a similar safety profile to a traditional pacemaker system.

Ex vivo diffusion tensor MRI of human hearts: relative effects of specimen decomposition.

Recently, diffusion tensor MRI has been utilized as a tool to reconstruct, with high resolution, the three-dimensional myofiber orientation of hearts ex vivo. However, because of limited availability of human hearts, it is common to recover specimens postmortem, after some degree of decomposition has occurred. In this study, we describe the ability to reconstruct local fiber orientation within a unique set of human hearts using diffusion tensor MRI; relative effects of specimen decomposition were also assessed. The mean diffusivity, fractional anisotropy, and principal eigenvalues (E1, E2, and E3) were measured in hearts with varying postmortem intervals from 0 to 27 days (n = 17), and local fiber orientations were reconstructed. Mean diffusivities and principal eigenvalues nonlinearly increased as a function of postmortem interval, while fractional anisotropies nonlinearly decreased. There were good correlations between postmortem intervals and changes in diffusion properties after linear transformation of the data (R(2) > 0.7). Thus, we determined that there were regional discontinuities in the reconstruction of local fiber orientation in hearts where postmortem intervals were greater than 3 days. Therefore, any delay in tissue fixation after death (if not properly preserved using organ transplantation techniques) will compromise measurement of fiber orientation and delineation of diseased pathology, e.g., based, in part, on fractional anisotropy.

Lipid Peroxidation Has Major Impact on Malondialdehyde-Derived but Only Minor Influence on Glyoxal and Methylglyoxal-Derived Protein Modifications in Carbohydrate-Rich Foods.

In the present work, the contribution of lipid peroxidation on modifications of lysine and arginine residues of proteins was investigated. Lipid peroxidation had a major impact on malondialdehyde-derived protein modifications; however, the influence on glyoxal and methylglyoxal-derived modifications in flat wafers was negligible. Therefore, vegetable oils (either linseed oil, sunflower oil, or coconut oil) were added to respective batters, and flat wafers were baked (150 °C, 3-10 min). Analysis of malondialdehyde indicated oxidation in linseed wafers, which was supported by the direct quantitation of three malondialdehyde protein adducts in the range of 0.09-23.5 mg/kg after enzymatic hydrolysis. In contrast, levels of free glyoxal and methylglyoxal were independent of the type of oil added, which was in line with the analysis of 13 advanced glycation end products. Comprehensive incubations of 40 mM N2-t-Boc-lysine (100 mM phosphate buffer, pH 7.4) with either 10% oil or an equimolar concentration of carbohydrates led to magnitudes higher (103-105) amounts of N6-carboxymethyl lysine, N6-glycolyl lysine, and N6-carboxyethyl lysine in the latter. Furthermore, malondialdehyde exceeded glyoxal and methylglyoxal in incubations of pure oils at 150 °C by factors of 30 and 100, respectively.

Novel Amidine Protein Cross-Links Formed by the Reaction of Glyoxal with Lysine.

One crucial aspect of the Maillard reaction is the formation of reactive α-dicarbonyl structures like glyoxal, which are prone toward further reactions with proteins, e.g., the N6-amino group of lysine. The initially formed labile glyoxal-imine was previously established as a key intermediate in the formation of the advanced glycation end products N6-carboxymethyl lysine (CML), glyoxal lysine amide (GOLA), glyoxal lysine dimer (GOLD), and N6-glycolyl lysine (GALA). Here, we introduce a novel amidine cross-link structure N1,N2-bis-(5-amino-5-carboxypentyl)-2-hydroxy-acetamidine (glyoxal lysine amidine, GLA), which is formed exclusively from glyoxal through the same isomerization cascade. After independent synthesis of the authentic reference standard, we were able to quantitate this cross-link in incubations of 40 mM N2-t-Boc-lysine with glyoxal and various sugars (40-100 mM) under mild conditions (pH 7.4, 37 °C) using an HPLC-MS/MS method. Furthermore, incubations of proteins (6 mg/mL) with 50 mM glyoxal confirmed the cross-linking by GLA, which was additionally identified in acidic hydrolyzed proteins of butter biscuits after HPLC enrichment.

Analysis of Glyoxal- and Methylglyoxal-Derived Advanced Glycation End Products during Grilling of Porcine Meat.

The reaction of the N6-amino group of lysine residues and 1,2-dicarbonyl compounds during Maillard processes leads to advanced glycation end products (AGEs). In the present work, we deliver a comprehensive analysis of changes of carbohydrates, dicarbonyl structures, and 11 AGEs during the grilling of porcine meat patties. While raw meat contained mainly glyoxal-derived N6-carboxymethyl lysine (CML), grilling led to an increase of predominantly methylglyoxal-derived AGEs N6-carboxyethyl lysine (CEL), N6-lactoyl lysine, methylglyoxal lysine dimer (MOLD), and methylglyoxal lysine amide (MOLA). Additionally, we identified and quantitated a novel methylglyoxal-derived amidine compound N1,N2-di-(5-amino-5-carboxypentyl)-2-lactoylamidine (methylglyoxal lysine amide, MGLA) in heated meat. Analysis of carbohydrates suggested that approximately 50% of the methylglyoxal stemmed from the fragmentation of triosephosphates during the heat treatment. Surprisingly, N6-lactoyl lysine was the major AGE, and based on model incubations, we propose that approximately 90% must be explained by the nonenzymatic acylation of lysine through S-lactoylglutathione, which was quantitated for the first time in meat herein.

Implant, performance, and retrieval of an atrial leadless pacemaker in sheep.

BACKGROUND: Medtronic is developing an atrial Micra Transcatheter Pacing System (Medtronic, Minneapolis, Minnesota) and associated retrieval system. OBJECTIVE: The purpose of this study was to evaluate chronic atrial Micra retrieval, reimplantation, and chronic pacing performance. METHODS: Sheep were implanted in 2 groups: group 1 (n = 6) for 6 months, a second device implanted, and first retrieved and studied for an additional 6 months; group 2 (n = 6) for 6 months, devices were retrieved, and a second device implanted and observed acutely. Both groups underwent histopathological evaluation. Pacing capture thresholds (PCTs), p wave amplitude, and pacing impedances were measured chronically. Device retrieval times were recorded, and intracardiac echocardiography was used. RESULTS: At 24 weeks, PCTs for group 1 were low and stable for both the first device (0.55 ± 0.14 V) and the second device (0.57 ± 0.09 V), in which the average retrieval time was 17:35 minutes. For group 2, the average retrieval time was 6:12 minutes, chronic PCTs in the first device were 0.53 ± 0.11 V, and acute PCTs for the second device were 0.71 ± 0.19 V. Pathological findings were within an expected range of tissue responses for similar Micra acute and chronic implants and device retrievals. p waves and impedances were stable and within an expected range for implant site and electrode design. Complications included 1 early dislodgment and 1 death attributed to a prototype retrieval tool. CONCLUSION: In an animal model, an atrial Micra can be easily implanted with excellent chronic pacing performance and is easily retrievable at 6 months. A second device can successfully be implanted with low, chronic stable thresholds. A developed prototype retrieval tool was easy to use and, with modifications, complication free.

MRI assessment of pacing induced ventricular dyssynchrony in an isolated human heart.

This study demonstrates the capabilities of MRI in the assessment of cardiac pacing induced ventricular dyssynchrony, and the findings support the need for employing more physiological pacing. A human donor heart deemed non-viable for transplantation, was reanimated using an MR compatible, four-chamber working perfusion system. The heart was imaged using a 1.5T MR scanner while being paced from the right ventricular apex (RVA) via an epicardial placed lead. Four-chamber, short-axis, and tagged short-axis cines were acquired in order to track wall motion and intramyocardial strain during pacing. The results of this study revealed that the activation patterns of the left ventricle (LV) during RVA pacing demonstrated intraventricular dyssynchrony; as the left ventricular mechanical activation proceeded from the septum and anterior wall to the lateral wall, with the posterior wall being activated last. As such, the time difference to peak contraction between the septum and lateral wall was approximately 125 msec. Likewise, interventricular dyssynchrony was demonstrated from the four-chamber cine as the time difference between the peak LV and RV free wall motion was 180 msec. With the ongoing development of MR safe and MR compatible pacing systems, we can expect MRI to be added to the list of imaging modalities used to optimize cardiac resynchronization therapy (CRT) and/or alternate site pacing.

Comprehensive analysis of posttranslational protein modifications in aging of subcellular compartments.

Enzymatic and non-enzymatic posttranslational protein modifications by oxidation, glycation and acylation are key regulatory mechanisms in hallmarks of aging like inflammation, altered epigenetics and decline in proteostasis. In this study a mouse cohort was used to monitor changes of posttranslational modifications in the aging process. A protocol for the extraction of histones, cytosolic and mitochondrial proteins from mouse liver was developed and validated. In total, 6 lysine acylation structures, 7 advanced glycation endproducts, 6 oxidative stress markers, and citrullination were quantitated in proteins of subcellular compartments using HPLC-MS/MS. Methionine sulfoxide, acetylation, formylation, and citrullination were the most abundant modifications. Histone proteins were extraordinary high modified and non-enzymatic modifications accumulated in all subcellular compartments during the aging process. Compared to acetylation of histone proteins which gave between 350 and 305 µmol/mol leucine equivalents in young and old animals, modifications like acylation, glycation, and citrullination raised to 43%, 20%, and 18% of acetylation, respectively. On the other hand there was an age related increase of selected oxidative stress markers by up to 150%. The data and patterns measured in this study are mandatory for further studies and will strongly facilitate understanding of the molecular mechanisms in aging.

The role of climate in the trend and variability of Ethiopia's cereal crop yields.

Food security has been and will continue to be a major challenge in Ethiopia. The country's smallholder, rainfed agriculture renders its food production system extremely vulnerable to climate variability and extremes. In this study, we investigate the impact of past climate variability and change on the yields of five major cereal crops in Ethiopia-barley, maize, millet, sorghum, and wheat-during the period 1979-2014 using the Decision Support System for Agrotechnology Transfer (DSSAT) crop model. The model is calibrated at both the site and agroecological-zone scales. At the sites studied, the model results suggest that climate in the past four decades may have contributed to an increasing trend in maize yield, a decreasing trend in wheat yield, and no clear trend in the yields of barley and millet; cereal crop yield is positively correlated with growing season solar radiation and temperature, but negatively correlated with growing season precipitation. For modeled cereal crops across the nation during the study period, yield in western Ethiopia is positively correlated with solar radiation and day time temperature; in the eastern and southeastern Ethiopia where water is a limiting factor for growth, yield is positively correlated with precipitation but negatively correlated with solar radiation and both day time and night time temperature. The national average of simulated yields of most crops (except maize) showed an overall decreasing (although not statistically significant) trend induced by past climate variability and changes. Over a large portion of the highly productive areas where there is a negative correlation between yield and temperature, yield is simulated to have significantly decreased over the past four decades, an indication of adverse climate impact in the past and potential food security concern in the future.

Design and Evaluation of a Novel Fixation Mechanism for a Transcatheter Pacemaker.

GOAL: The purpose of this paper was to evaluate a nitinol tine fixation design for a transcatheter pacemaker in order to determine if the tines could be easily deployed and safely removed from the myocardium, enable low, stable pacing thresholds, and minimize the potential for dislodgment. METHODS: The penetration properties of 13 human hearts were compared to the deployment and fixation energy of the tines to determine if the tines could be easily deployed and removed from the myocardium. The safety factor for dislodgement was calculated by comparing the kinetic energy of the device to the fixation energy of the tines. The fixation stability was tested in 113 chronic implants across 89 animals via pacing threshold measurements or evidence of dislodgement at necropsy. RESULTS: Based on the tine fixation and tissue energy analysis, the tines can easily penetrate the heart. The tines can be safely removed from the myocardium based on the increased tine surface area during retraction. There were no dislodgements observed in the animals and the mean pacing threshold at implant was 0.59 +/- 0.21 V and at termination was 0.65 +/- 0.36 V. The safety factor for dislodgement was determined to be 15X during simulated exercise conditions. CONCLUSION: The nitinol tine fixation design enabled the implant of a self-contained pacemaker within the right ventricle and was effective in meeting the design requirements. SIGNIFICANCE: This fixation technology provides a novel solution to enable the attachment of a transcatheter pacemaker directly within the heart.

Novel imaging of atrial septal defects in isolated human hearts.

Within the adult population living with congenital heart defects, approximately 20 % have an atrial septal defect, which suggests that only 0.4-0.05 % of the entire adult population has an atrial septal defect (ASD). In patients with a left to right atrial shunt, treatments may include closure of the defect with a transcatheter device and/or surgical repair. From the perspective of a physician or engineer, it is vitally important to understand the anatomical nuances of such defects, not only to offer the most optimal treatment for the patient but also to call attention to the potential anatomy of ASDs which may go undetected. To do so, we reanimated two human hearts deemed not viable for transplant from 56-year-old and 68-year-old males. Neither patient history reported any heart conditions that would suggest an atrial defect, yet an ASD was found in each heart. Here, we present sets of images, videos, and 3D reconstructions that provide a clearer view of the anatomy of ASDs in functional human hearts. With an enhanced understanding of 3D functional aspects of ASDs, physicians can make improved decisions regarding treatment options and engineers can optimize device designs.

The benefits of the Atlas of Human Cardiac Anatomy website for the design of cardiac devices.

This paper describes how the Atlas of Human Cardiac Anatomy website can be used to improve cardiac device design throughout the process of development. The Atlas is a free-access website featuring novel images of both functional and fixed human cardiac anatomy from over 250 human heart specimens. This website provides numerous educational tutorials on anatomy, physiology and various imaging modalities. For instance, the 'device tutorial' provides examples of devices that were either present at the time of in vitro reanimation or were subsequently delivered, including leads, catheters, valves, annuloplasty rings and stents. Another section of the website displays 3D models of the vasculature, blood volumes and/or tissue volumes reconstructed from computed tomography and magnetic resonance images of various heart specimens. The website shares library images, video clips and computed tomography and MRI DICOM files in honor of the generous gifts received from donors and their families.

Noninvasive mapping of transmural potentials during activation in swine hearts from body surface electrocardiograms.

The three-dimensional cardiac electrical imaging (3DCEI) technique was previously developed to estimate the initiation site(s) of cardiac activation and activation sequence from the noninvasively measured body surface potential maps (BSPMs). The aim of this study was to develop and evaluate the capability of 3DCEI in mapping the transmural distribution of extracellular potentials and localizing initiation sites of ventricular activation in an in vivo animal model. A control swine model (n = 10) was employed in this study. The heart-torso volume conductor model and the excitable heart model were constructed based on each animal's preoperative MR images and a priori known physiological knowledge. Body surface potential mapping and intracavitary noncontact mapping (NCM) were simultaneously conducted during acute ventricular pacing. The 3DCEI analysis was then applied on the recorded BSPMs. The estimated initiation sites were compared to the precise pacing sites; as a subset of the mapped transmural potentials by 3DCEI, the electrograms on the left ventricular endocardium were compared to the corresponding output of the NCM system. Over the 16 LV and 48 RV pacing studies, the averaged localization error was 6.1±2.3 mm, and the averaged correlation coefficient between the estimated endocardial electrograms by 3DCEI and from the NCM system was 0.62±0.09. The results demonstrate that the 3DCEI approach can well localize the sites of initiation of ectopic beats and can obtain physiologically reasonable transmural potentials in an in vivo setting during focal ectopic beats. This study suggests the feasibility of tomographic mapping of 3D ventricular electrograms from the body surface recordings.

Effect of bipolar electrode spacing on phrenic nerve stimulation and left ventricular pacing thresholds: an acute canine study.

BACKGROUND: Phrenic nerve stimulation (PNS) is a common complication of cardiac resynchronization therapy when left ventricular (LV) pacing occurs via a coronary vein. The purpose of this study was to evaluate the effects of bipolar electrode spacing on PNS and LV pacing thresholds. METHODS AND RESULTS: Electrophysiology catheters with standard (2 mm-5 mm-2 mm) or modified (1 mm-5 mm-1 mm) interelectrode spacing was, respectively, inserted in a posterior/lateral cardiac vein in a randomized order in 6 anesthetized dogs via jugular access. The phrenic nerve was dissected via a left minithoracotomy and repositioned over the vein as close as possible to one of the electrodes. The presence of PNS was verified (ie, PNS threshold <2 V at 0.5 ms in unipolar configuration). Bipolar pacing was delivered using the electrode closest to the phrenic nerve as the cathode, and multiple bipolar electrode spacing configurations were tested. During bipolar pacing, PNS threshold increased as bipolar electrode spacing was reduced (P<0.05), whereas LV pacing thresholds did not change significantly (P>0.05). Compared with a standard bipolar electrode spacing of 20 mm for LV leads, 1 and 2 mm bipolar electrode spacing resulted in a PNS threshold increase of 5.5±2.2 V (P=0.003) and 2.8±1.7 V (P<0.001), respectively. Similarly, PNS threshold increased by 6.5±3.7 V with 1 mm and by 3.8±1.9 V with 2 mm bipolar pacing (both P<0.001), compared with unipolar pacing. CONCLUSIONS: This study suggests that reducing LV bipolar electrode spacing from the standard 20 mm to 1 or 2 mm may significantly increase the PNS threshold without compromising LV pacing thresholds.

Localization of endocardial ectopic activity by means of noninvasive endocardial surface current density reconstruction.

Localization of the source of cardiac ectopic activity has direct clinical benefits for determining the location of the corresponding ectopic focus. In this study, a recently developed current-density (CD)-based localization approach was experimentally evaluated in noninvasively localizing the origin of the cardiac ectopic activity from body-surface potential maps (BSPMs) in a well-controlled experimental setting. The cardiac ectopic activities were induced in four well-controlled intact pigs by single-site pacing at various sites within the left ventricle (LV). In each pacing study, the origin of the induced ectopic activity was localized by reconstructing the CD distribution on the endocardial surface of the LV from the measured BSPMs and compared with the estimated single moving dipole (SMD) solution and precise pacing site (PS). Over the 60 analyzed beats corresponding to ten pacing sites (six for each), the mean and standard deviation of the distance between the locations of maximum CD value and the corresponding PSs were 16.9 mm and 4.6 mm, respectively. In comparison, the averaged distance between the SMD locations and the corresponding PSs was slightly larger (18.4 ± 3.4 mm). The obtained CD distribution of activated sources extending from the stimulus site also showed high consistency with the endocardial potential maps estimated by a minimally invasive endocardial mapping system. The present experimental results suggest that the CD method is able to locate the approximate site of the origin of a cardiac ectopic activity, and that the distribution of the CD can portray the propagation of early activation of an ectopic beat.