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Endothelial dysfunction has been demonstrated in patients with Continuous Flow-Left Ventricular Assist Devices (CF-LVADs) but association with adverse events has not been shown. We used a noninvasive, operator-independent device called VENDYS® to assess vasodilatory function based on digital thermal measurements postrelease of a brachial artery occlusion in ambulatory patients with CF-LVAD (n = 56). Aortic valve opening and pulse perception were also documented before the test. Median duration of CF-LVAD support was 438 days. The VENDYS® test generates a vascular reactivity index (VRI). Outcomes for the CF-LVAD patients were compared between VRI < 1 and VRI ≥ 1. The bleeding events were driven primarily by a difference in neurologic bleeds. Multivariate analysis showed that VRI < 1 correlated with future bleeding events (HR: 5.56; P = 0.01). The C-statistic with the VRI dichotomized as above was 0.82. There was a trend toward a worse survival in patients with poor endothelial function. Endothelial vasodilatory dysfunction measured by a simple test utilizing digital thermal monitoring can predict adverse bleeding events in patients with CF-LVADs.

We propose an online adaptive synchronization method for leader-follower networks of heterogeneous agents. Synchronization is achieved using a distributed Model Reference Adaptive Control (DMRAC-RL) that enables the improved performance of Reinforcement Learning (RL)-trained policies on a reference model. The leader observes the performance of the reference model, and the followers observe the states and actions of the agents they are connected to, but not the reference model. Notably, both the leader and followers models might differ from the reference model the RL-control policy was trained. DMRAC-RL uses an internal loop that adjusts the learned policy for the agents in the form of an augmented input to solve the distributed control problem. Numerical examples of the synchronization of a network of inverted pendulums support our theoretical findings.

We study a Wasserstein attraction approach for solving dynamic mass transport problems over networks. In the transport problem over networks, we start with a distribution over the set of nodes that needs to be “transported” to a target distribution accounting for the network topology. We exploit the specific structure of the problem, characterized by the computation of implicit gradient steps, and formulate an approach based on discretized flows. As a result, our proposed algorithm relies on the iterative computation of constrained Wasserstein barycenters. We show how the proposed method finds approximate solutions to the network transport problem, taking into account the topology of the network, the capacity of the communication channels, and the capacity of the individual nodes.

We study the problem of minimizing a convex function over probability measures supported in a graph. We build upon the recent formulation of optimal transport over discrete domains to propose a method that generates a sequence that provably converges to a minimum of the objective function and smoothly transports mass over the edges of the graph. Moreover, we identify novel relation between Riemannian gradient flows and perturbed best response protocols that provide sufficient conditions for the convergence of the proposed algorithm. Numerical results show practical advantages over existing approaches with respect to the implementability and convergence rates.

The modelling of many complex systems is usually approached by directed networks where nodes and connections represent the elements of the system and their interactions respectively. The degree-assortativity, which is the tendency of nodes to link to nodes of similar degree, has four components in the digraphs case. In comparison with the undirected graph case, the degree-assortativity of digraphs has not been well studied despite the potential effects that it has to constraint or influence the structural and dynamical properties of a network. Thus, we have considered a random directed network and numerically trained the assortativity profiles of the four components (in–out; out–in; in–in; out–out) by applying degree-preserving rewiring, but we interestingly found that the widely used two-swap method is severely limited. In consequence, we used a much powerful and rather forgotten three-swap method capable to achieve all different assortativities configurations of the given initial random graphs. Secondly, we characterized the obtained networks in relation to other common structural properties such as path length and algebraic connectivity. Finally, by simulating and analysing a dynamical process on the network, we have found that certain profiles cause the network to exhibit enhanced sensitivity to small perturbations without losing their stability.

Thrombotic events in patients with continuous flow left ventricular assist devices (CF-LVADs) are associated with significant morbidity and mortality. The objective of this study was to delineate the frequency, clinical characteristics, and outcomes of patients with hypercoagulable states who undergo CF-LVAD implantation.We performed a retrospective review of 168 consecutive patients who underwent CF-LVAD implantation between 2010 and 2013. Chart and laboratory data were reviewed for the presence of a hereditary and/or acquired hypercoagulable state. Adverse outcomes were defined as death, confirmed pump thrombosis, aortic root clot, stroke, deep vein thrombosis, and pulmonary embolism. Fisher's exact test and Kaplan-Meier estimate were used to analyze frequency of adverse outcomes and event free survival, respectively.A hypercoagulable state was identified in 20 patients (11.9%). There were 18 patients with acquired, 1 with a congenital, and 1 with both congenital and acquired hypercoagulable states. The median follow-up was 429 days and 475 days in patients with and without hypercoagulable states, respectively. During the study period, 15% (3/20) of the patients with a hypercoagulable state had a diagnosis of deep vein thrombosis vs 3% (4/148) of the patients without a hypercoagulable state (P = .030). Only patients with a hypercoagulable state had a subarachnoid hemorrhage (3/20 vs 0/148; P .01). The event-free survival was lower in the patients with hypercoagulable states (P = .005).Hypercoagulable states are not uncommon in patients with CF-LVADs and may be associated with increased morbidity. Prospective studies are needed to more accurately identify the incidence, prevalence, and significance of hypercoagulable states in patients being considered for CF-LVAD.

Background: MicroRNA (miR) dysregulation in the myocardium has been implicated in cardiac remodeling after injury or stress.Objectives: The aim of this study was to explore the role of miR ...

Background Cardiac Allograft Hypertrophy (CAH) assessed by left ventricular mass (LVM) on imaging at 1 year has been validated as an early predictor of mortality and vasculopathy. The biology of such changes could be starting much earlier in the life of the graft and reflect the beginning of a continuum of remodeling of the transplanted heart that finally leads to chronic rejection and graft failure. However, definitive mechanisms and predictors have not been established. Therefore, we aimed to study the molecular mechanisms of CAH characterized by abnormal echo mass in heart transplant patients. We hypothesized there is a specific genetic signature in the myocardium that can predict the morphological mechanisms of CAH. Methods We used data from our heart transplant biopsy repository where consented patients agree for an extra biopsy and blood to be stored for research during their protocol visits. Biopsies are stored at -80C in RNA later. We used samples from 6 month time-point in a small cohort of randomly selected patients and performed full gene expression profiling using Ilumina Beadarray Microarray Technology. Additionally, clinical and echocardiogram parameters were collected at the same time-point. LVM index and relative wall thickness at 6m from transplant were used to define CAH according to ASE Guidelines. Results A total of 16 patients were included in the analysis. 5 patients had normal LV geometry, 8 had concentric remodeling and 3 concentric hypertrophy (CH). Patients in the abnormal group were significantly older than the patients in the normal group (53.4 vs 60.7 years, respectively, p=0.0478) while there were no other statistically significant differences in the rest of the baseline and clinical parameters. Gene expression data showed a distinct signature on the heatmap for CH (Figure 1). There were 40 genes that were differentially expressed in CH group compared to the rest. Conclusion Only 31% of the patients have a normal echo LVM by 6 months and there is a distinct genetic signature for CH suggesting that there is a specific biological change occurring in the heart as early as 6 months that contribute to hypertrophy. We hope to elicit the biological basis of these changes so as to create therapeutic interventions to temper these changes and promote longevity of grafts.

The clinical era of continuous-flow left ventricular assist devices has debunked many myths about the dire need of a pulse for human existence. While this therapy has been documented to provide a clear survival benefit in end-stage heart failure patients, we are now faced with certain morbidity challenges that as of yet have no easy mechanistic physiological explanation. The effect of physiological changes on end-organ function in patients supported by continuous-flow ventricular assist devices may offer insight into some of these morbidities. We therefore present a review of current evidence documenting the impact of continuous flow on end-organ function.

Background: Endothelial to Mesenchymal Transition (EndMT) and the reverse phenomenon of mesenchymal to endothelial transitioning (MET) has been shown to contribute to fibrosis in rodent models of heart failure. There are no studies documenting the same in human cardiac tissue. Methods: We performed immunofluorescence dual staining on end stage heart failure myocardial samples obtained from our bio repository. Staining for endothelial and mesenchymal markers were performed with Anti-VE-Cadherin (Santa Cruz Biotechnologies) and anti-Fibroblast specific protein 1 (Dako Antibodies) respectively using standard immunofluoresence techniques. Presence of dual staining on fluorescence microscopy was considered as positive for the presence of EndMT. Vascular density was assessed using a DAB (3-3’ Diaminobenzidine) technique with Anti-CD31 (PECAM, Abcam). Results: Of the end stage heart failure samples, 18 were from left ventricular core during LVAD implant and 5 during a direct transplant as status 1A (axillary intraaortic balloon pump). 10 hearts of patients bridged to transplant with a continuous flow LVAD (Days under support 3436228) were also studied. Mean age was 55y with 82% males and 74% white. 70% of all samples had evidence of EndMT. The number of cells ranged from 1 to 5 per high power field. There was no significant difference between patient characteristics between those with evidence of EndMT versus not, except a higher prevalence of diabetes in the latter group. (Fig 1B) 74% of the end-stage heart failure samples and 60% of the post-VAD samples showed the presence of EndMT cells. Vascular Density was higher in the samples exhibiting EndMT phenomenon. (Figure 1A). Conclusion: We have documented for the first time, the existence of endothelial-mesenchymal transition in human end stage myocardial samples corroborating earlier pioneering studies in rodents. Interestingly the existence of such dual staining cells in end stage hearts (which is highly fibrotic) suggests a possible role of ongoing fibrosis with endothelial to mesenchymal transitioning or potential antifibrotic mechanism though mesenchymal to endothelial transitioning. Further studies of the later process will be warranted to explore potential anti-fibrotic therapeutic implications.

Background: Endothelial to Mesenchymal Transition (EndMT) and the reverse phenomenon of mesenchymal to endothelial transitioning (MET) has been shown to contribute to fibrosis in rodent models of heart failure. There are no studies documenting the same in human cardiac tissue. Methods: We performed immunofluorescence dual staining on end stage heart failure myocardial samples obtained from our bio repository. Staining for endothelial and mesenchymal markers were performed with Anti-VE-Cadherin (Santa Cruz Biotechnologies) and anti-Fibroblast specific protein 1 (Dako Antibodies) respectively using standard immunofluoresence techniques. Presence of dual staining on fluorescence microscopy was considered as positive for the presence of EndMT. Vascular density was assessed using a DAB (3-3’ Diaminobenzidine) technique with Anti-CD31 (PECAM, Abcam). Results: Of the end stage heart failure samples, 18 were from left ventricular core during LVAD implant and 5 during a direct transplant as status 1A (axillary intraaortic balloon pump). 10 hearts of patients bridged to transplant with a continuous flow LVAD (Days under support 3436228) were also studied. Mean age was 55y with 82% males and 74% white. 70% of all samples had evidence of EndMT. The number of cells ranged from 1 to 5 per high power field. There was no significant difference between patient characteristics between those with evidence of EndMT versus not, except a higher prevalence of diabetes in the latter group. (Fig 1B) 74% of the end-stage heart failure samples and 60% of the post-VAD samples showed the presence of EndMT cells. Vascular Density was higher in the samples exhibiting EndMT phenomenon. (Figure 1A). Conclusion: We have documented for the first time, the existence of endothelial-mesenchymal transition in human end stage myocardial samples corroborating earlier pioneering studies in rodents. Interestingly the existence of such dual staining cells in end stage hearts (which is highly fibrotic) suggests a possible role of ongoing fibrosis with endothelial to mesenchymal transitioning or potential antifibrotic mechanism though mesenchymal to endothelial transitioning. Further studies of the later process will be warranted to explore potential anti-fibrotic therapeutic implications.

Cardiac Arrhythmias in Patients with a HeartWare Ventricular Assist Device Salpy V. Pamboukian, Mark S. Slaughter, Howard K. Song, Charles T. Klodell, David R. Hathaway, Keith D. Aaronson; University of Alabama at Birmingham, Birmingham, AL; University of Louisville, Louisville, KY; Oregon Health and Science University, Portland, OR; University of Florida Health, Gainesville, FL; Heartware Inc, Framingham, MA; University of Michigan Medical Center, Ann Arbor, MI

Summary In this work, Trypanosoma ariarii, n. sp., has been described. This human parasite, found in the River Ariari Valley, Colombia, is characterized by an average size of 31 microns (in blood films), a nucleus anterior to the equator of the body, and a round, small, subterminal kinetoplast. T. ariarii shows division stages in the peripheral blood. Until now we have not found evolutionary forms in the viscera or tissues of experimental animals. Cebus fatuellus and the domestic dog have also been found naturally infected with T. ariarii. R. prolixus is experimentally infected quite easily with this protozoon. Also T. ariarii is cultivated in vitro without difficulty. So far, using parasites grown in cultures, we have only succeeded in infecting a few baby mice, two opossums (Didelphys paraguayensis paraguayensis), one rhesus monkey and human volunteers. During the period of observation (11 and 15 months) the experimental infection followed an asymptomatic course in the two volunteers in whom the infection was established. The frequency of human cases infected with T. ariarii in the Ariari Valley seems to be high. Out of 183 persons examined by blood cultures, 67 showed trypanosomes. It was possible to study completely the parasites isolated from 27 of these 67 infected people. The results were: 1 case with a mixed infection of both T. cruzi and T. ariarii, and 26 cases with single T. ariarii infections.

Alaria arisaemoides, n.sp., is described from the red fox, Vulpes fulva. The attachment of this parasite to its host and the host reaction are discussed in detail.