Large and Small Animal Models of Heart Failure With Reduced Ejection Fraction.

Heart failure (HF) describes a heterogenous complex spectrum of pathological conditions that results in structural and functional remodeling leading to subsequent impairment of cardiac function, including either systolic dysfunction, diastolic dysfunction, or both. Several factors chronically lead to HF, including cardiac volume and pressure overload that may result from hypertension, valvular lesions, acute, or chronic ischemic injuries. Major forms of HF include hypertrophic, dilated, and restrictive cardiomyopathy. The severity of cardiomyopathy can be impacted by other comorbidities such as diabetes or obesity and external stress factors. Age is another major contributor, and the number of patients with HF is rising worldwide in part due to an increase in the aged population. HF can occur with reduced ejection fraction (HF with reduced ejection fraction), that is, the overall cardiac function is compromised, and typically the left ventricular ejection fraction is lower than 40%. In some cases of HF, the ejection fraction is preserved (HF with preserved ejection fraction). Animal models play a critical role in facilitating the understanding of molecular mechanisms of how hearts fail. This review aims to summarize and describe the strengths, limitations, and outcomes of both small and large animal models of HF with reduced ejection fraction that are currently used in basic and translational research. The driving defect is a failure of the heart to adequately supply the tissues with blood due to impaired filling or pumping. An accurate model of HF with reduced ejection fraction would encompass the symptoms (fatigue, dyspnea, exercise intolerance, and edema) along with the pathology (collagen fibrosis, ventricular hypertrophy) and ultimately exhibit a decrease in cardiac output. Although countless experimental studies have been published, no model completely recapitulates the full human disease. Therefore, it is critical to evaluate the strength and weakness of each animal model to allow better selection of what animal models to use to address the scientific question proposed.

Zebrafish model of amyloid light chain cardiotoxicity: regeneration versus degeneration.

Cardiac dysfunction is the most frequent cause of morbidity and mortality in amyloid light chain (AL) amyloidosis caused by a clonal immunoglobulin light chain (LC). Previously published transgenic animal models of AL amyloidosis have not recapitulated the key phenotype of cardiac dysfunction seen in AL amyloidosis, which has limited our understanding of the disease mechanisms in vivo, as well as the development of targeted AL therapeutics. We have developed a transgenic zebrafish model in which a λ LC derived from a patient with AL amyloidosis is conditionally expressed in the liver under the control of the Gal4 upstream activation sequence enhancer system. Circulating LC levels of 125 µg/ml in these transgenic zebrafish are comparable to median pathological serum LC levels. Functional analysis links abnormal contractile function with evidence of cellular and molecular proteotoxicity in the heart, including increased cell death and autophagy. However, despite pathological and functional phenotypes analogous to human AL, the lifespan of the transgenic fish is comparable to control fish without the expressed AL-LC transgene. Nuclear labeling experiments suggest increased cardiac proliferation in the transgenic fish, which can be counteracted by treatment with a small molecule proliferation inhibitor leading to increased zebrafish mortality because of cardiac apoptosis and functional deterioration. This transgenic zebrafish model provides a platform to study underlying AL disease mechanisms in vivo further. NEW & NOTEWORTHY Heart failure is a major cause of mortality in amyloid light (AL) amyloidosis, yet it has been difficult to model in animals. We report the generation of a transgenic zebrafish model for AL amyloidosis with pathological concentration of circulating human light chain protein that results in cardiac dysfunction. The light chain toxicity triggers regeneration in the zebrafish heart resulting in functional compensation early in life, but with age develops into cardiac dysfunction.

Patient perspectives on self-monitoring of blood glucose: perceived recommendations, behaviors and barriers in a clinic sample of adults with type 2 diabetes.

BACKGROUND: Patient-centered perspectives on self-monitoring of blood glucose (SBMG) were assessed in adults with type 2 diabetes using a self-regulation conceptual framework. METHODS: Participants (N = 589; 53 % female) were adults with type 2 diabetes who were recruited during routine appointments at a diabetes outpatient clinic in the Southeastern/lower Midwestern region of the United States. RESULTS: Participant's had varying perceptions regarding provider recommendations for SMBG (responder n = 380). Personal blood glucose testing patterns were also varied and reports frequently omitted (responder n = 296). Respondent's most frequent personal pattern was to test "occasionally, as needed," which did not differ by insulin use status, gender or age. In those not prescribed insulin, HbA1c reflected better control in those testing at least once per week (p = .040) or with a blood glucose goal (p = .018). 30.9 % endorsed at least monthly perceived encounters with SMBG barriers, with higher reports by women (p = .005) and younger (p = .006) participants. Poorer glycemic control was observed for participants with more frequently reported scheduling (p = .025, .041) and discouragement (p = .003) barriers. CONCLUSIONS: Findings suggest that many may experience difficulty integrating SMBG into their lives and are unsure of recommendations and appropriate function. Research is needed to promote best practice recommendations for SMBG.

The recombinant vaccinia virus gene product, B18R, neutralizes interferon alpha and alleviates histopathological complications in an HIV encephalitis mouse model.

Interferon-alpha (IFN-α) has been identified as a neurotoxin that plays a prominent role in human immunodeficiency virus (HIV)-associated neurocognitive disorders and HIV encephalitis (HIVE) pathology. IFN-α is associated with cognitive dysfunction in other inflammatory diseases where IFN-α is upregulated. Trials of monoclonal anti-IFN-α antibodies have been generally disappointing possibly due to high specificity to limited IFN-α subtypes and low affinity. We investigated a novel IFN-α inhibitor, B18R, in an HIVE/severe combined immunodeficiency (SCID) mouse model. Immunostaining for B18R in systemically treated HIVE/SCID mice suggested the ability of B18R to cross the blood-brain barrier (BBB). Real-time PCR indicated that B18R treatment resulted in a decrease in gene expression associated with IFN-α signaling in the brain. Mice treated with B18R were found to have decreased mouse mononuclear phagocytes and significant retention of neuronal arborization compared to untreated HIVE/SCID mice. Increased mononuclear phagocytes and decreased neuronal arborization are key features of HIVE. These results suggest that B18R crosses the BBB, blocks IFN-α signaling, and it prevents key features of HIVE pathology. These data suggest that the high affinity and broad IFN-α subtype specificity of B18R make it a viable alternative to monoclonal antibodies for the inhibition of IFN-α in the immune-suppressed environment.

Overexpression of human amyloidogenic light chains causes heart failure in embryonic zebrafish: a preliminary report.

AL cardiomyopathy leading to heart failure (HF) represents a significant cause of morbidity and mortality in systemic amyloidosis. However, the paucity of robust in vivo models of AL-induced cardiac dysfunction has limited our ability to probe the mechanisms of AL heart disease. To address this problem, we have developed a model of AL HF in zebrafish embryos by injection of in vitro transcribed mRNA encoding amyloidogenic light chain (aLC) into fertilized oocytes. We demonstrate that expression of aLC causes cardiomyopathy in developing zebrafish without significantly impairing extracardiac development. The cardiac ventricle of embryos expressing aLC exhibit impaired contractility, smaller size, and increased myocardial thickness which result in congestion and edema, features paralleling the clinical manifestations of amyloid cardiomyopathy. Phosphorylated p38, a marker of oxidative stress, was increased in response to aLC expression. No evidence of amyloid fibril deposition was identified. Thus, expression of aLC mRNA in zebrafish results in cardio toxic effects without fibril deposition. This is consistent with prior evidence indicating that aLC oligomers mediate cardiac dysfunction in vitro. This model will allow exploration of amyloid pathophysiology and testing of interventions to reduce and reverse the deleterious effects of amyloidosis on myocardial function.

Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38alpha MAPK pathway.

Patients with primary (AL) cardiac amyloidosis suffer from progressive cardiomyopathy with a median survival of less than 8 months and a 5-year survival of <10%. Contributing to this poor prognosis is the fact that these patients generally do not tolerate standard heart failure therapies. The molecular mechanisms underlying this deadly form of heart disease remain unclear. Although interstitial amyloid fibril deposition of Ig light chain proteins is a major cause of cardiac dysfunction in AL cardiac amyloidosis, we have previously shown that amyloid precursor proteins directly impair cardiac function at the cellular and isolated organ levels, independent of fibril formation. In this study, we report that amyloidogenic light chain (AL-LC) proteins provoke oxidative stress, cellular dysfunction, and apoptosis in isolated adult cardiomyocytes through activation of p38 mitogen-activated protein kinase (MAPK). AL-LC-induced p38 activation was found to be independent of the upstream MAPK kinase, MKK3/6, and instead depends upon transforming growth factor-beta-activated protein kinase-1 binding protein-1 (TAB1)-mediated p38alpha MAPK autophosphorylation. Treatment of cardiomyocytes with SB203580, a selective p38 MAPK inhibitor, significantly attenuated AL-LC-induced oxidative stress, cellular dysfunction, and apoptosis. Our data provide a unique mechanistic insight into the pathogenesis of AL-LC cardiac toxicity and suggest that TAB1-mediated p38alpha MAPK autophosphorylation may serve as an important event leading to cardiac dysfunction and subsequent heart failure.

Three-dimensional speckle size in generalized optical systems with limiting apertures.

Correlation properties of speckle fields at the output of quadratic phase systems with hard square and circular apertures are examined. Using the linear canonical transform and ABCD ray matrix techniques to describe these general optical systems, we first derive analytical formulas for determining axial and lateral speckle sizes. Then using a numerical technique, we extend the analysis so that the correlation properties of nonaxial speckles can also be considered. Using some simple optical systems as examples, we demonstrate how this approach may be conveniently applied. The results of this analysis apply broadly both to the design of metrology systems and to speckle control schemes.

Lucky imaging and aperture synthesis with low-redundancy apertures.

Lucky imaging, used with some success in astronomical and even horizontal-path imaging, relies on fleeting conditions of the atmosphere that allow momentary improvements in image quality, at least in portions of an image. Aperture synthesis allows a larger aperture and, thus, a higher-resolution imaging system to be synthesized through the superposition of image spatial-frequency components gathered by cooperative combinations of smaller subapertures. A combination of lucky imaging and aperture synthesis strengthens both methods for obtaining improved images through the turbulent atmosphere. We realize the lucky imaging condition appropriate for aperture synthesis imaging for a pair of rectangular subapertures and demonstrate that this condition occurs when the signal energy associated with bandpass spatial-frequency components achieves its maximum value.

Controlling speckle using lenses and free space.

The correlation properties of speckle fields are studied for general paraxial systems. The previous studies on lateral and longitudinal speckle size for the case of free-space propagation (Fresnel transform) are generalized to the case of the linear canonical transform. These results have implications for the control of speckle size, through appropriate design of optical systems, with particular relevance for speckle interferometry.

Association of acquired von Willebrand syndrome with AL amyloidosis.

Acquired loss of functional von Willebrand factor (VWF) has been termed the acquired von Willebrand syndrome (AVWS). AVWS is a rare adult-onset bleeding diathesis that is clinically similar to congenital von Willebrand disease (VWD), and occurs with a variety of autoimmune, lymphoproliferative, or myeloproliferative disorders. We have identified four patients with AVWS in association with immunoglobulin light chain (AL) amyloidosis. These patients, lacking any pre-existing or family history of abnormal bleeding, developed cutaneous, mucosal, or gastrointestinal bleeding in the course of their disease without deficiency of clotting factor X or other factors; the activated partial thromboplastin time (aPTT) was prolonged in three out of the four cases. Despite normal VWF antigen levels, VWF ristocetin cofactor activity (VWF:RCo) was low. Electrophoresis patterns of high molecular weight (HMW) VWF multimers were abnormal in two of the four cases. Two of the patients were treated with high-dose intravenous melphalan followed by autologous stem cell transplantation (HDM/SCT) and achieved hematologic remission. In these two patients, the bleeding diathesis improved and the coagulation parameters normalized, confirming a causal relationship between the plasma cell dyscrasia and the AVWS. AVWS should be considered in AL amyloidosis patients with hemorrhagic diatheses and normal clotting factor levels.

Generalized Yamaguchi correlation factor for coherent quadratic phase speckle metrology systems with an aperture.

In speckle-based metrology systems, a finite range of possible motion or deformation can be measured. When coherent imaging systems with a single limiting aperture are used in speckle metrology, the observed decorrelation effects that ultimately define this range are described by the well-known Yamaguchi correlation factor. We extend this result to all coherent quadratic phase paraxial optical systems with a single aperture and provide experimental results to support our theoretical conclusions.

Paraxial speckle-based metrology systems with an aperture.

Digital speckle photography can be used in the analysis of surface motion in combination with an optical linear canonical transform (LCT). Previously [D. P. Kelly et al. Appl. Opt.44, 2720 (2005)] it has been shown that optical fractional Fourier transforms (OFRTs) can be used to vary the range and sensitivity of speckle-based metrology systems, allowing the measurement of both the magnitude and direction of tilting (rotation) and translation motion simultaneously, provided that the motion is captured in two separate OFRT domains. This requires two bulk optical systems. We extend the OFRT analysis to more general LCT systems with a single limiting aperture. The effect of a limiting aperture in LCT systems is examined in more detail by deriving a generalized Yamaguchi correlation factor. We demonstrate the benefits of using an LCT approach to metrology design. Using this technique, we show that by varying the curvature of the illuminating field, we can effectively change the output domain. From a practical perspective this means that estimation of the motion of a target can be achieved by using one bulk optical system and different illuminating conditions. Experimental results are provided to support our theoretical analysis.