Cardiac Amyloidosis Multimodal Imaging of Disease Activity and Response to Treatment

Cardiac amyloidosis (CA) is a disease characterized by the deposition of misfolded protein deposits in the myocardial interstitium. Although advanced CA confers significant morbidity and mortality, the magnitude of deposition and ensuing clinical manifestations vary greatly. Thus, an improved understanding of disease pathogenesis at both cellular and functional levels would afford critical insights that may improve outcomes. This review will summarize contemporary therapies for the 2 major types of CA, transthyretin and light chain amyloidosis, and outline the capacity of imaging modalities to both diagnose CA, inform prognosis, and follow response to available therapies. We explore the current landscape of echocardiography, cardiac magnetic resonance, and bone scintigraphy in the assessment of functional and cellular parameters of dysfunction in CA throughout disease pathogenesis. Finally, we examine the impact of concurrent advances in both therapeutics and imaging on future research questions that improve our understanding of underlying disease mechanisms. Multimodal imaging in CA affords an indispensable tool to offer individualized treatment plans and improve outcomes in patients with CA

Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum.

Autosomal recessive hereditary spastic paraplegia (ARHSP) with thin corpus callosum (TCC) is a common and clinically distinct form of familial spastic paraplegia that is linked to the SPG11 locus on chromosome 15 in most affected families. We analyzed 12 ARHSP-TCC families, refined the SPG11 candidate interval and identified ten mutations in a previously unidentified gene expressed ubiquitously in the nervous system but most prominently in the cerebellum, cerebral cortex, hippocampus and pineal gland. The mutations were either nonsense or insertions and deletions leading to a frameshift, suggesting a loss-of-function mechanism. The identification of the function of the gene will provide insight into the mechanisms leading to the degeneration of the corticospinal tract and other brain structures in this frequent form of ARHSP

Spatial-temporal variability of in situ cyanobacteria vertical structure in Western Lake Erie: Implications for remote sensing observations

Remote sensing has provided expanded temporal and spatial range to the study of harmful algal blooms (cyanoHABs) in western Lake Erie, allowing for a greater understanding of bloom dynamics than is possible through in situ sampling. However, satellites are limited in their ability to specifically target cyanobacteria and can only observe the water within the first optical depth. This limits the ability of remote sensing to make conclusions about full water column cyanoHAB biomass if cyanobacteria are vertically stratified. FluoroProbe data were collected at nine stations across western Lake Erie in 2015 and 2016 and analyzed to characterize spatio-temporal variability in cyanobacteria vertical structure. Cyanobacteria were generally homogenously distributed during the growing season except under certain conditions. As water depth increased and high surface layer concentrations were observed, cyanobacteria were found to be more vertically stratified and the assumption of homogeneity was less supported. Cyanobacteria vertical distribution was related to wind speed and wave height, with increased stratification at low wind speeds (bathymetry and environmental conditions could lead to improved biomass estimates. Additionally, cyanobacteria contributions to total chlorophyll-a were shown to change throughout the season and across depth, suggesting the need for remote sensing algorithms to specifically identify cyanobacteria

Expert Consensus Recommendations for the Suspicion and Diagnosis of Transthyretin Cardiac Amyloidosis

Cardiomyopathy is a manifestation of transthyretin amyloidosis (ATTR), which is an underrecognized systemic disease whereby the transthyretin protein misfolds to form fibrils that deposit in various tissues and organs. ATTR amyloidosis is debilitating and associated with poor life expectancy, especially in those with cardiac dysfunction, but a variety of treatment options have recently become available. Considered a rare disease, ATTR amyloidosis may be more prevalent than thought, particularly in older persons. Diagnosis is often delayed because of a lack of disease awareness and the heterogeneity of symptoms at presentation. Given the recent availability of effective treatments, early recognition and diagnosis are especially critical because treatment is likely more effective earlier in the disease course. The Amyloidosis Research Consortium recently convened a group of experts in ATTR amyloidosis who, through an iterative process, agreed on best practices for suspicion, diagnosis, and characterization of disease. This review describes these consensus recommendations for ATTR associated with cardiomyopathy as a resource to aid cardiologists and others in the recognition and diagnosis of ATTR associated with cardiomyopathy. Included in this review is an overview of red flag signs and symptoms and a recommended diagnostic approach, including testing for monoclonal protein, scintigraphy, or biopsy and, if ATTR associated with cardiomyopathy is identified, TTR genotyping

Persistent left superior vena cava: a case report and review of literature

Persistent left superior vena cava is rare but important congenital vascular anomaly. It results when the left superior cardinal vein caudal to the innominate vein fails to regress. It is most commonly observed in isolation but can be associated with other cardiovascular abnormalities including atrial septal defect, bicuspid aortic valve, coarctation of aorta, coronary sinus ostial atresia, and cor triatriatum. The presence of PLSVC can render access to the right side of heart challenging via the left subclavian approach, which is a common site of access utilized when placing pacemakers and Swan-Ganz catheters. Incidental notation of a dilated coronary sinus on echocardiography should raise the suspicion of PLSVC. The diagnosis should be confirmed by saline contrast echocardiography

Outcomes by Cardiac Stage in Patients With Newly Diagnosed AL Amyloidosis: Phase 3 ANDROMEDA Trial

BACKGROUND: Patients with amyloid light chain amyloidosis and severe cardiac dysfunction have a poor prognosis. Treatment options that induce rapid and deep hematologic and organ responses, irrespective of cardiac involvement, are needed. OBJECTIVES: The aim of this study was to evaluate the impact of baseline cardiac stage on efficacy and safety outcomes in the phase 3 ANDROMEDA trial. METHODS: Rates of overall complete hematologic response and cardiac and renal response at 6 months and median major organ deterioration–progression-free survival and major organ deterioration–event-free survival were compared across cardiac stages (I, II, or IIIA) and treatments (daratumumab, bortezomib, cyclophosphamide, and dexamethasone [D-VCd] or bortezomib, cyclophosphamide, and dexamethasone [VCd]). Rates of adverse events (AEs) were summarized for patients with and without baseline cardiac involvement and by cardiac stage. RESULTS: Median follow-up duration was 15.7 months. The proportions of stage I, II, and IIIA patients were 23.2%, 40.2%, and 36.6%. Across cardiac stages, hematologic and organ response rates were higher and major organ deterioration–progression-free survival and major organ deterioration–event-free survival were longer with D-VCd than VCd. AE rates were similar between treatments and by cardiac stage; serious AE rates were higher in patients with cardiac involvement and increased with increasing cardiac stage. The incidence of cardiac events was numerically greater with D-VCd vs VCd, but the rate of grade 3 or 4 events was similar. The exposure-adjusted incidence rate for cardiac events was lower with D-VCd than VCd (median exposure 13.4 and 5.3 months, respectively). CONCLUSIONS: These findings demonstrate the efficacy of D-VCd over VCd in patients with newly diagnosed amyloid light chain amyloidosis across cardiac stages, thus supporting its use in patients with cardiac involvement. (NCT03201965

Bio-optical Properties of Cyanobacteria Blooms in Western Lake Erie

There is a growing use of remote sensing observations for detecting and quantifying freshwater cyanobacteria populations, yet the inherent optical properties of these communities in natural settings, fundamental to bio-optical algorithms, are not well known. Toward bridging this knowledge gap, we measured a full complement of optical properties in western Lake Erie during cyanobacteria blooms in the summers of 2013 and 2014. Our measurements focus attention on the optical uniqueness of cyanobacteria blooms, which have consequences for remote sensing and bio-optical modeling. We found the cyanobacteria blooms in the western basin during our field work were dominated by Microcystis, while the waters in the adjacent central basin were dominated by Planktothrix. Chlorophyll concentrations ranged from 1 to over 135 μg/L across the study area with the highest concentrations associated with Microcystis in the western basin. We observed large, amorphous colonial Microcystis structures in the bloom area characterized by high phytoplankton absorption and high scattering coefficients with a mean particle backscatter ratio at 443 nm \u3e 0.03, which is higher than other plankton types and more comparable to suspended inorganic sediments. While our samples contained mixtures of both, our analysis suggests high contributions to the measured scatter and backscatter coefficients from cyanobacteria. Our measurements provide new insights into the optical properties of cyanobacteria blooms, and indicate that current semi-analytic models are likely to have problems resolving a closed solution in these types of waters as many of our observations are beyond the range of existing model components. We believe that different algorithm or model approaches are needed for these conditions, specifically for phytoplankton absorption and particle backscatter components. From a remote sensing perspective, this presents a challenge not only in terms of a need for new algorithms, but also for determining when to apply the best algorithm for a given situation. These results are new in the sense that they represent a complete description of the optical properties of freshwater cyanobacteria blooms, and are likely to be representative of bloom conditions for other systems containing Microcystis cells and colonies

Anatomy of the recurrent coastal sediment plume in Lake Michigan and its impacts on light climate, nutrients, and plankton

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94624/1/jgrc9664.pd

Quality of spirometry and related diagnosis in primary care with a focus on clinical use

Contains fulltext : 220998.pdf (publisher's version ) (Open Access