T ransthoracic echocardiography (TTE) is the standard clinical tool for initial assessment and longitudinal evaluation of patients with valvular heart disease.1 Current clinical guidelines for the management of adults with chronic valve regurgitation include clear recommendations for measuring regurgitant severity.1,2 Quantification is recommended as a tool to identify patients at risk of adverse long-term physiological consequences, including irreversible left ventricular (LV) contractile dysfunction, and to prevent adverse clinical outcomes, including heart failure, sudden death, and cardiovascular mortality. Clinical Perspective on p 57TTE allows measurement of regurgitant volume (RVol), fraction, and orifice area and has been well validated in both experimental and clinical studies. 2 In addition, regurgitant orifice area (ROA) has been shown to be predictive of clinical outcome for both aortic regurgitation (AR) and mitral regurgitation (MR). 3 However, echocardiographic quantification of valve regurgitation can be challenging because of poor acoustic windows, dynamic or eccentric jets, and geometric assumptions. 2,4,5 Cardiovascular magnetic resonance (CMR) is an alternative modality for assessing patients with chronic valve regurgitation based on measurement of LV volumes and phase-contrast velocity mapping.6-8 CMR has several potential advantages compared with TTE, including improved endocardial definition, fewer geometric assumptions, and less angle dependence for flow measurements. However there are few data on direct systematic comparisons, including reproducibility, between TTE and CMR for quantitation of AR and MR. Thus, we hypothesized that CMR has less interobserver variability when quantifying chronic AR and MR and thus may be preferable for longitudinal follow-up in individual patients.Background-Both transthoracic echocardiography (TTE) and cardiac magnetic resonance (CMR) imaging allow quantification of chronic aortic regurgitation (AR) and mitral regurgitation (MR). We hypothesized that CMR measurement of regurgitant volume (RVol) is more reproducible than TTE.Methods and Results-TTE and CMR performed on the same day in 57 prospectively enrolled adults (31 with AR, 26 with MR) were measured by 2 independent physicians. TTE RVol AR was calculated as Doppler left ventricular outflow minus inflow stroke volume. RVol MR was calculated by both the proximal isovelocity surface area method and Doppler volume flow at 2 sites. CMR RVol AR was calculated by phase-contrast velocity mapping at the aortic sinuses and RVol MR as total left ventricular minus forward stroke volume. Intraobserver and interobserver variabilities were similar. For AR, the Bland-Altman mean interobserver difference in RVol was −0.7 mL (95% confidence interval [CI], −5 to 4) for CMR and −9 mL (95% CI, −53 to −36) for TTE. The Pearson correlation was higher (P=0.001) between CMR (0.99) than TTE readers (0.89). For MR, the Bland-Altman mean difference in RVol between observers was −4 mL (95% CI, −21 to 13) for CMR compared with 0....

Highlights d Quantitative proteomics defines the interactome for the amyloidogenic light chain ALLC d ATF6 or XBP1s activation distinctly affect interactions between ALLC and ER proteins d ATF6 activation reduces ALLC secretion through increased targeting to ER chaperones d Enhanced quality control is based on global interaction changes coordinated by ATF6

Activation of the unfolded protein response (UPR)-associated transcription factor ATF6 has emerged as a promising strategy to selectively reduce the secretion and subsequent toxic aggregation of destabilized, amyloidogenic proteins implicated in diverse systemic amyloid diseases. However, the molecular mechanism by which ATF6 activation reduces the secretion of amyloidogenic proteins remains poorly defined. Here, we establish a quantitative interactomics platform with improved throughput and sensitivity to define how ATF6 activation selectively reduces secretion of a destabilized, amyloidogenic immunoglobulin light chain (LC) associated with Light Chain Amyloidosis (AL). We show that ATF6 activation increases the targeting of this destabilized LC to a select subset of pro-folding ER proteostasis factors that retains the amyloidogenic LC within the ER, preventing its secretion to downstream secretory environments. Our results define a molecular basis for the selective, ATF6-dependent reduction in destabilized LC secretion and highlight the advantage for targeting this endogenous UPR-associated transcription factor to reduce secretion of destabilized, amyloidogenic proteins implicated in AL and related systemic amyloid diseases.