Potential benefits of mesenchymal stem cell (MSC) therapy in heart failure may be related to paracrine properties and systemic effects, including anti-inflammatory activities. If this hypothesis is ...valid, intravenous administration of MSCs should improve outcomes in heart failure, an entity in which excessive chronic inflammation may play a pivotal role.
To assess the safety and preliminary efficacy of intravenously administered ischemia-tolerant MSCs (itMSCs) in patients with nonischemic cardiomyopathy.
This was a single-blind, placebo-controlled, crossover, randomized phase II-a trial of nonischemic cardiomyopathy patients with left ventricular ejection fraction ≤40% and absent hyperenhancement on cardiac magnetic resonance imaging. Patients were randomized to intravenously administered itMSCs (1.5×10
cells/kg) or placebo; at 90 days, each group received the alternative treatment. Overall, 22 patients were randomized to itMSC (n=10) and placebo (n=12) at baseline. After crossover, data were available for 22 itMSC patients. No major differences in death, hospitalization, or serious adverse events were noted between the 2 treatments. Change from baseline in left ventricular ejection fraction and ventricular volumes was not significantly different between therapies. Compared with placebo, itMSC therapy increased 6-minute walk distance (+36.47 m, 95% confidence interval 5.98-66.97; P=0.02) and improved Kansas City Cardiomyopathy clinical summary (+5.22, 95% confidence interval 0.70-9.74; P=0.02) and functional status scores (+5.65, 95% confidence interval -0.11 to 11.41; P=0.06). The data demonstrated MSC-induced immunomodulatory effects, the magnitude of which correlated with improvement in left ventricular ejection fraction.
In this pilot study of patients with nonischemic cardiomyopathy, itMSC therapy was safe, caused immunomodulatory effects, and was associated with improvements in health status and functional capacity.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT02467387.
The goal of this study was to evaluate the prognostic value of global longitudinal strain (GLS) derived from cardiac magnetic resonance (CMR) feature-tracking in a large multicenter population of ...patients with preserved ejection fraction.
Ejection fraction is the principal parameter used clinically to assess cardiac mechanics and provides prognostic information. However, significant abnormalities of myocardial deformation can be present despite preserved ejection fraction. CMR feature-tracking techniques now allow assessment of strain from routine cine images, without specialized pulse sequences. Whether abnormalities of strain measured by using CMR feature-tracking have prognostic value in patients with preserved ejection fraction is unknown.
Consecutive patients with preserved ejection fraction (≥50%) and a clinical indication for CMR at 4 U.S. medical centers were included in this retrospective study. Feature-tracking GLS was calculated from 3 long-axis cine views. The primary endpoint was all-cause death. Cox proportional hazards regression modeling was used to examine the independent association between GLS and death. The incremental prognostic value of GLS was assessed in nested models.
Of the 1,274 patients in this study, 115 died during a median follow-up of 6.2 years. By Kaplan-Meier analysis, patients with GLS ≥ median (-20%) had significantly reduced event-free survival compared with those with GLS < median (log-rank test, p < 0.001). By Cox multivariable regression modeling, each 1% worsening in GLS was associated with a 22.8% increased risk of death after adjustment for clinical and imaging risk factors (hazard ratio: 1.228 per percent; p < 0.001). Addition of GLS in this model resulted in significant improvement in the global chi-square test (94 to 183; p < 0.001) and Harrell's C-statistic (0.75 to 0.83; p < 0.001).
GLS derived from CMR feature-tracking is a powerful independent predictor of mortality in patients with preserved ejection fraction, incremental to common clinical and imaging risk factors.
Acute myocardial infarct (AMI) size depicted by late gadolinium enhancement cardiovascular magnetic resonance (CMR) is increasingly used as an efficacy endpoint in randomized trials comparing AMI ...therapies. Infarct size is quantified using manual planimetry (MANUAL), visual scoring (VISUAL), or automated techniques using signal-intensity thresholding (AUTO). Although AUTO is considered the most reproducible, prior studies did not account for the subjective determination of endocardial/epicardial borders, which all methods require. For MANUAL and VISUAL, prior studies did not address how to treat intermediate signal intensities due to partial volume.
To assess sources of variability, AMI size was measured in 30 patients and 12 controls by 3 core-laboratories using 8 methods, each separated by more than 2 months time (n = 720 evaluations). The methods were: (1,2) AUTO
, AUTO
(using Segment software or the full-width-at-half-maximum algorithm, respectively); (3,4) AUTO-UC
, AUTO-UC
(user correction for endocardial border pixels, no-reflow, etc.); (5) MANUAL; (6) MANUAL-ISI (adjustment for intermediate signal-intensities); (7) VISUAL; (8) VISUAL-ISI.
Mean infarct size varied between 16.8% and 27.2% of LV mass depending on method. Even automated techniques with no user interaction for infarct borders resulted in significant within-patient variability given the need to subjectively trace endocardial/epicardial contours. The coefficient-of-variation (CV) was 10.6% and 14.6% for AUTO
and AUTO
, respectively. For manual and visual categories, reproducibility was improved when intermediate signal-intensities were considered (MANUAL-ISI vs MANUAL: CV = 8.3% vs 14.4%; p = 0.03; VISUAL-ISI vs VISUAL: CV = 8.4% vs 10.9%; p = 0.01). For AUTO-UC
, MANUAL-ISI, and VISUAL-ISI (best technique in each category) within-patient variability due to the quantification method was less than 10% of total variability, and the required sample sizes for detecting a 5% absolute difference in infarct size were 62, 63, and 62 patients, respectively.
Among CMR core-laboratories, an important source of variability in infarct size quantification is the subjective delineation of endocardial/epicardial borders. When intermediate signal intensities are considered in manual planimetry and visual scoring, reproducibility and impact on sample size are similar to automated techniques.
Topotactic exsolution with ALD enables abundant alloy nanocatalysts as a new driving force applicable to perovskite systems.
With the need for more stable and active metal catalysts for dry reforming ...of methane, in situ grown nanoparticles using exsolution are a promising approach. However, in conventional exsolution, most nanoparticles remain underneath the surface because of the sluggish diffusion rate of cations. Here, we report the atomic layer deposition (ALD)–combined topotactic exsolution on La
0.6
Sr
0.2
Ti
0.85
Ni
0.15
O
3-δ
toward developing active and durable catalysts. The uniform and quantitatively controlled layer of Fe via ALD facilitates the topotactic exsolution, increasing finely dispersed nanoparticles. The introduction of Fe
2
O
3
yields the formation of Ni-Fe alloy owing to the spontaneous alloy formation energy of −0.43 eV, leading to an enhancement of the catalytic activity for dry methane reforming with a prolonged stability of 410 hours. Overall, the abundant alloy nanocatalysts via ALD mark an important step forward in the evolution of exsolution and its application to the field of energy utilization.
The goal of this study was to determine the prevalence of post-myocardial infarction (MI) left ventricular (LV) thrombus in the current era and to develop an effective algorithm (predicated on ...echocardiography echo) to discern patients warranting further testing for thrombus via delayed enhancement (DE) cardiac magnetic resonance (CMR).
LV thrombus affects post-MI management. DE-CMR provides thrombus tissue characterization and is a well-validated but an impractical screening modality for all patients after an MI.
A same-day echo and CMR were performed according to a tailored protocol, which entailed uniform echo contrast (irrespective of image quality) and dedicated DE-CMR for thrombus tissue characterization.
A total of 201 patients were studied; 8% had thrombus according to DE-CMR. All thrombi were apically located; 94% of thrombi occurred in the context of a left anterior descending (LAD) infarct-related artery. Although patients with thrombus had more prolonged chest pain and larger MI (p ≤ 0.01), only 18% had aneurysm on echo (cine-CMR 24%). Noncontrast (35%) and contrast (64%) echo yielded limited sensitivity for thrombus on DE-CMR. Thrombus was associated with stepwise increments in basal → apical contractile dysfunction on echo and quantitative cine-CMR; the echo-measured apical wall motion score was higher among patients with thrombus (p < 0.001) and paralleled cine-CMR decrements in apical ejection fraction and peak ejection rates (both p < 0.005). Thrombus-associated decrements in apical contractile dysfunction were significant even among patients with LAD infarction (p < 0.05). The echo-based apical wall motion score improved overall performance (area under the curve 0.89 ± 0.44) for thrombus compared with ejection fraction (area under the curve 0.80 ± 0.61; p = 0.01). Apical wall motion partitions would have enabled all patients with LV thrombus to be appropriately referred for DE-CMR testing (100% sensitivity and negative predictive value), while avoiding further testing in more than one-half (56% to 63%) of patients.
LV thrombus remains common, especially after LAD MI, and can occur even in the absence of aneurysm. Although DE-CMR yielded improved overall thrombus detection, apical wall motion on a noncontrast echocardiogram can be an effective stratification tool to identify patients in whom DE-CMR thrombus assessment is most warranted. (Diagnostic Utility of Contrast Echocardiography for Detection of LV Thrombi Post ST Elevation Myocardial Infarction; NCT00539045).
Regional left ventricular (LV) wall thinning is believed to represent chronic transmural myocardial infarction and scar tissue. However, recent case reports using delayed-enhancement cardiovascular ...magnetic resonance (CMR) imaging raise the possibility that thinning may occur with little or no scarring.
To evaluate patients with regional myocardial wall thinning and to determine scar burden and potential for functional improvement.
Investigator-initiated, prospective, 3-center study conducted from August 2000 through January 2008 in 3 parts to determine (1) in patients with known coronary artery disease (CAD) undergoing CMR viability assessment, the prevalence of regional wall thinning (end-diastolic wall thickness ≤5.5 mm), (2) in patients with thinning, the presence and extent of scar burden, and (3) in patients with thinning undergoing coronary revascularization, any changes in myocardial morphology and contractility.
Scar burden in thinned regions assessed using delayed-enhancement CMR and changes in myocardial morphology and function assessed using cine-CMR after revascularization.
Of 1055 consecutive patients with CAD screened, 201 (19% 95% CI, 17% to 21%) had regional wall thinning. Wall thinning spanned a mean of 34% (95% CI, 32% to 37% SD, 15%) of LV surface area. Within these regions, the extent of scarring was 72% (95% CI, 69% to 76% SD, 25%); however, 18% (95% CI, 13% to 24%) of thinned regions had limited scar burden (≤50% of total extent). Among patients with thinning undergoing revascularization and follow-up cine-CMR (n = 42), scar extent within the thinned region was inversely related to regional (r = -0.72, P < .001) and global (r = -0.53, P < .001) contractile improvement. End-diastolic wall thickness in thinned regions with limited scar burden increased from 4.4 mm (95% CI, 4.1 to 4.7) to 7.5 mm (95% CI, 6.9 to 8.1) after revascularization (P < .001), resulting in resolution of wall thinning. On multivariable analysis, scar extent had the strongest association with contractile improvement (slope coefficient, -0.03 95% CI, -0.04 to -0.02; P < .001) and reversal of thinning (slope coefficient, -0.05 95% CI, -0.06 to -0.04; P < .001).
Among patients with CAD referred for CMR and found to have regional wall thinning, limited scar burden was present in 18% and was associated with improved contractility and resolution of wall thinning after revascularization. These findings, which are not consistent with common assumptions, warrant further investigation.
Purine biosynthetic enzymes organize into dynamic cellular bodies called purinosomes. Little is known about the spatiotemporal control of these structures. Using super-resolution microscopy, we ...demonstrated that purinosomes colocalized with mitochondria, and these results were supported by isolation of purinosome enzymes with mitochondria. Moreover, the number of purinosome-containing cells responded to dysregulation of mitochondrial function and metabolism. To explore the role of intracellular signaling, we performed a kinome screen using a label-free assay and found that mechanistic target of rapamycin (mTOR) influenced purinosome assembly. mTOR inhibition reduced purinosome-mitochondria colocalization and suppressed purinosome formation stimulated by mitochondria dysregulation. Collectively, our data suggest an mTOR-mediated link between purinosomes and mitochondria, and a general means by which mTOR regulates nucleotide metabolism by spatiotemporal control over protein association.
This study sought to evaluate the prognostic value of cardiac magnetic resonance (CMR) feature-tracking-derived right ventricular (RV) free wall longitudinal strain (RVFWLS) in a large multicenter ...population of patients with severe functional tricuspid regurgitation.
Tricuspid regurgitation imposes a volume overload on the RV that can lead to progressive RV dilation and dysfunction. Overt RV dysfunction is associated with poor prognosis and increased operative risk. Abnormalities of myocardial strain may provide the earliest evidence of ventricular dysfunction. CMR feature-tracking techniques now allow assessment of strain from routine cine images, without specialized pulse sequences. Whether abnormalities of RV strain measured using CMR feature tracking have prognostic value in patients with tricuspid regurgitation is unknown.
Consecutive patients with severe functional tricuspid regurgitation undergoing CMR at 4 U.S. medical centers were included in this study. Feature-tracking RVFWLS was calculated from 4-chamber cine views. The primary endpoint was all-cause death. Cox proportional hazards regression modeling was used to examine the independent association between RVFWLS and death. The incremental prognostic value of RVFWLS was assessed in nested models.
Of the 544 patients in this study, 128 died during a median follow-up of 6 years. By Kaplan-Meier analysis, patients with RVFWLS ≥median (-16%) had significantly reduced event-free survival compared with those with RVFWLS <median (log-rank p < 0.001). By Cox multivariable regression modeling, RVFWLS was associated with increased risk-of-death after adjustment for clinical and imaging risk factors, including RV size and ejection fraction (hazard ratio: 1.14 per %; p < 0.001). Addition of RVFWLS in this model resulted in significant improvement in the global chi-square (31 to 78; p < 0.001).
CMR feature-tracking-derived RVFWLS is an independent predictor of mortality in patients with severe functional tricuspid regurgitation, incremental to common clinical and imaging risk factors.
Background Filtering facepiece respirators are the most common respirator worn by US health care and industrial workers, yet little is known on the physiologic impact of wearing this protective ...equipment. Methods Twenty young, healthy subjects exercised on a treadmill at a low-moderate (5.6 km/h) work rate while wearing 4 different models of N95 filtering facepiece respirators for 1 hour each, 2 models of which were equipped with exhalation valves, while being monitored for physiologic variables. Results Compared with controls, respirator use was associated with mean 1 hour increases in heart rate (range, 5.7-10.6 beats per minute, P < .001), respiratory rate (range, 1.4-2.4 breaths per minute, P < .05), and transcutaneous carbon dioxide (range, 1.7-3.0 mm Hg, P < .001). No significant differences in oxygen saturation between controls and respirators were noted ( P > .05). Conclusion The pulmonary and heart rate responses to wearing a filtering facepiece respirator for 1 hour at a low-moderate work rate are relatively small and should generally be well tolerated by healthy persons.
Transmissible spongiform encephalopathies (TSEs) are a group of neurodegenerative diseases that are associated with the conformational conversion of a normal prion protein, PrPC, to a misfolded ...aggregated form, PrPSc. The protein-only hypothesis asserts that PrPSc itself represents the infectious TSE agent. Although this model is supported by rapidly growing experimental data, unequivocal proof has been elusive. The protein misfolding cyclic amplification reactions have been recently shown to propagate prions using brain-derived or recombinant prion protein, but only in the presence of additional cofactors such as nucleic acids and lipids. Here, using a protein misfolding cyclic amplification variation, we show that prions causing transmissible spongiform encephalopathy in wild-type hamsters can be generated solely from highly purified, bacterially expressed recombinant hamster prion protein without any mammalian or synthetic cofactors (other than buffer salts and detergent). These findings provide strong support for the protein-only hypothesis of TSE diseases, as well as argue that cofactors such as nucleic acids, other polyanions, or lipids are non-obligatory for prion protein conversion to the infectious form.
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