Myocardial Extracellular Volume Fraction and Change in Hematocrit Level: MR Evaluation by Using T1 Mapping in an Experimental Model of Anemia.

Purpose To evaluate the effect of changes in hematocrit level on myocardial extracellular volume (ECV) fraction, as quantified with cardiac magnetic resonance (MR) imaging in an animal model. Materials and Methods Thirteen adult male Sprague-Dawley rats underwent cardiac MR imaging before and after induction of anemia. MR imaging procedures, including unenhanced and contrast material-enhanced T1 mapping, were performed by using a saturation recovery Look-Locker sequence with a 9.4-T unit. An optimized T1 mapping sequence was established in the phantom study. Systolic function of the left ventricle (LV) was calculated from the cine images. Native and postcontrast T1 values of the LV myocardium at the midcavity level and LV blood pool, partition coefficients, and ECV were calculated. Histopathologic examination of the heart was performed after sacrifice. Intergroup comparison of variables was performed with the paired t test. Results The postanemia models exhibited lower hematocrit levels, postcontrast T1 values of the LV pool, and partition coefficients (mean, 45.7% ± 5.2 [standard deviation]; 563.8 msec ± 155.7; and 29.2 ± 3.5, respectively) than did the preanemia models (mean, 59.0% ± 4.1; 690.2 msec ± 109.7; and 38.2 ± 4.4, respectively) (P < .05 for all comparisons). There were no differences between the pre- and postanemia groups in terms of LV ejection fraction (mean, 72.7% ± 2.1 vs 73.2% ± 4.7; P = .78) and ECV (mean, 15.5% ± 2.0 vs 16.0% ± 1.9; P = .24). Conclusion Myocardial ECV measured with contrast-enhanced T1 mapping cardiac MR imaging did not significantly change despite changes in hematocrit level in anemic rat models. Extrapolation of this finding from animal models to human subjects suggests that ECV measured with MR imaging could be a robust parameter in anemic patients.

Valvuloplasty with a paclitaxel-eluting balloon prevents restenosis in an experimental animal model of aortic stenosis.

BACKGROUND AND AIM OF THE STUDY: Restenosis occurs invariably within 12 months following balloon valvuloplasty (BAV) in calcific aortic valve disease (CAVD), and is a limiting factor of this treatment. Cellular proliferation secondary to balloon injury is thought to play a pivotal role in the mechanism of restenosis. The study aim was to investigate the potential role of a paclitaxel-eluting valvuloplasty balloon to mitigate the progression of restenosis in an animal model of CAVD. METHODS: Fifty-three rabbits were fed with an aortic stenosis (AS)-inducing diet (cholesterol 0.5% plus vitamin D3 50,000 IU/day) for three months. The surviving animals (n = 40) underwent echocardiographic and invasive assessments, followed by valvuloplasty, randomly using either a paclitaxel-coated (3 µg/mm2) or a plain balloon. At one month after BAV, the surviving animals (n = 28) underwent repeat assessments, followed by histology and micro-computed tomography (MicroCT) analysis of the aortic valve. RESULTS: The baseline and post-BAV transvalvular gradients, aortic valve area (AVA), left ventricular stroke work loss (SWL) and aortic valve resistance (AVR) were similar between the groups (14 rabbits were assigned to paclitaxel-eluting, and 14 to plain balloon). Significant differences between the groups were observed at one-month post-BAV, which was suggestive of diminished restenosis in the paclitaxel-balloon group (mean maximum transvalvular pressure gradient 7.7 ± 7.7 versus 3.6 ± 3.7 mmHg, p = 0.08; AVA 0.91 ± 0.59 versus 0.55 ± 0.22 cm2, p = 0.04; SWL 3.5 ± 4.0 versus 8.6 ± 8.0%, p = 0.047; AVR 86 ± 71 versus 177 ± 137 dynes/s/cm(-5), p = 0.039). Histology demonstrated decreased leaflet thickness (0.60 ± 0.15 versus 0.71 ± 0.17 mm, p = 0.03), proliferating cell nuclear antigen (PCNA) staining (grade 1.53 ± 0.04 versus 2.24 ± 0.55, p = 0.049), and calcification in the paclitaxel-balloon group. CONCLUSION: Use of a paclitaxel-eluting valvuloplasty balloon in an animal model of AS resulted in attenuated restenosis, secondary to decrease in valve proliferation and calcification.

Climate sensitivity constrained by CO2 concentrations over the past 420 million years.

A firm understanding of the relationship between atmospheric carbon dioxide concentration and temperature is critical for interpreting past climate change and for predicting future climate change. A recent synthesis suggests that the increase in global-mean surface temperature in response to a doubling of the atmospheric carbon dioxide concentration, termed 'climate sensitivity', is between 1.5 and 6.2 degrees C (5-95 per cent likelihood range), but some evidence is inconsistent with this range. Moreover, most estimates of climate sensitivity are based on records of climate change over the past few decades to thousands of years, when carbon dioxide concentrations and global temperatures were similar to or lower than today, so such calculations tend to underestimate the magnitude of large climate-change events and may not be applicable to climate change under warmer conditions in the future. Here we estimate long-term equilibrium climate sensitivity by modelling carbon dioxide concentrations over the past 420 million years and comparing our calculations with a proxy record. Our estimates are broadly consistent with estimates based on short-term climate records, and indicate that a weak radiative forcing by carbon dioxide is highly unlikely on multi-million-year timescales. We conclude that a climate sensitivity greater than 1.5 degrees C has probably been a robust feature of the Earth's climate system over the past 420 million years, regardless of temporal scaling.

Modal investigation of elastic anisotropy in shallow-water environments: anisotropy beyond vertical transverse isotropy.

Theoretical and numerical results are presented for modal characteristics of the seismo-acoustic wavefield in anisotropic range-independent media. General anisotropy affects the form of the elastic-stiffness tensor, particle-motion polarization, the frequency and angular dispersion curves, and introduces near-degenerate modes. Horizontally polarized particle motion (SH) cannot be ignored when anisotropy is present for low-frequency modes having significant bottom interaction. The seismo-acoustic wavefield has polarizations in all three coordinate directions even in the absence of any scattering or heterogeneity. Even weak anisotropy may have a significant impact on seismo-acoustic wave propagation. Unlike isotropic and transversely isotropic media with a vertical symmetry axis where acoustic signals comprise P-SV modes alone (in the absence of any scattering), tilted TI media allow both quasi-P-SV and quasi-SH modes to carry seismo-acoustic energy. Discrete modes for an anisotropic medium are best described as generalized P-SV-SH modes with polarizations in all three Cartesian directions. Conversion to SH is a loss that will mimic acoustic attenuation. An in-water explosion will excite quasi-SH.

Case report: percutaneous closure of residual leak following left atrial appendage occlusion.

BACKGROUND: Transcatheter left atrial appendage occlusion (LAAO) using Watchman device has been demonstrated to be efficacious in decreasing stroke risk in patients with atrial fibrillation who are not suitable for long-term anticoagulation. Residual leaks are frequently encountered following LAAO procedures and their clinical implications and optimal management remain controversial. CASE SUMMARY: In this report, we describe a case of peri-Watchman device leak treated successfully with percutaneous device closure using an Amplatzer Vascular Plug II device. DISCUSSION: The clinical implications of peri-device leaks remain controversial with general consensus to continue anticoagulation along with serial imaging for larger leaks (>5 mm). As an alternative strategy, percutaneous closure of these leaks has been attempted in hope of avoiding anticoagulation and minimizing the risk of stroke and should be studied further.

Functional Profiling of CFTR-Directed Therapeutics Using Pediatric Patient-Derived Nasal Epithelial Cell Models.

Functional profiling of CFTR-directed therapeutics offers the potential to provide significant benefits to young people with cystic fibrosis (CF). However, the development of 2D airway epithelial cell models for individual response tests in CF children remains a central task. The objective of this study was to determine the utility of EpiXTM technology for expansion of nasal epithelial cells for use in electrophysiological CFTR function measurements. An initial harvest of as few as 20,000 cells was sufficient to expand up to 50 million cells that were used to generate air-liquid interface (ALI) cultures for ion transport studies with the Ussing assay. CFTR function was assessed by measuring responses to forskolin and the CFTR potentiator VX-770 (ivacaftor) in ALI cultures generated from passage 3 and 4 cells. Short-circuit current (Isc) measurements of blocked CFTR currents (ΔICFTRinh) discriminated CFTR function between healthy control (wild type, WT) and patients with intermediate (F508del/R117H-7T: 56% WT) and severe (F508del/F508del: 12% WT) CF disease. For the mixed genotypes, CFTR activity for F508del/c.850dupA was 12% WT, R334W/406-1G>A was 24% WT, and CFTRdele2,3(21 kb)/CFTRdele2,3(21 kb) was 9% WT. The CFTR correctors VX-809 (lumacaftor) and VX-661 (tezacaftor) significantly increased CFTR currents for F508del/R117H to 73 and 67% WT, respectively. Cultures with the large deletion mutation CFTRdele2,3(21 kb) unexpectedly responded to VX-661 treatment (20% WT). Amiloride-sensitive sodium currents were robust and ranged between 20-80 µA/cm2 depending on the subject. In addition to characterizing the electrophysiological profile of mutant CFTR activity in cultures for five genotypes, our study exemplifies the promising paradigm of bed-to-bench side cooperation and personalized medicine.

State-of-the-art Structural Interventions in Heart Failure.

Heart failure (HF) is a leading cause of hospitalisation and healthcare costs worldwide. Acute decompensated heart failure accounts for more than 1 million hospitalisations in the US. Despite advances in the quality of acute and chronic HF disease management, gaps in knowledge about effective interventions to support the transition of care for patients with HF remain. Despite multiple trials of promising therapies, standard care consists of decongestion with IV diuretics and haemodynamic support with vasodilators and inotropes and this has remained largely unchanged during the past 45 years. Newer advances in medical innovations and structural heart disease interventions have now given promise to improved survival, outcomes and quality of life for patients with advanced HF of multiple aetiologies. In this article, we focus on structural interventions in the treatment of patients with HF.

Non-inferior low-dose coronary computed tomography angiography image quality with knowledge-based iterative model reconstruction for overweight patients.

We investigated the feasibility of low-dose coronary computed tomography angiography (CCTA), using a prospective electrocardiogram (ECG)-triggered axial scan protocol, knowledge-based iterative model reconstruction (IMR), and fixed tube current, in overweight subjects. Forty non-overweight (group A; body-mass index [BMI] < 25 kg/m2) and 40 overweight individuals (group B; BMI = 25-30 kg/m2), who underwent CCTA for coronary artery disease screening, were retrospectively and consecutively enrolled. A 64-slice CT scanner was used at 100-kVp tube voltage and 150-mA tube current, and images were reconstructed using IMR techniques. Image noise, attenuation at the aorta, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) at the proximal right and left main coronary arteries (pRCA and LMCA) were calculated. CCTA images were qualitatively evaluated using a four-point scale (1, poor; 4, excellent) and analyzed using a non-inferiority test with a pre-defined non-inferiority margin of -0.2. The mean CCTA radiation dose (Group A: 1.33 ± 0.02 mSv; Group B: 1.35 ± 0.10 mSv; p = 0.151) and mean aortic root CT attenuation values (Group A: 447.9 ± 81.6 HU; Group B: 439.5 ± 63.6 HU; p = 0.571) did not differ significantly between the two groups. The mean noise in groups A and B was 26.0 ± 4.8 HU and 29.2 ± 4.4 HU, respectively (p = 0.005). The noise reduction ratio in the groups, compared to filtered back projection, was 65.0% and 68.1%, respectively. The mean grade of image quality did not differ significantly (3.75 ± 0.04 vs. 3.71 ± 0.04, p = 0.478). Group B CCTA image quality was non-inferior (mean difference = -0.043, 95% CI = -0.162-0.077) to that of Group A. We concluded that low-dose CCTA with prospective ECG-triggering and IMR might be applied to overweight subjects, as well as to normal-weight subjects, by using a fixed tube current without an increase in tube current based on the patient's body size.

Early Detection and Serial Monitoring of Anthracycline-Induced Cardiotoxicity Using T1-mapping Cardiac Magnetic Resonance Imaging: An Animal Study.

A reliable, non-invasive diagnostic method is needed for early detection and serial monitoring of cardiotoxicity, a well-known side effect of chemotherapy. This study aimed to assess the feasibility of T1-mapping cardiac magnetic resonance imaging (CMR) for evaluating subclinical myocardial changes in a doxorubicin-induced cardiotoxicity rabbit model. Adult male New Zealand White rabbits were injected twice-weekly with doxorubicin and subjected to CMR on a clinical 3T MR system before and every 2-4 weeks post-drug administration. Native T1 and extracellular volume (ECV) values were measured at six mid-left ventricle (LV) and specific LV lesions. Histological assessments evaluated myocardial injury and fibrosis. Three pre-model and 11 post-model animals were included. Myocardial injury was observed from 3 weeks. Mean LV myocardium ECV values increased significantly from week 3 before LV ejection fraction decreases (week 6), and ECVs of the RV upper/lower insertion sites and papillary muscle exceeded those of the LV. The mean native T1 value in the mid-LV increased significantly increased from week 6, and LV myocardium ECV correlated strongly with the degree of fibrosis (r = 0.979, p < 0.001). Myocardial T1 mapping, particularly ECV values, reliably and non-invasively detected early cardiotoxicity, allowing serial monitoring of chemotherapy-induced cardiotoxicity.

Effect of a rapid clinical protocol to the conversion from central venous hemodialysis catheter to arteriovenous access.

PURPOSE: Evaluation of the rapid conversion protocol that includes an ambulatory dialysis access center (DAC), and a three-step clinical pathway, to the conversion rate from central venous hemodialysis (HD) catheter to functioning arteriovenous (AV) access. METHODS: Prospective data were collected on 97 consecutive catheter-dependent HD patients. DAC is defined as an ambulatory unit, able to accommodate clinic visits, ultrasound examinations, surgical, interventional and hybrid procedures. Step I: initial evaluation, vein mapping and creation of AV access. Step II: clinical evaluation in two weeks and if failure identified, secondary procedure to restore function. Step III: evaluation in four weeks after creation, and additional procedure to promote maturation if indicated. The success rate, time to conversion and time to catheter removal were recorded. RESULTS: From the 97 consecutive referred patients, eight patients were excluded. From the remaining 89 patients, 99% were successfully converted to AV access. Seventy-three percent of the patients were converted to native arteriovenous fistulae and 27% of the patients to prosthetic arteriovenous shunts. The median time from creation to HD catheter removal was 63 (SD 41) days. Fifty-two percent of the patients required at least one additional secondary procedure to accomplish successful conversion. CONCLUSIONS: High rates of timely conversion from catheter to AV access, primarily AV fistulae, can be accomplished within the context of the rapid conversion protocol.

Earth's free oscillations excited by the 26 December 2004 Sumatra-Andaman earthquake.

At periods greater than 1000 seconds, Earth's seismic free oscillations have anomalously large amplitude when referenced to the Harvard Centroid Moment Tensor fault mechanism, which is estimated from 300- to 500-second surface waves. By using more realistic rupture models on a steeper fault derived from seismic body and surface waves, we approximated free oscillation amplitudes with a seismic moment (6.5 x 10(22) Newton.meters) that corresponds to a moment magnitude of 9.15. With a rupture duration of 600 seconds, the fault-rupture models represent seismic observations adequately but underpredict geodetic displacements that argue for slow fault motion beneath the Nicobar and Andaman islands.

Seismic anisotropy: tracing plate dynamics in the mantle.

Elastic anisotropy is present where the speed of a seismic wave depends on its direction. In Earth's mantle, elastic anisotropy is induced by minerals that are preferentially oriented in a directional flow or deformation. Earthquakes generate two seismic wave types: compressional (P) and shear (S) waves, whose coupling in anisotropic rocks leads to scattering, birefringence, and waves with hybrid polarizations. This varied behavior is helping geophysicists explore rock textures within Earth's mantle and crust, map present-day upper-mantle convection, and study the formation of lithospheric plates and the accretion of continents in Earth history.

Seismic evidence for catastrophic slab loss beneath Kamchatka.

In the northwest Pacific Ocean, a sharp corner in the boundary between the Pacific plate and the North American plate joins a subduction zone running along the southern half of the Kamchatka peninsula with a region of transcurrent motion along the western Aleutian arc. Here we present images of the seismic structure beneath the Aleutian-Kamchatka junction and the surrounding region, indicating that: the subducting Pacific lithosphere terminates at the Aleutian-Kamchatka junction; no relict slab underlies the extinct northern Kamchatka volcanic arc; and the upper mantle beneath northern Kamchatka has unusually slow shear wavespeeds. From the tectonic and volcanic evolution of Kamchatka over the past 10 Myr (refs 3-5) we infer that at least two episodes of catastrophic slab loss have occurred. About 5 to 10 Myr ago, catastrophic slab loss shut down island-arc volcanic activity north of the Aleutian-Kamchatka junction. A later episode of slab loss, since about 2 Myr ago, seems to be related to the activity of the world's most productive island-arc volcano, Klyuchevskoy. Removal of lithospheric mantle is commonly discussed in the context of a continental collision, but our findings imply that episodes of slab detachment and loss are also important agents in the evolution of oceanic convergent margins.