A conserved core region of the scaffold NEMO is essential for signal-induced conformational change and liquid-liquid phase separation.

Scaffold proteins help mediate interactions between protein partners, often to optimize intracellular signaling. Herein, we use comparative, biochemical, biophysical, molecular, and cellular approaches to investigate how the scaffold protein NEMO contributes to signaling in the NF-κB pathway. Comparison of NEMO and the related protein optineurin from a variety of evolutionarily distant organisms revealed that a central region of NEMO, called the Intervening Domain (IVD), is conserved between NEMO and optineurin. Previous studies have shown that this central core region of the IVD is required for cytokine-induced activation of IκB kinase (IKK). We show that the analogous region of optineurin can functionally replace the core region of the NEMO IVD. We also show that an intact IVD is required for the formation of disulfide-bonded dimers of NEMO. Moreover, inactivating mutations in this core region abrogate the ability of NEMO to form ubiquitin-induced liquid-liquid phase separation droplets in vitro and signal-induced puncta in vivo. Thermal and chemical denaturation studies of truncated NEMO variants indicate that the IVD, while not intrinsically destabilizing, can reduce the stability of surrounding regions of NEMO due to the conflicting structural demands imparted on this region by flanking upstream and downstream domains. This conformational strain in the IVD mediates allosteric communication between the N- and C-terminal regions of NEMO. Overall, these results support a model in which the IVD of NEMO participates in signal-induced activation of the IKK/NF-κB pathway by acting as a mediator of conformational changes in NEMO.

Physician assessment of aortic stenosis severity, quantitative parameters, and long-term outcomes: Results from the KP-VALVE project.

BACKGROUND: Contemporary outcomes for aortic stenosis (AS) and the association between physician-assessed AS severity and quantitative parameters is poorly understood. We aimed to evaluate AS natural history, compare outcomes for physicians' AS assessment vs. quantitative parameters, and identify AS parameters with the most explanatory power. METHODS: We ascertained physician-assessed AS severity, echocardiographic parameters, and clinical data for 546,769 patients from 2008-2018, examined multivariable associations of physician-assessed AS severity and number of quantitative severe AS parameters with death, cardiovascular hospitalization, and aortic valve replacement, and estimated the relative contribution of different quantitative AS parameters on outcomes. RESULTS: Among 49,604 AS patients (mean [SD] age 77 [11] years), 17.6% had moderate, 3.6% moderate-severe, and 9.4% severe AS. During median 3.7 [IQR 1.7-6.8] years, physician-assessed AS severity strongly correlated with outcomes, with moderate AS patients tracking closest to mild AS, and moderate-to-severe AS patients more comparable to severe AS. Although the number of quantitative severe AS parameters strongly predicted outcomes (adjusted HR [95% CI] for death 1.40 [1.34-1.46], 1.70 [1.56-1.85], and 1.78 [1.63-1.94] for 1, 2, and 3 parameters, respectively), aortic valve area <1.0 cm2 was the most frequent severe AS parameter, explained the largest relative contribution (67%), and was common in patients classified as moderate (21%) or moderate-severe (56%) AS. CONCLUSIONS: Physician-assessed AS severity predicts outcomes, with cumulative effects for each severe AS parameter. Moderate AS includes a wide spectrum of patients, with discordant AVA <1.0 cm2 being both common and predictive. Better identification of non-classical severe AS phenotypes may improve outcomes.

Intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR): a randomized, placebo-controlled, double-blinded trial.

AIMS: Cardiosphere-derived cells (CDCs) are cardiac progenitor cells that exhibit disease-modifying bioactivity in various models of cardiomyopathy and in previous clinical studies of acute myocardial infarction (MI), dilated cardiomyopathy, and Duchenne muscular dystrophy. The aim of the study was to assess the safety and efficacy of intracoronary administration of allogeneic CDCs in the multicentre, randomized, double-blinded, placebo-controlled, intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR) trial. METHODS AND RESULTS: We enrolled patients 4 weeks to 12 months after MI, with left ventricular ejection fraction (LVEF) ≤45% and LV scar size ≥15% of LV mass by magnetic resonance imaging (MRI). A pre-specified interim analysis was performed when 6-month MRI data were available. The trial was subsequently stopped due to the low probability of detecting a significant treatment effect of CDCs based on the primary endpoint. Patients were randomly allocated in a 2:1 ratio to receive CDCs or placebo in the infarct-related artery by stop-flow technique. The primary safety endpoint was the occurrence, during 1-month post-intracoronary infusion, of acute myocarditis attributable to allogeneic CDCs, ventricular tachycardia- or ventricular fibrillation-related death, sudden unexpected death, or a major adverse cardiac event (death or hospitalization for heart failure or non-fatal MI or need for left ventricular assist device or heart transplant). The primary efficacy endpoint was the relative percentage change in infarct size at 12 months post-infusion as assessed by contrast-enhanced cardiac MRI. We randomly allocated 142 eligible patients of whom 134 were treated (90 to the CDC group and 44 to the placebo group). The mean baseline LVEF was 40% and the mean scar size was 22% of LV mass. No primary safety endpoint events occurred. There was no difference in the percentage change from baseline in scar size (P = 0.51) between CDCs and placebo groups at 6 months. Compared with placebo, there were significant reductions in LV end-diastolic volume (P = 0.02), LV end-systolic volume (P = 0.02), and N-terminal pro b-type natriuretic peptide (NT-proBNP) (P = 0.02) at 6 months in CDC-treated patients. CONCLUSION: Intracoronary infusion of allogeneic CDCs in patients with post-MI LV dysfunction was safe but did not reduce scar size relative to placebo at 6 months. Nevertheless, the reductions in LV volumes and NT-proBNP reveal disease-modifying bioactivity of CDCs. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01458405.

Enhanced Inflammation is a Marker for Risk of Post-Infarct Ventricular Dysfunction and Heart Failure.

Acute ST-segment elevation myocardial infarction (STEMI) activates inflammation that can contribute to left ventricular systolic dysfunction (LVSD) and heart failure (HF). The objective of this study was to examine whether high-sensitivity C-reactive protein (CRP) concentration is predictive of long-term post-infarct LVSD and HF. In 204 patients with a first STEMI, CRP was measured at hospital admission, 24 h (CRP24), discharge (CRPDC), and 1 month after discharge (CRP1M). LVSD at 6 months after discharge (LVSD6M) and hospitalization for HF in long-term multi-year follow-up were prospectively evaluated. LVSD6M occurred in 17.6% of patients. HF hospitalization within a median follow-up of 5.6 years occurred in 45.7% of patients with LVSD6M vs. 4.9% without LVSD6M (p < 0.0001). Compared to patients without LVSD6M, the patients with LVSD6M had higher CRP24 and CRPDC and persistent CRP1M ≥ 2 mg/L. CRP levels were also higher in patients in whom LVSD persisted at 6 months (51% of all patients who had LVSD at discharge upon index STEMI) vs. patients in whom LVSD resolved. In multivariable analysis, CRP24 ≥ 19.67 mg/L improved the prediction of LVSD6M with an increased odds ratio of 1.47 (p < 0.01). Patients with LVSD6M who developed HF had the highest CRP during index STEMI. Elevated CRP concentration during STEMI can serve as a synergistic marker for risk of long-term LVSD and HF.

A Central Region of NF-κB Essential Modulator Is Required for IKKß-Induced Conformational Change and for Signal Propagation.

NF-κB essential modulator (NEMO) regulates NF-κB signaling by acting as a scaffold for the kinase IKKß to direct its activity toward the NF-κB inhibitor, IκBα. Here, we show that a highly conserved central region of NEMO termed the intervening domain (IVD, amino acids 112-195) plays a key role in NEMO function. We determined a structural model of full-length NEMO by small-angle X-ray scattering and show that full-length, wild-type NEMO becomes more compact upon binding of a peptide comprising the NEMO binding domain of IKKß (amino acids 701-745). Mutation of conserved IVD residues (9SG-NEMO) disrupts this conformational change in NEMO and abolishes the ability of NEMO to propagate NF-κB signaling in cells, although the affinity of 9SG-NEMO for IKKß compared to that of the wild type is unchanged. On the basis of these results, we propose a model in which the IVD is required for a conformational change in NEMO that is necessary for its ability to direct phosphorylation of IκBα by IKKß. Our findings suggest a molecular explanation for certain disease-associated mutations within the IVD and provide insight into the role of conformational change in signaling scaffold proteins.

Accuracy of left ventricular ejection fraction determined by automated analysis of handheld echocardiograms: A comparison of experienced and novice examiners.

BACKGROUND: Handheld ultrasound devices have been developed that facilitate imaging in new clinical settings. However, quantitative assessment has been difficult. Software algorithms have recently been developed with the aim of providing rapid measurements of left ventricular ejection fraction (LVEF) with minimal operator input. METHODS: We prospectively enrolled a cohort of 70 patients scheduled to undergo echocardiography at the University of California, San Diego. Each patient underwent a standard echocardiography examination by an experienced sonographer as well as a handheld ultrasound with automated software by both the sonographer and an inexperienced resident. RESULTS: There was a positive correlation between the LVEFs obtained from the standard transthoracic echocardiogram and handheld device in the hands of a novice (r = 0.62; 95% CI 0.45-0.75) and experienced sonographer (r = 0.69; 95% CI 0.54-0.80). The sensitivity and specificity to detect a reduced LVEF (<50%) were 69% and 96% for the novice and 64% and 98% for the experienced sonographer. The sensitivity and specificity to detect a severely reduced LVEF (<35%) were 67% and 97% for the novice and 56% and 93% for the experienced sonographer, but when limited to recordings of at least adequate quality, improved to 100% and 100% for the novice and 100% and 98% for the experienced sonographer, respectively. CONCLUSION: These data demonstrate that the handheld ultrasound device paired with novel software can provide a clinically useful estimate of LVEF when the images are of adequate quality and yield results by novice examiners that are similar to experienced sonographers.

4D flow MRI quantification of mitral and tricuspid regurgitation: Reproducibility and consistency relative to conventional MRI.

BACKGROUND: In patients with mitral or tricuspid valve regurgitation, evaluation of regurgitant severity is essential for determining the need for surgery. While transthoracic echocardiography is widely accessible, it has limited reproducibility for grading inlet valve regurgitation. Multiplanar cardiac MRI is the quantitative standard but requires specialized local expertise, and is thus not widely available. Volumetric 4D flow MRI has potential for quantitatively grading the severity of inlet valve regurgitation in adult patients. PURPOSE: To evaluate the accuracy and reproducibility of volumetric 4D flow MRI for quantification of inlet valvular regurgitation compared to conventional multiplanar MRI, which may simplify and improve accessibility of cardiac MRI. STUDY TYPE: This retrospective, HIPAA-compliant imaging-based comparison study was conducted at a single institution. SUBJECTS: Twenty-one patients who underwent concurrent multiplanar and 4D flow cardiac MRI between April 2015 and January 2017. FIELD STRENGTH/SEQUENCES: 3T; steady-state free-precession (SSFP), 2D phase contrast (2D-PC), and postcontrast 4D flow. ASSESSMENT: We evaluated the intertechnique (4D flow vs. 2D-PC), intermethod (direct vs. indirect measurement), interobserver and intraobserver reproducibility of measurements of regurgitant flow volume (RFV), fraction (RF), and volume (RVol). STATISTICAL TESTS: Statistical analysis included Pearson correlation, Bland-Altman statistics, and intraclass correlation coefficients. RESULTS: There was high concordance between 4D flow and multiplanar MRI, whether using direct or indirect methods of quantifying regurgitation (r = 0.813-0.985). Direct interrogation of the regurgitant jet with 4D flow showed high intraobserver consistency (r = 0.976-0.999) and interobserver consistency (r = 0.861-0.992), and correlated well with traditional indirect measurements obtained as the difference between stroke volume and forward outlet valve flow. DATA CONCLUSION: 4D flow MRI provides highly reproducible measurements of mitral and tricuspid regurgitant volume, and may be used in place of conventional multiplanar MRI. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;48:1147-1158.

Ixmyelocel-T for patients with ischaemic heart failure: a prospective randomised double-blind trial.

BACKGROUND: Ixmyelocel-T is an expanded, multicellular therapy produced from a patient's own bone marrow by selectively expanding two key types of bone marrow mononuclear cells: CD90+ mesenchymal stem cells and CD45+ CD14+ auto-fluorescent+ activated macrophages. Early phase clinical trials suggest that intramyocardial delivery of ixmyelocel-T might improve clinical, functional, symptomatic, and quality-of-life outcomes in patients with heart failure due to ischaemic dilated cardiomyopathy. We aimed to assess the safety and efficacy of catheter-based transendocardial injection of ixmyelocel-T cell therapy in patients with heart failure and reduced ejection fractions. METHODS: In this randomised, double-blind, placebo-controlled phase 2B trial (ixCELL-DCM), patients from 31 sites in North America with New York Heart Association class III or IV symptomatic heart failure due to ischaemic dilated cardiomyopathy, who had left ventricular ejection fraction 35% or less, an automatic implantable cardioverter defibrillator, and who were ineligible for revascularisation procedures were randomly assigned (1:1) to receive ixmyelocel-T or placebo at the time of bone marrow aspiration and followed for 12 months. Randomisation was done through an interactive (voice/web) response system. The pharmacist, treating physician, and coordinator at each site were unblinded, but the the follow-up team was completely blinded. The primary endpoint was a composite of all-cause death, cardiovascular admission to hospital, and unplanned clinic visits to treat acute decompensated heart failure based on the blinded adjudication of an independent clinical endpoint committee. Primary efficacy endpoint analyses and safety analyses were done by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01670981. FINDINGS: Between April 2, 2013, and Jan 28, 2015, 126 participants were randomly assigned to receive either ixmyelocel-T (n=66) or placebo (n=60). 114 (90%) patients comprised the modified intention-to-treat population and 109 (87%) patients were included in the per-protocol primary efficacy analysis (58 in the ixmyelocel-T group and 51 in the placebo group). The primary efficacy endpoint was observed in 47 patients: 50 events in 25 (49%) of 51 patients in the placebo group and 38 events in 22 (38%) of 58 patients in the ixmyelocel-T group, which represents a 37% reduction in cardiac events compared with placebo (risk ratio 0·63 [95% CI 0·42-0·97]; p=0·0344). 41 (75%) of 51 participants in the placebo group had serious adverse events versus 31 (53%) of 58 in the ixmyelocel-T group (p=0·0197). INTERPRETATION: To the best of our knowledge, ixCELL-DCM is the largest cell therapy study done in patients with heart failure so far. The transendocardial delivery of ixmyelocel-T in patients with heart failure and reduced ejection fraction due to ischaemic dilated cardiomyopathy resulted in a significant reduction in adjudicated clinical cardiac events compared with placebo leading to improved patient outcomes. FUNDING: Vericel Corporation.

A Phase II Dose-Escalation Study of Allogeneic Mesenchymal Precursor Cells in Patients With Ischemic or Nonischemic Heart Failure.

RATIONALE: Allogeneic mesenchymal precursor cells (MPCs) have been effective in large animal models of ischemic and nonischemic heart failure (HF). OBJECTIVE: To evaluate the feasibility and safety of 3 doses (25, 75, or 150 million cells) of immunoselected allogeneic MPCs in chronic HF patients in a phase 2 trial. METHODS AND RESULTS: We sequentially allocated 60 patients to a dosing cohort (20 per dose group) and randomized them to transendocardial MPC injections (n=15) or mock procedures (n=5). The primary objective was safety, including antibody testing. Secondary efficacy end points included major adverse cardiac events (MACE; cardiac death, myocardial infarction, or revascularization), left ventricular imaging, and other clinical-event surrogates. Safety and MACE were evaluated for up to 3 years. MPC injections were feasible and safe. Adverse events were similar across groups. No clinically symptomatic immune responses were noted. MACE was seen in 15 patients: 10 of 45 (22%) MPC-treated and 5 of 15 (33%) control patients. We found no differences between MPC-treated and control patients in survival probability, MACE-free probability, and all-cause mortality. We conducted a post hoc analysis of HF-related MACE (HF hospitalization, successfully resuscitated cardiac death, or cardiac death) and events were significantly reduced in the 150 million MPC group (0/15) versus control (5/15; 33%), 25 million MPC group (3/15; 20%), and 75 million MPC group (6/15; 40%); the 150 million MPC group differed significantly from all groups according to Kaplan-Meier statistics >3 years (P=0.025 for 150 million MPC group versus control). CONCLUSIONS: Transendocardial injections of allogeneic MPCs were feasible and safe in chronic HF patients. High-dose allogeneic MPCs may provide benefits in this population.

Acute right heart failure caused by tacrolimus after renal transplantation: Serial observation by speckle tracking and Doppler echocardiography.

Tacrolimus is an immunosuppressive agent well known to be capable of producing renal impairment. Acute renal failure with right heart failure caused by tacrolimus is rarely described. We report the findings of one such case in which tacrolimus caused acute renal failure with severe tricuspid regurgitation and right ventricular failure documented by echocardiography.

Tricuspid annular plane systolic excursion in chronic thromboembolic pulmonary hypertension before and after pulmonary thromboendarterectomy.

BACKGROUND: Right ventricular function is impaired in chronic thromboembolic pulmonary hypertension (CTEPH). Tricuspid annular plane systolic excursion (TAPSE) and right ventricular fractional area change (RVFAC) have been shown to help assess right ventricular function in pulmonary hypertension. Our goal was to (1) assess TAPSE and RVFAC before and after PTE, and (2) assess correlation of these variables with right heart catheterization data and PVR. METHODS: We evaluated 67 consecutive patients with CTEPH for pulmonary thromboendarterectomy (PTE). Of these 67 patients, 48 were deemed surgical candidates. Preoperative right heart catheterization was performed within 1.3±1.2 days of the preoperative echocardiogram. All postoperative right heart catheterizations were performed on the first postoperative day. RESULTS: TAPSE dropped from 18±6 to 10±3 mm after PTE (P<.0001). RVFAC remained the same (25%±10% vs 30%±12%). Mean pulmonary artery (mPAP) pressure dropped from 45±12 to 28±6 mm Hg after PTE, and pulmonary vascular resistance (PVR) decreased from 757±406 to 306±147 dyne-s/cm5 (P<.0001 for both). Before PTE, TAPSE correlated inversely with PVR (r=-.57, P<.0001, TAPSE=-5.904×ln[PVR]+56.318). RVFAC did not correlate well with PVR or mean pulmonary artery pressure. After PTE, both TAPSE and RVFAC correlated poorly with PVR (r=-.12 and .01, respectively). CONCLUSION: In patients with CTEPH, TAPSE paradoxically decreased by 50% early after PTE. TAPSE correlated inversely with PVR prior to PTE, but this correlation was lost completely after PTE. Thus, despite the immediate and marked decrease in afterload postoperatively, TAPSE did not improve; thus, TAPSE cannot be used as an early marker for surgical success.

Right ventricular strain before and after pulmonary thromboendarterectomy in patients with chronic thromboembolic pulmonary hypertension.

BACKGROUND: Right ventricular (RV) function is significantly impaired in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Two-dimensional speckle tracking RV strain and strain rate are novel methods to assess regional RV systolic function in CTEPH patients before and after pulmonary thromboendarterectomy (PTE). Our goal was to (1) assess baseline longitudinal strain and strain rate of the basal RV free wall in CTEPH and (2) measure early changes in RV strain and strain rate after PTE. METHODS: We performed echocardiography on 30 consecutive patients with CTEPH referred for PTE with adequate pre- and post-PTE strain imaging. Strain and strain rate were assessed 6.4 ± 4.5 days before and 9.1 ± 3.9 after PTE. RESULTS: Basal RV free wall strain and time to peak strain-but not basal RV strain rate and time to peak strain rate-changed significantly after PTE. Unexpectedly, basal RV strain became less negative, from -24.3% to -18.9% after PTE (P = 0.005). Time to peak strain decreased from 356 to 287 msec after PTE (P < 0.001). Preoperatively, RV strain correlated with pulmonary vascular resistance (PVR) and mean pulmonary artery pressure (mPAP) but this relationship was not evident postoperatively. Furthermore, the change in RV strain did not correlate with the change in mPAP or PVR. CONCLUSIONS: In patients with CTEPH, RV basal strain paradoxically became less negative (i.e., relative systolic shortening decreased) following PTE. This change in RV strain could be due to intraoperative RV ischemia and/or postoperative stunning. Thus, RV basal strain cannot be used as a surrogate marker for surgical success early after PTE.

Cardiac Limited Ultrasound Examination Techniques to Augment the Bedside Cardiac Physical Examination.

The current practice of physical diagnosis is dependent on physician skills and biases, inductive reasoning, and time efficiency. Although the clinical utility of echocardiography is well known, few data exist on how to integrate 2-dimensional screening "quick-look" ultrasound applications into a novel, modernized cardiac physical examination. We discuss the evidence basis behind ultrasound "signs" pertinent to the cardiovascular system and elemental in synthesis of bedside diagnoses and propose the application of a brief cardiac limited ultrasound examination based on these signs. An ultrasound-augmented cardiac physical examination can be taught in traditional medical education and has the potential to improve bedside diagnosis and patient care.

Validation of stroke volume and cardiac output by electrical interrogation of the brachial artery in normals: assessment of strengths, limitations, and sources of error.

The goal of this study is to validate a new, continuous, noninvasive stroke volume (SV) method, known as transbrachial electrical bioimpedance velocimetry (TBEV). TBEV SV was compared to SV obtained by cardiac magnetic resonance imaging (cMRI) in normal humans devoid of clinically apparent heart disease. Thirty-two (32) volunteers were enrolled in the study. Each subject was evaluated by echocardiography to assure that no aortic or mitral valve disease was present. Subsequently, each subject underwent electrical interrogation of the brachial artery by means of a high frequency, low amplitude alternating current. A first TBEV SV estimate was obtained. Immediately after the initial TBEV study, subjects underwent cMRI, using steady-state precession imaging to obtain a volumetric estimate of SV. Following cMRI, the TBEV SV study was repeated. Comparing the cMRI-derived SV to that of TBEV, the two TBEV estimates were averaged and compared to the cMRI standard. CO was computed as the product of SV and heart rate. Statistical methods consisted of Bland-Altman and linear regression analysis. TBEV SV and CO estimates were obtained in 30 of the 32 subjects enrolled. Bland-Altman analysis of pre- and post-cMRI TBEV SV showed a mean bias of 2.87 % (2.05 mL), precision of 13.59% (11.99 mL) and 95% limits of agreement (LOA) of +29.51% (25.55 mL) and -23.77% (-21.45 mL). Regression analysis for pre- and post-cMRI TBEV SV values yielded y = 0.76x + 25.1 and r(2) = 0.71 (r = 0.84). Bland-Altman analysis comparing cMRI SV with averaged TBEV SV showed a mean bias of -1.56% (-1.53 mL), precision of 13.47% (12.84 mL), 95% LOA of +24.85% (+23.64 mL) and -27.97% (-26.7 mL) and percent error = 26.2 %. For correlation analysis, the regression equation was y = 0.82x + 19.1 and correlation coefficient r(2) = 0.61 (r = 0.78). Bland-Altman analysis of averaged pre- and post-cMRI TBEV CO versus cMRI CO yielded a mean bias of 5.01% (0.32 L min(-1)), precision of 12.85% (0.77 L min(-1)), 95% LOA of +30.20 % (+0.1.83 L min(-1)) and -20.7% (-1.19 L min(-1)) and percent error = 24.8%. Regression analysis yielded y = 0.92x + 0.78, correlation coefficient r(2) = 0.74 (r = 0.86). TBEV is a novel, noninvasive method, which provides satisfactory estimates of SV and CO in normal humans.

Assessment of left atrial volume before and after pulmonary thromboendarterectomy in chronic thromboembolic pulmonary hypertension.

BACKGROUND: Impaired left ventricular diastolic filling is common in chronic thromboembolic pulmonary hypertension (CTEPH), and recent studies support left ventricular underfilling as a cause. To investigate this further, we assessed left atrial volume index (LAVI) in patients with CTEPH before and after pulmonary thromboendarterectomy (PTE). METHODS: Forty-eight consecutive CTEPH patients had pre- & post-PTE echocardiograms and right heart catheterizations. Parameters included mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR), cardiac index, LAVI, & mitral E/A ratio. Echocardiograms were performed 6 ± 3 days pre-PTE and 10 ± 4 days post-PTE. Regression analyses compared pre- and post-PTE LAVI with other parameters. RESULTS: Pre-op LAVI (mean 19.0 ± 7 mL/m2) correlated significantly with pre-op PVR (R = -0.45, p = 0.001), mPAP (R = -0.28, p = 0.05) and cardiac index (R = 0.38, p = 0.006). Post-PTE, LAVI increased by 18% to 22.4 ± 7 mL/m2 (p = 0.003). This change correlated with change in PVR (765 to 311 dyne-s/cm5, p = 0.01), cardiac index (2.6 to 3.2 L/min/m2, p = 0.02), and E/A (.95 to 1.44, p = 0.002). CONCLUSION: In CTEPH, smaller LAVI is associated with lower cardiac output, higher mPAP, and higher PVR. LAVI increases by ~20% after PTE, and this change correlates with changes in PVR and mitral E/A. The rapid increase in LAVI supports the concept that left ventricular diastolic impairment and low E/A pre-PTE are due to left heart underfilling rather than inherent left ventricular diastolic dysfunction.

Investigating the impact of alliance-focused training on interpersonal process and therapists' capacity for experiential reflection.

OBJECTIVE: In this article we present preliminary findings from a research program designed to investigate the value of alliance-focused training (AFT), a supervision approach designed to enhance therapists' ability to work constructively with negative therapeutic process. METHOD: In the context of a multiple baseline design, all therapists began treating their patients using cognitive therapy and then joined AFT supervision groups at either session 8 or 16 of a 30 session protocol. Study I investigated the impact of AFT on patient and therapist interpersonal process as assessed through the Structural Analysis of Social Behavior (SASB). Study 2 investigated the impact of AFT on therapists' tendency to reflect on their relationships with their patients in an experientially grounded fashion, as assessed via the Experiencing Scale (EXP). Since one of the goals of AFT is to train therapists to use their own emerging feelings as important clues regarding what may be taking place in the therapeutic relationship, we hypothesized that they would show increased levels of EXP after undergoing AFT. RESULTS AND CONCLUSION: The results of both studies 1 and 2 were for the most part consistent with hypotheses. Implications and future research directions are discussed.

The medical device development ecosystem: Current regulatory state and challenges for future development: A review.

BACKGROUND/PURPOSE: There has been increasing emphasis on the development of new technology to mitigate unmet clinical needs in cardiovascular disease. This emphasis results in part from recognition that many devices, although being initially developed in the United States, were studied, and then eventually approved abroad before being returned to the U.S. for clinical application. The FDA (Food and Drug Administration) guidance document on Early Feasibility Studies (EFS) and then the 21st Century Cures Act from 2013 to 2016 focused on these issues. MATERIALS/METHODS: There are multiple components of medical device translational pathways to be considered in continuing to reach the goal of providing early access to safe and effective products to the U.S. POPULATION: This review article documents the various stages from early idea innovation to device design and iteration to clinical testing and then potential approval and application in the wide clinical practice of cardiovascular health care. RESULTS: The CDRH (Centers for Devices and Radiological Health) has focused on key components including EFS, Breakthrough Devices Program, Total Product Life Cycle, the Unique Device Identification Program, the establishment of a Digital Health Center of Excellence, and leveraging Collaborative Communities. Each of these initiatives focuses on improving the Medical Device Development Ecosystem. CONCLUSIONS: Major changes in device translational research have improved the device research climate in the United States. Goals remain including increased training and education for constituencies aspiring to work in the field of device development and regulation as part of a continuous health care learning system.