Ligand-based targeting of c-kit using engineered γδ T cells as a strategy for treating acute myeloid leukemia.

The application of immunotherapies such as chimeric antigen receptor (CAR) T therapy or bi-specific T cell engager (BiTE) therapy to manage myeloid malignancies has proven more challenging than for B-cell malignancies. This is attributed to a shortage of leukemia-specific cell-surface antigens that distinguish healthy from malignant myeloid populations, and the inability to manage myeloid depletion unlike B-cell aplasia. Therefore, the development of targeted therapeutics for myeloid malignancies, such as acute myeloid leukemia (AML), requires new approaches. Herein, we developed a ligand-based CAR and secreted bi-specific T cell engager (sBite) to target c-kit using its cognate ligand, stem cell factor (SCF). c-kit is highly expressed on AML blasts and correlates with resistance to chemotherapy and poor prognosis, making it an ideal candidate for which to develop targeted therapeutics. We utilize γδ T cells as a cytotoxic alternative to αß T cells and a transient transfection system as both a safety precaution and switch to remove alloreactive modified cells that may hinder successful transplant. Additionally, the use of γδ T cells permits its use as an allogeneic, off-the-shelf therapeutic. To this end, we show mSCF CAR- and hSCF sBite-modified γδ T cells are proficient in killing c-kit+ AML cell lines and sca-1+ murine bone marrow cells in vitro. In vivo, hSCF sBite-modified γδ T cells moderately extend survival of NSG mice engrafted with disseminated AML, but therapeutic efficacy is limited by lack of γδ T-cell homing to murine bone marrow. Together, these data demonstrate preclinical efficacy and support further investigation of SCF-based γδ T-cell therapeutics for the treatment of myeloid malignancies.

Invasive Assessment of Microvascular Resistance in Hypertrophic Cardiomyopathy With Echocardiographic Correlates.

INTRODUCTION: Hypertrophic cardiomyopathy (HCM) is often associated with ischaemia despite lack of focal epicardial coronary stenosis. Our aim was to assess invasive coronary microvascular circulation and correlate findings with echocardiography. METHODS: We prospectively enrolled patients with HCM and controls who were referred for diagnostic coronary angiography. A pressure-temperature sensor coronary guidewire was used with intracoronary injections of room-temperature saline to measure mean coronary transit time during rest and hyperaemia induced with intravenous adenosine. The index of microvascular resistance (IMR) was calculated. Left ventricular mass was calculated during echocardiographic studies. RESULTS: Patients with HCM (n=12) and controls (n=7), had similar demographics. Left ventricular ejection fraction was higher in HCM (76.7%±11.0% vs 55.0%±15.9%, p=0.003). IMR was non-significantly higher in HCM (21.7±10.2 vs 15.3±4.8, p=0.16). Only patients with HCM had abnormal IMR (>25). Coronary flow reserve was non-significantly higher in HCM (2.7±1.6 vs 2.1±1.2, p=0.34). IMR correlated with left ventricular mass in hypertrophic cardiomyopathy subjects (Pearson r=0.68, p=0.02). CONCLUSIONS: Microvascular dysfunction as assessed by IMR may be abnormal in HCM and is correlated with left ventricular mass.

Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect.

The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young, otherwise healthy, individuals. We conducted genome-wide association studies and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases) and nine left ventricular (LV) traits (19,260 UK Biobank participants with structurally normal hearts). We identified 16 loci associated with HCM, 13 with DCM and 23 with LV traits. We show strong genetic correlations between LV traits and cardiomyopathies, with opposing effects in HCM and DCM. Two-sample Mendelian randomization supports a causal association linking increased LV contractility with HCM risk. A polygenic risk score explains a significant portion of phenotypic variability in carriers of HCM-causing rare variants. Our findings thus provide evidence that polygenic risk score may account for variability in Mendelian diseases. More broadly, we provide insights into how genetic pathways may lead to distinct disorders through opposing genetic effects.

ALU transposition induces familial hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy (LVH) in the absence of predisposing cardiovascular conditions. Pathogenic variants in at least 16 cardiac sarcomeric genes have been implicated in HCM, most of which act in a dominant-negative fashion. However loss-of-function (haploinsufficiency) is the most common disease mechanism for pathogenic variants in MYBPC3, suggesting that MYBPC3 complete deletion may play a role in HCM pathogenesis. Here, we investigate MYBPC3 complete deletion as a disease mechanism in HCM by analyzing two unrelated patients with confirmed diagnosis of HCM that tested negative by Sanger sequencing analysis. METHODS: MYBPC3 complete deletion was investigated by Multiplex ligation-dependent probe amplification (MLPA) and microarray analyses. The mechanism of deletion was investigated by interrogating the SINEBase database. RESULTS: Patient-1 was diagnosed with nonobstructive HCM in his mid-40s while undergoing assessment for palpitations, and patient-2 with obstructive HCM in his late-20s while undergoing systolic heart murmur assessment for an unrelated illness. MLPA testing revealed a heterozygous deletion of all MYBPC3 exons in both patients. Subsequent microarray testing confirmed these deletions which extended beyond the 5' and 3' ends of MYBPC3. Genomic assessment suggested that these deletions resulted from Alu/Alu-homologous recombination. CONCLUSION: Our results demonstrate that haploinsufficiency resulting from MYBPC3 complete deletion, potentially mediated by Alu recombination, is an important disease mechanism in cardiomyopathy and emphasizes the importance of copy number variation analysis in patients clinically suspected of HCM.

An original method for staging sleep based on dynamical analysis of a single EEG signal.

BACKGROUND: The dynamical complexity of brain electrical activity manifested in the EEG is quantifiable using recurrence analysis (RA). Employing RA, we described and validated an originative method for automatically classifying epochs of sleep that is conceptually and instrumentally distinct from the existing method. NEW METHOD: Complexity in single overnight EEGs was characterized second-by-second using four RA variables that were each averaged over consecutive 30-sec epochs to form four-component vectors. The vectors were staged using four-component cluster analysis. Method validity and utility were established by showing: (1) inter- and intra-subject consistency of staging results (method insusceptible to nonstationarity of the EEG); (2) use of method to eliminate costly and arduous visual staging in a binary classifications task for detecting a neurogenic disorder; (3) ability of method to provide new physiological insights into brain activity during sleep. RESULTS: RA of sleep-acquired EEGs yielded four continuous measures of complexity and its change-rate that allowed automatic classification of epochs into four statistically distinct clusters ("stages"). Matched subjects with and without mental distress were accurately classified using biomarkers based on stage designations. COMPARISON WITH EXISTING METHODS: For binary-classification purposes, the method was cheaper, faster, and at least as accurate as the existing staging method. Epoch-by-epoch comparison of new versus existing methods revealed that the latter assigned epochs having widely different dynamical complexities into the same stage (dynamical incoherence). CONCLUSIONS: Sleep can be automatically staged using an originative method that is fundamentally different from the existing method.

Novel galeterone analogs act independently of AR and AR-V7 for the activation of the unfolded protein response and induction of apoptosis in the CWR22Rv1 prostate cancer cell model.

The androgen receptor (AR) has long been the primary target for the treatment of prostate cancer (PC). Despite continuous efforts to block AR activity through ligand depletion, AR antagonism, AR depletion and combinations thereof, advanced PC tumors remain resilient. Herein, we evaluate two galeterone analogs, VNPT-178 and VNLG-74A, in PC cell models of diverse androgen and AR dependence attempting to delineate their mechanisms of action and potential clinical utility. Employing basic biochemical techniques, we determined that both analogs have improved antiproliferative and anti-AR activities compared to FDA-approved abiraterone and enzalutamide. However, induction of apoptosis in these models is independent of the AR and its truncated variant, AR-V7, and instead likely results from sustained endoplasmic reticulum stress and deregulated calcium homeostasis. Using in silico molecular docking, we predict VNPT-178 and VNLG-74A bind the ATPase domain of BiP/Grp78 and Hsp70-1A with greater affinity than the AR. Disruption of 70 kDa heat shock protein function may be the underlying mechanism of action for these galeterone analogs. Therefore, despite simultaneously antagonizing AR activity, AR and/or AR-V7 expression alone may inadequately predict a patient's response to treatment with VNPT-178 or VNLG-74A. Future studies evaluating the context-specific limitations of these compounds may provide clarity for their clinical application.

Contribution of mitral valve leaflet length and septal wall thickness to outflow tract obstruction in patients with hypertrophic cardiomyopathy.

We sought to examine whether elongation of the mitral valve leaflets in patients with hypertrophic cardiomyopathy (HCM) is synergistic to septal wall thickness (SWT) in the development of left ventricular outflow tract obstruction (LVOTO). HCM is a common genetic cardiac disease characterized by asymmetric septal hypertrophy and predisposition towards LVOTO. It has been reported that elongation of the mitral valve leaflets may be a primary phenotypic feature and contribute to LVOTO. However, the relative contribution of this finding versus SWT has not been studied. 152 patients (76 with HCM and 76 non-diseased age, race and BSA-matched controls) and 18 young, healthy volunteers were studied. SWT and the anterior mitral valve leaflet length (AMVLL) were measured using cine MRI. The combined contribution of these variables (SWT × AMVLL) was described as the Septal Anterior Leaflet Product (SALP). Peak LVOT pressure gradient was determined by Doppler interrogation and defined as "obstructive" if ≥ 30 mmHg. Patients with HCM were confirmed to have increased AMVLL compared with controls and volunteers (p < 0.01). Among HCM patients, both SWT and SALP were significantly higher in patients with LVOTO (N = 17) versus without. SALP showed modest improvement in predictive accuracy for LVOTO (AUC = 0.81) among the HCM population versus SWT alone (AUC = 0.77). However, in isolated patients this variable identified patients with LVOTO despite modest SWT. Elongation of the AMVLL is a primary phenotypic feature of HCM. While incremental contributions to LVOTO appear modest at a population level, specific patients may have dominant contribution to LVOTO. The combined marker of SALP allows for maintained identification of such patients despite modest increases in SWT.

Ventricular pacing site separation by cardiac computed tomography: validation for the prediction of clinical response to cardiac resynchronization therapy.

Cardiac Resynchronization Therapy (CRT) fails to provide benefit in up to one-third of patients. Maximizing the geographic separation of right and left ventricular pacing lead sites has been suggested as one way to improve response. Cardiac CT provides an opportunity to explore 3-dimensional inter-lead distance (ILD) measures for the prediction of CRT response. The objective of this study was to investigate associations between standardized measures of ILD by cardiac CT and echocardiographic response to CRT. Forty-two consecutive patients undergoing CRT had serial clinical and echocardiographic evaluations performed in addition to a post-procedural cardiac-gated CT with blinded measurement of direct and circumferential (via the myocardium) ILD measures. Clinical response to CRT, the primary clinical outcome, was defined as a ≥15% reduction in LVESV using echocardiography at 6-months. The mean age and ejection fraction was 63.6 ± 8.9 years and 25.2 ± 7.8%, respectively. The primary outcome occurred in 35 of 42 patients (83%). Both direct and circumferential CT-based ILD measures were associated with the primary outcome by univariate analysis. Receiver Operator Characteristic analysis identified Circumferential ILD to have the strongest predictive accuracy (AUC 0.78). Inter- and intra-observer reproducibility of CT-derived ILD measures was excellent. Circumferential ILD measures on cardiac CT are predictive of clinical response to CRT. Incorporation of these measures into the selection of optimal pacing targets, particularly from pre-procedural CT coronary vein imaging may be of therapeutic benefit and warrants further investigation.

Should learners reason one step at a time? A randomised trial of two diagnostic scheme designs.

CONTEXT: Making a diagnosis can be difficult for learners as they must integrate multiple clinical variables. Diagnostic schemes can help learners with this complex task. A diagnostic scheme is an algorithm that organises possible diagnoses by assigning signs or symptoms (e.g. systolic murmur) to groups of similar diagnoses (e.g. aortic stenosis and aortic sclerosis) and provides distinguishing features to help discriminate between similar diagnoses (e.g. carotid pulse). The current literature does not identify whether scheme layouts should guide learners to reason one step at a time in a terminally branching scheme or weigh multiple variables simultaneously in a hybrid scheme. We compared diagnostic accuracy, perceptual errors and cognitive load using two scheme layouts for cardiac auscultation. METHODS: Focused on the task of identifying murmurs on Harvey, a cardiopulmonary simulator, 86 internal medicine residents used two scheme layouts. The terminally branching scheme organised the information into single variable decisions. The hybrid scheme combined single variable decisions with a chart integrating multiple distinguishing features. Using a crossover design, participants completed one set of murmurs (diastolic or systolic) with either the terminally branching or the hybrid scheme. The second set of murmurs was completed with the other scheme. A repeated measures manova was performed to compare diagnostic accuracy, perceptual errors and cognitive load between the scheme layouts. RESULTS: There was a main effect of the scheme layout (Wilks' λ = 0.841, F3,80 = 5.1, p = 0.003). Use of a terminally branching scheme was associated with increased diagnostic accuracy (65 versus 53%, p = 0.02), fewer perceptual errors (0.61 versus 0.98 errors, p = 0.001) and lower cognitive load (3.1 versus 3.5/7, p = 0.023). CONCLUSIONS: The terminally branching scheme was associated with improved diagnostic accuracy, fewer perceptual errors and lower cognitive load, suggesting that terminally branching schemes are effective for improving diagnostic accuracy. These findings can inform the design of schemes and other clinical decision aids.

Fungal mobile mass on echocardiogram: native mitral valve Aspergillus fumigatus endocarditis.

The most common type of infective endocarditis is bacterial endocarditis. However, fungal infections have been seen more frequently, mostly in the immunocompromised population. We report a case of invasive Aspergillus fumigatus native mitral valve endocarditis. The patient received appropriate empiric antifungal treatment with a combination of liposomal amphotericin B and flucytosine, associated with surgical debridement, valve replacement and chordae tendineae repair. Despite receiving the standard treatment of Aspergillus endocarditis, and susceptibility of the microorganism to the antifungal regimen, the patient, unexpectedly, developed early-onset septic emboli. It is surprising to see that the patient had developed such complications early, despite attempts to eliminate the source of infection with surgical intervention.

Bioengineering and serum free expansion of blood-derived γδ T cells.

BACKGROUND AIMS: Cellular immunotherapy relies on several highly variable patient-specific parameters, such as (i) cell number before and after expansion, (ii) targeting of cells to tumors, (iii) cell survival and function after infusion, and (iv) on- and off-target adverse events. Cellular approaches such as the specific expansion of γδ T cells as opposed to αß T cells are being pursued. γδ T cells are reasonable candidates for immunotherapy because they (i) possess intrinsic anti-tumorigenicity, (ii) require no priming, (iii) direct tumor killing via recognition of stress-responsive ligands, and (iv), as we now show, can be expanded to clinical cell doses in current Good Manufacturing Practice serum-free media (SFM). METHODS: γδ T-cell expansion was evaluated in several SFMs. Additionally, the expanded γδ T cells were evaluated for their transduction efficiency using lentiviral vectors (LV). RESULTS: Of the SFM cultures, robust expansion was only observed in OpTmizer supplemented with high-dose interleukin-2. γδ T-cell percentages and numbers were sufficient for clinical use. Using cells from several donors, transduction efficiencies ranged from 13 to 33%, which is similar to transduction levels observed using αß T cells with similar multiplicity of infection. DISCUSSION: An optimized method of γδT-cell expansion and transduction was developed that can be tested in early-phase clinical trials. With appropriate elimination of the αßT cell-component, the absence of MHC-restriction affords the opportunity for use in the allogeneic setting with limited risk of graft versus host disease. Finally, the use of SFM provides clinically safer, widely applicable and potentially more efficacious cellular immunotherapy.

Effect of growth hormone treatment on diastolic function in patients who have developed growth hormone deficiency after definitive treatment of acromegaly.

OBJECTIVE: Although growth hormone (GH) replacement is prescribed for patients with hypopituitarism due to many etiologies, it is not routinely prescribed for patients with GH deficiency (GHD) after cure of acromegaly (acroGHD). This study was designed to investigate the effect of GH replacement on cardiac parameters in acroGHD. DESIGN: We prospectively evaluated for 12months 23 patients with acroGHD: 15 subjects on GH replacement and eight subjects not on GH replacement. Main outcome measures included LV mass corrected for body surface area (LVM/BSA) and measures of diastolic dysfunction (E/A ratio and deceleration time), as assessed by echocardiography. RESULTS: After 12months of follow-up, there were no differences between the GH-treated group and the untreated group in LVM/BSA (GH: 74.4±22.5g/m(2) vs untreated: 72.9±21.3g/m(2), p=0.89), E/A ratio (GH: 1.21±0.39 vs untreated: 1.08±0.39, p=0.50) or deceleration time (GH: 224.5±60.1ms vs untreated: 260±79.8ms, p=0.32). The overall degree of diastolic function was similar between the groups with 42.9% of untreated subjects and 50% of GH-treated subjects (p=0.76) classified as having normal diastolic function at follow-up. CONCLUSIONS: There were no significant differences in LVM/BSA or parameters of diastolic function in patients with a history of acromegaly treated for GHD as compared to those who were untreated. These data are reassuring with respect to cardiovascular safety with GH use after treatment for acromegaly, although further longer term study is necessary to evaluate the safety and efficacy of GH treatment in this population.

The Fingerprint of Rapid Eye Movement: Its Algorithmic Detection in the Sleep Electroencephalogram Using a Single Derivation.

The strong associations of rapid eye movement (REM) sleep with dreaming and memory consolidation imply the existence of REM-specific brain electrical activity, notwithstanding the visual similarity of the electroencephalograms (EEGs) in REM and wake states. Our goal was to detect REM sleep by means of algorithmic analysis of the EEG. We postulated that novel depth and fragmentation variables, defined in relation to temporal changes in the signal (recurrences), could be statistically combined to allow disambiguation of REM epochs. The cohorts studied were consecutive patients with obstructive sleep apnea (OSA) recruited from a sleep medicine clinic, and clinically normal participants selected randomly from a national database (N = 20 in each cohort). Individual discriminant analyses were performed, for each subject based on 4 recurrence biomarkers, and used to classify every 30-second epoch in the subject's overnight polysomnogram as REM or NotREM (wake or any non-REM sleep stage), using standard clinical staging as ground truth. The primary outcome variable was the accuracy of algorithmic REM classification. Average accuracies of 90% and 87% (initial and cross-validation analyses) were achieved in the OSA cohort; corresponding results in the normal cohort were 87% and 85%. Analysis of brain recurrence allowed identification of REM sleep, disambiguated from wake and all other stages, using only a single EEG lead, in subjects with or without OSA.

A pilot study: portable out-of-center sleep testing as an early sleep apnea screening tool in acute ischemic stroke.

INTRODUCTION: Prompt diagnosis of obstructive sleep apnea (OSA) after acute ischemic stroke (AIS) is critical for optimal clinical outcomes, but in-laboratory conventional polysomnograms (PSG) are not routinely practical. Though portable out-of-center type III cardiopulmonary sleep studies (out-of-center cardiopulmonary sleep testing [OCST]) are widely available, these studies have not been validated in patients who have recently suffered from AIS. We hypothesized that OCST in patients with AIS would yield similar results when compared to conventional PSG. METHODS: Patients with AIS had simultaneous type III OCST and PSG studies performed within 72 hours from symptom onset. The accuracy of OCST was compared to PSG using: chi-square tests, receiver operatory characteristic curves, Bland-Altman plot, paired Student's t-test/Wilcoxon signed-rank test, and calculation of sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: Twenty-one out of 23 subjects with AIS (age 61±9.4 years; 52% male; 58% African-American) successfully completed both studies (9% technical failure). Nearly all (95%) had Mallampati IV posterior oropharynx; the mean neck circumference was 16.8±1.6 in. and the mean body mass index (BMI) was 30±7 kg/m(2). The apnea hypopnea index (AHI) provided by OCST was similar to that provided by PSG (19.8±18.0 vs 22.0±22.7, respectively; P=0.49). On identifying subjects by OCST with an AHI ≥5 on PSG, OCST had the following parameters: sensitivity 100%, specificity 85.7%, PPV 93%, and NPV 100%. On identifying subjects with an AHI ≥15 on PSG, OCST parameters were as follows: sensitivity 100%, specificity 83.3%, PPV 81.8%, and NPV 100%. Bland-Altman plotting showed an overall diagnostic agreement between OCST and PSG modalities for an AHI cutoff >5, despite fine-grained differences in estimated AHIs. CONCLUSION: Compared with PSG, OCST provides similar diagnostic information when run simultaneously in AIS patients. OCST is a reliable screening tool for early diagnosis of OSA in AIS patients.

One-year outcome of the sevoflurane in acute myocardial infarction randomized trial.

BACKGROUND: Sevoflurane is an inhalation anesthetic that has cardioprotective effects. There is limited information regarding its use outside of the operating room and its potential protective effect for patients presenting with myocardial infarction. METHODS: In the Sevoflurane In Acute Myocardial Infarction trial, patients with a first acute ST-elevation myocardial infarction (STEMI) who were treated by primary percutaneous coronary intervention were randomized to inhalation of sevoflurane or oxygen (control). From the time of the patient's arrival for cardiac catheterization, the anesthesia team administered sevoflurane or oxygen for 30 min using a tight-fitting mask. In this substudy, we report the one-year outcomes. Patients were followed clinically for one year; they underwent a thallium cardiac viability study at six months and an echocardiogram at one year. RESULTS: Forty-six patients completed follow-up. One patient in the sevoflurane group died. The mean [standard deviation (SD)] ejection fraction by single-photon emission computed tomography at six months was 51.7 (7.7)% in the sevoflurane group and 51 (9.1)% in the control group (mean difference, 0.7%; 95% confidence interval [CI], -5.9 to 7.3; P = 0.831). The median [interquartile range] amount of scarring at six months was 0% [0 - 8] in the sevoflurane group and 2.5% [0 - 7.1] in control group (mean difference, -0.1%; 95% CI, -4.6 to 4.4; P = 0.700). The mean (SD) percentage of hibernating myocardium was similar in both groups 0% [0, 5] (mean difference, -1.3%; 95% CI, -3.4 to 0.9; P = 0.259). The mean (SD) ejection fraction at one year increased compared with baseline by 8.0 (9.1)% (P < 0.001). CONCLUSIONS: In this study, we did not find an effect of sevoflurane on left ventricular function or myocardial injury at one year post STEMI. This trial was registered at www.clinicaltrials.gov ; identifier: NCT00971607.

Recurrence analysis of the EEG during sleep accurately identifies subjects with mental health symptoms.

Analysis of brain recurrence (ABR) is a novel computational method that uses two variables for sleep depth and two for sleep fragmentation to quantify temporal changes in non-random brain electrical activity. We postulated that ABR of the sleep-staged EEG could identify an EEG signature specific for the presence of mental health symptoms. Using the Mental Health Inventory Questionnaire (MHI-5) as ground truth, psychological distress was assessed in a study cohort obtained from the Sleep Heart Health Study. Subjects with MHI-5 <50 (N=34) were matched for sex, BMI, age, and race with 34 subjects who had MHI-5 scores >50. Sixteen ABR markers derived from the EEG were analyzed using linear discriminant analysis to identify marker combinations that reliably classified individual subjects. A biomarker function computed from 12 of the markers accurately classified the subjects based on their MHI-5 scores (AUROC=82%). Use of additional markers did not improve classification accuracy. Subgroup analysis (20 highest and 20 lowest MHI-5 scores) improved classification accuracy (AUROC=89%). Biomarker values for individual subjects were significantly correlated with MHI-5 score (r=0.36, 0.54 for N=68, 40, respectively). ABR of EEGs obtained during sleep successfully classified subjects with regard to the severity of mental health symptoms, indicating that mood systems were reflected in brain electrical activity.

Model-based navigation of left and right ventricular leads to optimal targets for cardiac resynchronization therapy: a single-center feasibility study.

BACKGROUND: Left ventricular (LV) and right ventricular pacing site characteristics have been shown to influence response to cardiac resynchronization therapy (CRT). This study aimed to determine the clinical feasibility of image-guided lead delivery using a 3-dimensional navigational model displaying both LV and right ventricular (RV) pacing targets. Serial echocardiographic measures of clinical response and procedural metrics were evaluated. METHODS AND RESULTS: Thirty-one consecutive patients underwent preimplant cardiac MRI with the generation of a 3-dimensional navigational model depicting optimal segmental targets for LV and RV leads. Lead delivery was guided by the model in matched views to intraprocedural fluoroscopy. Blinded assessment of final lead tip location was performed from postprocedural cardiac computed tomography. Clinical and LV remodeling response criteria were assessed at baseline, 3 months, and 6 months using a 6-minute hall walk, quality of life questionnaire, and echocardiography. Mean age and LV ejection fraction was 66 ± 8 years and 26 ± 8%, respectively. LV leads were successfully delivered to a target or adjacent segment in 30 of 31 patients (97%), 68% being nonposterolateral. RV leads were delivered to a target or adjacent segment in 30 of 31 patients (97%), 26% being nonapical. Twenty-three patients (74%) met standard criteria for response (LV end-systolic volume reduction ≥ 15%), 18 patients (58%) for super-response (LV end-systolic volume reduction ≥ 30%). LV ejection fraction improved at 6 months (31 ± 8 versus 26 ± 8%, P=0.04). CONCLUSIONS: This study demonstrates clinical feasibility of dual cardiac resynchronization therapy lead delivery to optimal targets using a 3-dimensional navigational model. High procedural success, acceptable procedural times, and a low rate of early procedural complications were observed. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01640769.

Nocturnal hypoxemia biomarker predicts sleepiness in patients with severe obstructive sleep apnea.

PURPOSE: This study aims to assess the association between excessive daytime sleepiness (EDS) and variables extracted from the pulse-oximetry signal obtained during overnight polysomnography. METHODS: A cross-sectional design was used to study the relation between four hypoxemia variables and EDS as determined by Epworth Sleepiness Scale scores (ESSS) in 200 consecutive patients, newly diagnosed with obstructive sleep apnea (OSA), as defined by an apnea-hypopnea index (AHI)≥ 15. Hypoxemia measurements were compared between sleepy (ESSS ≥ 10) and nonsleepy (ESSS<10) patients before and after dichotomizing the cohort for each hypoxemia variable (and for AHI) such that there were 35 (165) patients in each of the corresponding higher (lower) subcohorts. The hypoxemia variables were combined into a biomarker, and its accuracy for predicting sleepiness in individual patients was evaluated. We planned to interpret prediction accuracy above 80 % as evidence that hypoxemia predicted EDS. RESULTS: Hypoxemia was unassociated with sleepiness in OSA patients with AHI in the range of 15 to 50. In patients with AHI>50, the hypoxemia biomarker (but not individual hypoxemia variables) predicted sleepiness with 82 % accuracy. CONCLUSION: Nocturnal hypoxemia as determined by a polyvariable biomarker reliably predicted EDS in patients with severe OSA (AHI>50), indicating that oxygen fluctuation had a direct role in the development of EDS in patients with severe OSA.