Technology and Tool Development for BACPAC: Qualitative and Quantitative Analysis of Accelerated Lumbar Spine MRI with Deep-Learning Based Image Reconstruction at 3T.

OBJECTIVES: To evaluate whether combining fast acquisitions with deep-learning reconstruction can provide diagnostically useful images and quantitative assessment comparable to standard-of-care acquisitions for lumbar spine magnetic resonance imaging (MRI). METHODS: Eighteen patients were imaged with both standard protocol and fast protocol using reduced signal averages, each protocol including sagittal fat-suppressed T2-weighted, sagittal T1-weighted, and axial T2-weighted 2D fast spin-echo sequences. Fast-acquisition data was additionally reconstructed using vendor-supplied deep-learning reconstruction with three different noise reduction factors. For qualitative analysis, standard images as well as fast images with and without deep-learning reconstruction were graded by three radiologists on five different categories. For quantitative analysis, convolutional neural networks were applied to sagittal T1-weighted images to segment intervertebral discs and vertebral bodies, and disc heights and vertebral body volumes were derived. RESULTS: Based on noninferiority testing on qualitative scores, fast images without deep-learning reconstruction were inferior to standard images for most categories. However, deep-learning reconstruction improved the average scores, and noninferiority was observed over 24 out of 45 comparisons (all with sagittal T2-weighted images while 4/5 comparisons with sagittal T1-weighted and axial T2-weighted images). Interobserver variability increased with 50 and 75% noise reduction factors. Deep-learning reconstructed fast images with 50% and 75% noise reduction factors had comparable disc heights and vertebral body volumes to standard images (r2≥ 0.86 for disc heights and r2≥ 0.98 for vertebral body volumes). CONCLUSIONS: This study demonstrated that deep-learning-reconstructed fast-acquisition images have the potential to provide noninferior image quality and comparable quantitative assessment to standard clinical images.

APOE Genotype Modifies the Association of Fusiform Gyrus Cerebral Metabolic Rate of Oxygen Consumption and Object Naming Performance.

BACKGROUND: The apolipoprotein E (APOE) ɛ4 allele confers risk for age and Alzheimer's disease related cognitive decline but the mechanistic link remains poorly understood. Blood oxygenation level dependent (BOLD) response in the fusiform gyrus (FG) during object naming appears greater among APOEɛ4 carriers even in the face of equivalent cognitive performance, suggesting neural compensation. However, BOLD is susceptible to known age and APOE-related vascular changes that could confound its interpretation. OBJECTIVE: To address this limitation, we used calibrated fMRI during an object naming task and a hypercapnic challenge to obtain a more direct measure of neural function - percent change cerebral metabolic rate of oxygen consumption (%ΔCMRO2). METHODS: Participants were 45 older adults without dementia (28 ɛ4-, 17 ɛ4+) between the ages of 65 and 85. We examined APOE-related differences in %ΔCMRO2 in the FG during object naming and the extent to which APOE modified associations between FG %ΔCMRO2 and object naming accuracy. Exploratory analyses also tested the hypothesis that %ΔCMRO2 is less susceptible to vascular compromise than are measures of %ΔCBF and %ΔBOLD. RESULTS: We observed a modifying role of APOE on associations between FG %ΔCMRO2 and cognition, with ɛ4 carriers (but not non-carriers) demonstrating a positive association between right FG %ΔCMRO2 and object naming accuracy. CONCLUSION: Results suggest that the relationship between neural function and cognition is altered among older adult APOEɛ4 carriers prior to the onset of dementia, implicating CMRO2 response as a potential mechanism to support cognition in APOE-related AD risk.

Cerebrovascular reactivity measurements using simultaneous 15O-water PET and ASL MRI: Impacts of arterial transit time, labeling efficiency, and hematocrit.

Cerebrovascular reactivity (CVR) reflects the capacity of the brain to meet changing physiological demands and can predict the risk of cerebrovascular diseases. CVR can be obtained by measuring the change in cerebral blood flow (CBF) during a brain stress test where CBF is altered by a vasodilator such as acetazolamide. Although the gold standard to quantify CBF is PET imaging, the procedure is invasive and inaccessible to most patients. Arterial spin labeling (ASL) is a non-invasive and quantitative MRI method to measure CBF, and a consensus guideline has been published for the clinical application of ASL. Despite single post labeling delay (PLD) pseudo-continuous ASL (PCASL) being the recommended ASL technique for CBF quantification, it is sensitive to variations to the arterial transit time (ATT) and labeling efficiency induced by the vasodilator in CVR studies. Multi-PLD ASL controls for the changes in ATT, and velocity selective ASL is in theory insensitive to both ATT and labeling efficiency. Here we investigate CVR using simultaneous 15O-water PET and ASL MRI data from 19 healthy subjects. CVR and CBF measured by the ASL techniques were compared using PET as the reference technique. The impacts of blood T1 and labeling efficiency on ASL were assessed using individual measurements of hematocrit and flow velocity data of the carotid and vertebral arteries measured using phase-contrast MRI. We found that multi-PLD PCASL is the ASL technique most consistent with PET for CVR quantification (group mean CVR of the whole brain = 42±19% and 40±18% respectively). Single-PLD ASL underestimated the CVR of the whole brain significantly by 15±10% compared with PET (p<0.01, paired t-test). Changes in ATT pre- and post-acetazolamide was the principal factor affecting ASL-based CVR quantification. Variations in labeling efficiency and blood T1 had negligible effects.

The Cerebral Blood Flow Biomedical Informatics Research Network (CBFBIRN) data repository.

Arterial spin labeling (ASL) MRI provides an accurate and reliable measure of cerebral blood flow (CBF). A rapidly growing number of CBF measures are being collected both in clinical and research settings around the world, resulting in a large volume of data across a wide spectrum of study populations and health conditions. Here, we describe a central CBF data repository with integrated processing workflows, referred to as the Cerebral Blood Flow Biomedical Informatics Research Network (CBFBIRN). The CBFBIRN provides an integrated framework for the analysis and comparison of CBF measures across studies and sites. In this work, we introduce the main capabilities of the CBFBIRN (data storage, processing, and sharing), describe what types of data are available, explain how users can contribute to the data repository and access existing data from it, and discuss our long-term plans for the CBFBIRN.

Increased cerebral blood flow associated with better response inhibition in bipolar disorder.

Impairment on inhibitory tasks has been well documented in bipolar disorder (BD). Differences in cerebral blood flow (CBF) between BD patients and healthy comparison (HC) participants have also been reported. Few studies have examined the relationship between cognitive performance and regional CBF in this patient population. We hypothesized that group differences on an inhibitory task (the Delis-Kaplan Executive Function Scale's Color-Word Inhibition task) would be associated with differential CBF in bilateral anterior cingulate cortex (ACC), inferior parietal lobule (IPL) and dorsolateral prefrontal cortex (DLPFC) regions. Whole brain resting CBF was measured using Multiphase Pseudocontinuous Arterial Spin Labeling MR imaging for 28 euthymic BD and 36 HC participants. Total gray matter (GM) CBF was measured, and regional CBF values were extracted for each region of interest (ROI) using Freesurfer-based individual parcellations. Group, CBF, and group-by-CBF interaction were examined as predictors of inhibition performance. Groups did not differ in age, gender or education. BD patients performed significantly worse on Color-Word inhibition. There were no significant group differences in CBF in either total GM or in any ROI. There was a group by CBF interaction in the bilateral ACC, right IPL and right DLPFC such that better inhibitory performance was generally associated with higher resting state CBF in BD subjects, but not HC participants. Although CBF was not abnormal in this euthymic BD sample, results confirm previous reports of inter-episode inhibitory deficits and indicate that the perfusion-cognition relationship is different in BD compared to HC individuals.

Elevated cerebrovascular resistance index is associated with cognitive dysfunction in the very-old.

INTRODUCTION: Age-related vascular changes, including blood pressure elevation and cerebral blood flow (CBF) reduction, are associated with cognitive decline and Alzheimer's disease (AD). Evidence suggests that the relationship between blood pressure and dementia risk varies between younger and older samples within the elderly population. METHODS: We examined the relationship between mean arterial pressure (MAP), CBF, and cognition in young-old (60 to 75 years of age) versus very-old (80+ years of age) adults. Fifty-eight non-demented older adults completed an arterial spin labeling MRI scan, and an index of cerebrovascular resistance (CVRi) was estimated for each participant by calculating the ratio of MAP and CBF. RESULTS: Results demonstrated a similar negative relationship between MAP and CBF across both age groups. However, very-old participants exhibited elevated CVRi and reduced CBF compared to young-old participants in regions implicated in AD and cerebral small vessel disease. Furthermore, significant age by CVRi interactions revealed that elevated CVRi in the thalamus was inversely related to verbal fluency performance in the very-old group. CONCLUSIONS: Findings support CVRi as a potential vascular biomarker and suggest that regionally-specific vascular changes may contribute to cognitive decline, particularly in the very-old.

The Cerebral Blood Flow Biomedical Informatics Research Network (CBFBIRN) database and analysis pipeline for arterial spin labeling MRI data.

Arterial spin labeling (ASL) is a magnetic resonance imaging technique that provides a non-invasive and quantitative measure of cerebral blood flow (CBF). After more than a decade of active research, ASL is now emerging as a robust and reliable CBF measurement technique with increased availability and ease of use. There is a growing number of research and clinical sites using ASL for neuroscience research and clinical care. In this paper, we present an online CBF Database and Analysis Pipeline, collectively called the Cerebral Blood Flow Biomedical Informatics Research Network (CBFBIRN) that allows researchers to upload and share ASL and clinical data. In addition to serving the role as a central data repository, the CBFBIRN provides a streamlined data processing infrastructure for CBF quantification and group analysis, which has the potential to accelerate the discovery of new scientific and clinical knowledge. All capabilities and features built into the CBFBIRN are accessed online using a web browser through a secure login. In this work, we begin with a general description of the CBFBIRN system data model and its architecture, then devote the remainder of the paper to the CBFBIRN capabilities. The latter part of our work is divided into two processing modules: (1) Data Upload and CBF Quantification Module; (2) Group Analysis Module that supports three types of analysis commonly used in neuroscience research. To date, the CBFBIRN hosts CBF maps and associated clinical data from more than 1,300 individual subjects. The data have been contributed by more than 20 different research studies, investigating the effect of various conditions on CBF including Alzheimer's, schizophrenia, bipolar disorder, depression, traumatic brain injury, HIV, caffeine usage, and methamphetamine abuse. Several example results, generated by the CBFBIRN processing modules, are presented. We conclude with the lessons learned during implementation and deployment of the CBFBIRN and our experience in promoting data sharing.

Altered cerebral perfusion in executive, affective, and motor networks during adolescent depression.

OBJECTIVE: Although substantial literature has reported regional cerebral blood flow (rCBF) abnormalities in adults with depression, these studies commonly necessitated the injection of radioisotopes into subjects. The recent development of arterial spin labeling (ASL), however, allows noninvasive measurements of rCBF. Currently, no published ASL studies have examined cerebral perfusion in adolescents with depression. Thus, the aim of the present study was to examine baseline cerebral perfusion in adolescent depression using a newly developed ASL technique: pseudocontinuous arterial spin labeling (PCASL). METHOD: A total of 25 medication-naive adolescents (13-17 years of age) diagnosed with major depressive disorder (MDD) and 26 well-matched control subjects underwent functional magnetic resonance imaging. Baseline rCBF was measured via a novel PCASL method that optimizes tagging efficiency. RESULTS: Voxel-based whole brain analyses revealed significant frontal, limbic, paralimbic, and cingulate hypoperfusion in the group with depression (p < .05, corrected). Hyperperfusion was also observed within the subcallosal cingulate, putamen, and fusiform gyrus (p < .05, corrected). Similarly, region-of-interest analyses revealed amygdalar and insular hypoperfusion in the group with depression, as well as hyperperfusion in the putamen and superior insula (p < .05, corrected). CONCLUSIONS: Adolescents with depression and healthy adolescents appear to differ on rCBF in executive, affective, and motor networks. Dysfunction in these regions may contribute to the cognitive, emotional, and psychomotor symptoms commonly present in adolescent depression. These findings point to possible biomarkers for adolescent depression that could inform early interventions and treatments, and establishes a methodology for using PCASL to noninvasively measure rCBF in clinical and healthy adolescent populations.

Interaction of age and APOE genotype on cerebral blood flow at rest.

We investigated the impact of APOE genotype on cerebral blood flow (CBF) in older and younger adults. Forty cognitively normal older adults (16 ε4 carriers, 24 non-ε4 carriers) and 30 younger adults (15 ε4 carriers, 15 non-ε4 carriers) completed a resting-state whole-brain pulsed arterial spin labeling magnetic resonance scan. Main effects of aging were demonstrated wherein older adults had decreased gray matter CBF corrected for partial volume effects compared to younger adults in widespread brain regions. Main effects of APOE genotype were also observed wherein ε4 carriers displayed greater CBF in the left lingual gyrus and precuneus than non-carriers. An interaction between age and APOE genotype in the left anterior cingulate cortex (ACC) was characterized by reduced CBF in older ε4 carriers and increased CBF in young ε4 carriers. Increased CBF in the left ACC resulting from the interaction of age group and APOE genotype was positively correlated with executive functioning in young ε4 adults (r = 0.61, p = 0.04). Results demonstrate APOE genotype differentially impacts cerebrovascular function across the lifespan and may modify the relationship between CBF and cognition. Findings may partially support suggestions that the gene exerts antagonistic pleiotropic effects.

Sustained high-altitude hypoxia increases cerebral oxygen metabolism.

Acute mountain sickness (AMS) is a common condition occurring within hours of rapid exposure to high altitude. Despite its frequent occurrence, the pathophysiological mechanisms that underlie the condition remain poorly understood. We investigated the role of cerebral oxygen metabolism (CMR(O(2))) in AMS. The purpose of this study was to test 1) if CMR(O(2)) changes in response to hypoxia, and 2) if there is a difference in how individuals adapt to oxygen metabolic changes that may determine who develops AMS and who does not. Twenty-six normal human subjects were recruited into two groups based on Lake Louise AMS score (LLS): those with no AMS (LLS ≤ 2), and those with unambiguous AMS (LLS ≥ 5). [Subjects with intermediate scores (LLS 3-4) were not included.] CMR(O(2)) was calculated from cerebral blood flow and arterial-venous difference in O(2) content. Cerebral blood flow was measured using arterial spin labeling MRI; venous O(2) saturation was calculated from the MRI of transverse relaxation in the superior sagittal sinus. Arterial O(2) saturation was measured via pulse oximeter. Measurements were made during normoxia and after 2-day high-altitude exposure at 3,800 m. In all subjects, CMR(O(2)) increased with sustained high-altitude hypoxia [1.54 (0.37) to 1.82 (0.49) µmol·g(-1)·min(-1), n = 26, P = 0.045]. There was no significant difference in CMR(O(2)) between AMS and no-AMS groups. End-tidal Pco(2) was significantly reduced during hypoxia. Low arterial Pco(2) is known to increase neural excitability, and we hypothesize that the low arterial Pco(2) resulting from ventilatory acclimatization causes the observed increase in CMR(O(2)).

Effect of mild cognitive impairment and APOE genotype on resting cerebral blood flow and its association with cognition.

Using whole-brain pulsed arterial spin labeling magnetic resonance imaging, resting cerebral blood flow (CBF) was measured in 20 mild cognitive impairment (MCI; 11 ɛ3 and 9 ɛ4) and 40 demographically matched cognitively normal (CN; 27 ɛ3 and 13 ɛ4) participants. An interaction of apolipoprotein (APOE) genotype (ɛ3 and ɛ4) and cognitive status (CN and MCI) on quantified gray-matter CBF corrected for partial volume effects was found in the left parahippocampal and fusiform gyri (PHG/FG), right middle frontal gyrus, and left medial frontal gyrus. In the PHG/FG, CBF was elevated for CN ɛ4 carriers but decreased for MCI ɛ4 carriers. The opposite pattern was seen in frontal regions: CBF was decreased for CN ɛ4 carriers but increased for MCI ɛ4 carriers. Cerebral blood flow in the PHG/FG was positively correlated with verbal memory for CN ɛ4 adults (r=0.67, P=0.01). Cerebral blood flow in the left medial frontal gyrus was positively correlated with verbal memory for MCI ɛ4 adults (r=0.70, P=0.05). Findings support dynamic pathophysiologic processes in the brain associated with Alzheimer's disease risk and indicate that cognitive status and APOE genotype have interactive effects on CBF. Correlations between CBF and verbal memory suggest a differential neurovascular compensatory response in posterior and anterior cortices with cognitive decline in ɛ4 adults.

Computer-controlled, MR-compatible foot-pedal device to study dynamics of the muscle tendon complex under isometric, concentric, and eccentric contractions.

PURPOSE: To design a computer-controlled, magnetic resonance (MR)-compatible foot pedal device that allows in vivo mapping of changes in morphology and in strain of different musculoskeletal components of the lower leg under passive, isometric, concentric, and eccentric contractions. MATERIALS AND METHODS: A programmable servomotor in the control room pumped hydraulic fluid to rotate a foot-pedal inside the magnet. To validate the performance of the device, six subjects were imaged with gated velocity-encoded phase-contrast (VE-PC) imaging to investigate the dynamics of muscle and aponeurotic structures. RESULTS: Artifact-free VE-PC imaging clearly delineated different muscle compartments by differences in distribution of mechanical strains. High repeatability of contraction cycles allowed establishing that fascicles lengthened 6.1% more during passive compared with eccentric contractions. Aponeurosis separation during passive (range between three locations: -2.6≈1.3 mm) and active (range: -2.4≈1.6 mm) contractions were similar but significantly different from concentric (range: -0.9≈3.3 mm), with proximal and distal regions showing mostly negative values for the first two modes, but positive for the last. CONCLUSION: The device was sufficiently robust and artifact-free to accurately assess, using VE-PC imaging, physiologically important structure and dynamics of the musculotendon complex.

Pseudocontinuous arterial spin labeling with optimized tagging efficiency.

The adiabatic inversion of blood in pseudocontinuous arterial spin labeling (PCASL) is highly sensitive to off-resonance effects and gradient imperfections and this sensitivity can lead to tagging efficiency loss and unpredictable variations in cerebral blood flow estimates. This efficiency loss is caused by a phase tracking error between the RF pulses and the flowing spins. This article introduces a new method, referred to as Optimized PCASL (OptPCASL), that minimizes the phase tracking error by applying an additional compensation RF phase term and in-plane gradients to the PCASL pulse train. The optimal RF phase and gradient amplitudes are determined using a prescan procedure, which consists of a series of short scans interleaved with automated postprocessing routines integrated to the scanner console. The prescan procedure is shown to minimize the phase tracking error in a robust and time efficient manner. As an example of its application, the use of OptPCASL for the improved detection of functional activation in the visual cortex is demonstrated and temporal signal-to-noise ratio (SNR), image SNR, and baseline cerebral blood flow measures are compared to those acquired from conventional PCASL.

Reduction in tendon elasticity from unloading is unrelated to its hypertrophy.

Tendinous tissues respond to chronic unloading with adaptive changes in mechanical, elastic, and morphological properties. However, little is known about the changes in the detailed structures of the entire tendinous tissue and whether the change in tendon stiffness is related to morphology. We investigated changes in dimensional (volume, cross-sectional area, segmented lengths) and elastic (Young's modulus) properties of the Achilles tendon and distal aponeurosis in response to chronic unilateral lower limb suspension (ULLS) using velocity encoded phase contrast (VE-PC) and three-dimensional morphometric magnetic resonance imaging (MRI). Five healthy subjects underwent ULLS for 4 wk. Axial morphometric MRI was acquired along the entire length from the calcaneous to the medial gastrocnemius insertion. An oblique sagittal VE-PC MRI was also acquired. The Young's modulus could be calculated from this cine dynamic sequence of velocity encoded images from the slope of the stress-strain curve during the submaximal isometric plantar flexion. After 4 wk of ULLS, we found significant (46.7%) decrease in maximum plantar flexion torque. The total volumes of entire tendinous tissue (determined as the sum of the Achilles tendon and distal aponeurosis) increased significantly by 6.4% (11.9 vs. 12.7 ml) after ULLS. In contrast, Young's modulus decreased significantly by 10.4% (211.7 vs. 189.6 MPa) for the Achilles tendon and 29.0% for the distal aponeurosis (158.8 vs. 113.0 MPa) following ULLS. There was no significant correlation between relative change in volume and Young's modulus with 4 wk of ULLS. It is suggested that, although tendon hypertrophy can be expected to adversely affect tendon stiffness, the absence of any significant correlation between the magnitude of tendon hypertrophy and reduced Young's modulus indicates that dimensional factors were not critical to the elastic properties.

Finite element modeling reveals complex strain mechanics in the aponeuroses of contracting skeletal muscle.

A finite element model was used to investigate the counter-intuitive experimental observation that some regions of the aponeuroses of a loaded and contracting muscle may shorten rather than undergo an expected lengthening. The model confirms the experimental findings and suggests that pennation angle plays a significant role in determining whether regions of the aponeuroses stretch or shorten. A smaller pennation angles (25 degrees ) was accompanied by aponeurosis lengthening whereas a larger pennation angle (47 degrees ) was accompanied by mixed strain effects depending upon location along the length of the aponeurosis. This can be explained by the Poisson effect during muscle contraction and a Mohr's circle analogy. Constant volume constraint requires that fiber cross sectional dimensions increase when a fiber shortens. The opposing influences of these two strains upon the aponeurosis combine in proportion to the pennation angle. Lower pennation angles emphasize the influence of fiber shortening upon the aponeurosis and thus favor aponeurosis compression, whereas higher pennation angles increase the influence of cross sectional changes and therefore favor aponeurosis stretch. The distance separating the aponeuroses was also found to depend upon pennation angle during simulated contractions. Smaller pennation angles favored increased aponeurosis separation larger pennation angles favored decreased separation. These findings caution that measures of the mechanical properties of aponeuroses in intact muscle may be affected by contributions from adjacent muscle fibers and that the influence of muscle fibers on aponeurosis strain will depend upon the fiber pennation angle.

In vivo intramuscular fascicle-aponeuroses dynamics of the human medial gastrocnemius during plantarflexion and dorsiflexion of the foot.

Velocity-encoded phase-contrast magnetic resonance (MR) imaging techniques and a computer-controlled MR-compatible foot pedal device were used to investigate the medial gastrocnemius muscle and aponeurosis deformations during passive and active eccentric movements of the plantarflexors. Intrafascicular strain, measured as the ratio of strain in the fascicle segment at its insertion to strain at its origin, was nonuniform along the proximodistal axis of the muscle (P < 0.01), progressively increasing from the proximal to distal direction. The high intrafascicular strain regions appeared to correlate with the muscle regions that are likely to encounter high stress concentrations, i.e., the regions where the muscle physiological cross section decreases close to the tendons. The architectural gear ratio, i.e., the mechanical amplification ratio of fascicle length displacement to that of tendon/aponeuroses in a pennate muscle, also exhibited significant regional differences, with the highest ratios in the proximal region of the muscle accompanied by a higher initial pennation angle and a larger range of fascicular rotation about the origin. Values close to unity in the distal region of the muscle suggest that the aponeurosis separation may decrease in this region. Fascicle length and pennation angle changes were significantly influenced by force generation in the muscle, probably due to a shortening of the loaded muscle fibers relative to a passive condition. Overall, our data illustrate significant proximodistal intramuscular heterogeneity as supported by a regionally variable end-to-end strain ratio of fascicles and angle changes in the medial gastrocnemius muscle during passive and active ankle movements. These observations emphasize the need to reassess current conceptual models of muscle-tendon mechanics.

Characterization and prognostic value of persistent hyponatremia in patients with severe heart failure in the ESCAPE Trial.

BACKGROUND: Mild hyponatremia is relatively common in patients hospitalized with heart failure (HF). To our knowledge, the association of hyponatremia with outcomes has not been evaluated in the context of in-hospital clinical course including central hemodynamics and changes in serum sodium level. METHODS: The ESCAPE trial (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) was a randomized, controlled study designed to evaluate the utility of a pulmonary artery catheter plus clinical assessment vs clinical assessment alone in guiding therapy in patients hospitalized with New York Heart Association class IV HF due to systolic dysfunction (left ventricular ejection fraction <30%). A Cox proportional hazards model with baseline serum sodium level as a continuous variable was used to examine the association of serum sodium level with 6-month postdischarge mortality, HF rehospitalization, and death or rehospitalization. A categorical analysis was also performed comparing persistent and corrected hyponatremia. RESULTS: A total of 433 hospitalized patients with HF were enrolled in ESCAPE. Hyponatremia (serum sodium level < or = 134 mEq/L) was present in 103 patients (23.8%). (To convert serum sodium to millimoles per liter, multiply by 1.0.) Of these, 71 had persistent hyponatremia (68.9%). Hyponatremia was associated with higher 6-month mortality after covariate adjustment (hazard ratio [HR] for each 3-mEq/L decrease in sodium level, 1.23; 95% confidence interval [CI], 1.05-1.43) (P = .01). After controlling for baseline variables and clinical response, we found that patients with persistent hyponatremia had an increased risk of all-cause mortality (31% vs 16%; HR, 1.82) (P = .04), HF rehospitalization (62% vs 43%; HR, 1.52) (P = .03), and death or rehospitalization (73% vs 50%; HR, 1.54) (P = .01) compared with normonatremic patients. CONCLUSION: Persistent hyponatremia was an independent predictor of mortality, HF hospitalization, and death or rehospitalization despite clinical and hemodynamic improvements that were similar to those in patients without hyponatremia.

Prognostic value of blood urea nitrogen in patients hospitalized with worsening heart failure: insights from the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Chronic Heart Failure (ACTIV in CHF) study.

BACKGROUND: Hospitalization for acute decompensated heart failure (ADHF) is associated with a high postdischarge mortality and readmission rate. The association between baseline blood urea nitrogen (BUN) and clinical outcomes in patients admitted for ADHF was evaluated in a post-hoc analysis of the ACTIV in CHF trial. METHODS AND RESULTS: Patients were categorized into quartiles according to baseline BUN. Cox proportional hazards regression was used to test the association between BUN, mortality, and death or readmission within 60 days. Patients in the highest quartile (>40 mg/dL) had the highest 60-day mortality (14.3%, 9.3%, 4.0%, 0%, respectively; P < .001) and the highest rate of death or heart failure hospitalization (30.0%, 21.3% 18.4%, 8.6%; P < .001). After adjustment for covariates, BUN was a statistically significant predictor of both mortality and the composite endpoint of death or heart failure hospitalization at 60 days after hospital discharge. Serum creatinine and estimated creatinine clearance did not predict mortality after covariate adjustment. CONCLUSIONS: Higher baseline BUN is a powerful predictor of increased postdischarge mortality in patients hospitalized for heart failure, even in the absence of severe renal failure. Even mild to moderate elevations in baseline BUN were predictive. BUN remains an easily accessible risk stratification tool that physicians should closely monitor in the hospital setting.

Improvement in hyponatremia during hospitalization for worsening heart failure is associated with improved outcomes: insights from the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Chronic Heart Failure (ACTIV in CHF) trial.

BACKGROUND: Hyponatremia predicts poor outcome in patients with acute heart failure syndromes. This study evaluated the relationship between baseline serum sodium, change in serum sodium, and 60-day mortality in hospitalized heart failure patients. METHODS: A post-hoc analysis of the ACTIV in CHF trial was performed. ACTIV in CHF randomized 319 patients hospitalized for worsening heart failure to placebo or one of three tolvaptan doses. Cox proportional hazards regression-analysis was used to explore the relationship between baseline hyponatremia, sodium change during the hospitalization, and 60-day mortality. RESULTS: Hyponatremia was observed in 69 patients (21.6%). After covariate adjustment, baseline hyponatremia was a statistically significant predictor of 60-day mortality (P = 0.0016). Follow-up serum sodium data were available in 68 patients. At hospital discharge, 45 of 68 (66.2%) hyponatremic patients had improvements in serum sodium levels (> or = 2 mmol/l). Hyponatremic patients with a serum sodium improvement had a mortality rate of 11.1% at 60 days post discharge, compared with a 21.7% mortality rate in those showing no improvement. After covariate adjustment, change in serum sodium was a statistically significant predictor of 60-day mortality (HR: 0.736, 95% CI: 0.569-0.952 for each 1-mmol/l increase in serum sodium from baseline). CONCLUSIONS: Serum sodium improvements during hospitalization for heart failure were associated with improved survival at 60 days.

Early pharmacological treatment of acute heart failure syndromes: a systematic review of clinical trials.

CONTEXT: Acute Heart Failure Syndromes (AHFS) is a common admission diagnosis associated with high mortality and hospital readmissions. Given the mixed results of recent clinical trials, the early management of AHFS remains controversial. OBJECTIVE: To review the recent evidence regarding current and investigational therapies for the early management of AHFS. DATA SOURCES: A systematic search of peer-reviewed publications was performed on MEDLINE and EMBASE from January 1990 to August 2006. The results of unpublished or ongoing trials were obtained from presentations at national and international meetings and pharmaceutical industry releases. Bibliographies from these references were also reviewed, as were additional articles identified by content experts. STUDY SELECTION AND DATA EXTRACTION: Criteria used for study selection were controlled study design, relevance to clinicians and validity based on venue of publication and power analysis. DATA SYNTHESIS: Although all current intravenous therapies for the early management of AHFS appear to improve hemodynamics, this may not always translate into short-term clinical benefit. CONCLUSION: The results of the trials conducted to date in AHFS have generally been disappointing. There is, therefore, an unmet need for new therapeutic approaches for the early management of AHFS that may improve the short-term and long-term outcomes.