The origin recognition complex requires chromatin tethering by a hypervariable intrinsically disordered region that is functionally conserved from sponge to man.

The first step toward eukaryotic genome duplication is loading of the replicative helicase onto chromatin. This 'licensing' step initiates with the recruitment of the origin recognition complex (ORC) to chromatin, which is thought to occur via ORC's ATP-dependent DNA binding and encirclement activity. However, we have previously shown that ATP binding is dispensable for the chromatin recruitment of fly ORC, raising the question of how metazoan ORC binds chromosomes. We show here that the intrinsically disordered region (IDR) of fly Orc1 is both necessary and sufficient for recruitment of ORC to chromosomes in vivo and demonstrate that this is regulated by IDR phosphorylation. Consistently, we find that the IDR confers the ORC holocomplex with ATP-independent DNA binding activity in vitro. Using phylogenetic analysis, we make the surprising observation that metazoan Orc1 IDRs have diverged so markedly that they are unrecognizable as orthologs and yet we find that these compositionally homologous sequences are functionally conserved. Altogether, these data suggest that chromatin is recalcitrant to ORC's ATP-dependent DNA binding activity, necessitating IDR-dependent chromatin tethering, which we propose poises ORC to opportunistically encircle nucleosome-free regions as they become available.

18F-FDG PET/CT and radiolabeled leukocyte SPECT/CT imaging for the evaluation of cardiovascular infection in the multimodality context: ASNC Imaging Indications (ASNC I2) Series Expert Consensus Recommendations from ASNC, AATS, ACC, AHA, ASE, EANM, HRS, IDSA, SCCT, SNMMI, and STS.

This document on cardiovascular infection, including infective endocarditis, is the first in the American Society of Nuclear Cardiology Imaging Indications (ASNC I2) series to assess the role of radionuclide imaging in the multimodality context for the evaluation of complex systemic diseases with multi-societal involvement including pertinent disciplines. A rigorous modified Delphi approach was used to determine consensus clinical indications, diagnostic criteria, and an algorithmic approach to diagnosis of cardiovascular infection including infective endocarditis. Cardiovascular infection incidence is increasing and is associated with high morbidity and mortality. Current strategies based on clinical criteria and an initial echocardiographic imaging approach are effective but often insufficient in complicated cardiovascular infection. Radionuclide imaging with 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) and single photon emission computed tomography/CT leukocyte scintigraphy can enhance the evaluation of suspected cardiovascular infection by increasing diagnostic accuracy, identifying extracardiac involvement, and assessing cardiac implanted device pockets, leads, and all portions of ventricular assist devices. This advanced imaging can aid in key medical and surgical considerations. Consensus diagnostic features include focal/multi-focal or diffuse heterogenous intense 18F-FDG uptake on valvular and prosthetic material, perivalvular areas, device pockets and leads, and ventricular assist device hardware persisting on non-attenuation corrected images. There are numerous clinical indications with a larger role in prosthetic valves, and cardiac devices particularly with possible infective endocarditis or in the setting of prior equivocal or non-diagnostic imaging. Illustrative cases incorporating these consensus recommendations provide additional clarification. Future research is necessary to refine application of these advanced imaging tools for surgical planning, to identify treatment response, and more.

Protein intrinsically disordered regions have a non-random, modular architecture.

MOTIVATION: Protein sequences can be broadly categorized into two classes: those which adopt stable secondary structure and fold into a domain (i.e. globular proteins), and those that do not. The sequences belonging to this latter class are conformationally heterogeneous and are described as being intrinsically disordered. Decades of investigation into the structure and function of globular proteins has resulted in a suite of computational tools that enable their sub-classification by domain type, an approach that has revolutionized how we understand and predict protein functionality. Conversely, it is unknown if sequences of disordered protein regions are subject to broadly generalizable organizational principles that would enable their sub-classification. RESULTS: Here, we report the development of a statistical approach that quantifies linear variance in amino acid composition across a sequence. With multiple examples, we provide evidence that intrinsically disordered regions are organized into statistically non-random modules of unique compositional bias. Modularity is observed for both low and high-complexity sequences and, in some cases, we find that modules are organized in repetitive patterns. These data demonstrate that disordered sequences are non-randomly organized into modular architectures and motivate future experiments to comprehensively classify module types and to determine the degree to which modules constitute functionally separable units analogous to the domains of globular proteins. AVAILABILITY AND IMPLEMENTATION: The source code, documentation, and data to reproduce all figures are freely available at https://github.com/MWPlabUTSW/Chi-Score-Analysis.git. The analysis is also available as a Google Colab Notebook (https://colab.research.google.com/github/MWPlabUTSW/Chi-Score-Analysis/blob/main/ChiScore_Analysis.ipynb).

18F-FDG PET/CT and radiolabeled leukocyte SPECT/CT imaging for the evaluation of cardiovascular infection in the multimodality context: ASNC Imaging Indications (ASNC I2) Series Expert Consensus Recommendations from ASNC, AATS, ACC, AHA, ASE, EANM, HRS, IDSA, SCCT, SNMMI, and STS.

This document on cardiovascular infection, including infective endocarditis, is the first in the American Society of Nuclear Cardiology Imaging Indications (ASNC I2) series to assess the role of radionuclide imaging in the multimodality context for the evaluation of complex systemic diseases with multi-societal involvement including pertinent disciplines. A rigorous modified Delphi approach was used to determine consensus clinical indications, diagnostic criteria, and an algorithmic approach to diagnosis of cardiovascular infection including infective endocarditis. Cardiovascular infection incidence is increasing and is associated with high morbidity and mortality. Current strategies based on clinical criteria and an initial echocardiographic imaging approach are effective but often insufficient in complicated cardiovascular infection. Radionuclide imaging with 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (CT) and single photon emission computed tomography/CT leukocyte scintigraphy can enhance the evaluation of suspected cardiovascular infection by increasing diagnostic accuracy, identifying extracardiac involvement, and assessing cardiac implanted device pockets, leads, and all portions of ventricular assist devices. This advanced imaging can aid in key medical and surgical considerations. Consensus diagnostic features include focal/multi-focal or diffuse heterogenous intense 18F-FDG uptake on valvular and prosthetic material, perivalvular areas, device pockets and leads, and ventricular assist device hardware persisting on non-attenuation corrected images. There are numerous clinical indications with a larger role in prosthetic valves, and cardiac devices particularly with possible infective endocarditis or in the setting of prior equivocal or non-diagnostic imaging. Illustrative cases incorporating these consensus recommendations provide additional clarification. Future research is necessary to refine application of these advanced imaging tools for surgical planning, to identify treatment response, and more.

Observer studies of image quality of denoising reduced-count cardiac single photon emission computed tomography myocardial perfusion imaging by three-dimensional Gaussian post-reconstruction filtering and deep learning.

BACKGROUND: The aim of this research was to asses perfusion-defect detection-accuracy by human observers as a function of reduced-counts for 3D Gaussian post-reconstruction filtering vs deep learning (DL) denoising to determine if there was improved performance with DL. METHODS: SPECT projection data of 156 normally interpreted patients were used for these studies. Half were altered to include hybrid perfusion defects with defect presence and location known. Ordered-subset expectation-maximization (OSEM) reconstruction was employed with the optional correction of attenuation (AC) and scatter (SC) in addition to distance-dependent resolution (RC). Count levels varied from full-counts (100%) to 6.25% of full-counts. The denoising strategies were previously optimized for defect detection using total perfusion deficit (TPD). Four medical physicist (PhD) and six physician (MD) observers rated the slices using a graphical user interface. Observer ratings were analyzed using the LABMRMC multi-reader, multi-case receiver-operating-characteristic (ROC) software to calculate and compare statistically the area-under-the-ROC-curves (AUCs). RESULTS: For the same count-level no statistically significant increase in AUCs for DL over Gaussian denoising was determined when counts were reduced to either the 25% or 12.5% of full-counts. The average AUC for full-count OSEM with solely RC and Gaussian filtering was lower than for the strategies with AC and SC, except for a reduction to 6.25% of full-counts, thus verifying the utility of employing AC and SC with RC. CONCLUSION: We did not find any indication that at the dose levels investigated and with the DL network employed, that DL denoising was superior in AUC to optimized 3D post-reconstruction Gaussian filtering.

Structural mechanism of laforin function in glycogen dephosphorylation and lafora disease.

Glycogen is the major mammalian glucose storage cache and is critical for energy homeostasis. Glycogen synthesis in neurons must be tightly controlled due to neuronal sensitivity to perturbations in glycogen metabolism. Lafora disease (LD) is a fatal, congenital, neurodegenerative epilepsy. Mutations in the gene encoding the glycogen phosphatase laforin result in hyperphosphorylated glycogen that forms water-insoluble inclusions called Lafora bodies (LBs). LBs induce neuronal apoptosis and are the causative agent of LD. The mechanism of glycogen dephosphorylation by laforin and dysfunction in LD is unknown. We report the crystal structure of laforin bound to phosphoglucan product, revealing its unique integrated tertiary and quaternary structure. Structure-guided mutagenesis combined with biophysical and biochemical analyses reveal the basis for normal function of laforin in glycogen metabolism. Analyses of LD patient mutations define the mechanism by which subsets of mutations disrupt laforin function. These data provide fundamental insights connecting glycogen metabolism to neurodegenerative disease.

Perspectives on Secondary Mitral Regurgitation in Heart Failure.

PURPOSE OF THE REVIEW: This review focuses on broader perspectives of mitral regurgitation (MR) in patients with heart failure. RECENT FINDINGS: The ratio of regurgitant volume to end-diastolic volume appears to help identify patients who may benefit from valve interventions. Secondary MR is not only attributed to geometric changes of the LV but also related to the structural changes in the mitral valve that include fibrosis of the mitral leaflets and changes in the extracellular matrix. The transition from mild to severe secondary MR can occur at different rates, from a slow LV remodeling process to a more abrupt process precipitated by an inciting event such as atrial fibrillation. Septal flash and apical rocking, two new visual markers of LV mechanical dyssynchrony, appear to be predictive of MR reduction following cardiac resynchronization therapy. Optimal guideline-directed medical therapy has been shown to decrease the severity of secondary MR effectively. A theoretical framework to characterize secondary MR as it relates to the onset of MR is proposed. Type A: Early onset of MR contemporaneous with myocardial injury. The maladaptive LV remodeling occurs in parallel with MR. Type B: LV remodeling proceeds without significant MR until the LV is moderately dilated, which coincides with or without inciting factors such as atrial fibrillation. Type C: LV remodeling proceeds after myocardial injury without significant MR until the LV is severely dilated. MR is a late manifestation of LV remodeling.

Serial echocardiography for valve dysfunction and aortic dilation in bicuspid aortic valves.

BACKGROUND AND AIMS: Complications of bicuspid aortic valve commonly include aortic stenosis, aortic regurgitation, and ascending aortic dilation. The progression of these lesions is not well described. MATERIALS AND METHODS: We reviewed 249 bicuspid aortic valve patients with at least two echocardiograms from 2006 to 2016. Valve morphology (right-left or right-noncoronary cusp fusion) was confirmed by visual inspection, and aortic stenosis and regurgitation were quantified according to current guidelines; the ascending aorta was measured at end-systole 2-3 cm above the sinotubular junction. Annualized progression of stenosis, regurgitation, and aortic dilation from first to most recent echocardiogram were compared between right-left and right-nonfused valves using multivariable logistic regression to adjust for baseline differences in groups. RESULTS: Among 249 bicuspid aortic valve patients (mean age 47.6 ± 13.5 years, 66.3% male), 75.9% had right-left cusp fusion. At baseline, aortic stenosis was absent or mild in 80.3%; aortic regurgitation was absent or mild in 80.7%; and aortic diameters were 35.0 ± 5.7 mm (sinuses of Valsalva) and 37.4 ± 6.2 mm (ascending). Mean annualized decrease in aortic valve area was 0.07 cm2 /year, with 30% of bicuspid aortic valve patients progressing ≥0.1 cm2 /year. Aortic regurgitation progressed ≥1 grade in 37 patients. Mean annualized increase in ascending aorta diameter was 0.36 mm/year in right-left and 0.65 mm/year in right-nonbicuspid valves. CONCLUSIONS: In this serial echocardiographic study of bicuspid aortic valve patients, cusp orientation was not associated with progression of valve dysfunction. Right-noncoronary cusp fusion was associated with ascending aortic diameter progression.

Design, synthesis, and evaluation of a novel benzamidine-based inhibitor of VEGF-C binding to Neuropilin-2.

The Neuropilin (Nrp) family of cell surface receptors have key physiological and pathological functions. Nrp2 is of particular interest due to its involvement in tumor metastasis. Currently, peptide and small molecule inhibitors that target Nrp utilize arginine-based molecules which have limitations due to high inherent flexibility and issues related to stability. Further, there are no known small molecule inhibitors specific for Nrp2. Recent molecular insights identify a key ligand binding region in the b1 domain of Nrp2 responsible for binding the C-terminus of its cognate ligand VEGF-C. Based on this, we report the discovery of a novel benzamidine-based inhibitor that functions through competitive inhibition of VEGF-C binding to Nrp2. Further, we have explored inhibitor functionality and selectivity by defining its structure-activity relationship (SAR) providing valuable insights on this benzamidine-based family of Nrp2 inhibitors. This study provides the basis for further development of a potent and specific small molecule inhibitor that competitively targets pathological Nrp2 function.

Comparative infinite lottery logic.

As an application of his Material Theory of Induction, Norton (2018; manuscript) argues that the correct inductive logic for a fair infinite lottery, and also for evaluating eternal inflation multiverse models, is radically different from standard probability theory. This is due to a requirement of label independence. It follows, Norton argues, that finite additivity fails, and any two sets of outcomes with the same cardinality and co-cardinality have the same chance. This makes the logic useless for evaluating multiverse models based on self-locating chances, so Norton claims that we should despair of such attempts. However, his negative results depend on a certain reification of chance, consisting in the treatment of inductive support as the value of a function, a value not itself affected by relabeling. Here we define a purely comparative infinite lottery logic, where there are no primitive chances but only a relation of 'at most as likely' and its derivatives. This logic satisfies both label independence and a comparative version of additivity as well as several other desirable properties, and it draws finer distinctions between events than Norton's. Consequently, it yields better advice about choosing between sets of lottery tickets than Norton's, but it does not appear to be any more helpful for evaluating multiverse models. Hence, the limitations of Norton's logic are not entirely due to the failure of additivity, nor to the fact that all infinite, co-infinite sets of outcomes have the same chance, but to a more fundamental problem: We have no well-motivated way of comparing disjoint countably infinite sets.

Mechanisms and regulation of DNA replication initiation in eukaryotes.

Cellular DNA replication is initiated through the action of multiprotein complexes that recognize replication start sites in the chromosome (termed origins) and facilitate duplex DNA melting within these regions. In a typical cell cycle, initiation occurs only once per origin and each round of replication is tightly coupled to cell division. To avoid aberrant origin firing and re-replication, eukaryotes tightly regulate two events in the initiation process: loading of the replicative helicase, MCM2-7, onto chromatin by the origin recognition complex (ORC), and subsequent activation of the helicase by its incorporation into a complex known as the CMG. Recent work has begun to reveal the details of an orchestrated and sequential exchange of initiation factors on DNA that give rise to a replication-competent complex, the replisome. Here, we review the molecular mechanisms that underpin eukaryotic DNA replication initiation - from selecting replication start sites to replicative helicase loading and activation - and describe how these events are often distinctly regulated across different eukaryotic model organisms.

The presbycardia phenotype: Cardiac remodeling and valvular degeneration in nonagenarians.

BACKGROUND: Nonagenarians (NON) are a growing segment of the population and have a high prevalence of cardiac disease. Many findings encountered on their echocardiograms are also found in younger individuals with valvular or myocardial disease. Therefore, the purpose of this study was to describe this distinct echocardiographic phenotype. METHODS: We identified our study population by querying our echo database to identify unique septuagenarians (SEPT) and nonagenarians (NON) who underwent a transthoracic echocardiogram (TTE) from January 1, 2010 to December 31, 2014. Exclusion criteria were LVEF < 50%, any akinetic wall segment, aortic stenosis, moderate-severe AR and/or severe MR, coronary revascularization within 60 days of study echo, and prior valve surgery. RESULTS: The mean age of SEPT was 73.0 ± 2.0 and NON was 92.0 ± 2.1 (P < 0.001). There was no gender difference between groups. NON had significantly smaller LV end-diastolic diameters than SEPT (41.6 ± 5.7 mm vs 48.0 ± 7.0 mm, P < 0.001). NON had a greater relative wall thickness (0.51 ± 0.10 vs 0.40 ± 0.08, P < 0.001) and more frequently had concentric remodeling or hypertrophy. NON had higher E/Ea ratios and estimated LA pressures (P < 0.01). 48% of NON had moderate-severe mitral annular calcification compared to 25.0% of SEPT (P < 0.01). CONCLUSIONS: Herein, we provide the first comprehensive echocardiographic description of 'presbycardia'; concentric LVH, asymmetric septal hypertrophy, mitral and aortic valve calcification, and increased epicardial fat thickness. This pattern of findings may be increasingly seen as the population ages.

An assessment of the safety, hemodynamic response, and diagnostic accuracy of commonly used vasodilator stressors in patients with severe aortic stenosis.

BACKGROUND: Increasing numbers of patients are undergoing transcatheter aortic valve replacement, which often involves assessment of coronary artery disease ischemic burden. The safety and diagnostic accuracy of vasodilator stress agents in patients with severe aortic stenosis (AS) undergoing SPECT myocardial perfusion imaging (MPI) has not been established. METHODS: Patients with severe AS (valve area <1 cm2) on echocardiography who underwent vasodilator stress SPECT MPI at two centers were identified. Patients with aortic valve intervention prior to MPI or who underwent concurrent exercise during stress testing were excluded. AS patients were matched to controls without AS based on age, gender, BMI, ejection fraction, and stress agent. Symptoms, serious adverse events, hemodynamic response, and correlation to invasive angiography were assessed. RESULTS: A total of 95 cases were identified with 45% undergoing regadenoson, 31% dipyridamole, and 24% adenosine stress. A significant change in systolic blood pressure (BP), cases vs controls, was observed with adenosine [-17.9 ± 20.1 vs -2.6 ± 24.9 P = .03)], with a trend toward significance with regadenoson [-16.8 ± 20.3 vs -9.4 ± 17.9 (P = .08)] and dipyridamole [-17.8 ± 20.6 vs -9.0 ± 12.1 (P = .05)]. The change in heart rate was significantly different only for adenosine [5.3 ± 16.8 vs 14.2 ± 10.8 (P = .04)]. Overall, 45% of cases vs 24% of controls (P = .004) had a >20 mmHg decrease in systolic BP. Age, BMI, and resting systolic BP were related to a >20 mmHg decrease in systolic BP on univariate analysis, although only higher resting systolic BP was a predictor on multivariate analysis. In 33 patients who underwent angiography, the sensitivity, specificity, and diagnostic accuracy of vasodilator stress MPI was 77%, 69%, and 73%, respectively. No serious adverse events occurred in the severe AS patients. CONCLUSION: Severe AS patients are more likely to have a hemodynamically significant decrease in systolic BP with vasodilator stress. There were no serious adverse events in this severe AS cohort with good diagnostic performance of MPI compared to angiography.

Effect of an Educational Intervention on the Accuracy of Data Submitted to a National Quality Registry.

BACKGROUND: We hypothesize that data-entry errors within the National Cardiovascular Data Registry® (NCDR) ICD Registry™ may be an important reason behind labeling many cases as nonevidence-based. OBJECTIVE: To describethe frequency of data-entry errors in implantable cardioverter-defibrillator (lCD) implant data from our institution and develop a plan for quality improvement using the Deming cycle. METHODS AND RESULTS: We assessed data of patient report forms from2007to 2010 and compared these data with forms submitted from 2011 to 2012 after implementation of a continuous multicomponent staff education and training program. Of 211 ICD implants between 2007 and 2010, 36 (17%) were labeled nonevidence-based. Twenty-four (11.4%) resulted from misclassification due to data entry errors and 12 (5.7%) were actual nonevidence-based. Postintervention, review of 97 submitted patients' data revealed one (1%) data-entry error and three (3.1%) actual nonevidence-based implants. CONCLUSIONS: Multicomponent educational intervention was effective in reducing errors in data sub- mitted to the NCDR ICD Registry.

Dynamic LVOT Obstruction and Aortic Stenosis in the Same Patient: A Case of Challenging Doppler Hemodynamics.

We present a patient with both dynamic left ventricular outflow tract obstruction and valvular aortic stenosis. The aortic valve was calcified, and velocities and gradients measured by continuous-wave Doppler met standard criteria for severe aortic stenosis. The increased subvalvular velocities invalidated assumptions of the simplified Bernoulli equation; correction using the longer form of the Bernoulli equation suggested a lower but still significant gradient. The complex shape of the subvalvular spectral Doppler envelope indicated supranormal systolic function and dynamic left ventricular outflow obstruction. Left heart catheterization with an end-hole catheter was required to determine the subvalvular and valvular components of the obstruction.

Caseous Calcification of Mitral Annulus: A Rare Monster Leading to Cerebrovascular Accident.

Caseous calcification of the mitral annulus (CCMA) is a rare variant of mitral annular calcification that maybe easily misdiagnosed or confused with an abscess, a tumor, or infective vegetation. The main pathophysiological mechanism leading to CCMA involves degeneration and calcium deposition on the mitral valve. We present a case of CCMA to help understand this clinical entity.

Relationship between quantitative cardiac neuronal imaging with ¹²³I-meta-iodobenzylguanidine and hospitalization in patients with heart failure.

PURPOSE: Hospitalization in patients with systolic heart failure is associated with morbidity, mortality, and cost. Myocardial sympathetic innervation, imaged by (123)I-meta-iodobenzylguanidine ((123)I-mIBG), has been associated with cardiac events in a recent multicenter study. The present analysis explored the relationship between (123)I-mIBG imaging findings and hospitalization. METHODS: Source documents from the ADMIRE-HF trial were reviewed to identify hospitalization events in patients with systolic heart failure following cardiac neuronal imaging using (123)I-mIBG. Time to hospitalization was analyzed with the Kaplan-Meier method and compared to the mIBG heart-to-mediastinum (H/M) ratio using multiple-failure Cox regression. RESULTS: During 1.4 years of median follow-up, 362 end-point hospitalizations occurred in 207 of 961 subjects, 79 % of whom had H/M ratio <1.6. Among subjects hospitalized for any cause, 88 % had H/M ratio <1.6 and subjects with H/M ratio <1.6 experienced hospitalization earlier than subjects with higher H/M ratios (log-rank p = 0.003). After adjusting for elevated brain natriuretic peptide (BNP) and time since heart failure diagnosis, a low mIBG H/M ratio was associated with cardiac-related hospitalization (HR 1.48, 95 % CI 1.05 - 2.0; p = 0.02). CONCLUSION: The mIBG H/M ratio may risk-stratify patients with heart failure for cardiac-related hospitalization, especially when used in conjunction with BNP. Further studies are warranted to examine these relationships.

Microplate-based screening for small molecule inhibitors of neuropilin-2/vascular endothelial growth factor-C interactions.

Vascular endothelial growth factor-C (VEGF-C) is a secreted growth factor essential for lymphangiogenesis. VEGF-C functions in both physiological and pathological lymphangiogenesis, particularly in tumor metastasis, making it an attractive therapeutic target. Members of two families of cell surface receptors transduce VEGF-C signals: neuropilin-2 (Nrp2) and VEGF-receptor (VEGFR)-2/3. Nrp2 is a promising target for inhibition because it is highly expressed in lymphatic vessels. Here we describe a microplate-based assay for discovery of VEGF-C/Nrp2 inhibitors. We optimize this assay for use in screening an inhibitor library and identify three novel Nrp2/VEGF-C binding inhibitors from the National Institutes of Health (NIH) Clinical Collection small molecule library.

Stress-only SPECT myocardial perfusion imaging: a review.

Myocardial perfusion imaging (MPI) has enjoyed considerable success for decades due to its diagnostic accuracy and wealth of prognostic data. Despite this success several limitations such as lengthy protocols and radiation exposure remain. Advancements to address these shortcomings include abbreviated stress-only MPI (SO MPI) protocols, PET and both hardware and software methods to reduce radiation exposure and time. SO MPI has advantages in protocol time and radiation reduction with a wealth of supporting data in terms of diagnostic validity and prognostic value. Newer technologies such as attenuation correction, and advanced camera technologies have enabled SO MPI to be more efficient in reducing the time of acquisition and radiation dose and improving accuracy. This review examines the literature available, regarding accuracy, patient outcomes, implementation strategies, and newer developments associated with SO MPI.

Impact of angina frequency on health utility values of patients with chronic stable angina.

BACKGROUND: Chronic angina is a profoundly symptomatic disease. We evaluated the relationship between angina frequency and health utility. METHODS: We used data from stable angina patients reporting ≥3 attacks/week enrolled in the Efficacy of Ranolazine in Chronic Angina (ERICA) trial. Angina frequency was classified using the Seattle Angina Questionnaire angina frequency (SAQAF) domain into no (100); monthly (61-99); weekly (31-60); and daily (0-30) angina. EuroQol (EQ)-5D health utility scores were derived from SAQ data using two mapping equations. Median EQ-5D utility scores for each SAQAF classification after the 6-week trial period were calculated (reported as: Equation 1/Equation 2). Changes in EQ-5D utility scores from baseline to end-of-trial for patients achieving and not achieving a ≥20-point improvement in SAQAF score and improving and not improving ≥1 SAQAF classification were compared. RESULTS: Median EQ-5D utility scores (n = 548) were 0.68/0.60. Compared to patients reporting no angina symptoms (n = 28; 0.89/0.87) patients reporting monthly (n = 188; 0.80/0.76), weekly (n = 283; 0.72/0.65) and daily (n = 49; 0.65/0.54) symptoms had poorer health utility (p < 0.001 for both equations). Patients improving ≥1SAQAF classification (n = 254/541, 47%) experienced a median 0.05/0.07 greater improvement in EQ-5D health utility compared to those not improving ≥1 classification (p < 0.001 for both equations). Patients improving ≥20-points on the SAQAF (n = 355/541, 66%) experienced a median 0.06/0.07 greater improvement in health utility compared to those not achieving a ≥20-point improvement (p < 0.001 for both). CONCLUSIONS: Chronic angina patient health utility decreases as angina frequency increases. Patients reporting clinically important improvement in angina frequency experience a tangible improvement in health utility. CLINICAL TRIAL REGISTRATION: NCT00091429.