Search

ATRX, a chromatin remodeling protein of the Snf2 family, participates in diverse cellular functions including regulation of gene expression and chromosome alignment during mitosis and meiosis. Mutations in the human gene cause alpha thalassemia mental retardation, X-linked (ATR-X) syndrome, a rare disorder characterized by severe cognitive deficits, microcephaly and epileptic seizures. Conditional inactivation of the Atrx gene in the mouse forebrain leads to neonatal lethality and defective neurogenesis manifested by increased cell death and reduced cellularity in the developing neocortex and hippocampus. Here, we show that Atrx-null forebrains do not generate dentate granule cells due to a reduction in precursor cell number and abnormal migration of differentiating granule cells. In addition, fewer GABA-producing interneurons are generated that migrate from the ventral telencephalon to the cortex and hippocampus. Staining for cleaved caspase 3 demonstrated increased apoptosis in both the hippocampal hem and basal telencephalon concurrent with p53 pathway activation. Elimination of the tumor suppressor protein p53 in double knock-out mice rescued cell death in the embryonic telencephalon but only partially ameliorated the Atrx-null phenotypes at birth. Together, these findings show that ATRX deficiency leads to p53-dependent neuronal apoptosis which is responsible for some but not all of the phenotypic consequences of ATRX deficiency in the forebrain.

Clinical practice guidelines for patients with atrial fibrillation (AF) recommended a heart rate (HR) of 60 to 80 beats/min at rest and 90 to 115 at moderate exercise. The degree to which HR control at rest and with exercise in patients with AF complies with these recommendations is unknown. HR at rest and at peak exercise was retrospectively examined in 1,097 consecutive patients with AF referred for exercise myocardial perfusion imaging. In a subgroup of 195 patients, HR was also measured at an intermediate "moderate" level. Median HR at rest was 80 beats/min, at the upper end of the recommended range of 60 to 80. Only patients administered a beta blocker (BB; 31%) had lower (p <0.001) median HRs at rest. Median HR at moderate exercise was 128 beats/min, higher than the range of 90 to 115 recommended by the guidelines. Only patients administered a BB had significantly reduced HRs (p <0.003) at moderate exercise. Median peak exercise HR was 147 beats/min. Forty-five percent of patients exceeded their age-predicted maximal HR. Patients administered BBs were significantly less likely (p <0.01) to exceed their age-predicted maximal HR. In conclusion, in patients with AF, HR control at rest and during exercise often did not comply with guideline recommendations. Regimens including a BB were more effective in achieving HR control.

The American Heart Association's (AHA's) mission is "to build healthier lives, free of cardiovascular diseases and stroke." This first article in a 2-part series will serve to present an overview of the work the AHA has undertaken to translate evidence into practice for healthcare professionals. It describes the extensive work of the AHA to support and further the delivery of evidence-based medicine, which includes the following: (1) supporting scientific discovery and the next generation of healthcare professionals and researchers; (2) disseminating scientific information; (3) developing evidence-based guidelines and statements; (4) creating and advocating for the implementation of performance indicators/measures; (5) developing clinical decision support and quality improvement tools; and (6) developing directed-cause campaigns, all of which can lead to improved patient care. This article also discusses the need for novel approaches and some of the AHA's evolving strategies to help address gaps in care. The second article, which will be published shortly after this one, will examine the AHA's efforts to engage and empower healthcare consumers to become more involved with their own health and health care.

ATRX belongs to the SNF2 family of proteins, many of which have been demonstrated to have chromatin remodeling activity. Constitution mutations in the X-encoded gene give rise to alpha thalassemia mental retardation (ATR-X) syndrome and a variety of related conditions that are often associated with profound developmental delay, facial dysmorphism, genital abnormalities, and alpha thalassemia. Acquired mutations in ATRX are observed in the preleukemic condition alpha thalassemia myelodysplastic syndrome (ATMDS). Mutations in ATRX have been shown to perturb gene expression and DNA methylation. This is a comprehensive report of 127 mutations including 32 reported here for the first time. Missense mutations are shown to cluster in the two main functional domains. The truncating mutations appear to be "rescued" to some degree and so it appears likely that most if not all constitutional ATRX mutations are hypomorphs., ((c) 2008 Wiley-Liss, Inc.)

Background: The value of distal protection devices during rescue PCI has not been studied., Methods: The population enrolled in a prospective, randomized multicenter trial of distal microcirculatory protection in ST-elevation MI, was stratified for those undergoing rescue (n = 93) or primary (n = 408) PCI; we performed the prespecified comparisons of distal protection in rescue and primary PCI., Results: Compared to primary PCI, rescue patients had higher baseline rates of TIMI-3 flow, but lower rates of post PCI TIMI-3 flow. However, no differences in the primary endpoints of complete ST-segment resolution (STR) at 30 minutes or infarct size, or 6 month mortality were present. In rescue PCI patients, randomization to distal protection did not significantly affect infarct size, STR, mortality or other clinical events., Conclusion: Despite reduced rates of post-procedural TIMI-3 flow, patients undergoing rescue PCI compared to primary PCI have similar myocardial perfusion, infarct size and clinical outcomes. Distal protection did not offer any detectable benefit in this patient population.

Background: Systemic hypertension and an exaggerated blood pressure (BP) response with exercise have been associated with 'false-positive' findings on stress electrocardiography and echocardiography; however, limited data is available for stress myocardial perfusion imaging (MPI). The purpose of this study was to investigate whether an exaggerated elevation in BP with exercise is associated with an increased prevalence of abnormal MPI., Methods: BP responses to exercise were assessed in a cohort of 7,205 patients who underwent stress testing with technetium 99m-SPECT MPI (7/1999-6/2005) for the evaluation of chest pain or dyspnea., Results: A hypertensive response, defined as a peak systolic BP > or = 220 mmHg, occurred in 355 (4.9%) and was not associated with higher rates of ischemic ECG changes (16.1 versus 16.6%; P = .7), differences in Duke treadmill scores (4.7 +/- 4 versus 5.1 +/- 5; P = .3) or an increased prevalence of abnormal perfusion images (30.1% versus 32.9%; P = .3) to those without a hypertensive exercise response. Patients with a hypertensive response and either intermediate or high-risk MPI (on the basis of summed-difference-scores) referred for coronary angiography, had a high prevalence of coronary artery disease which was similar to those without a hypertensive response (88% versus 83%; P = .5). In an analysis of a community-based patient subset, a hypertensive response was not associated with a difference in either all-cause mortality or subsequent myocardial infarction, coronary revascularization or cardiac death (8% versus 9%; P = .7)., Conclusion: A hypertensive BP response to exercise is not associated with increased rates of ischemic ECG changes, higher-risk Duke treadmill scores, greater degrees of abnormal MPI or worse clinical outcome.

Objectives: The purpose of this study was to apply published appropriateness criteria for single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) in a single academic medical center., Background: The American College of Cardiology Foundation (ACCF) and the American Society of Nuclear Cardiology (ASNC) have developed appropriateness criteria for stress SPECT MPI to address concern about the growth in cardiac imaging studies., Methods: We retrospectively examined 284 patients who underwent stress SPECT MPI and 298 patients who underwent stress echocardiography before publication of these criteria., Results: The overall level of agreement in characterizing appropriateness between 2 experienced cardiovascular nurse abstractors was modest (kappa = 0.56), but noticeably poorer (kappa = 0.27) for patients with previous SPECT or echo studies. Similar percentages of each imaging modality were assigned to the 3 appropriateness categories: 64% of stress SPECT and 64% of stress echo studies were classified appropriate; 11% of stress SPECT and 9% of stress echo were of uncertain appropriateness; and 14% of stress SPECT and 18% of stress echo were inappropriate. Of the inappropriate studies, 88% were performed for 1 of 4 indications. Approximately 10% of the patients were unclassifiable., Conclusions: Application of existing SPECT MPI appropriateness criteria is demanding and requires an established database or detailed data collection, as well as a number of assumptions. Fourteen percent of stress SPECT studies and 18% of stress echo studies were performed for inappropriate reasons. Quality improvement efforts directed at reducing the number of these inappropriate studies may improve efficiency in the health care system.

Introduction: Cardiac resynchronization therapy (CRT) can improve left ventricular (LV) hemodynamics and function. Recent data suggest the energy cost of such improvement is favorable. The effects of sequential CRT on myocardial oxidative metabolism (MVO(2)) and efficiency have not been previously assessed., Methods and Results: Eight patients with NYHA class III heart failure were studied 196 +/- 180 days after CRT implant. Dynamic [(11)C]acetate positron emission tomography (PET) and echocardiography were performed after 1 hour of: 1) AAI pacing, 2) simultaneous CRT, and 3) sequential CRT. MVO(2) was calculated using the monoexponential clearance rate of [(11)C]acetate (k(mono)). Myocardial efficiency was expressed in terms of the work metabolic index (WMI). P values represent overall significance from repeated measures analysis. Global LV and right ventricular (RV) MVO(2) were not significantly different between pacing modes, but the septal/lateral MVO(2) ratio differed significantly with the change in pacing mode (AAI pacing = 0.696 +/- 0.094 min(-1), simultaneous CRT = 0.975 +/- 0.143 min(-1), and sequential CRT = 0.938 +/- 0.189 min(-1); overall P = 0.001). Stroke volume index (SVI) (AAI pacing = 26.7 +/- 10.4 mL/m(2), simultaneous CRT = 30.6 +/- 11.2 mL/m(2), sequential CRT = 33.5 +/- 12.2 mL/m(2); overall P < 0.001) and WMI (AAI pacing = 3.29 +/- 1.34 mmHg*mL/m(2)*10(6), simultaneous CRT = 4.29 +/- 1.72 mmHg*mL/m(2)*10(6), sequential CRT = 4.79 +/- 1.92 mmHg*mL/m(2)*10(6); overall P = 0.002) also differed between pacing modes. Compared with simultaneous CRT, additional changes in septal/lateral MVO(2), SVI, and WMI with sequential CRT were not statistically significant on post hoc analysis., Conclusion: In this small selected population, CRT increases LV SVI without increasing MVO(2), resulting in improved myocardial efficiency. Additional improvements in LV work, oxidative metabolism, and efficiency from simultaneous to sequential CRT were not significant.

Objective: To determine whether asymptomatic patients with atherosclerosis, indicated by the presence of coronary artery calcium on electron beam computed tomography, are at enough risk for progression of disease to justify a repeated stress single-photon emission computed tomography (SPECT) examination after an initial normal to low-risk perfusion study., Patients and Methods: We retrospectively identified patients who had abnormal results on electron beam computed tomography (coronary artery calcium score > 0) and normal to low-risk results on SPECT (defined as a summed stress score of 0-3) within a 3-month period from January 1, 1995, to October 31, 2002. Of the 504 identified patients, 285 remained after exclusion criteria were applied. Of the 285 patients, 69 (mean +/- SD age, 58.2 +/- 7.6 years; 91% male) underwent at least 1 repeated myocardial perfusion SPECT imaging study within 4 years of their initial assessment as normal or at low risk without recurrence of symptoms. The value of repeated SPECT imaging was assessed by detection of a substantial change in the repeated SPECT study and by documentation of a clinical event (death, nonfatal myocardial infarction, or revascularization). Follow-up was 100% complete at a mean of 4.3 +/- 1.6 years., Results: Only 4 patients (6%) had a substantial progression in their SPECT risk category; substantial changes on the SPECT scans occurred only in patients with a coronary artery calcium score greater than 100. Three patients underwent revascularization, yielding a 5-year rate for survival free of revascularization of 94% (95% confidence interval, 88%-100%). No deaths or nonfatal myocardial infarctions were reported., Conclusion: The principal findings of this study indicate that asymptomatic patients with initial normal or low-risk results from stress SPECT performed because of abnormal coronary artery calcium scores who remain asymptomatic are at low risk of death, myocardial infarction, or coronary revascularization. Three patients underwent revascularization by percutaneous coronary intervention despite the absence of symptoms. A substantial change in SPECT results (defined as progression from normal or low-risk summed stress score to intermediate- or high-risk summed stress score) affected 6% of patients and was not associated with any adverse hard events (nonfatal myocardial infarction or death).

To address the mechanism by which the human globin genes are activated during erythropoiesis, we have used a tiled microarray to analyze the pattern of transcription factor binding and associated histone modifications across the telomeric region of human chromosome 16 in primary erythroid and nonerythroid cells. This 220-kb region includes the alpha globin genes and 9 widely expressed genes flanking the alpha globin locus. This un-biased, comprehensive analysis of transcription factor binding and histone modifications (acetylation and methylation) described here not only identified all known cis-acting regulatory elements in the human alpha globin cluster but also demonstrated that there are no additional erythroid-specific regulatory elements in the 220-kb region tested. In addition, the pattern of histone modification distinguished promoter elements from potential enhancer elements across this region. Finally, comparison of the human and mouse orthologous regions in a unique mouse model, with both regions coexpressed in the same animal, showed significant differences that may explain how these 2 clusters are regulated differently in vivo.

Determinates of infarct size in patients with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI) have been incompletely characterized, in part because of the limited sample size of previous studies. Databases therefore were pooled from 4 contemporary trials of primary or rescue PCI (EMERALD, COOL-MI, AMIHOT, and ICE-IT), in which the primary end point was infarct size assessed using technetium-99m sestamibi single-photon emission computed tomographic imaging, measured at the same core laboratory. Of 1,355 patients, infarct size was determined using technetium-99m sestamibi imaging in 1,199 patients (88.5%), at a mean time of 23 +/- 15 days. Median infarct size of the study population was 10% (interquartile range 0% to 23%; mean 14.9 +/- 16.1%). Using multiple linear regression analysis of 18 variables, left anterior descending infarct artery, baseline Thrombolysis In Myocardial Infarction grade 0/1 flow, male gender, and prolonged door-to-balloon time were powerful independent predictors of infarct size (all p <0.0001). Other independent correlates of infarct size were final Thrombolysis In Myocardial Infarction grade <3 flow (p = 0.0001), previous AMI (p = 0.005), symptom-onset-to-door time (p = 0.021), and rescue angioplasty (p = 0.026). In conclusion, anterior infarction, time to reperfusion, epicardial infarct artery patency before and after reperfusion, male gender, previous AMI, and failed thrombolytic therapy were important predictors of infarct size after angioplasty in patients with AMI assessed using technetium-99m sestamibi imaging and should be considered when planning future trials of investigational drugs or devices designed to enhance myocardial recovery.

Background: Diabetic patients with acute myocardial infarction (MI) have higher mortality than nondiabetic patients. The purpose of this study was to examine if larger infarct size explains the higher mortality in diabetic patients with acute ST-segment-elevation MI., Methods: In the CORE trial (n = 2948), subsets of patients underwent quantitative radionuclide measurement of technetium Tc 99m sestamibi infarct size (n = 1164) or gated equilibrium left ventricular ejection fraction (LVEF) (n = 1137) at days 6 to 16 after thrombolytic therapy. Clinical follow-up was 96.7% complete at 6 months., Results: The prevalence of diabetes in these patient imaging subsets was 16% to 17%. Higher risk clinical characteristics including older age and a greater prevalence of prior MI were more common in diabetic patients. Median infarct size was larger in diabetic patients (22% vs 17% of the left ventricle, P = .04), a difference that remained significant after adjustment for clinical variables (P = .048). Patients with diabetes also had lower median LVEF (48% vs 51%, unadjusted P = .002, adjusted P = .007). Six-month mortality was higher in diabetic patients: infarct size subset, 5.9% vs 1.6% (P = .0016); LVEF subset, 6.1% vs 1.0% (P < .0001). Multivariable models demonstrated that diabetes and each imaging variable were independent predictors of mortality., Conclusions: Infarct size is modestly larger and LVEF modestly lower in diabetic patients with ST-segment-elevation MI. The substantially higher (4- to 6-fold) mortality rate in diabetic vs nondiabetic patients is only partially explained by relatively small differences in infarct size and LVEF.

Objectives: We sought to determine if screening for coronary artery disease (CAD) with stress single-photon emission computed tomography (SPECT) is of value in patients with atrial fibrillation (AF) who do not have symptoms of chest pain or dyspnea., Background: Although noninvasive stress testing is often done to screen for CAD in asymptomatic patients with AF and is considered to be appropriate in selected patients, its potential utility has not been demonstrated., Methods: A retrospective study was conducted of 374 asymptomatic patients with AF referred for the detection of CAD. Mean follow-up was 5.7 +/- 3.8 years. The study group was compared with a control group of 374 asymptomatic age and gender-matched patients without AF., Results: The mean summed stress score (SSS) was not significantly different between AF patients and control subjects (3.6 +/- 5.3 vs. 3.5 +/- 5.9; p = 0.35). Compared with controls, asymptomatic AF patients had similar rates of abnormal SPECT studies (51.6% vs. 48.4%; p = 0.38) and high-risk studies (14.4% vs. 14.4%; p = 1.0). The SSS was a significant predictor of outcome in both AF patients and control subjects. However, total mortality was significantly greater in AF patients (5-year overall mortality 27% vs. 18%, 10-year overall mortality 47% vs. 40%; p < 0.001), and this difference persisted (p = 0.01) after adjusting for multiple clinical variables and the SSS., Conclusions: Screening for CAD using stress SPECT in asymptomatic AF patients has a yield similar to age- and gender-matched control patients without AF. Although SSS predicts mortality in patients with and without AF, patients with AF have increased total mortality independent of the findings on stress SPECT. These results suggest that factors other than obstructive CAD are responsible for the increased mortality in AF.

Background: The prevalence and prognosis of reduced left ventricular ejection fraction (LVEF) in asymptomatic diabetic patients without known coronary artery disease (CAD) are not known., Methods: We examined 1046 asymptomatic diabetic patients (age 60 +/- 13 years, 69% male) without known CAD referred to a tertiary referral center for stress single-photon emission computed tomography (SPECT) and assessment of LVEF. Patients were stratified according to the presence of normal LVEF (> or = 50%), mildly reduced LVEF (35%-49%), or moderately/severely reduced LVEF (< 35%). Single-photon emission computed tomographic images were classified as low, intermediate, or high risk based on the summed stress score (normal = 56). The mean follow-up was 5.3 +/- 3.3 years., Results: The prevalence of reduced LVEF was 16.7% (n = 175, mean LVEF 40.0% +/- 7.7%). This group was older (63 +/- 11 vs 59 +/- 14 years, P = .005), had more peripheral arterial disease (45% vs 29%, P < .001), and had a higher prevalence of electrocardiographic Q waves (21% vs 9%, P < .001) than the group without reduced LVEF. Mean summed stress (44.8 +/- 9.8 vs 51.7 +/- 6.3, P < .001), summed reversibility (4.7 +/- 5.0 vs 2.9 +/- 4.5, P < .001), and summed rest scores (49.4 +/- 7.2 vs 54.6 +/- 3.1, P < .001) were significantly more abnormal in the reduced LVEF group. High-risk summed stress score was significantly more common in the reduced LVEF group (46% vs 16%, P < .001). Survival was significantly lower in patients with any reduction in LVEF compared with those without reduced LVEF (10-year survival, 29% vs 57%, P < .0001). By multivariate analysis, reduced LVEF was independently associated with increased mortality (adjusted chi2 = 6.26, P = .01)., Conclusions: In this population of asymptomatic diabetic patients without known CAD referred for stress SPECT, 1 in 6 patients had reduced LVEF. Most of these patients have intermediate-/high-risk SPECT scans. The annual mortality rates of the groups with and without reduced LVEF were 7% and 4%, respectively.

Objectives: This study sought to determine whether hyperoxemic reperfusion with aqueous oxygen (AO) improves recovery of ventricular function after percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI)., Background: Hyperbaric oxygen reduces myocardial injury and improves ventricular function when administered during ischemia-reperfusion., Methods: In a prospective, multicenter study, 269 patients with acute anterior or large inferior AMI undergoing primary or rescue PCI (<24 h from symptom onset) were randomly assigned after successful PCI to receive hyperoxemic reperfusion (treatment group) or normoxemic blood autoreperfusion (control group). Hyperoxemic reperfusion was performed for 90 min using intracoronary AO. The primary end points were final infarct size at 14 days, ST-segment resolution, and delta regional wall motion score index of the infarct zone at 3 months., Results: At 30 days, the incidence of major adverse cardiac events was similar between the control and AO groups (5.2% vs. 6.7%, p = 0.62). There was no significant difference in the incidence of the primary end points between the study groups. In post-hoc analysis, anterior AMI patients reperfused <6 h who were treated with AO had a greater improvement in regional wall motion (delta wall motion score index = 0.54 in control group vs. 0.75 in AO group, p = 0.03), smaller infarct size (23% of left ventricle in control group vs. 9% of left ventricle in AO group, p = 0.04), and improved ST-segment resolution compared with normoxemic controls., Conclusions: Intracoronary hyperoxemic reperfusion was safe and well tolerated after PCI for AMI, but did not improve regional wall motion, ST-segment resolution, or final infarct size. A possible treatment effect was observed in anterior AMI patients reperfused <6 h of symptom onset.

The chromatin-associated protein ATRX was originally identified because mutations in the ATRX gene cause a severe form of syndromal X-linked mental retardation associated with alpha-thalassemia. Half of all of the disease-associated missense mutations cluster in a cysteine-rich region in the N terminus of ATRX. This region was named the ATRX-DNMT3-DNMT3L (ADD) domain, based on sequence homology with a family of DNA methyltransferases. Here, we report the solution structure of the ADD domain of ATRX, which consists of an N-terminal GATA-like zinc finger, a plant homeodomain finger, and a long C-terminal alpha-helix that pack together to form a single globular domain. Interestingly, the alpha-helix of the GATA-like finger is exposed and highly basic, suggesting a DNA-binding function for ATRX. The disease-causing mutations fall into two groups: the majority affect buried residues and hence affect the structural integrity of the ADD domain; another group affects a cluster of surface residues, and these are likely to perturb a potential protein interaction site. The effects of individual point mutations on the folding state and stability of the ADD domain correlate well with the levels of mutant ATRX protein in patients, providing insights into the molecular pathophysiology of ATR-X syndrome.

Extreme skewing of X-chromosome inactivation (XCI) is rare in the normal female population but is observed frequently in carriers of some X-linked mutations. Recently, it has been shown that various forms of X-linked mental retardation (XLMR) have a strong association with skewed XCI in female carriers, but the mechanisms underlying this skewing are unknown. ATR-X syndrome, caused by mutations in a ubiquitously expressed, chromatin-associated protein, provides a clear example of XLMR in which phenotypically normal female carriers virtually all have highly skewed XCI biased against the X chromosome that harbors the mutant allele. Here, we have used a mouse model to understand the processes causing skewed XCI. In female mice heterozygous for a null Atrx allele, we found that XCI is balanced early in embryogenesis but becomes skewed over the course of development, because of selection favoring cells expressing the wild-type Atrx allele. Unexpectedly, selection does not appear to be the result of general cellular-viability defects in Atrx-deficient cells, since it is restricted to specific stages of development and is not ongoing throughout the life of the animal. Instead, there is evidence that selection results from independent tissue-specific effects. This illustrates an important mechanism by which skewed XCI may occur in carriers of XLMR and provides insight into the normal role of ATRX in regulating cell fate.

Background: Stress single photon emission computed tomography (SPECT) is commonly performed in patients with abnormal electron beam computed tomography (EBCT) to define risk stratification, but the published prognostic data for patients undergoing both SPECT and EBCT are limited. The objective of the study was to examine the association and prognostic value between EBCT, coronary artery calcium score (CACS), and stress SPECT imaging., Methods: We identified 835 patients (age 54.8 +/- 10.0 years, 77% male) who underwent EBCT and stress SPECT within a 3-month period. Coronary artery calcium score was categorized as normal (0), minimal (1-10), mild (11-100), moderate (101-400), and severe (>400). Single photon emission computed tomography summed stress score (SSS) was categorized as normal, low risk, intermediate risk, and high risk per Cedar Sinai criteria. Average follow-up was 4.8 +/- 3.2 years. End points were all-cause death, death/myocardial infarction (MI), and death/MI/late revascularization., Results: The correlation of CACS to SSS was weak but statistically significant (r = +0.19, P < .001). The percentage of high-risk SSS increased with higher CACS scores; 4% of patients with normal EBCT and 18% with severe CACS had high-risk SSS. Coronary artery calcium score (chi2 = 11.4, P < .001), diabetes mellitus (chi2 = 4.6, P = .031), and chest pain class (chi2 = 8.7, P = .003) were independently associated with high-risk SPECT. The SSS (chi2 = 6.9, P = .009) and CACS (chi2 = 7.8, P = .005) were independently associated with mortality, as well as with both secondary end points of death/MI and death/MI/late revascularization. Only CACS predicted mortality in the 408 asymptomatic patients (chi2 = 5.2, P = .02), but these patients had an annual mortality of only 0.4% over the next 5 years., Conclusions: In selected patients undergoing both EBCT and SPECT, CACS is weakly correlated with SPECT SSS, likely reflecting the different information provided by EBCT and SPECT. Coronary artery calcium score is independently associated with high-risk SPECT after adjustment for clinical variables. Coronary artery calcium score and SSS are complementary for the prediction of mortality in symptomatic patients. Only CACS predicted mortality in the asymptomatic patients, but they had a low annual mortality.

Background: The effectiveness of stress single photon emission computed tomography (SPECT) as a gatekeeper for coronary angiography has not been extensively investigated. The characteristics of patients referred for early angiography after a normal stress SPECT study have not been described., Methods and Results: Over a 10-year period, 14,273 patients without documented coronary artery disease (CAD) underwent stress SPECT. Images were abnormal in 47% and normal in 53%. The overall survival rate at 15 years was 55% for patients with abnormal images versus 71% for those with normal images (P < .001). Early coronary angiography (< or =3 months) was performed in only 97 patients (1.3%) with normal SPECT studies versus 1,756 patients (26%) with abnormal SPECT studies (P < .001). Most patients with normal SPECT studies referred for early angiography (85%) had clinical, exercise, or scintigraphic findings worrisome for CAD. Two thirds of these highly selected patients with normal SPECT studies who underwent angiography did not have significant CAD; the remaining one third had primarily 1- and 2-vessel CAD., Conclusions: Stress SPECT is an effective gatekeeper for coronary angiography. The annual overall mortality rate for patients with normal images was 1.9%. Only 1.3% of patients with normal images were referred for early angiography.

Aims: The purpose of this analysis was to determine whether the efficacy of adenosine vs. placebo was dependent on the timing of reperfusion therapy in the second Acute Myocardial Infarction Study of Adenosine (AMISTAD-II)., Methods and Results: Patients presenting with ST-segment elevation anterior AMI were randomized to receive placebo vs. adenosine (50 or 70 microg/kg/min) for 3 h starting within 15 min of reperfusion therapy. In the present post hoc hypothesis generating study, the results were stratified according to the timing of reperfusion, i.e. > or = or < the median 3.17 h, and by reperfusion modality. In patients receiving reperfusion < 3.17 h, adenosine compared with placebo significantly reduced 1-month mortality (5.2 vs. 9.2%, respectively, P = 0.014), 6-month mortality (7.3 vs. 11.2%, P = 0.033), and the occurrence of the primary 6-month composite clinical endpoint of death, in-hospital CHF, or rehospitalization for CHF at 6 months (12.0 vs. 17.2%, P = 0.022). Patients reperfused beyond 3 h did not benefit from adenosine., Conclusion: In this post hoc analysis, 3 h adenosine infusion administered as an adjunct to reperfusion therapy within the first 3.17 h onset of evolving anterior ST-segment elevation AMI enhanced early and late survival, and reduced the composite clinical endpoint of death or CHF at 6 months.

Background: Dyspnea is a complex system with multiple etiologies, including myocardial ischemia ("anginal equivalent"). Few studies have examined the utility of stress testing to detect coronary artery disease in this setting. The purpose of this study was to examine the prevalence, severity, and prognostic value of perfusion defects detected by stress single photon emission computed tomography (SPECT) imaging in patients with dyspnea., Methods: SPECT imaging was performed in 1864 patients (age 65.8 +/- 10.2 years, 52% male, 23% diabetic, 89% overweight/obese) without known coronary artery disease referred for evaluation of dyspnea. Dyspnea was rated mild, moderate, or severe. SPECT scans were categorized low, intermediate, or high risk. The associations of stress SPECT imaging results with clinical variables and mortality were analyzed., Results: An abnormal perfusion SPECT image was present in 45% of patients and a high-risk scan in 11%. Male sex, diabetes, and clinical severity of dyspnea were the strongest predictors of both an abnormal and high-risk SPECT scan. A high-risk scan was present in 5% of nondiabetic women with mild dyspnea versus 22% of diabetic men with dyspnea of any severity. At 10 years, survival by SPECT scan category was low risk 75%, intermediate risk 68%, and high risk 53% (P < .001)., Conclusions: In this population of older overweight patients referred for evaluation of dyspnea, there was a high prevalence of abnormal (45%) and high-risk (11%) SPECT scans. High-risk scans were associated with much worse 10-year survival.

Background: Some studies suggested that the poststress left ventricle ejection fraction (LV EF) is lower than rest LV EF in patients with stress-induced ischemia., Methods and Results: By using a 2-day protocol and 30 mCi Tc-99m sestamibi, LV EF, end-systolic volume (ESV), and end-diastolic volume (EDV) were measured with gated SPECT. Of 99 eligible patients, 91 had technically adequate studies. Poststress LV EF minus rest LV EF was defined as DeltaLV EF. DeltaEDV and DeltaESV were similarly defined. Rest and poststress LV EF (r = 0.89), EDV (r = 0.78), and ESV (r = 0.93) were highly correlated (P <.001). Rest LV EF, EDV, and ESV were not significantly different between patients with and without stress-induced ischemia. DeltaLV EF was significantly lower in patients with stress-induced ischemia (-3.5% +/- 4.5% vs -1.1% +/- 4.7%, P = .02). Mean LV EF poststress in ischemic patients was 55.0% +/- 10.5% vs 61.2% +/- 10.0% in nonischemic patients (P = .008). However, only 1 patient (3%) with ischemia had DeltaLV EF that exceeded the 95% confidence limit of DeltaLV EF for normal patients. Ischemia was significantly associated with increased DeltaEDV and DeltaESV (P < .01)., Conclusions: Stress-induced ischemia is associated with poststress reduction in LV EF and increased poststress EDV and ESV. However, the effect of ischemia on the difference between poststress and rest EF measurements is modest and rarely exceeds the confidence limits in normal patients undergoing 2-day protocols. In most patients, poststress LV EF is an accurate reflection of rest LV EF.

Purpose: Heart failure (HF) is associated with blunted HR recovery after exercise. The determinants of altered HR recovery in HF are unknown. The aim of this study was to investigate clinical correlates of HR recovery in HF patients., Methods: Echocardiography, pulmonary function tests, exercise testing, and neurohormonal measurements were performed in 98 HF patients. HR recovery was calculated as the difference between heart rate at peak exercise and at 1 min into a recovery period. Study subjects were divided into three groups based on HR recovery tertiles: group 1 (HR recovery < or = 6 bpm), group 2 (7 < or = HR recovery < or = 12), and group 3 (HR recovery > or = 13)., Results: There were significant differences between the groups in multiple parameters. Compared with group 3, patients in group 1 had greater E/A ratios (1.81 +/- 0.26 vs 0.98 +/- 0.12, P = 0.011), shorter deceleration time (170 +/- 11 vs 223 +/- 11 ms, P = 0.016), and higher plasma atrial natriuretic peptide levels (207 +/- 32 vs 101 +/- 12 pg.mL, P = 0.008), indicating higher left ventricular filling pressures and elevated left atrial pressures. Pulmonary function tests were suggestive of greater restrictive changes in the lungs. Finally, subjects in group 1 had impaired exercise capacity, as evidenced by shorter exercise duration (5.2 +/- 0.2 vs 8.3 +/- 0.4 min, P < 0.001), lower peak VO2 (14.6 +/- 0.6 vs 22.2 +/- 1.0 mL.kg(-1).min(-1), P < 0.001), higher VE/VCO2 ratios (36.4 +/- 1.1 vs 31.1 +/- 0.9, P = 0.001), and reduced chronotropic responses to exercise (39 +/- 3 vs 69 +/- 4 bpm, P < 0.001)., Conclusion: HR recovery may be a clinically useful index identifying HF patients with distinct echocardiographic, neurohormonal, and hemodynamic characteristics. This may have implications for our understanding of the pathophysiology of impaired HR recovery in HF as well as for the clinical evaluation of such patients.

Unlabelled: PET absolute myocardial blood flow (MBF) with H(2)15O and 13NH3 are widely used in clinical and research settings. However, their reproducibility with a 16-myocardial segment model has not been examined in chronic coronary artery disease (CAD). We examined the short-term reproducibility of PET H(2)15O MBF and PET 13NH3 MBF in an animal model of chronic CAD., Methods: Twelve swine (mean weight +/- SD, 38 +/- 5 kg) underwent percutaneous placement of a copper stent in the mid circumflex coronary artery, resulting in an intense inflammatory fibrotic reaction with luminal stenosis at 4 wk. Each animal underwent repeated resting MBF measurements by PET H(2)15O and PET 13NH3. Attenuation-corrected images were analyzed using commercial software to yield absolute MBF (mL/min/g) in 16 myocardial segments. MBF was also normalized to the rate.pressure product (RPP)., Results: By Bland-Altman reproducibility plots, the mean difference was 0.01 +/- 0.18 mL/min/g and 0.01 +/- 0.11 mL/min/g, with confidence limits of +/-0.36 and +/-0.22 mL/min/g for uncorrected regional PET H(2)15O MBF and for uncorrected regional PET 13NH3 MBF, respectively. The repeatability coefficient ranged from 0.09 to 0.43 mL/min/g for H(2)15O and from 0.09 to 0.18 mL/min/g for 13NH3 regional MBF. RPP correction did not improve reproducibility for either PET H(2)15O or PET 13NH3 MBF. The mean difference in PET H(2)15O MBF was 0.03 +/- 0.14 mL/min/g and 0.02 +/- 0.19 mL/min/g for infarcted and remote regions, respectively, and in PET 13NH3 MBF was 0.03 +/- 0.11 mL/min/g and 0.00 +/- 0.09 mL/min/g for infarcted and remote regions, respectively., Conclusion: PET H(2)15O and PET 13NH3 resting MBF showed excellent reproducibility in a closed-chest animal model of chronic CAD. Resting PET 13NH3 MBF was more reproducible than resting PET H(2)15O MBF. A high level of reproducibility was maintained in areas of lower flow with infarction for both isotopes.

X-linked alpha thalassemia mental retardation (ATR-X) syndrome is associated with profound developmental delay, facial dysmorphism, genital abnormalities, and alpha thalassemia. Patients with ATR-X syndrome frequently present with gastrointestinal problems, in particular feeding difficulties, regurgitation and vomiting, abdominal pain, distension, and chronic constipation. Parental reports of prolonged food refusal and distress in these children are common and although these episodes are suspected to be gastro-intestinal in origin they are rarely investigated. Death in early childhood from aspiration of vomitus or from pneumonia presumed to be secondary to aspiration has been recorded in a number of ATR-X cases. In this report we review the gastrointestinal phenotype of ATR-X syndrome in 128 cases. We also demonstrate that in two siblings, regurgitation was secondary to gastric pseudo-volvulus, a condition in which the stomach does not have a normal system of peritoneal ligaments and changes position with possible torsion around itself. Furthermore, ultra-short Hirschsprung disease with colonic hypoganglionosis was shown and this may contribute to the severe constipation affecting these children., (Copyright 2006 Wiley-Liss, Inc.)

We describe a pathogenetic mechanism underlying a variant form of the inherited blood disorder alpha thalassemia. Association studies of affected individuals from Melanesia localized the disease trait to the telomeric region of human chromosome 16, which includes the alpha-globin gene cluster, but no molecular defects were detected by conventional approaches. After resequencing and using a combination of chromatin immunoprecipitation and expression analysis on a tiled oligonucleotide array, we identified a gain-of-function regulatory single-nucleotide polymorphism (rSNP) in a nongenic region between the alpha-globin genes and their upstream regulatory elements. The rSNP creates a new promoterlike element that interferes with normal activation of all downstream alpha-like globin genes. Thus, our work illustrates a strategy for distinguishing between neutral and functionally important rSNPs, and it also identifies a pathogenetic mechanism that could potentially underlie other genetic diseases.

We describe a patient with acquired alpha-thalassemia myelodysplastic syndrome (ATMDS). A previously healthy 66-year-old man presented with hemoglobin of 9.3 g/dL, mean corpuscular volume 59 fL, and a bone marrow aspirate with increased erythroid precursors and hypolobulated megakaryocytes. Hemoglobin H inclusions were seen in most red cells after 1% brilliant cresyl blue supravital stain of the peripheral blood. At the molecular level, we identified of a novel mutation in the most 3' exon of the ATRX gene (CGA-->TGA substitution in codon 2407) resulting in a premature termination codon (p.R2407X). This case provides further evidence for a link between ATRX mutations and ATMDS, and suggests a possible role for the conserved Q-box element in ATRX function.

Context: Peer review should evaluate the merit and quality of abstracts but may be biased by geographic location or institutional prestige. The effectiveness of blinded peer review at reducing bias is unknown., Objective: To evaluate the effect of blinded review on the association between abstract characteristics and likelihood of abstract acceptance at a national research meeting., Design and Setting: All abstracts submitted to the American Heart Association's annual Scientific Sessions research meeting from 2000-2004. Abstract review included the author's name and institution (open review) from 2000-2001, and this information was concealed (blinded review) from 2002-2004. Abstracts were categorized by country, primary language, institution prestige, author sex, and government and industry status., Main Outcome Measure: Likelihood of abstract acceptance during open and blinded review, by abstract characteristics., Results: The mean number of abstracts submitted each year for evaluation was 13,455 and 28.5% were accepted. During open review, 40.8% of US and 22.6% of non-US abstracts were accepted (relative risk [RR], 1.81; 95% confidence interval [CI], 1.75-1.88), whereas during blinded review, 33.4% of US and 23.7% of non-US abstracts were accepted (RR, 1.41; 95% CI, 1.37-1.45; P<.001 for comparison between peer review periods). Among non-US abstracts, during open review, 31.1% from English- speaking countries and 20.9% from non-English-speaking countries were accepted (RR, 1.49; 95% CI, 1.39-1.59), whereas during blinded review, 28.8% and 22.8% of abstracts were accepted, respectively (RR, 1.26; 95% CI, 1.19-1.34; P<.001). Among abstracts from US academic institutions, during open review, 51.3% from highly prestigious and 32.6% from nonprestigious institutions were accepted (RR, 1.57; 95% CI, 1.48-1.67), whereas during blinded review, 38.8% and 29.0% of abstracts were accepted, respectively (RR, 1.34; 95% CI, 1.26-1.41; P<.001)., Conclusions: This study provides evidence of bias in the open review of abstracts, favoring authors from the United States, English-speaking countries outside the United States, and prestigious academic institutions. Moreover, blinded review at least partially reduced reviewer bias.

ATRX is an X-encoded member of the SNF2 family of ATPase/helicase proteins thought to regulate gene expression by modifying chromatin at target loci. Mutations in ATRX provided the first example of a human genetic disease associated with defects in such proteins. To better understand the role of ATRX in development and the associated abnormalities in the ATR-X (alpha thalassemia mental retardation, X-linked) syndrome, we conditionally inactivated the homolog in mice, Atrx, at the 8- to 16-cell stage of development. The protein, Atrx, was ubiquitously expressed, and male embryos null for Atrx implanted and gastrulated normally but did not survive beyond 9.5 days postcoitus due to a defect in formation of the extraembryonic trophoblast, one of the first terminally differentiated lineages in the developing embryo. Carrier female mice that inherit a maternal null allele should be affected, since the paternal X chromosome is normally inactivated in extraembryonic tissues. Surprisingly, however, some carrier females established a normal placenta and appeared to escape the usual pattern of imprinted X-inactivation in these tissues. Together these findings demonstrate an unexpected, specific, and essential role for Atrx in the development of the murine trophoblast and present an example of escape from imprinted X chromosome inactivation., Competing Interests: Competing interests. The authors have declared that no competing interests exist.

Background: Data derived from stress myocardial perfusion imaging (MPI) carry prognostic significance in young patients with hypertrophic cardiomyopathy (HCM), but there are limited data on the utility of stress MPI in patients with HCM who are older. This study examined the prognostic significance of stress MPI in an adult population of patients with HCM., Methods: We examined 158 patients with HCM (aged 60 +/- 16 years, 61% men) who underwent exercise or pharmacologic stress MPI. Summed stress score (SSS, normal = 56) and summed reversibility scores were calculated for each patient. Follow-up was complete in 157 (99%) patients at a median duration of 5.2 years., Results: Normal single-photon emission computed tomography (SPECT) images were present in 38% of the population. Summed stress score (P = .01) and summed reversibility score (P = .03) were both significantly associated with cardiovascular death. Survival at 10 years was significantly better in those with normal versus abnormal SPECT (89% vs 67%, P = .04). Ten-year survival also was better in those without versus those with ischemia (90% vs 64%, P = .02). Five-year survival could be stratified by SSS risk categories: low risk (SSS > or = 53), 97%; intermediate risk (SSS = 48-52), 94%; and high risk (SSS < or = 47), 79% (P = .04). Bivariate models of SSS and other significant covariates supported an independent relation of SSS to cardiovascular death., Conclusions: In an older population of patients with HCM referred for SPECT imaging, abnormal stress MPI identifies those at increased risk of cardiovascular death.

Mutation at the ATR-X locus is associated with severe mental retardation. Several conditions, initially reported as clinically distinct phenotypes, have now been attributed to ATR-X mutation. Asplenia, in association with severe mental retardation, has been reported and subsequently demonstrated in one family to be due to ATR-X mutation. We now report on a second instance of a patient presenting with mental retardation and asplenia who has been shown to have a mutation at the ATR-X locus.

Background: Noninvasive methods are needed to evaluate reperfusion success in patients with acute myocardial infarction (MI). The AMISTAD trial was analyzed to compare MI size and myocardial salvage determined by electrocardiogram (ECG) with technetium Tc 99m sestamibi single-photon emission computerized tomography (SPECT) imaging., Methods: Of 236 patients enrolled in AMISTAD, 166 (70 %) with no ECG confounding factors and no prior MI were included in this analysis. Of these, group 1 (126 patients, 53%) had final infarct size (FIS) available by both ECG and SPECT. Group 2 (56 patients, 24%) had myocardium at risk, FIS, and salvage index (SI) assessed by both SPECT and ECG techniques. Aldrich/Clemmensen scores for myocardium at risk and the Selvester QRS score for final MI size were used. Salvage index was calculated as follows: SI = (myocardium at risk-FIS)/(myocardium at risk)., Results: In group 1, FIS was 15% (6, 24) as measured by ECG and 11% (2, 27) as measured by SPECT. In the adenosine group, FIS was 12% (6, 21) and 11% (2, 22). In the placebo group, FIS was 16.5% (7.5, 24) and 11.5% (3.0, 38.5) by ECG and SPECT, respectively. The overall correlation between SPECT and ECG for FIS was 0.58 (P = .0001): 0.60 in the placebo group (P = .0001) and 0.54 (P = .0001) in the adenosine group. In group 2, myocardium at risk was 23% (17, 30) and 26% (10, 50) with ECG and SPECT, respectively (P = .0066). Final infarct size was 17% (6, 21) and 12% (1, 24) (P < .0001). The SI was 29% (-7, 57) and 46% (15, 79) with ECG and SPECT, respectively (P = .0510)., Conclusions: The ECG measurement of infarct size has a moderate relationship with SPECT infarct size measurements in the population with available assessments. This ECG algorithm must further be validated on clinical outcomes.

Revascularization is a treatment option for moderate-to-severe ischemic cardiomyopathy. Limitations of the current literature, lack of completed randomized trials, and higher periprocedural risks create significant uncertainty about the optimal treatment strategy. This review focuses on the available literature describing the effect of revascularization on outcome and the role of noninvasive viability testing. It attempts to identify a subset of patients likely to benefit from therapy.

Purpose: Scoring systems based on clinical variables are available but not widely applied for evaluating patients with chronic coronary artery disease. The purpose of this study was to validate the prognostic value of a simple clinical scoring system, originally developed in patients referred for a nuclear stress test at a tertiary-care medical center, in a less-selected, community-based population undergoing stress testing for known or suspected coronary artery disease., Subjects and Methods: Over a 4-year period, 3546 residents of Olmsted County, Minn, underwent stress testing. A previously developed clinical score was calculated for every patient by assigning 1 point each for: male sex, history of myocardial infarction, typical angina, diabetes, insulin use, and each decade of age beginning at age 40. The associations between the assigned score and clinical endpoints were tested using logistic regression. A previously established cutoff point of 5 was used to establish risk groups., Results: During follow-up (7.6 +/- 2.7 years) there were 363 total deaths, 109 cardiac deaths, and 132 nonfatal myocardial infarctions. The clinical score was strongly associated with overall mortality, cardiac death, and cardiac death/myocardial infarction (P <0.001 for all 3 endpoints). Annual mortality was .6% for the 3076 patients (86%) with a score < or =4, 2.4% for 275 patients (8%) with a score = 5 and 6.2% for the 215 patients (6%) with a score > or =6., Conclusions: This study enhances the generalizability of this simple clinical score, which was highly effective for risk-stratifying this community-based population undergoing evaluation of chronic coronary artery disease.

Inactivation of tumour suppressor genes is central to the development of cancer. Although this inactivation was once considered to be secondary to intragenic mutations, it is now clear that silencing of these genes often occurs by epigenetic means. Hypermethylation of CpG islands associated with the tumour suppressor genes was the first manifestation of this phenomenon to be described. It is apparent, however, that this is one of a host of chromatin modifications which characterize gene silencing. Although we know little about what determines which loci are affected, our understanding of the nature of the epigenetic marks and how they are established has blossomed. There is no compelling evidence that cancer ever develops by purely epigenetic means, but it is apparent that perturbations in the apparatus which establish the epigenome may contribute to the development of cancer. This review will focus on the role of two classes of chromatin remodelling enzymes, those that alter histones by the addition or removal of acetyl and methyl groups and those of the SWI/SNF family of proteins that change the topology of the nucleosome and its DNA strand via the hydrolysis of ATP, and we shall examine the consequence of mutations in, or mis-expression of, these factors. In some cases, mutations in these factors appear to play a direct role in cancer development. However, their general role as important intermediaries involved in regulating gene expression makes them attractive therapeutic targets. In exciting developments, it has been shown that inhibition of these factors leads to the reversal of tumour suppressor gene silencing and the inhibition of cancer cell growth.