Marco V Perez

p300/MDM2 Complexes Participate in MDM2-Mediated p53 Degradation

Control of p53 turnover is critical to p53 function. E1A binding to p300/CBP translates into enhanced p53 stability, implying that these coactivator proteins normally operate in p53 turnover control. In this regard, the p300 C/H1 region serves as a specific in vivo binding site for both p53 and MDM2, a naturally occurring p53 destabilizer. Moreover, most of the endogenous MDM2 is bound to p300, and genetic analysis implies that specific interactions of p53 and MDM2 with p300 C/H1 are important steps in the MDM2-directed turnover of p53. A specific role for p300 in endogenous p53 degradation is underscored by the p53-stabilizing effect of overproducing the p300 C/H1 domain. Taken together, the data indicate that specific interactions between p300/CBP C/H1, p53, and MDM2 are intimately involved in the MDM2-mediated control of p53 abundance.

Systematic Review: The Comparative Effectiveness of Percutaneous Coronary Interventions and Coronary Artery Bypass Graft Surgery

Context The relative benefits and harms of coronary artery bypass graft surgery (CABG) versus percutaneous coronary intervention (PCI) are sometimes unclear. Contribution This systematic review of 23 randomized trials found that survival at 10 years was similar for CABG and PCI, even among diabetic patients. Procedural strokes and angina relief were more common after CABG (risk difference, 0.6% and about 5% to 8%, respectively), whereas repeated revascularization procedures were more common after PCI (risk difference, 24% at 1 year). Caution Only 1 small trial used drug-eluting stents. Few patients with extensive coronary disease or poor ventricular function were enrolled. The Editors Coronary artery bypass graft (CABG) surgery and catheter-based percutaneous coronary intervention (PCI), with or without coronary stents, are alternative approaches to mechanical coronary revascularization. These 2 coronary revascularization techniques are among the most common major medical procedures performed in North America and Europe: In 2005, 261000 CABG procedures and 645000 PCI procedures were performed in the United States alone (1). However, the comparative effectiveness of CABG and PCI remains poorly understood for patients in whom both procedures are technically feasible and coronary revascularization is clinically indicated. In patients with left main or triple-vessel coronary artery disease with reduced left ventricular function, CABG is generally preferred because randomized, controlled trials (RCTs) have shown that it improves survival compared with medical therapy (2, 3). In patients with most forms of single-vessel disease, PCI is generally the preferred form of coronary revascularization (4), in light of its lower clinical risk and the evidence that PCI reduces angina and myocardial ischemia in this subset of patients (5). Most RCTs comparing CABG and PCI have been conducted in populations with coronary artery disease between these extremes, namely patients with single-vessel, proximal left anterior descending disease; most forms of double-vessel disease; or less extensive forms of triple-vessel disease. We sought to evaluate the evidence from RCTs on the comparative effectiveness of PCI and CABG. We included trials using balloon angioplasty or coronary stents because quantitative reviews have shown no differences in mortality or myocardial infarction between these PCI techniques (6, 7). We also included trials using standard or minimally invasive CABG or both procedures (8, 9). We sought to document differences between PCI and CABG in survival, cardiovascular complications (such as stroke and myocardial infarction), and freedom from angina. Finally, we reviewed selected observational studies to assess the generalizability of the RCTs. Methods Data Sources We searched the MEDLINE, EMBASE, and Cochrane databases for studies published between January 1966 and August 2006 by using such terms as angioplasty, coronary, and coronary artery bypass surgery, as reported in detail elsewhere (10). We also sought additional studies by reviewing the reference lists of included articles, conference abstracts, and the bibliographies of expert advisors. We did not limit the searches to the English language. Study Selection We sought RCTs that compared health outcomes of PCI and CABG. We excluded trials that compared PCI alone or CABG alone with medical therapy, those that compared 2 forms of PCI, and those that compared 2 forms of CABG. The outcomes of interest were survival, myocardial infarction, stroke, angina, and use of additional revascularization procedures. Two investigators independently reviewed titles, abstracts, and the full text as needed to determine whether studies met inclusion criteria. Conflicts between reviewers were resolved through re-review and discussion. We did not include results published solely in abstract form. Data Extraction and Quality Assessment Two authors independently abstracted data on study design; setting; population characteristics (sex, age, race/ethnicity, comorbid conditions, and coronary anatomy); eligibility and exclusion criteria; procedures performed; numbers of patients screened, eligible, enrolled, and lost to follow-up; method of outcome assessment; and results for each outcome. We assessed the quality of included trials by using predefined criteria and graded their quality as A, B, or C by using methods described in detail elsewhere (10). In brief, a grade of A indicates a high-quality trial that clearly described the population, setting, interventions, and comparison groups; randomly allocated patients to alternative treatments; had low dropout rates; and reported intention-to-treat analysis of outcomes. A grade of B indicates a randomized trial with incomplete information about methods that might mask important limitations. A grade of C indicates that the trial had evident flaws, such as improper randomization, that could introduce significant bias. Data Synthesis and Analysis We used random-effects models to compute weighted mean rates and SEs for each outcome. We computed summary risk differences and odds ratios between PCI and CABG and the 95% CI for each outcome of interest at annual intervals. Because the results did not differ materially when risk differences and odds ratios (10) were used and the low rate of several outcomes (for example, procedural mortality) made the risk difference a more stable outcome metric (11, 12), we report here only the risk differences. We assessed heterogeneity of effects by using chi-square and I 2 statistics (13). When effects were heterogeneous (I 2 > 50%), we explored the effects of individual studies on summary effects by removing each study individually. We assessed the possibility of publication bias by visual inspection of funnel plots and calculated the number of missing studies required to change a statistically significant summary effect to not statistically significant (11). We performed analyses by using Comprehensive Meta-Analysis software, version 2.0 (Biostat, Englewood, New Jersey). Inclusion of Observational Studies We also searched for observational data to evaluate the generalizability of the RCT results, as reported in detail elsewhere (10). In brief, we included observational studies from clinical or administrative databases that included at least 1000 recipients of each revascularization procedure and provided sufficient information about the patient populations (such as demographic characteristics, preprocedure coronary anatomy, and comorbid conditions) and procedures performed (such as balloon angioplasty vs. bare-metal stents vs. drug-eluting stents). Role of the Funding Source This project was supported by the Agency for Healthcare Research and Quality. Representatives of the funding agency reviewed and commented on the study protocol and drafts of the manuscript, but the authors had final responsibility for the design, conduct, analysis, and reporting of the study. Results We identified 1695 potentially relevant articles, of which 204 merited full-text review (Appendix Figure). A total of 113 articles reporting on 23 unique RCTs met inclusion criteria (Table 1 [14126]). These trials enrolled a total of 9963 patients, of whom 5019 were randomly assigned to PCI and 4944 to CABG. Most trials were conducted in Europe, the United Kingdom, or both locations; only 3 trials were performed in the United States. The early studies (patient entry from 1987 to 1993) used balloon angioplasty as the PCI technique, and the later studies (patient entry from 1994 to 2002) used stents as the PCI technique. Only 1 small trial of PCI versus CABG used drug-eluting stents (116). Nine trials limited entry to patients with single-vessel disease of the proximal left anterior descending artery, whereas the remaining 14 trials enrolled patients with multivessel disease, either predominantly (3 trials) or exclusively (11 trials). Appendix Figure. Study flow diagram. CABG= coronary artery bypass grafting; CAD= coronary artery disease; PCI= percutaneous coronary intervention; RCT= randomized, controlled trial. Table 1. Overview of Randomized, Controlled Trials The quality of 21 trials was graded as A, and 1 trial (117) was graded as B. One trial (116) was graded as C because randomization may not have been properly executed (details are available elsewhere [10]). We performed sensitivity analyses by removing these studies from the analysis, and our summary results did not change statistically significantly. The average age of the trial participants was 61 years, 27% were women, and most were of European ancestry. Roughly 20% had diabetes, half had hypertension, and half had hyperlipidemia. Whereas approximately 40% of patients had a previous myocardial infarction, few had heart failure or poor left ventricular function. Among studies that enrolled patients with multivessel coronary disease, most had double-vessel rather than triple-vessel disease. Revascularization procedures were performed by using standard methods for the time the trial was conducted (Table 1). Among patients with multivessel disease, more grafts were placed during CABG than vessels were dilated during PCI. Among patients assigned to PCI, stents were commonly used in the recent studies, but in the earlier trials, balloon angioplasty was standard. Among patients assigned to CABG, arterial grafting with the left internal mammary artery was frequently done, especially in more recent trials. Some studies used minimally invasive, direct coronary artery bypass and off-pump operations to perform CABG in patients with single-vessel left anterior descending disease (Table 1). Short-Term and Procedural Outcomes Survival (within 30 days of the procedure) was high for both procedures: 98.9% for PCI and 98.2% for CABG. When data from all trials were combined, the survival difference between PCI and CABG was small and not statistically significant (0.2% [95% CI, 0.3% to 0.6%]) (Figure 1

Interpretation of the Electrocardiogram of Young Athletes

Sudden cardiac death in a young athlete is a tragic and high-profile event. The best way to prevent such deaths is, however, highly debated. The Italian experience informed the European recommendation for the inclusion of a 12-lead ECG in screening tests for all athletes.1,2 Although American authors have acknowledged the possible benefits of such an approach, many have expressed concern over the portability of such a model to the US healthcare system. Concern has focused in particular on the idea of mandatory testing, cost effectiveness, the availability of practitioners qualified to interpret ECGs, and the burden of false-positive results. With professional sports organizations such as the International Olympic Committee, the National Basketball Association, the National Football League, and the Union of European Football Associations endorsing or implementing screening programs for their athletes, with a recent analysis suggesting a degree of cost effectiveness in line with other accepted medical interventions,3 and with the American Heart Association offering a cautious endorsement to the idea of local programs,4 volunteer-led testing programs across the US have begun to emerge. Thus, although no detailed guidance for the interpretation of the athletes ECG exists, many physicians will be called on to interpret an athletes ECG. Editorial see p 669 A principal obstacle to such interpretation is the difficulty in distinguishing abnormal patterns from physiological effects of training. Many clinical and ECG findings that may be a cause of concern in the general population are normal for athletes. In addition, the test characteristics of the ECG for different findings vary according to age, sex, ethnicity, sport, and level of training. In particular, different challenges exist for younger athletes because of the evolution of the ECG with age. This is further complicated by historical …

Early Repolarization in an Ambulatory Clinical Population

Background— The significance of early repolarization, particularly regarding the morphology of the R-wave downslope, has come under question. Methods and Results— We evaluated 29 281 resting ambulatory ECGs from the VA Palo Alto Health Care System. With PR interval as the isoelectric line and amplitude criteria ≥0.1 mV, ST-segment elevation is defined at the end of the QRS, J wave as an upward deflection, and slur as a conduction delay on the QRS downstroke. Associations of ST-segment elevation patterns, J waves, and slurs with cardiovascular mortality were analyzed with Cox analysis. With a median follow-up of 7.6 years, there were 1995 cardiac deaths. Of 29 281 subjects, 87% were male (55±14 years) and 13% were female (56±17 years); 13% were black, 6% were Hispanic, and 81% were white or other. Six hundred sixty-four (2.3%) had inferior or lateral ST-segment elevation: 185 (0.6%) in inferior leads and 479 (1.6%) in lateral leads, 163 (0.6%) in both, and 0.4% had global elevation. A total of 4041 ECGs were analyzed with enhanced display, and 583 (14%) had J waves or slurring, which were more prevalent in those with than in those without ST-segment elevation (61% versus 13%; P<0.001). ST-segment elevation occurred more in those with than in those without J waves or slurs (12% versus 1.3%; P<0.001). Except when involving only inferior leads, all components of early repolarization were more common in young individuals, male subjects, blacks, and those with bradycardia. All patterns and components of early repolarization were associated with decreased cardiovascular mortality, but this was not significant after adjustment for age. Conclusions— We found no significant association between any components of early repolarization and cardiac mortality.

Gene coexpression network topology of cardiac development, hypertrophy, and failure.

Background—Network analysis techniques allow a more accurate reflection of underlying systems biology to be realized than traditional unidimensional molecular biology approaches. Using gene coexpression network analysis, we define the gene expression network topology of cardiac hypertrophy and failure and the extent of recapitulation of fetal gene expression programs in failing and hypertrophied adult myocardium. Methods and Results—We assembled all myocardial transcript data in the Gene Expression Omnibus (n=1617). Because hierarchical analysis revealed species had primacy over disease clustering, we focused this analysis on the most complete (murine) dataset (n=478). Using gene coexpression network analysis, we derived functional modules, regulatory mediators, and higher-order topological relationships between genes and identified 50 gene coexpression modules in developing myocardium that were not present in normal adult tissue. We found that known gene expression markers of myocardial adaptation were members of upregulated modules but not hub genes. We identified ZIC2 as a novel transcription factor associated with coexpression modules common to developing and failing myocardium. Of 50 fetal gene coexpression modules, 3 (6%) were reproduced in hypertrophied myocardium and 7 (14%) were reproduced in failing myocardium. One fetal module was common to both failing and hypertrophied myocardium. Conclusions—Network modeling allows systems analysis of cardiovascular development and disease. Although we did not find evidence for a global coordinated program of fetal gene expression in adult myocardial adaptation, our analysis revealed specific gene expression modules active during both development and disease and specific candidates for their regulation.

Isolated Disease of the Proximal Left Anterior Descending Artery: Comparing the Effectiveness of Percutaneous Coronary Interventions and Coronary Artery Bypass Surgery

OBJECTIVES This study sought to systematically compare the effectiveness of percutaneous coronary intervention and coronary artery bypass surgery in patients with single-vessel disease of the proximal left anterior descending (LAD) coronary artery. BACKGROUND It is uncertain whether percutaneous coronary interventions (PCI) or coronary artery bypass grafting (CABG) surgery provides better clinical outcomes among patients with single-vessel disease of the proximal LAD. METHODS We searched relevant databases (MEDLINE, EMBASE, and Cochrane from 1966 to 2006) to identify randomized controlled trials that compared outcomes for patients with single-vessel proximal LAD assigned to either PCI or CABG. RESULTS We identified 9 randomized controlled trials that enrolled a total of 1,210 patients (633 received PCI and 577 received CABG). There were no differences in survival at 30 days, 1 year, or 5 years, nor were there differences in the rates of procedural strokes or myocardial infarctions, whereas the rate of repeat revascularization was significantly less after CABG than after PCI (at 1 year: 7.3% vs. 19.5%; at 5 years: 7.3% vs. 33.5%). Angina relief was significantly greater after CABG than after PCI (at 1 year: 95.5% vs. 84.6%; at 5 years: 84.2% vs. 75.6%). Patients undergoing CABG spent 3.2 more days in the hospital than those receiving PCI (95% confidence interval: 2.3 to 4.1 days, p < 0.0001), required more transfusions, and were more likely to have arrhythmias immediately post-procedure. CONCLUSIONS In patients with single-vessel, proximal LAD disease, survival was similar in CABG-assigned and PCI-assigned patients; CABG was significantly more effective in relieving angina and led to fewer repeat revascularizations.

International recommendations for electrocardiographic interpretation in athletes

Sudden cardiac death (SCD) is the leading cause of mortality in athletes during sport. A variety of mostly hereditary, structural, or electrical cardiac disorders are associated with SCD in young athletes, the majority of which can be identified or suggested by abnormalities on a resting 12-lead electrocardiogram (ECG). Whether used for diagnostic or screening purposes, physicians responsible for the cardiovascular care of athletes should be knowledgeable and competent in ECG interpretation in athletes. However, in most countries a shortage of physician expertise limits wider application of the ECG in the care of the athlete. A critical need exists for physician education in modern ECG interpretation that distinguishes normal physiological adaptations in athletes from distinctly abnormal findings suggestive of underlying pathology. Since the original 2010 European Society of Cardiology recommendations for ECG interpretation in athletes, ECG standards have evolved quickly over the last decade; pushed by a growing body of scientific data that both tests proposed criteria sets and establishes new evidence to guide refinements. On February 26-27, 2015, an international group of experts in sports cardiology, inherited cardiac disease, and sports medicine convened in Seattle, Washington, to update contemporary standards for ECG interpretation in athletes. The objective of the meeting was to define and revise ECG interpretation standards based on new and emerging research and to develop a clear guide to the proper evaluation of ECG abnormalities in athletes. This statement represents an international consensus for ECG interpretation in athletes and provides expert opinion-based recommendations linking specific ECG abnormalities and the secondary evaluation for conditions associated with SCD.

Electrocardiographic predictors of atrial fibrillation

BACKGROUND Atrial fibrillation (AF) is the most prevalent arrhythmia in the United States and accounts for more than 750,000 strokes per year. Noninvasive predictors of AF may help identify patients at risk of developing AF. Our objective was to identify the electrocardiographic characteristics associated with onset of AF. METHODS This was a retrospective cohort analysis of 42,751 patients with electrocardiograms (ECGs) ordered by physicians discretion and analyzed using a computerized system. The population was followed for detection of AF on subsequent ECGs. Cox proportional hazard regression analysis was performed to test the association between these ECG characteristics and development of AF. RESULTS For a mean follow-up of 5.3 years, 1,050 (2.4%) patients were found to have AF on subsequent ECG recordings. Several ECG characteristics, such as P-wave dispersion (the difference between the widest and narrowest P waves), premature atrial contractions, and an abnormal P axis, were predictive of AF with hazard ratio of approximately 2 after correcting for age and sex. P-wave index, the SD of P-wave duration across all leads, was one of the strongest predictors of AF with a concordance index of 0.62 and a hazard ratio of 2.7 (95% CI 2.1-3.3) for a P-wave index >35. These were among the several independently predictive markers identified on multivariate analysis. CONCLUSIONS Several ECG markers are independently predictive of future onset of AF. The P index, a measurement of disorganized atrial depolarization, is one of the strongest predictors of AF. The ECG contains valuable prognostic information that can identify patients at risk of AF.

Obesity, Physical Activity, and Their Interaction in Incident Atrial Fibrillation in Postmenopausal Women

Background Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with increased risk of stroke and death. Obesity is an independent risk factor for AF, but modifiers of this risk are not well known. We studied the roles of obesity, physical activity, and their interaction in conferring risk of incident AF. Methods and Results The Womens Health Initiative (WHI) Observational Study was a prospective observational study of 93 676 postmenopausal women followed for an average of 11.5 years. Incident AF was identified using WHI‐ascertained hospitalization records and diagnostic codes from Medicare claims. A multivariate Coxs hazard regression model adjusted for demographic and clinical risk factors was used to evaluate the interaction between obesity and physical activity and its association with incident AF. After exclusion of women with prevalent AF, incomplete data, or underweight body mass index (BMI), 9792 of the remaining 81 317 women developed AF. Women were, on average, 63.4 years old, 7.8% were African American, and 3.6% were Hispanic. Increased BMI (hazard ratio [HR], 1.12 per 5‐kg/m2 increase; 95% confidence interval [CI], 1.10 to 1.14) and reduced physical activity (>9 vs. 0 metabolic equivalent task hours per week; HR, 0.90; 95% CI, 0.85 to 0.96) were independently associated with higher rates of AF after multivariate adjustment. Higher levels of physical activity reduced the AF risk conferred by obesity (interaction P=0.033). Conclusions Greater physical activity is associated with lower rates of incident AF and modifies the association between obesity and incident AF.

The prognostic value of early repolarization with ST-segment elevation in African Americans

BACKGROUND Increased prevalence of classic early repolarization, defined as ST-segment elevation (STE) in the absence of acute myocardial injury, in African Americans is well established. The prognostic value of this pattern in different ethnicities remains controversial. OBJECTIVE Measure association between early repolarization and cardiovascular mortality in African Americans. METHODS The resting electrocardiograms of 45,829 patients were evaluated at the Palo Alto Veterans Affairs Hospital. Subjects with inpatient status or electrocardiographic evidence of acute myocardial infarction were excluded, leaving 29,281 subjects. ST-segment elevation, defined as an elevation of >0.1 mV at the end of the QRS, was electronically flagged and visually adjudicated by 3 observers blinded to outcomes. An association between ethnicity and early repolarization was measured by using multivariate logistic regression. We analyzed associations between early repolarization and cardiovascular mortality by using the Cox proportional hazards regression analysis. RESULTS Subjects were 13% women and 13.3% African Americans, with an average age of 55 years and followed for an average of 7.6 years, resulting in 1995 cardiovascular deaths. There were 479 subjects with lateral STE and 185 with inferior STE. After adjustment for age, sex, heart rate, and coronary artery disease, African American ethnicity was associated with lateral or inferior STE (odds ratio 3.1; P = .0001). While lateral or inferior STE in non-African Americans was independently associated with cardiovascular death (hazard ratio 1.6; P = .02), it was not associated with cardiovascular death in African Americans (hazard ratio 0.75; P = .50). CONCLUSIONS Although early repolarization is more prevalent in African Americans, it is not predictive of cardiovascular death in this population and may represent a distinct electrophysiologic phenomenon.