Baseline Range of Motion, Strength, Motor Function, and Participation in Youth with Hutchinson-Gilford Progeria Syndrome.

AIMS: Limited information is available on impairments, activity limitations and participation restrictions in youth with Hutchinson-Gilford progeria syndrome (HGPS), a rare genetic premature aging disease. The purposes were to: (1) describe range of motion (ROM), grip, pinch and quadriceps strength, functional balance, walking endurance, and gross motor limitations and participation restrictions; (2) evaluate the association between ROM impairments and age; and (3) evaluate the association between the Gross Motor Function Measure-88 (GMFM) scores and lower extremity (LE) ROM, quadriceps strength, and age. METHODS: Upper and LE ROM, grip, pinch and quadriceps strength, Timed Up and Go (TUG), Six Minute Walk Test, GMFM-88, and Canadian Occupational Performance Measure data were recorded for 38 participants with HGPS. RESULTS: All youth exhibited ROM impairments and most displayed decreased grip and pinch strength, walking endurance, and gross motor skills when compared to same-aged peers. However, the majority had good functional balance with TUG scores in the normal range. Participation restrictions included difficulty keeping up with peers when walking and difficulty completing activities of daily living. Some ROM measurements were negatively associated with age indicating that older participants had more extensive ROM limitation than younger participants. CONCLUSIONS: Physical and occupational therapists can use this information when evaluating youth with HGPS, designing a plan of care, and providing treatment interventions.

Predictors of response to synchronized transcranial magnetic stimulation for major depressive disorder.

BACKGROUND: Synchronized transcranial magnetic stimulation (sTMS) is a new modality to reduce symptoms of major depressive disorder (MDD). sTMS uses rotating neodymium magnets to deliver low-field stimulation matched to the individual alpha frequency (IAF). A previous multisite study showed that sTMS significantly reduced MDD symptoms in the per-protocol sample. To this end, we evaluated clinical features associated with optimal sTMS outcomes. METHODS: Using the per-protocol sample (n = 120) from the parent sham-controlled trial, we performed univariate and stepwise linear regression to identify predictors of response after 6 weeks of sTMS. A subsample (n = 83) that entered a 4-week open/active continuation phase also was examined. Candidate variables included age, sex, comorbid anxiety, number of failed antidepressants in the current depressive episode, MDD severity (17-item Hamilton Depression Rating Scale; HAMD17), anxiety symptom severity (HAMD17 anxiety/somatization factor), and IAF. RESULTS: We found that greater baseline depressive (p < 0.001) and anxiety (p < 0.001) symptom severity were associated with better response to active sTMS, whereas fewer failed antidepressant trials predicted superior response to sham (p < 0.001). MDD severity and antidepressant resistance predicted outcomes in open/active phase sTMS; lower IAF predicted poorer response in participants who received 10 weeks of active sTMS (p = 0.001). CONCLUSIONS: Participants with greater severity of depression and higher anxiety had superior responses to active sTMS, whereas treatment naïve individuals exhibited a greater response to sham. These results lend support to the primary efficacy findings, and support further investigation of sTMS as a therapeutic noninvasive brain stimulation modality.

Long-term clinical and quality of life outcomes after stenting of femoropopliteal artery stenosis: 3-year results from the STROLL study.

OBJECTIVES: To evaluate the clinical and health status outcomes of patients undergoing superficial femoral artery (SFA) revascularization using the Shape Memory Alloy Recoverable Technology (S.M.A.R.T.®) nitinol self-expanding stent through 3 years of follow-up. BACKGROUND: Limited long-term data are available describing the durability of benefits after femoropopliteal revascularization. METHODS: In a multicenter, prospective, core-lab adjudicated study, 250 subjects with de novo or restenotic femoropopliteal arterial lesions were treated with the S.M.A.R.T.® stent. The primary endpoint of target vessel patency, a composite of ultrasound-assessed patency and freedom from clinically driven target lesion revascularization (TLR), was evaluated through 3 years. Secondary endpoints included stent fracture and health status. Health status was measured using generic and disease-specific instruments, including the Peripheral Artery Questionnaire (PAQ). RESULTS: At 3-year follow-up, Kaplan-Meier estimated target vessel patency was 72.7%, freedom from clinically driven TLR was 78.5%, and the incidence of stent fracture was 3.6%. The PAQ summary score was markedly impaired at baseline (mean 37.3 ± 19.6 points) and improved substantially at 1 month (mean change from baseline of 31.4 points, 95% CI: 28.5-34.3; P < 0.001). Disease-specific health status benefits assessed by the PAQ were largely preserved through 3 years of follow-up (mean change from baseline, 28.0 points, 95% CI: 24.3-31.7; P < 0.0001). CONCLUSIONS: In patients undergoing revascularization for moderately complex SFA disease, use of the self-expanding S.M.A.R.T® stent was associated with a high rate of target vessel patency through 3 years and led to substantial and sustained health status benefits.

Association of Lonafarnib Treatment vs No Treatment With Mortality Rate in Patients With Hutchinson-Gilford Progeria Syndrome.

Importance: Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare fatal premature aging disease. There is no approved treatment. Objective: To evaluate the association of monotherapy using the protein farnesyltransferase inhibitor lonafarnib with mortality rate in children with HGPS. Design, Setting, and Participants: Cohort study comparing contemporaneous (birth date ≥1991) untreated patients with HGPS matched with treated patients by age, sex, and continent of residency using conditional Cox proportional hazards regression. Treatment cohorts included patients from 2 single-group, single-site clinical trials (ProLon1 [n = 27; completed] and ProLon2 [n = 36; ongoing]). Untreated patients originated from a separate natural history study (n = 103). The cutoff date for patient follow-up was January 1, 2018. Exposure: Treated patients received oral lonafarnib (150 mg/m2) twice daily. Untreated patients received no clinical trial medications. Main Outcomes and Measures: The primary outcome was mortality. The primary analysis compared treated patients from the first lonafarnib trial with matched untreated patients. A secondary analysis compared the combined cohorts from both lonafarnib trials with matched untreated patients. Results: Among untreated and treated patients (n = 258) from 6 continents, 123 (47.7%) were female; 141 (54.7%) had a known genotype, of which 125 (88.7%) were classic (c.1824C>T in LMNA). When identified (n = 73), the primary cause of death was heart failure (79.4%). The median treatment duration was 2.2 years. Median age at start of follow-up was 8.4 (interquartile range [IQR], 4.8-9.5) years in the first trial cohort and 6.5 (IQR, 3.7-9.0) years in the combined cohort. There was 1 death (3.7%) among 27 patients in the first trial group and there were 9 deaths (33.3%) among 27 patients in the matched untreated group. Treatment was associated with a lower mortality rate (hazard ratio, 0.12; 95% CI, 0.01-0.93; P = .04). In the combined cohort, there were 4 deaths (6.3%) among 63 patients in the treated group and 17 deaths (27.0%) among 63 patients in the matched untreated group (hazard ratio, 0.23; 95% CI, 0.06-0.90; P = .04). Conclusions and Relevance: Among patients with HGPS, lonafarnib monotherapy, compared with no treatment, was associated with a lower mortality rate after 2.2 years of follow-up. Study interpretation is limited by its observational design.

Clinical Trial of the Protein Farnesylation Inhibitors Lonafarnib, Pravastatin, and Zoledronic Acid in Children With Hutchinson-Gilford Progeria Syndrome.

BACKGROUND: Hutchinson-Gilford progeria syndrome is an extremely rare, fatal, segmental premature aging syndrome caused by a mutation in LMNA yielding the farnesylated aberrant protein progerin. Without progerin-specific treatment, death occurs at an average age of 14.6 years from an accelerated atherosclerosis. A previous single-arm clinical trial demonstrated that the protein farnesyltransferase inhibitor lonafarnib ameliorates some aspects of cardiovascular and bone disease. This present trial sought to further improve disease by additionally inhibiting progerin prenylation. METHODS: Thirty-seven participants with Hutchinson-Gilford progeria syndrome received pravastatin, zoledronic acid, and lonafarnib. This combination therapy was evaluated, in addition to descriptive comparisons with the prior lonafarnib monotherapy trial. RESULTS: No participants withdrew because of side effects. Primary outcome success was predefined by improved per-patient rate of weight gain or carotid artery echodensity; 71.0% of participants succeeded (P<0.0001). Key cardiovascular and skeletal secondary variables were predefined. Secondary improvements included increased areal (P=0.001) and volumetric (P<0.001-0.006) bone mineral density and 1.5- to 1.8-fold increases in radial bone structure (P<0.001). Median carotid artery wall echodensity and carotid-femoral pulse wave velocity demonstrated no significant changes. Percentages of participants with carotid (5% to 50%; P=0.001) and femoral (0% to 12%; P=0.13) artery plaques and extraskeletal calcifications (34.4% to 65.6%; P=0.006) increased. Other than increased bone mineral density, no improvement rates exceeded those of the prior lonafarnib monotherapy treatment trial. CONCLUSIONS: Comparisons with lonafarnib monotherapy treatment reveal additional bone mineral density benefit but likely no added cardiovascular benefit with the addition of pravastatin and zoledronic acid. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00879034 and NCT00916747.

Impact of farnesylation inhibitors on survival in Hutchinson-Gilford progeria syndrome.

BACKGROUND: Hutchinson-Gilford progeria syndrome is an ultrarare segmental premature aging disease resulting in early death from heart attack or stroke. There is no approved treatment, but starting in 2007, several recent single-arm clinical trials administered inhibitors of protein farnesylation aimed at reducing toxicity of the disease-producing protein progerin. No study assessed whether treatments influence patient survival. The key elements necessary for this analysis are a robust natural history of survival and comparison with a sufficiently large patient population that has been treated for a sufficient time period with disease-targeting medications. METHODS AND RESULTS: We generated Kaplan-Meier survival analyses for the largest untreated Hutchinson-Gilford progeria syndrome cohort to date. Mean survival was 14.6 years. Comparing survival for treated versus age- and sex-matched untreated cohorts, hazard ratio was 0.13 (95% confidence interval, 0.04-0.37; P<0.001) with median follow-up of 5.3 years from time of treatment initiation. There were 21 of 43 deaths in untreated versus 5 of 43 deaths among treated subjects. Treatment increased mean survival by 1.6 years. CONCLUSIONS: This study provides a robust untreated disease survival profile that can be used for comparisons now and in the future to assess changes in survival with treatments for Hutchinson-Gilford progeria syndrome. The current comparisons estimating increased survival with protein farnesylation inhibitors provide the first evidence of treatments influencing survival for this fatal disease. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique Indentifiers: NCT00425607, NCT00879034, and NCT00916747.

S.M.A.R.T. self-expanding nitinol stent for the treatment of atherosclerotic lesions in the superficial femoral artery (STROLL): 1-year outcomes.

PURPOSE: To assess safety and efficacy of the S.M.A.R.T. Vascular Stent System (Cordis Corp, Fremont, California) in obstructive superficial femoral artery (SFA) disease. MATERIALS AND METHODS: The single-arm, multicenter STROLL study (S.M.A.R.T. Nitinol Self-Expanding Stent in the Treatment of Obstructive Superficial Femoral Artery Disease) included 250 patients (250 lesions in SFA or proximal popliteal artery). The efficacy endpoint was primary patency defined by freedom from binary restenosis (peak systolic velocity ratio > 2.5) as derived by duplex ultrasound plus clinically driven target lesion revascularization (TLR) at 12 months. RESULTS: Mean age of patients was 67.7 years ± 10.3; 47.2% of patients had diabetes; distribution of Rutherford/Becker classes 2, 3, and 4 was 45.8%, 51.4%, and 2.8%. Mean lesion length and reference vessel diameter were 77.3 mm ± 35.3 and 4.9 mm ± 0.7, respectively (23.6% cases with total occlusions). The 30-day freedom from major adverse events (death, index limb amputation, clinically driven TLR) was 100%. The 1-year primary patency was 81.7% by Kaplan-Meier estimate. The presence of diabetes or total occlusion had no effect on primary patency. Ankle-brachial index was 0.4-0.8 in 84.6% of patients at baseline and improved to > 0.8 in 81.0% of patients at 12 months. The proportion of patients in Rutherford/Becker class 3-4 was reduced from 54.2% at baseline to 8.0% at 12 months. Four patients (2.0%) experienced single-stent strut fracture (type I) at 1 year, without associated loss of stent patency. CONCLUSIONS: The S.M.A.R.T. Vascular Stent System proved to be safe and effective for endovascular treatment of obstructive SFA and proximal popliteal artery disease, based on 1-year vessel patency and associated hemodynamic and clinical improvements.

Application of Cut-Points for Low Muscle Strength and Lean Mass in Mobility-Limited Older Adults.

BACKGROUND: The Sarcopenia Definitions and Outcomes Consortium (SDOC) is a collaborative initiative seeking to develop and evaluate cut-points for low muscle strength and lean mass that predict an increased risk for slowness (usual walking speed <.8 m/s) among older adults. OBJECTIVES: The goal of the present study was to provide clinicians and researchers with an understanding of the diagnostic implications of using SDOC variables and cut-points in mobility-limited older adults. Using data from older individuals with specific conditions that render them at increased risk for mobility limitation, we evaluated the performance characteristics (ie, sensitivity and specificity) of five putative sarcopenia parameters and then compared these values with previously recommended diagnostic criteria for sarcopenia. DESIGN: Retrospective analysis of six randomized controlled trials enriched in persons at risk for mobility limitation. SETTING: National and international geriatric clinical research centers. PARTICIPANTS: A total of 925 mobility-limited older adults (≥55 years of age; 58% women) were included in the analysis. MEASUREMENTS: The prevalence of low muscle strength and lean mass were assessed using five candidate metrics discriminative of slowness. Analyses of sensitivity and specificity were used to compare muscle weakness criteria with published diagnostics for sarcopenia. RESULTS: Odds ratios (ORs) supported maximal grip strength (Grip max <35.5 and 20.0 in men and women, respectively) as the most discriminative of slowness in both men and women (OR = 3.66 and 3.53, respectively). More men (58%) than women (30%) fell below sex-specific maximal grip cut-points. When applying previously recommended sarcopenia component definitions in our population, we found that fewer individuals met those criteria (range = 6%-32%). CONCLUSION: A greater number of individuals fall below SDOC Grip max cut-points compared with previous recommendations. Clinicians and researchers working with older adults may consider these thresholds as an inclusive means to identify candidates for low-risk lifestyle promyogenic and function-promoting therapies. J Am Geriatr Soc 68:1445-1453, 2020.

Bivariate heritability of total and regional brain volumes: the Framingham Study.

Heritability and genetic and environmental correlations of total and regional brain volumes were estimated from a large, generally healthy, community-based sample, to determine if there are common elements to the genetic influence of brain volumes and white matter hyperintensity (WMH) volume. There were 1538 Framingham Heart Study participants with brain volume measures from quantitative magnetic resonance imaging who were free of stroke and other neurologic disorders that might influence brain volumes and who were members of families with at least 2 Framingham Heart Study participants. Heritability was estimated using variance component methodology and adjusting for the components of the Framingham stroke risk profile. Genetic and environmental correlations between traits were obtained from bivariate analysis. Heritability estimates ranging from 0.46 to 0.60 were observed for total brain, WMH, hippocampal, temporal lobe, and lateral ventricular volumes. Moderate, yet significant, heritability was observed for the other measures. Bivariate analyses demonstrated that relationships between brain volume measures, except for WMH, reflected both moderate to strong shared genetic and shared environmental influences. This study confirms strong genetic effects on brain and WMH volumes. These data extend current knowledge by showing that these 2 different types of magnetic resonance imaging measures do not share underlying genetic or environmental influences.

Acute detection of ST-elevation myocardial infarction missed on standard 12-Lead ECG with a novel 80-lead real-time digital body surface map: primary results from the multicenter OCCULT MI trial.

STUDY OBJECTIVE: Although 80-lead ECG body surface mapping is more sensitive for ST-elevation myocardial infarction (STEMI) than the 12-lead ECG, its clinical utility in chest pain in the emergency department (ED) has not been studied. We sought to determine the prevalence, clinical care patterns, and clinical outcomes of patients with STEMI identified on 80-lead but not on 12-lead (80-lead-only STEMI). METHODS: The Optimal Cardiovascular Diagnostic Evaluation Enabling Faster Treatment of Myocardial Infarction trial was a multicenter prospective observational study of moderate- to high-risk chest pain patients presenting to the ED. Patients received simultaneous 12-lead and 80-lead ECGs as part of their initial evaluation and were treated according to the standard of care, with clinicians blinded to the 80-lead results. The primary outcome of the trial was door-to-sheath time in patients with 80-lead-only STEMI versus patients with STEMI identified by 12-lead alone (12-lead STEMI). Secondary outcomes included angiographic and clinical outcomes at 30 days. RESULTS: One thousand eight hundred thirty patients were evaluated, 91 had a discharge diagnosis of 12-lead STEMI, and 25 patients met criteria for 80-lead-only STEMI. Eighty-four of the 91 12-lead STEMI patients underwent cardiac catheterization, with a median door-to-sheath time of 54 minutes, versus 14 of the 25 80-lead-only STEMI patients, with a door-to-sheath time of 1,002 minutes (estimated treatment difference in median=881; 95% confidence interval 181 to 1,079 minutes). Clinical outcomes and revascularization rates, however, were similar between 80-lead-only STEMI and 12-lead STEMI patients. CONCLUSION: The 80-lead ECG provides an incremental 27.5% increase in STEMI detection versus the 12-lead. Patients with 80-lead-only STEMI have adverse outcomes similar to those of 12-lead STEMI patients but are treated with delayed or conservative invasive strategies.

Outcomes of Impella 5.0 in Cardiogenic Shock: A Systematic Review and Meta-analysis.

OBJECTIVE: The aim of the study was to comprehensively summarize the survival outcomes and complications of Impella 5.0 (Abiomed Inc, Danvers, MA USA) use in patients with cardiogenic shock (CS). METHODS: We performed a literature review for relevant studies by searching in Medline, Medline In-Process, EMBASE, and the CENTRAL bibliographic databases on April 30, 2017. Nonoverlapping studies with 10 patients or more supported for cardiogenic shock with Impella 5.0 or Impella left direct were included. Data on patient characteristics, indication of support, and outcomes were extracted. A random effect was used to pool the various outcomes. RESULTS: This meta-analysis included six studies totaling 163 patients (mean ± SD age = 56.3 ± 12.0, male 81%). Indications for support included 88 (54.0%) for acute on chronic decompensated heart failure, 35 (21.5%) for postcardiotomy cardiogenic shock, 27 (16.6%) for acute myocardial infarction complicated by cardiogenic shock, and, 13 (8.0%) for cardiogenic shock due to other reasons. Survival to next therapy was 73.5% in patients supported for acute on chronic decompensated heart failure. The survival to device explant among patients supported for postcardiotomy cardiogenic shock or acute myocardial infarction complicated by cardiogenic shock was 90.2%, and of those, myocardial recovery was achieved in 73.8%. The overall estimated survival to discharge, 30, 180, and 365 days was 73.5%, 72.6%, 62.7%, and 58.4%, respectively. Patients supported for postcardiotomy cardiogenic shock had the highest heart recovery among survivors to explant (92.1%) and highest survival at 30 (89.5%) and 365 days (69.5%). CONCLUSIONS: Impella 5.0/LD is associated with favorable survival outcomes and higher rate of myocardial recovery in patients with cardiogenic shock.

Pubertal Progression in Female Adolescents with Progeria.

STUDY OBJECTIVE: This study identified the prevalence of menarche and coincident sexual characteristics in female adolescents with Hutchinson-Gilford Progeria Syndrome (HGPS). DESIGN: Data were examined to determine the prevalence of menarche in female adolescents older than 12 years; all were participants in clinical trials between 2007 and 2016. SETTING: Pediatric hospital in Boston, Massachusetts. PARTICIPANTS: Fifteen female adolescents, median age 15 (range, 12.0-20.3) years with a confirmed diagnosis of HGPS. INTERVENTIONS AND MAIN OUTCOME MEASURES: Report of menarche, anthropometric and serum hormonal measures, Tanner pubertal staging, and body composition using dual-energy x-ray absorptiometry. RESULTS: Nine of 15 (60%) participants reported spontaneous menarche at a median age of 14.4 years (range, 12.0-16.5 years). In those experiencing menarche vs not, median age was older (16.5 vs 13.6 years; P = .02), whereas body mass index did not differ (10.5 vs 10.4; P = .53) nor percentage body fat (19.4% vs. 19.3%; P = .98) or serum leptin levels (0.40 vs 0.40 ng/mL; P = .23). Among those who achieved menarche, 2 of 9 (22%) had Tanner II breast development and 2 of 9 (22%) exhibited Tanner II Pubic hair, all reflecting minimal pubertal development. Only early signs of puberty were similarly seen in the non-menstruating group, including 1 of 6 (17%) with Tanner II breasts and 2 of 6 (33%) with Tanner II pubic hair, and Tanner staging did not differ between those who reported menarche vs those who did not (each P = 1.0). None of the participants achieved Tanner IV or V thelarche over the course of the study. CONCLUSION: Menarche was achieved in more than half of adolescent girls with HGPS, in the setting of little to no physical signs of pubertal development and minimal body fat.

Evaluation of a combined supported computer education and employment training program for persons with psychiatric disabilities.

Meaningful work is described as one of the functional indicators of healing and growth beyond the disability and is seen as critical in recovering a personal sense of worth and value. We describe a supported education-supported employment program which focused on teaching computer, recovery and work skills. A program evaluation was implemented on four consecutive classes of this program. Four classes with a convenience sample of sixty-one students were involved in the evaluation over years. The program utilized a one group pretest, posttest design, with repeated measures over time. Following the 10-month classroom training phase, students entered a 2-month internship to give them computer office work experience. Students were interviewed quarterly using standardized assessments involving work and other subjective outcomes. Results suggest that overall the students experienced a positive change in work status and income and a decrease in mental health services utilization. In addition, non-vocational outcomes, specifically self-esteem and empowerment improved. The program represents a successful integration of supported education and supported employment program models.

Association of Multiorgan Computed Tomographic Phenomap With Adverse Cardiovascular Health Outcomes: The Framingham Heart Study.

Importance: Increased ability to quantify anatomical phenotypes across multiple organs provides the opportunity to assess their cumulative ability to identify individuals at greatest susceptibility for adverse outcomes. Objective: To apply unsupervised machine learning to define the distribution and prognostic importance of computed tomography-based multiorgan phenotypes associated with adverse health outcomes. Design, Setting, and Participants: This asymptomatic community-based cohort study included 2924 Framingham Heart Study participants between July 2002 and April 2005 undergoing computed tomographic imaging of the chest and abdomen. Participants are from the offspring and third-generation cohorts. Exposures: Eleven computed tomography-based measures of valvular/vascular calcification, adiposity, and muscle attenuation. Main Outcomes and Measures: All-cause mortality and cardiovascular disease (myocardial infarction, stroke, or cardiovascular death). Results: The median age of the participants was 50 years (interquartile range, 43-60 years), and 1422 (48.6%) were men. Principal component analysis identified 3 major anatomic axes: (1) global calcification (defined by aortic, thoracic, coronary, and valvular calcification); (2) adiposity (defined by pericardial, visceral, hepatic, and intrathoracic fat); and (3) muscle attenuation that explained 65.7% of the population variation. Principal components showed different evolution with age (continuous increase in global calcification, decrease in muscle attenuation, and U-shaped association with adiposity) but similar patterns in men and women. Using unsupervised clustering approaches in the offspring cohort (n = 1150), we identified a cohort (n = 232; 20.2%) with an unfavorable multiorgan phenotype across all 3 anatomic axes as compared with a favorable multiorgan phenotype. Membership in the unfavorable phenotypic cluster was associated with a greater prevalence of cardiovascular disease risk factors and with increased all-cause mortality (hazard ratio, 2.61; 95% CI, 1.74-3.92; P < .001), independent of coronary artery calcium score, visceral adipose tissue, and 10-year global cardiovascular disease Framingham risk, and it provided improvement in metrics of discrimination and reclassification. Conclusions and Relevance: This proof-of-concept analysis demonstrates that unsupervised machine learning, in an asymptomatic community cohort, identifies an unfavorable multiorgan phenotype associated with adverse health outcomes, especially in elderly American adults. Future investigations in larger populations are required not only to validate the present results, but also to harness clinical, biochemical, imaging, and genetic markers to increase our understanding of healthy cardiovascular aging.

Calcium concentration of individual coronary calcified plaques as measured by multidetector row computed tomography.

BACKGROUND: Characteristics of individual calcified plaques, especially calcium concentration (CC), may provide incremental value to global calcium scores in the assessment of plaque burden and risk of coronary events and evaluation of therapeutic intervention. In this study, therefore, we assessed the characteristics of individual calcified plaques and their relationship to other parameters derived from CT analysis of coronary calcium in a community-based cross-sectional cohort. METHODS AND RESULTS: Coronary artery calcium (CAC) was analyzed in 612 participants of the Framingham Heart Study (third-generation and offspring cohorts) using prospectively ECG-triggered multidetector CT. We determined the CC, Agatston score, calcified volume, and mineral mass of individual calcified plaques in each subject. Heterogeneity of CC was defined as the standard deviation of CC of all individual calcified plaques in a subject. CAC was detected in 274 of 605 subjects. After excluding 57 subjects (21%) because of motion artifacts, we identified a total of 956 calcified coronary plaques in 217 subjects (74 women, 143 men; mean age, 57.1+/-10.8 years) with detectable CAC and no image artifacts. CC of individual calcified plaques was independent of subject age (P=0.76) and sex (197.8+/-74.8 versus 183.6+/-52.8 mg/cm3 for men versus women; P=0.21). Among a subgroup of 125 subjects with multiple (> or =3) individual calcified plaques, CC was heterogeneous within individual subjects (mean SD of CC, 43.6+/-23.1 mg/cm3). The degree of heterogeneity of CC in these subjects was independent of age (P=0.60), sex (P=0.99), and number of plaques (P=0.06). CONCLUSIONS: The CC of individual calcified plaques is independent of age and sex but heterogeneous within a subject, which may reflect that the pathological process of calcified plaque formation and progression is the same in men and women regardless of age. CC may have incremental value to global calcium scores in the assessment of plaque burden and risk of coronary events and the evaluation of therapeutic intervention. Further studies are warranted to confirm that individual plaque analysis is preferable to global CAC scores to evaluate progression of atherosclerosis and to assess whether individual plaque analysis may be complementary to global CAC measures to assess coronary event risk.

Responsibilities of Data Monitoring Committees: Consensus Recommendations.

BACKGROUND: A data monitoring committee (DMC) has special responsibilities for protecting the safety of clinical trial participants. Few guidance documents are available that address the operations and mechanics of establishing, serving on, or reporting to a DMC. This article provides a practical guide to sponsors, institutions, and individuals responsible for, or serving on, a DMC. METHODS: A workgroup of professionals from academia and not-for-profit and commercial organizations that included investigators, statisticians, patient advocates, and ethicists met to define the essential elements of planning, coordinating, and populating a DMC. All members of the group have formed, served on, advised, or worked with DMCs. RESULTS: The group outlined the objectives and mechanics of running a DMC, including operational and practical considerations, membership characteristics, roles, members' liability, and indemnification. Further, it delineated the roles and responsibilities of each DMC member. CONCLUSIONS: The group recommended practices for each phase of the DMC process from inception through execution of a clinical trial, with appropriate considerations for confidentiality. The group's practical guidance should assist in comprehensive oversight of appropriate clinical trials and should help DMC members execute their obligations with greater assurance.

Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis.

BACKGROUND: The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease. We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent coronary heart disease. METHODS AND RESULTS: We studied a total of 25 109 European ancestry and African ancestry participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52 869 participants with common carotid intima-media thickness measured by ultrasonography within the CHARGE Consortium (Cohorts for Heart and Aging Research in Genomic Epidemiology). Participants were genotyped for 247 870 DNA sequence variants (231 539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and carotid intima-media thickness. APOB p.Arg3527Gln was associated with 4-fold excess CAC (P=3×10-10). The APOE ε2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC (P=1×10-12) and 1.4% reduced carotid intima-media thickness (P=4×10-14) in carriers compared with noncarriers. In secondary analyses conditioning on low-density lipoprotein cholesterol concentration, the ε2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ε2 was associated with reduced risk for coronary heart disease (odds ratio 0.77; P=1×10-11). CONCLUSIONS: Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE ε2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities, as well as clinical coronary heart disease.

Reproducibility of a novel computed-tomography based measurement of renal papillary density in the Framingham Heart Study.

BACKGROUND: Renal papillary calcification is a compelling candidate risk factor for chronic kidney disease (CKD) and nephrolithiasis. Renal papillary density (RPD), as assessed by computed tomography (CT), is a potential marker for calcification that has not been well studied. We developed a protocol to measure RPD using CT scans and assessed its reproducibility in participants from the Framingham Heart Study. METHODS: We assessed RPD of right kidneys from a single abdominal CT slice in 100 representative participants from the Framingham Heart Study (47% female, mean age 59.9 years) using a novel protocol. We selected the kidney slice with the most open sinus space and assessed RPD using the average of three 20 mm(2) ellipses from upper, middle and lower papillary regions. Two different readers performed RPD measurements and the first reader repeated all measurements to determine both intra- and inter-reader reproducibility, respectively. RESULTS: Of 100 total individuals included in the replication dataset, six were excluded for poor scan quality. Average RPD across all individuals was 48.7 ± 4.7 (range 38.7-61.7) Hounsfield Units (HU). The intra- and inter-reader correlation coefficients were 0.86 and 0.79, respectively. Bland-Altman analysis suggested no systematic bias between the different reads. CONCLUSION: Measuring RPD is practical and reproducible using MDCT scans from a small sample of a community-based cohort.

Clinical outcome of patients with and without diabetes mellitus after percutaneous coronary intervention with the resolute zotarolimus-eluting stent: 2-year results from the prospectively pooled analysis of the international global RESOLUTE program.

OBJECTIVES: The aim of this study was to describe the process to obtain Food and Drug Administration (FDA) approval for the expanded indication for treatment with the Resolute zotarolimus-eluting stent (R-ZES) (Medtronic, Inc., Santa Rosa, California) in patients with coronary artery disease and diabetes. BACKGROUND: The R-ZES is the first drug-eluting stent specifically indicated in the United States for percutaneous coronary intervention in patients with diabetes. METHODS: We pooled patient-level data for 5,130 patients from the RESOLUTE Global Clinical Program. A performance goal prospectively determined in conjunction with the FDA was established as a rate of target vessel failure at 12 months of 14.5%. In addition to the FDA pre-specified cohort of less complex patients with diabetes (n = 878), we evaluated outcomes of the R-ZES in all 1,535 patients with diabetes compared with all 3,595 patients without diabetes at 2 years. RESULTS: The 12-month rate of target vessel failure in the pre-specified diabetic cohort was 7.8% (upper 95% confidence interval: 9.51%), significantly lower than the performance goal of 14.5% (p < 0.001). After 2 years, the cumulative incidence of target lesion failure in patients with noninsulin-treated diabetes was comparable to that of patients without diabetes (8.0% vs. 7.1%). The higher risk insulin-treated population demonstrated a significantly higher target lesion failure rate (13.7%). In the whole population, including complex patients, rates of stent thrombosis were not significantly different between patients with and without diabetes (1.2% vs. 0.8%). CONCLUSIONS: The R-ZES is safe and effective in patients with diabetes. Long-term clinical data of patients with noninsulin-treated diabetes are equivalent to patients without diabetes. Patients with insulin-treated diabetes remain a higher risk subset. (The Medtronic RESOLUTE Clinical Trial; NCT00248079; Randomized, Two-arm, Non-inferiority Study Comparing Endeavor-Resolute Stent With Abbot Xience-V Stent [RESOLUTE-AC]; NCT00617084; The Medtronic RESOLUTE US Clinical Trial (R-US); NCT00726453; RESOLUTE International Registry: Evaluation of the Resolute Zotarolimus-Eluting Stent System in a 'Real-World' Patient Population [R-Int]; NCT00752128; RESOLUTE Japan-The Clinical Evaluation of the MDT-4107 Drug-Eluting Coronary Stent [RJ]; NCT00927940).

Incremental benefit of 80-lead electrocardiogram body surface mapping over the 12-lead electrocardiogram in the detection of acute coronary syndromes in patients without ST-elevation myocardial infarction: Results from the Optimal Cardiovascular Diagnostic Evaluation Enabling Faster Treatment of Myocardial Infarction (OCCULT MI) trial.

BACKGROUND: The initial 12-lead (12L) electrocardiogram (ECG) has low sensitivity to detect myocardial infarction (MI) and acute coronary syndromes (ACS) in the emergency department (ED). Yet, early therapies in these patients have been shown to improve outcomes. OBJECTIVES: The Optimal Cardiovascular Diagnostic Evaluation Enabling Faster Treatment of Myocardial Infarction (OCCULT-MI) trial was a multicenter trial comparing a novel 80-lead mapping system (80L) to standard 12L ECG in patients with chest pain and presumed ACS. This secondary analysis analyzed the incremental value of the 80L over the 12L in the detection of high-risk ECG abnormalities (ST-segment elevation or ST depression) in patients with MI and ACS, after eliminating all patients diagnosed with ST-elevation MI (STEMI) by 12L ECG. METHODS: Chest pain patients presenting to one of 12 academic EDs were diagnosed and treated according to the standard care of that site and its clinicians; the clinicians were blinded to 80L results. MI was defined by discharge diagnosis of non-ST-elevation MI (NSTEMI) or unstable angina (UA) with an elevated troponin. ACS was defined as discharge diagnosis of NSTEMI or UA with at least one positive test result (troponin, stress test, angiogram) or revascularization procedure. RESULTS: Of the 1,830 patients enrolled in the trial, 91 patients with physician-diagnosed STEMI and 225 patients with missing 80L or 12L data were eliminated from the analysis; no discharge diagnosis was available for one additional patient. Of the remaining 1,513 patients, 408 had ACS, 206 had MI, and one had missing status. The sensitivity of the 80L was significantly higher than that of the 12L for detecting MI (19.4% vs. 10.4%, p = 0.0014) and ACS (12.3% vs. 7.1%, p = 0.0025). Specificities remained high for both tests, but were somewhat lower for 80L than for 12L for detecting both MI and ACS. Negative and positive likelihood ratios (LR) were not statistically different between groups. In patients with severe disease (defined by stenosis > 70% at catheterization, percutaneous coronary intervention, coronary artery bypass graft, or death from any cause), the 80L had significantly higher sensitivity for detecting MI (with equivalent specificity), but not ACS. CONCLUSIONS: Among patients without ST elevation on the 12L ECG, the 80L body surface mapping technology detects more patients with MI or ACS than the 12L, while maintaining a high degree of specificity.