Asya Lyass

Galectin-3, a marker of cardiac fibrosis, predicts incident heart failure in the community.

OBJECTIVES The aim of this study was to examine the relation of galectin-3 (Gal-3), a marker of cardiac fibrosis, with incident heart failure (HF) in the community. BACKGROUND Gal-3 is an emerging prognostic biomarker in HF, and experimental studies suggest that Gal-3 is an important mediator of cardiac fibrosis. Whether elevated Gal-3 concentrations precede the development of HF is unknown. METHODS Gal-3 concentrations were measured in 3,353 participants in the Framingham Offspring Cohort (mean age 59 years; 53% women). The relation of Gal-3 to incident HF was assessed using proportional hazards regression. RESULTS Gal-3 was associated with increased left ventricular mass in age-adjusted and sex-adjusted analyses (p = 0.001); this association was attenuated in multivariate analyses (p = 0.06). A total of 166 participants developed incident HF and 468 died during a mean follow-up period of 11.2 years. Gal-3 was associated with risk for incident HF (hazard ratio [HR]: 1.28 per 1 SD increase in log Gal-3; 95% confidence interval [CI]: 1.14 to 1.43; p < 0.0001) and remained significant after adjustment for clinical variables and B-type natriuretic peptide (HR: 1.23; 95% CI: 1.04 to 1.47; p = 0.02). Gal-3 was also associated with risk for all-cause mortality (multivariable-adjusted HR: 1.15; 95% CI: 1.04 to 1.28; p = 0.01). The addition of Gal-3 to clinical factors resulted in negligible changes to the C-statistic and minor improvements in net reclassification improvement. CONCLUSIONS Higher concentration of Gal-3, a marker of cardiac fibrosis, is associated with increased risk for incident HF and mortality. Future studies evaluating the role of Gal-3 in cardiac remodeling may provide further insights into the role of Gal-3 in the pathophysiology of HF.

Cardiac Dysfunction and Noncardiac Dysfunction as Precursors of Heart Failure With Reduced and Preserved Ejection Fraction in the Community

Background— Heart failure (HF) is a clinical syndrome characterized by signs and symptoms involving multiple organ systems. Longitudinal data demonstrating that asymptomatic cardiac dysfunction precedes overt HF are scarce, and the contribution of noncardiac dysfunction to HF progression is unclear. We hypothesized that subclinical cardiac and noncardiac organ dysfunction would accelerate the manifestation of HF. Methods and Results— We studied 1038 participants of the Framingham Heart Study original cohort (mean age, 76±5 years; 39% men) with routine assessment of left ventricular systolic and diastolic function. Major noncardiac organ systems were assessed with the use of serum creatinine (renal), serum albumin (hepatic), ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1:FVC ratio; pulmonary), hemoglobin concentration (hematologic/oxygen-carrying capacity), and white blood cell count (systemic inflammation). On follow-up (mean, 11 years), there were 248 incident HF events (146 in women). After adjustment for established HF risk factors, antecedent left ventricular systolic dysfunction (hazard ratio, 2.33; 95% confidence interval, 1.43 to 3.78) and diastolic dysfunction (hazard ratio, 1.32; 95% confidence interval, 1.01 to 1.71) were associated with increased HF risk. After adjustment for cardiac dysfunction, higher serum creatinine, lower FEV1:FVC ratios, and lower hemoglobin concentrations were associated with increased HF risk (all P<0.05); serum albumin and white blood cell count were not. Subclinical dysfunction in each noncardiac organ system was associated with a 30% increased risk of HF (P=0.013). Conclusions— Antecedent cardiac dysfunction and noncardiac organ dysfunction are associated with increased incidence of HF, supporting the notion that HF is a progressive syndrome and underscoring the importance of noncardiac factors in its occurrence.

The Kinesin Motor KIF3A Is a Component of the Presynaptic Ribbon in Vertebrate Photoreceptors

Kinesin motors are presumed to transport various membrane compartments within neurons, but their specific in vivofunctions, cargoes, and expression patterns in the brain are unclear. We have investigated the distribution of KIF3A, a member of the heteromeric family of kinesins, in the vertebrate retina. We find KIF3A at two distinct sites within photoreceptors: at the basal body of the connecting cilium axoneme and at the synaptic ribbon. Immunoelectron microscopy of the photoreceptor ribbon synapse shows KIF3A to be concentrated both at the ribbon matrix and on vesicles docked at the ribbon, a result that is consistent with the presence of both detergent-extractable and resistant KIF3A fractions at these synapses. KIF3A is also present in the inner plexiform layer, again at presynaptic ribbons. These findings suggest that within a single cell, the photoreceptor, one kinesin polypeptide, KIF3A, can serve two distinct functions, one specific for ribbon synapses.

A reciprocal tensin-3-cten switch mediates EGF-driven mammary cell migration

Cell migration driven by the epidermal growth factor receptor (EGFR) propels morphogenesis and involves reorganization of the actin cytoskeleton. Although de novo transcription precedes migration, transcript identity remains largely unknown. Through their actin-binding domains, tensins link the cytoskeleton to integrin-based adhesion sites. Here we report that EGF downregulates tensin-3 expression, and concomitantly upregulates cten, a tensin family member that lacks the actin-binding domain. Knockdown of cten or tensin-3, respectively, impairs or enhances mammary cell migration. Furthermore, cten displaces tensin-3 from the cytoplasmic tail of integrin β1, thereby instigating actin fibre disassembly. In invasive breast cancer, cten expression correlates not only with high EGFR and HER2, but also with metastasis to lymph nodes. Moreover, treatment of inflammatory breast cancer patients with an EGFR/HER2 dual-specificity kinase inhibitor significantly downregulated cten expression. In conclusion, a transcriptional tensin-3–cten switch may contribute to the metastasis of mammary cancer.

Predictors of New-Onset Heart Failure: Differences in Preserved Versus Reduced Ejection Fraction

Background— About one half of patients with heart failure (HF) have preserved ejection fraction (HFPEF) rather than reduced ejection fraction (HFREF). The differences in risk factors predisposing to the 2 subtypes of HF are poorly understood. We sought to identify clinical predictors of new-onset HF and to explore differences in HFPEF versus HFREF. Methods and Results— We studied new-onset HF cases between 1981 and 2008 in Framingham Heart Study participants, classified into HFPEF and HFREF (ejection fraction >45% versus ≤45%). We used Cox multivariable regression to examine predictors of 8-year risk of incident HF and competing-risks analysis to identify predictors that differed between HFPEF and HFREF. Among 6340 participants (60±12 years) with 97 808 person-years of follow-up, 512 developed incident HF. Of 457 participants with left ventricular ejection fraction evaluation at the time of HF diagnosis, 196 (43%) were classified as HFPEF and 261 (56%) as HFREF. Fourteen predictors of overall HF were identified. Older age, diabetes mellitus, and a history of valvular disease predicted both types of HF ( P ≤0.0025 for all). Higher body mass index, smoking, and atrial fibrillation predicted HFPEF only, whereas male sex, higher total cholesterol, higher heart rate, hypertension, cardiovascular disease, left ventricular hypertrophy, and left bundle-branch block predicted risk of HFREF. Conclusions— Although multiple risk factors preceded overall HF, distinct clusters of risk factors determine risk for new-onset HFPEF versus HFREF. This knowledge may enable the design of clinical trials of targeted prevention and the introduction of therapeutic strategies for prevention of HF and its 2 major subtypes.Background—About one half of patients with heart failure (HF) have preserved ejection fraction (HFPEF) rather than reduced ejection fraction (HFREF). The differences in risk factors predisposing to the 2 subtypes of HF are poorly understood. We sought to identify clinical predictors of new-onset HF and to explore differences in HFPEF versus HFREF. Methods and Results—We studied new-onset HF cases between 1981 and 2008 in Framingham Heart Study participants, classified into HFPEF and HFREF (ejection fraction >45% versus ⩽45%). We used Cox multivariable regression to examine predictors of 8-year risk of incident HF and competing-risks analysis to identify predictors that differed between HFPEF and HFREF. Among 6340 participants (60±12 years) with 97 808 person-years of follow-up, 512 developed incident HF. Of 457 participants with left ventricular ejection fraction evaluation at the time of HF diagnosis, 196 (43%) were classified as HFPEF and 261 (56%) as HFREF. Fourteen predictors of overall HF were identified. Older age, diabetes mellitus, and a history of valvular disease predicted both types of HF (P⩽0.0025 for all). Higher body mass index, smoking, and atrial fibrillation predicted HFPEF only, whereas male sex, higher total cholesterol, higher heart rate, hypertension, cardiovascular disease, left ventricular hypertrophy, and left bundle-branch block predicted risk of HFREF. Conclusions—Although multiple risk factors preceded overall HF, distinct clusters of risk factors determine risk for new-onset HFPEF versus HFREF. This knowledge may enable the design of clinical trials of targeted prevention and the introduction of therapeutic strategies for prevention of HF and its 2 major subtypes.

Sustained and Shorter Bouts of Physical Activity are Related to Cardiovascular Health

PURPOSE Whereas greater physical activity (PA) is known to prevent cardiovascular disease (CVD), the relative importance of performing PA in sustained bouts of activity versus shorter bouts of activity on CVD risk is not known. The objective of this study was to investigate the relationship between moderate-to-vigorous PA (MVPA), measured in bouts ≥10 and <10 min, and CVD risk factors in a well-characterized community-based sample of white adults. METHODS We conducted a cross-sectional analysis of 2109 participants in the Third Generation Cohort of the Framingham Heart Study (mean age = 47 yr, 55% women) who underwent objective assessment of PA by accelerometry over 5-7 d. Total MVPA, MVPA done in bouts ≥10 min (MVPA(10+)), and MVPA done in bouts <10 min (MVPA(<10)) were calculated. MVPA exposures were related to individual CVD risk factors, including measures of adiposity and blood lipid and glucose levels, using linear and logistic regression. RESULTS Total MVPA was significantly associated with higher HDL levels and with lower triglycerides, BMI, waist circumference, and Framingham risk score (P < 0.0001). MVPA(<10) showed similar statistically significant associations with these CVD risk factors (P < 0.001). Compliance with national guidelines (≥150 min of total MVPA) was significantly related to lower BMI, triglycerides, Framingham risk score, waist circumference, higher HDL, and a lower prevalence of obesity and impaired fasting glucose (P < 0.001 for all). CONCLUSIONS Our cross-sectional observations on a large middle-age community-based sample confirm a positive association of MVPA with a healthier CVD risk factor profile and indicate that accruing PA in bouts <10 min may favorably influence cardiometabolic risk. Additional investigations are warranted to confirm our findings.

An Investigation of Reasonable Workplace Accommodations for People with Psychiatric Disabilities: Quantitative Findings from a Multi-Site Study

Despite the requirement of many employers to provide accommodations in the workplace for individuals with disabilities under Section 504 of the Rehabilitation Act of 1973, the preponderance of accommodations that have been described in the literature concern physical rather than psychiatric disabilities. This study was an exploratory, descriptive, longitudinal, multi-site investigation of reasonable workplace accommodations for individuals with psychiatric disabilities involved in supported employment programs. We discuss the functional limitations and reasonable accommodations provided to 191 participants and the characteristics of 204 employers and 22 service provider organizations participating in the study. Implications for service providers and administrators in supported employment programs are discussed.

Relations of Exercise Blood Pressure Response to Cardiovascular Risk Factors and Vascular Function in the Framingham Heart Study

Background— Exercise blood pressure (BP) is an important marker of left ventricular hypertrophy, incident hypertension, and future cardiovascular events. Although impaired vascular function is hypothesized to influence the BP response during exercise, limited data exist on the association of vascular function with exercise BP in the community. Methods and Results— Framingham Offspring cohort participants (n=2115, 53% women, mean age 59 years) underwent a submaximal exercise test (first 2 stages of the Bruce protocol), applanation tonometry, and brachial artery flow-mediated dilation testing. We related exercise systolic and diastolic BP at second stage of the Bruce protocol to standard cardiovascular risk factors and to vascular function measures. In multivariable linear regression models, exercise systolic BP was positively related to age, standing BP, standing heart rate, smoking, body mass index, and the total cholesterol–to–high-density cholesterol ratio (P⩽0.01 for all). Similar associations were observed for exercise diastolic BP. Carotid-femoral pulse wave velocity (P=0.02), central pulse pressure (P<0.0001), mean arterial pressure (P=0.04), and baseline brachial flow (P=0.002) were positively associated with exercise systolic BP, whereas flow-mediated dilation was negatively associated (P<0.001). For exercise diastolic BP, forward pressure wave amplitude was negatively related (P<0.0001), whereas mean arterial pressure was positively related (P<0.0001). Conclusions— Increased arterial stiffness and impaired endothelial function are significant correlates of a higher exercise systolic BP response. Our findings suggest that impaired vascular function may contribute to exaggerated BP responses during daily living, resulting in repetitive increments in load on the heart and vessels and increased cardiovascular disease risk.

The Nature and Dimensions of Social Support Among Individuals with Severe Mental Illnesses

Recent research suggests that social support is associated with recovery from chronic diseases, greater life satisfaction, and enhanced ability to cope with life stressors. To further research in the area of social support and serious psychiatric disabilities, more reliable and valid measures are needed to assess this construct. The purpose of this study was to assess the psychometric properties of a widely used measure of social support (the Interpersonal Support Evaluation Checklist) among people with severe mental illness. We collected data on the ISELs relationship to quality of life, self-esteem, psychiatric symptoms and vocational status among 147 participants. Factor and reliability analyses, as well as correlational analyses were undertaken. We found evidence for the reliability and validity of the ISEL when used with persons with severe mental illness. Taken together, our findings suggested that self-esteem, quality of life, and psychiatric symptoms were able to predict 38% of the variance in perceived social support. More favorable social supports increased the odds of being employed at 9months into the study and social support was predictive of experiencing fewer psychiatric symptoms. Some forms of social support were perceived less favorably with age, but no other demographic or clinical variables significantly predicted perceived social supports.

Association of physical activity and heart failure with preserved vs. reduced ejection fraction in the elderly: the Framingham Heart Study

Reduced physical activity is associated with increased risk of heart failure (HF) in middle‐aged individuals. We hypothesized that physical inactivity is also associated with greater HF risk in older individuals, and examined if the association was consistent for HF with preserved ejection fraction (HFPEF) vs. HF with a reduced ejection fraction (HFREF).