Braunwald E.,Brigham and Womens Hospital |
Braunwald E.,Harvard University
The Lancet | Year: 2015
Heart failure is a global problem with an estimated prevalence of 38 million patients worldwide, a number that is increasing with the ageing of the population. It is the most common diagnosis in patients aged 65 years or older admitted to hospital and in high-income nations. Despite some progress, the prognosis of heart failure is worse than that of most cancers. Because of the seriousness of the condition, a declaration of war on five fronts has been proposed for heart failure. Efforts are underway to treat heart failure by enhancing myofilament sensitivity to Ca2+; transfer of the gene for SERCA2a, the protein that pumps calcium into the sarcoplasmic reticulum of the cardiomyocyte, seems promising in a phase 2 trial. Several other abnormal calcium-handling proteins in the failing heart are candidates for gene therapy; many short, non-coding RNAs - ie, microRNAs (miRNAs) - block gene expression and protein translation. These molecules are crucial to calcium cycling and ventricular hypertrophy. The actions of miRNAs can be blocked by a new class of drugs, antagomirs, some of which have been shown to improve cardiac function in animal models of heart failure; cell therapy, with autologous bone marrow derived mononuclear cells, or autogenous mesenchymal cells, which can be administered as cryopreserved off the shelf products, seem to be promising in both preclinical and early clinical heart failure trials; and long-term ventricular assistance devices are now used increasingly as a destination therapy in patients with advanced heart failure. In selected patients, left ventricular assistance can lead to myocardial recovery and explantation of the device. The approaches to the treatment of heart failure described, when used alone or in combination, could become important weapons in the war against heart failure. © 2015 Elsevier Ltd.
Humphreys B.D.,Brigham and Womens Hospital
Nature Cell Biology | Year: 2014
Generation of differentiated kidney cell types from pluripotent stem cells would be enormously useful for research and therapeutic purposes, but progress towards this goal has so far been limited. In three recent reports, mature kidney cell types and three-dimensional nephron-like structures were generated from pluripotent cells rapidly and efficiently. A detailed understanding of the signals that drive nephrogenesis proved critical for these achievements. © 2014 Macmillan Publishers Limited.
Chasman D.I.,Brigham and Womens Hospital
Circulation | Year: 2011
BACKGROUND - C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We sought to identify genetic variants that are associated with CRP levels. METHODS AND RESULTS - We performed a genome-wide association analysis of CRP in 66 185 participants from 15 population-based studies. We sought replication for the genome-wide significant and suggestive loci in a replication panel comprising 16 540 individuals from 10 independent studies. We found 18 genome-wide significant loci, and we provided evidence of replication for 8 of them. Our results confirm 7 previously known loci and introduce 11 novel loci that are implicated in pathways related to the metabolic syndrome (APOC1, HNF1A, LEPR, GCKR, HNF4A, and PTPN2) or the immune system (CRP, IL6R, NLRP3, IL1F10, and IRF1) or that reside in regions previously not known to play a role in chronic inflammation (PPP1R3B, SALL1, PABPC4, ASCL1, RORA, and BCL7B). We found a significant interaction of body mass index with LEPR (P<2.9×10). A weighted genetic risk score that was developed to summarize the effect of risk alleles was strongly associated with CRP levels and explained ≈5% of the trait variance; however, there was no evidence for these genetic variants explaining the association of CRP with coronary heart disease. CONCLUSIONS - We identified 18 loci that were associated with CRP levels. Our study highlights immune response and metabolic regulatory pathways involved in the regulation of chronic inflammation. © 2011 American Heart Association, Inc.
Flynn-Evans E.E.,Brigham and Womens Hospital
Journal of the National Cancer Institute | Year: 2013
Background Shiftwork has been implicated as a risk factor for prostate cancer. Results from prior studies have been mixed but generally support an association between circadian disruption and prostate cancer. Our aim was to investigate the relationship between shiftwork and prostate-specific antigen (PSA) test obtained as part of the National Health and Nutrition Examination Survey (NHANES) study. Methods We combined three NHANES surveys (2005-2010) to obtain current work schedule among employed men aged 40 to 65 years with no prior history of cancer (except nonmelanoma skin cancer). Men who reported working regular night shifts or rotating shifts were considered shiftworkers. We obtained the total and percentage free PSA test results for these men and dichotomized total PSA into less than 4.0 ng/mL or 4.0 ng/mL or greater and total PSA of 4.0 ng/mL or greater combined with percentage free PSA less than or equal to 25%. Using multivariable logistic regression models, we compared PSA level among current shiftworkers and nonshiftworkers. All statistical tests were two-sided. Results We found a statistically significant, age-adjusted association between current shiftwork and elevated PSA at the 4.0 ng/mL or greater level (odds ratio = 2.48, 95% confidence interval [CI] = 1.08 to 5.70; P = .03). The confounderadjusted odds ratio was 2.62 (95% CI = 1.16 to 5.95; P = .02). The confounder-adjusted odds ratio for those with total PSA of 4.0 ng/mL or greater and free PSA less than or equal to 25% was 3.13 (95% CI = 1.38 to 7.09; P = .01). Conclusions We observed a strong positive association with shiftwork and elevated PSA level. Our data support the notion that sleep or circadian disruption is associated with elevated PSA, indicating that shiftworking men likely have an increased risk of developing prostate cancer. © The Author 2013. Published by Oxford University Press. All rights reserved.
Blankstein R.,Brigham and Womens Hospital
Journal of the American College of Cardiology | Year: 2011
Our aim was to identify risk factors for coronary heart disease (CHD) events among asymptomatic persons with low (≤ 130 mg/dl) low-density lipoprotein cholesterol (LDL-C). Even among persons with low LDL-C, some will still experience CHD events and may benefit from more aggressive pharmacologic and lifestyle therapies. The MESA (Multi-Ethnic Study of Atherosclerosis) is a prospective cohort of 6,814 participants free of clinical cardiovascular disease. Of 5,627 participants who were not receiving any baseline lipid-lowering therapies, 3,714 (66%) had LDL-C ≤ 130 mg/dl and were included in the present study. Unadjusted and adjusted hazard ratios were calculated to assess the association of traditional risk factors and biomarkers with CHD events. To determine if subclinical atherosclerosis markers provided additional information beyond traditional risk factors, coronary artery calcium (CAC) and carotid intima media thickness were each separately added to the multivariable model. During a median follow-up of 5.4 years, 120 (3.2%) CHD events were observed. In unadjusted analysis, age, male sex, hypertension, diabetes mellitus, low high-density lipoprotein cholesterol (HDL-C), high triglycerides, and subclinical atherosclerosis markers (CAC >0; carotid intima media thickness ≥1 mm) predicted CHD events. Independent predictors of CHD events included age, male sex, hypertension, diabetes, and low HDL-C. After accounting for all traditional risk factors, the predictive value of CAC was attenuated but remained highly significant. The relationship of all independent clinical predictors remained robust even after accounting for elevated CAC. Among persons with low LDL-C, older age, male sex, hypertension, diabetes, and low HDL-C are associated with adverse CHD events. Even after accounting for all such variables, the presence of CAC provided incremental prognostic value. These results may serve as a basis for deciding which patients with low LDL-C may be considered for more aggressive therapies. Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.