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Whitaker, United States

Jefferson A.L.,Whitaker Cardiovascular Institute | Jefferson A.L.,Boston University
Journal of Alzheimer's Disease | Year: 2010

Heart failure has served as a clinically useful model for understanding how cardiac dysfunction is associated with neuroanatomic and neuropsychological changes in aging adults, theoretically because systemic hypoperfusion disrupts cerebral perfusion, contributing to clinical brain injury. This review summarizes more recent data suggesting that subtle cardiac dysfunction or low normal levels of cardiac function, as quantified by cardiac output, are related to cognitive and neuroimaging markers of abnormal brain aging in the absence of heart failure or severe cardiomyopathy. Additional work is required, but such associations suggest that reduced cardiac output may be a risk factor for Alzheimer's disease (AD) and abnormal brain aging through the propagation or exacerbation of neurovascular processes, microembolism due to thrombosis, and AD neuropathological processes. Such mechanistic pathways are discussed in the context of a theoretical model that posits a direct pathway of injury between cardiac output and abnormal brain aging (i.e., reduced systemic blood flow disrupts cerebral blood flow homeostasis), contributing to clinical brain injury, independent of shared risk factors for both cardiac dysfunction and abnormal brain aging. © 2010 - IOS Press and the authors. Source

Lubitz S.A.,Massachusetts General Hospital | Lubitz S.A.,Brigham and Womens Hospital | Benjamin E.J.,Whitaker Cardiovascular Institute | Benjamin E.J.,Boston University | And 2 more authors.
Heart Failure Clinics | Year: 2010

Atrial fibrillation and congestive heart failure are morbid conditions that have common risk factors and frequently coexist. Each condition predisposes to the other, and the concomitant presence of the two identifies individuals at increased risk for mortality. Recent data have emerged that help elucidate the complex genetic and nongenetic pathophysiological mechanisms that contribute to the development of atrial fibrillation in individuals with congestive heart failure. Clinical trial results offer insights into the noninvasive prevention and management of these conditions, although newer technologies, such as catheter ablation for atrial fibrillation, have yet to be studied extensively in patients with congestive heart failure. © 2010 Elsevier Inc. All rights reserved. Source

Gall J.M.,Boston University | Wong V.,Boston University | Pimental D.R.,Whitaker Cardiovascular Institute | Havasi A.,Boston University | And 5 more authors.
Kidney International | Year: 2011

Hexokinase (HK), the rate-limiting enzyme in glycolysis, controls cell survival by promoting metabolism and/or inhibiting apoptosis. Since HK isoforms I and II have mitochondrial targeting sequences, we attempted to separate the protective effects of HK on cell metabolism from those on apoptosis. We exposed renal epithelial cells to metabolic stress causing ATP depletion in the absence of glucose and found that this activated glycogen synthase kinase 3Β (GSK3Β) and Bax caused mitochondrial membrane injury and apoptosis. ATP depletion led to a progressive HK II dissociation from mitochondria, released mitochondrial apoptosis inducing factor and cytochrome c into the cytosol, activated caspase-3, and reduced cell survival. Compared with control, adenoviral-mediated HK I or II overexpression improved cell survival following stress, but did not prevent GSK3Β or Bax activation, improve ATP content, or reduce mitochondrial fragmentation. HK I or HK II overexpression increased mitochondria-associated isoform-specific HK content, and decreased mitochondrial membrane injury and apoptosis after stress. In vivo, HK II localized exclusively to the proximal tubule. Ischemia reduced total renal HK II content and dissociated HK II from proximal tubule mitochondria. In cells overexpressing HK II, Bax and HK II did not interact before or after stress. While the mechanism by which HK antagonizes Bax-mediated apoptosis is unresolved by these studies, one possible scenario is that the two proteins compete for a common binding site on the outer mitochondrial membrane. © 2011 International Society of Nephrology. Source

Seldin D.C.,Boston University | Seldin D.C.,Boston Medical Center | Berk J.L.,Boston University | Sam F.,Boston University | And 3 more authors.
Heart Failure Clinics | Year: 2011

Amyloidotic cardiomyopathy (ACMP) occurs in the setting of rare genetic diseases, blood dyscrasias, chronic infection and inflammation, and advanced age. Cardiologists are on the front lines of diagnosis of ACMP when evaluating patients with unexplained dyspnea, congestive heart failure, or arrhythmias. Noninvasive detection of diastolic cardiac dysfunction and unexplained left ventricular hypertrophy should be followed by biopsy to demonstrate the presence of amyloid deposits and appropriate genetic, biochemical, and immunologic testing to accurately define the type of amyloid. Growing numbers of treatment options exist for these diseases, and timely diagnosis and institution of therapy is essential for preservation of cardiac function. © 2011 Elsevier Inc. Source

Schnabel R.B.,Boston University | Larson M.G.,Boston University | Larson M.G.,Whitaker Cardiovascular Institute | Pencina M.J.,Whitaker Cardiovascular Institute | And 10 more authors.
Circulation | Year: 2010

Background: Biomarkers of multiple pathophysiological pathways have been related to incident atrial fibrillation (AF), but their predictive ability remains controversial. Methods and Results: In 3120 Framingham cohort participants (mean age 58.4±9.7 years, 54% women), we related 10 biomarkers that represented inflammation (C-reactive protein and fibrinogen), neurohormonal activation (B-type natriuretic peptide [BNP] and N-terminal proatrial natriuretic peptide), oxidative stress (homocysteine), the renin-angiotensin-aldosterone system (renin and aldosterone), thrombosis and endothelial function (D-dimer and plasminogen activator inhibitor type 1), and microvascular damage (urinary albumin excretion; n=2673) to incident AF (n=209, 40% women) over a median follow-up of 9.7 years (range 0.05 to 12.8 years). In multivariable-adjusted analyses, the biomarker panel was associated with incident AF (P<0.0001). In stepwise-selection models (P<0.01 for entry and retention), log-transformed BNP (hazard ratio per SD 1.62, 95% confidence interval 1.41 to 1.85, P<0.0001) and C-reactive protein (hazard ratio 1.25, 95% confidence interval 1.07 to 1.45, P=0.004) were chosen. The addition of BNP to variables recently combined in a risk score for AF increased the C-statistic from 0.78 (95% confidence interval 0.75 to 0.81) to 0.80 (95% confidence interval 0.78 to 0.83) and showed an integrated discrimination improvement of 0.03 (95% confidence interval 0.02 to 0.04, P<0.0001), with 34.9% relative improvement in reclassification analysis. The combined analysis of BNP and C-reactive protein did not appreciably improve risk prediction over the model that incorporated BNP in addition to the risk factors. Conclusions: BNP is a predictor of incident AF and improves risk stratification based on well-established clinical risk factors. Whether knowledge of BNP concentrations may be used to target individuals at risk of AF for more intensive monitoring or primary prevention requires further investigation. © 2010 American Heart Association. All rights reserved. Source

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