Whitaker Cardiovascular Institute

Whitaker, United States

Whitaker Cardiovascular Institute

Whitaker, United States
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Mitchell G.F.,Edgewater | Wang N.,Boston University | Palmisano J.N.,Boston University | Larson M.G.,Boston University | And 10 more authors.
Circulation | Year: 2010

Background: Systolic blood pressure and pulse pressure are substantially higher in older adults. The relative contributions of increased forward versus reflected pressure wave amplitude or earlier arrival of the reflected wave to elevated pulse pressure remain controversial. Methods and Results: We measured proximal aortic pressure and flow, forward pressure wave amplitude, global wave reflection, reflected wave timing, and pulse wave velocity noninvasively in 6417 (age range, 19 to 90 years; 53% women) Framingham Heart Study Third Generation and Offspring participants. Variation in forward wave amplitude paralleled pulse pressure throughout adulthood. In contrast, wave reflection and pulse pressure were divergent across adulthood: In younger participants, pulse pressure was lower and wave reflection was higher with advancing age, whereas in older participants, pulse pressure was higher and wave reflection was lower with age. Reflected wave timing differed modestly across age groups despite considerable differences in pulse wave velocity. Forward wave amplitude explained 80% (central) and 66% (peripheral) of the variance in pulse pressure in younger participants (<50 years) and 90% and 84% in the older participants (≤50 years; all P<0.0001). In a stepwise model that evaluated age-pulse pressure relations in the full sample, the late accelerated increases in central and peripheral pulse pressure were markedly attenuated when variation in forward wave amplitude was considered. Conclusions: Higher pulse pressure at any age and higher pulse pressure with advancing age is associated predominantly with a larger forward pressure wave. The influence of wave reflection on age-related differences in pulse pressure was minor. © 2010 American Heart Association. All rights reserved.

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.

Torjesen A.A.,Edgewater | Wang N.,Boston University | Larson M.G.,Boston University | Larson M.G.,Blood Institutes Framingham Study | And 10 more authors.
Hypertension | Year: 2014

Central pressure augmentation is associated with greater backward wave amplitude and shorter transit time and is higher in women for reasons only partially elucidated. Augmentation also is affected by left ventricular function and shapes of the forward and backward waves. The goal of this study was to examine the relative contributions of forward and backward wave morphology to central pressure augmentation in men and women. From noninvasive measurements of central pressure and flow in 7437 participants (4036 women) aged from 19 to 90 years (mean age, 51 years), we calculated several variables: augmentation index, backward wave arrival time, reflection factor, forward wave amplitude, forward wave peak width, and slope of the backward wave upstroke. Linear regression models for augmentation index, adjusted for height and heart rate, demonstrated nonlinear relations with age (age: B=4.6±0.1%; P<0.001; age: B=-4.2±0.1%; P<0.001) and higher augmentation in women (B=4.5±0.4%; P<0.001; model R=0.35). Addition of reflection factor and backward wave arrival time improved model fit (R=0.62) and reduced the age coefficients: age (B=2.3±0.1%; P<0.001) and age (B=-2.2±0.1%; P<0.001). Addition of width of forward wave peak, slope of backward wave upstroke, and forward wave amplitude further improved model fit (R=0.75) and attenuated the sex coefficient (B=1.9±0.2%; P<0.001). Thus, shape and amplitude of the forward wave may be important correlates of augmentation index, and part of the sex difference in augmentation index may be explained by forward and backward wave morphology. © 2014 American Heart Association, Inc.

Hamburg N.M.,Whitaker Cardiovascular Institute | Hamburg N.M.,Boston University | Larson M.G.,Boston University | Lehman B.T.,Boston University | And 7 more authors.
Hypertension | Year: 2011

Impaired vascular function contributes to the development of clinical cardiovascular disease. The relation between vasodilator function assessed noninvasively in the brachial and digital arteries remains incompletely defined. In the Framingham Offspring, Third Generation and Omni Cohorts, we measured flow-mediated dilation (FMD; n=7031; age 48±13 years; age range, 19 to 88 years; 54% women) and peripheral arterial tonometry (PAT) ratio (n=4352; 55±16 years; age range, 19 to 90 years; 51% women). Abnormal vascular function for each measure was defined by the sex-specific fifth percentile in a reference group free of conventional cardiovascular risk factors. The prevalence of abnormal FMD but not abnormal PAT ratio was higher with advancing age. In multivariable models, higher body mass index was associated with a higher prevalence of both abnormal FMD and PAT ratio. Additional correlates of abnormal FMD included increasing age and higher systolic blood pressure. In contrast, correlates of abnormal PAT ratio included lower systolic blood pressure, increasing total/high-density lipoprotein cholesterol ratio, diabetes, smoking, and lipid-lowering medication. Whereas women had higher FMD and PAT ratios compared with men, using sex-specific reference values, women had a higher prevalence of abnormal brachial and digital vascular function. In participants who had concurrent testing (n=1843), PAT ratio was not significantly associated with FMD in multivariable models. In this large, community-based cohort, brachial and digital measures of vascular function had differing relations with cardiovascular risk factors and were nearly uncorrelated with each other. These results suggest that FMD and PAT provide distinct information regarding vascular function in conduit versus smaller digital vessels. © 2011 American Heart Association, Inc.

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.

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.

Lubitz S.A.,Massachusetts General Hospital | Lubitz S.A.,Brigham and Women's 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.

Kateifides A.K.,Whitaker Cardiovascular Institute | Kateifides A.K.,University of Crete | Gorshkova I.N.,Whitaker Cardiovascular Institute | Gorshkova I.N.,Boston University | And 4 more authors.
Journal of Lipid Research | Year: 2011

In this study, we investigated the role of positively and negatively charged amino acids within the 89-99 region of apolipoprotein A-I (apoA-I), which are highly conserved in mammals, on plasma lipid homeostasis and the biogenesis of HDL. We previously showed that deletion of the 89-99 region of apoA-I increased plasma cholesterol and phospholipids, but it did not affect plasma triglycerides. Functional studies using adenovirus-mediated gene transfer of two apoA-I mutants in apoA-I-deficient mice showed that apoAI[ D89A/E91A/E92A] increased plasma cholesterol and caused severe hypertriglyceridemia. HDL levels were reduced, and approximately 40% of the apoA-I was distributed in VLDL/IDL. The HDL consisted of mostly spherical and a few discoidal particles and contained preβ1 and α4-HDL subpopulations. The lipid, lipoprotein, and HDL profi les generated by the apoA-I[K94A/K96A] mutant were similar to those of wild-type (WT) apoA-I. Coexpression of apoA-I[D89A/E91A/E92A] and human lipoprotein lipase abolished hypertriglyceridemia, restored in part the α1,2,3,4 HDL subpopulations, and redistributed apoA-I in the HDL2/HDL3 regions, but it did not prevent the formation of discoidal HDL particles. Physicochemical studies showed that the apoA-I[D89A/E91A/E92A] mutant had reduced α-helical content and effective enthalpy of thermal denaturation, increased exposure of hydrophobic surfaces, and increased affinity for triglyceride-rich emulsions. We conclude that residues D89, E91, and E92 of apoA-I are important for plasma cholesterol and triglyceride homeostasis as well as for the maturation of HDL. Copyright © 2011 by the American Society for Biochemistry and Molecular Biology, Inc.

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.

Johnston-Cox H.A.,Whitaker Cardiovascular Institute | Koupenova M.,Whitaker Cardiovascular Institute | Ravid K.,Whitaker Cardiovascular Institute | Ravid K.,The Interdisciplinary Center
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2012

Cardiovascular disease, a leading cause of death and morbidity, is regulated, among various factors, by inflammation. The level of the metabolite adenosine is augmented under stress, including inflammatory, hypoxic, or injurious events. Adenosine has been shown to affect various physiological and pathological processes, largely through 1 or more of its 4 types of receptors: the A1 and A3 adenylyl cyclase inhibitory receptors and the A2A and A2B adenylyl cyclase stimulatory receptors. This article focuses on reviewing common and distinct effects of the 2 A2-type adenosine receptors on vascular disease and the mechanisms involved. Understanding the pathogenesis of vascular disease mediated by these receptors is important to the development of therapeutics and to the prevention and management of disease. © 2012 American Heart Association, Inc.

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