Wake Forest, NC, United States
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Shao Q.,Harbin Medical University | Cheng H.-J.,Section on Cardiovascular Medicine | Cheng H.-J.,Wake forest University | Kitzman D.W.,Section on Cardiovascular Medicine | And 2 more authors.
International Journal of Cardiology | Year: 2016

Background Altered nitric oxide synthase (NOS) has been implicated in the pathophysiology of heart failure (HF). Recent evidence links hypothyroidism to the pathology of HF. However, the precise mechanisms are incompletely understood. The alterations and functional effects of cardiac NOS in hypothyroidism are unknown. We tested the hypothesis that hypothyroidism increases cardiomyocyte inducible NOS (iNOS) expression, which plays an important role in hypothyroidism-induced depression of cardiomyocyte contractile properties, [Ca2 +]i transient ([Ca2+]iT), and β-adrenergic hyporesponsiveness. Methods and results We simultaneously evaluated LV functional performance and compared myocyte three NOS, β-adrenergic receptors (AR) and SERCA2a expressions and assessed cardiomyocyte contractile and [Ca2+]iT responses to β-AR stimulation with and without pretreatment of iNOS inhibitor (1400 W, 10- 5 mol/L) in 26 controls and 26 rats with hypothyroidism induced by methimazole (~ 30 mg/kg/day for 8 weeks in the drinking water). Compared with controls, in hypothyroidism, total serum T3 and T4 were significantly reduced followed by significantly decreased LV contractility (EES) with increased LV time constant of relaxation. These LV abnormalities were accompanied by concomitant significant decreases in myocyte contraction (dL/dtmax), relaxation (dR/dtmax), and [Ca2+]iT. In hypothyroidism, isoproterenol (10- 8 M) produced significantly smaller increases in dL/dtmax, dR/dtmax and [Ca2+]iT. These changes were associated with decreased β1-AR and SERCA2a, but significantly increased iNOS. Moreover, only in hypothyroidism, pretreatment with iNOS inhibitor significantly improved basal and isoproterenol-stimulated myocyte contraction, relaxation and [Ca2 +]iT. Conclusions Hypothyroidism produces intrinsic defects of LV myocyte force-generating capacity and relaxation with β-AR desensitization. Up-regulation of cardiomyocyte iNOS may promote progressive cardiac dysfunction in hypothyroidism. © 2015 Elsevier Ireland Ltd. All rights reserved.

PubMed | U.S. National Institute on Aging, Section on Nephrology, Section on Cardiovascular Medicine, University of California and 14 more.
Type: Journal Article | Journal: JAMA | Year: 2016

The appropriate treatment target for systolic blood pressure (SBP) in older patients with hypertension remains uncertain.To evaluate the effects of intensive (<120 mm Hg) compared with standard (<140 mm Hg) SBP targets in persons aged 75 years or older with hypertension but without diabetes.A multicenter, randomized clinical trial of patients aged 75 years or older who participated in the Systolic Blood Pressure Intervention Trial (SPRINT). Recruitment began on October 20, 2010, and follow-up ended on August 20, 2015.Participants were randomized to an SBP target of less than 120 mm Hg (intensive treatment group, n=1317) or an SBP target of less than 140 mm Hg (standard treatment group, n=1319).The primary cardiovascular disease outcome was a composite of nonfatal myocardial infarction, acute coronary syndrome not resulting in a myocardial infarction, nonfatal stroke, nonfatal acute decompensated heart failure, and death from cardiovascular causes. All-cause mortality was a secondary outcome.Among 2636 participants (mean age, 79.9 years; 37.9% women), 2510 (95.2%) provided complete follow-up data. At a median follow-up of 3.14 years, there was a significantly lower rate of the primary composite outcome (102 events in the intensive treatment group vs 148 events in the standard treatment group; hazard ratio [HR], 0.66 [95% CI, 0.51-0.85]) and all-cause mortality (73 deaths vs 107 deaths, respectively; HR, 0.67 [95% CI, 0.49-0.91]). The overall rate of serious adverse events was not different between treatment groups (48.4% in the intensive treatment group vs 48.3% in the standard treatment group; HR, 0.99 [95% CI, 0.89-1.11]). Absolute rates of hypotension were 2.4% in the intensive treatment group vs 1.4% in the standard treatment group (HR, 1.71 [95% CI, 0.97-3.09]), 3.0% vs 2.4%, respectively, for syncope (HR, 1.23 [95% CI, 0.76-2.00]), 4.0% vs 2.7% for electrolyte abnormalities (HR, 1.51 [95% CI, 0.99-2.33]), 5.5% vs 4.0% for acute kidney injury (HR, 1.41 [95% CI, 0.98-2.04]), and 4.9% vs 5.5% for injurious falls (HR, 0.91 [95% CI, 0.65-1.29]).Among ambulatory adults aged 75 years or older, treating to an SBP target of less than 120 mm Hg compared with an SBP target of less than 140 mm Hg resulted in significantly lower rates of fatal and nonfatal major cardiovascular events and death from any cause.clinicaltrials.gov Identifier: NCT01206062.

PubMed | Section on Nephrology, Section on Cardiovascular Medicine and Federal University of Rio de Janeiro
Type: | Journal: The journals of gerontology. Series A, Biological sciences and medical sciences | Year: 2016

Age-associated changes in cardiac structure and function, together with estrogen loss, contribute to the progression of heart failure with preserved ejection fraction in older women. To investigate the effects of aging and estrogen loss on the development of its precursor, asymptomatic left ventricular diastolic dysfunction, echocardiograms were performed in 10 middle-aged (20 months) and 30 old-aged (30 months) female Fischer344Brown-Norway rats, 4 and 8 weeks after ovariectomy (OVX) and sham procedures (gonads left intact). The cardioprotective potential of administering chronic G1, the selective agonist to the new G-protein-coupled estrogen receptor (GPER), was further evaluated in old rats (Old-OVX+G1) versus age-matched, vehicle-treated OVX and gonadal intact rats. Advanced age and estrogen loss led to decreases in myocardial relaxation and elevations in filling pressure, in part, due to reductions in phosphorylated phospholamban and increases in cardiac collagen deposition. Eight weeks of G-protein-coupled estrogen receptor activation in Old-OVX+G1 rats reversed the adverse effects of age and estrogen loss on myocardial relaxation through increases in sarcoplasmic reticulum Ca

PubMed | Section on Cardiovascular Medicine, North Carolina State University, University of Waterloo and Virginia Polytechnic Institute and State University
Type: Journal Article | Journal: Annals of biomedical engineering | Year: 2016

The purpose of this study was to (1) develop and present a technique to quantitatively assess three-dimensional distribution and clustering of intramuscular fat and (2) use the technique to compare spatial characteristics of intramuscular fat in rotator cuff muscles of older adults with and without a supraspinatus tear. Morans Index (I), an existing quantitative measure of clustering, was extended for use with MRI to allow comparisons across individuals with different size muscles. Sixteen older adults (>60years) with (N=6) and without (N=10) a degenerative supraspinatus tear participated. Following 3D Dixon MRIs of the shoulder, which separates fat from water, rotator cuff muscles were segmented and sectioned and fat% and Morans I were calculated to assess distribution and clustering, respectively. Morans I ranged was 0.40-0.92 and 0.39-0.76 for the tear and control subjects, respectively. Compared to uninjured controls, tear subjects demonstrated increased fat distribution (p=0.036) and clustering (p=0.020) distally in the supraspinatus. Tear subjects had more pronounced distribution (p<0.001) and clustering distally (p<0.001) than proximally. Other rotator cuff muscles exhibited different patterns of fat clustering and distribution. This technique, which we applied to quantify spatial characteristics of intramuscular fat, can be applied to assess clustering of fat in other pathologies and tissues.

PubMed | Section on Cardiovascular Medicine, Harbin Medical University and Wake forest University
Type: | Journal: International journal of cardiology | Year: 2017

Angiotensin-(1-7) [Ang-(1-7)] exhibits cardiovascular effects opposite those of angiotensin II (Ang II), thus providing protection against heart disease. However, how Ang-(1-7) imparts cardioprotection is unclear, and its direct cardiac effects are controversial. Whether heart failure (HF) alters cardiac contractile responses to Ang-(1-7) remains undetermined. We tested the hypothesis that in HF, Ang-(1-7) may produce positive modulation on [CaWe measured LV contractility changes after Ang-(1-7) (650ng/kg, iv) and compared myocyte functional and [CaIn a rat model of HF, Ang-(1-7) increases [Ca

Tian Y.,Virginia Polytechnic Institute and State University | Zhang B.,Johns Hopkins University | Hoffman E.P.,Research Center for Genetic Medicine | Clarke R.,Georgetown University | And 5 more authors.
BMC Systems Biology | Year: 2014

Background: Modeling biological networks serves as both a major goal and an effective tool of systems biology in studying mechanisms that orchestrate the activities of gene products in cells. Biological networks are context-specific and dynamic in nature. To systematically characterize the selectively activated regulatory components and mechanisms, modeling tools must be able to effectively distinguish significant rewiring from random background fluctuations. While differential networks cannot be constructed by existing knowledge alone, novel incorporation of prior knowledge into data-driven approaches can improve the robustness and biological relevance of network inference. However, the major unresolved roadblocks include: big solution space but a small sample size; highly complex networks; imperfect prior knowledge; missing significance assessment; and heuristic structural parameter learning.Results: To address these challenges, we formulated the inference of differential dependency networks that incorporate both conditional data and prior knowledge as a convex optimization problem, and developed an efficient learning algorithm to jointly infer the conserved biological network and the significant rewiring across different conditions. We used a novel sampling scheme to estimate the expected error rate due to " random" knowledge. Based on that scheme, we developed a strategy that fully exploits the benefit of this data-knowledge integrated approach. We demonstrated and validated the principle and performance of our method using synthetic datasets. We then applied our method to yeast cell line and breast cancer microarray data and obtained biologically plausible results. The open-source R software package and the experimental data are freely available at http://www.cbil.ece.vt.edu/software.htm.Conclusions: Experiments on both synthetic and real data demonstrate the effectiveness of the knowledge-fused differential dependency network in revealing the statistically significant rewiring in biological networks. The method efficiently leverages data-driven evidence and existing biological knowledge while remaining robust to the false positive edges in the prior knowledge. The identified network rewiring events are supported by previous studies in the literature and also provide new mechanistic insight into the biological systems. We expect the knowledge-fused differential dependency network analysis, together with the open-source R package, to be an important and useful bioinformatics tool in biological network analyses. © 2014 Tian et al.; licensee BioMed Central.

Jordan J.H.,Section on Cardiovascular Medicine | Thwin S.S.,Boston University | Thwin S.S.,Massachusetts Veterans Epidemiology Research and Information Center | Lash T.L.,Emory University | And 10 more authors.
Breast Cancer Research and Treatment | Year: 2014

Five-year breast cancer survivors, diagnosed after 65 years of age, may develop more incident comorbidities than similar populations free of cancer. We investigated whether older breast cancer survivors have a similar comorbidity burden 6-15 years after cancer diagnosis to matched women free of breast cancer at start of follow-up and whether incident comorbidities are associated with all-cause mortality. In this prospective cohort study, 1,361 older 5-year early-stage breast cancer survivors diagnosed between 1990 and 1994 and 1,361 age- and health system-matched women were followed for 10 years. Adjudicated medical record review captured prevalent and incident comorbidities during follow-up or until death as collected from the National Death Index. Older 5-year breast cancer survivors did not acquire incident comorbidities more often than matched women free of breast cancer in the subsequent 10 years [hazard ratio (HR) 1.0, 95 % confidence interval (95 % CI) 0.93, 1.1]. Adjusted for cohort membership, women with incident comorbidities had a higher mortality rate than those without incident comorbidities (HR 4.8, 95 % CI 4.1, 5.6). A breast cancer history continued to be a hazard for mortality 6-15 years after diagnosis (HR 1.3, 95 % CI 1.1, 1.4). We found that older breast cancer survivors who developed comorbidities had an increased all-cause mortality rate even after adjusting for age and prevalent comorbidity burden. Additionally, survivors acquire comorbidities at a rate similar to older women free of breast cancer. These results highlight the association between comorbidity burden and long-term mortality risk among older breast cancer survivors and their need for appropriate oncology and primary care follow-up. © 2014 Springer Science+Business Media.

Zhou P.,Section on Cardiovascular Medicine | Cheng C.P.,Section on Cardiovascular Medicine | Li T.,Section on Cardiovascular Medicine | Li T.,Harbin Medical University | And 3 more authors.
Therapeutic Advances in Cardiovascular Disease | Year: 2015

Objective: Recent evidence has shown that, in heart failure (HF), clinically relevant concentrations of angiotensin-(1-7) [Ang-(1-7)] counteracts angiotensin II induced cardiac depression and produces positive inotropic effects in both left ventricle (LV) and myocytes. However, the underlying electrophysiological mechanism is unclear. We investigated the role and mechanism of Ang-(1-7) on LV myocyte L-type calcium current (ICa,L) responses in normal state and in HF. Method: We compared the effect of Ang-(1-7) (10-5 M) on ICa,L responses in isolated LV myocytes obtained from 11 rats with isoproterenol (ISO) induced HF (3 months after 170 mg/kg subcutaneous for 2 days) and from 8 age-matched normal control rats by patch clamp technique. Results: In normal myocytes, compared with baseline, superfusion of Ang-(1-7) caused no significant changes in ICa,L (8.2 ± 0.2 versus 8.0 ± 0.3 pA/pF, p= not significant). In HF myocytes, the baseline ICa,L was significantly reduced (5.3 ± 0.1 versus 8.0 ± 0.3 pA/pF, p 0.01). Ang-(1-7) produced a 21% increase in ICa,L (6.4±0.1 versus 5.3±0.1 pA/pF, p 0.01). Pretreatment of HF myocytes with a nitric oxide (NO) synthase inhibitor (L-NAME, 10-5 M) resulted in a significantly greater increase in ICa,L (28%, 8.4 ± 0.1 versus 6.5 ± 0.1 pA/pF, p 0.01) during Ang-(1-7) superfusion. In contrast, during incubation with the bradykinin (BK) inhibitor HOE 140 (10-6 M), Ang-(1-7) induced increase in ICa,L was significantly decreased. The Ang-(1-7) induced increase in ICa,L was abolished by [D-Ala7]-Ang-(1-7) (A-779, 10-5 M). Conclusions: HF alters the response of ICa,L to Ang-(1-7). In normal myocytes, Ang-(1-7) has no significant effect on ICa,L. However, in HF myocytes, Ang-(1-7) increases ICa,L. These effects are mediated by the Ang-(1-7) Mas receptors and involve activation of NO/BK pathways. © The Author(s), 2015.

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