Section of Cardiology

Little Rock, AR, United States

Section of Cardiology

Little Rock, AR, United States
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Drafts B.C.,Section of Cardiology | Twomley K.M.,Section of Cardiology | Lawrence J.,Section Hematology and Oncology | Ellis L.R.,Section Hematology and Oncology | And 5 more authors.
JACC: Cardiovascular Imaging | Year: 2013

Objectives The goal of this study was to determine if low to moderate doses of anthracycline-based chemotherapy (Anth-bC) are associated with subclinical cardiovascular (CV) injury. Background Cancer survivors who receive Anth-bC experience premature CV events. It is unknown whether low to moderate doses of anthracyclines promote early subclinical CV disease manifested by deteriorations in left ventricular ejection fraction (LVEF) or increases in aortic stiffness, or if these doses are associated with changes in quality of life (QOL). Methods In 53 men and women with breast cancer, leukemia, or lymphoma, we assessed left ventricular volumes, LVEF, circumferential strain, aortic pulse wave velocity, late gadolinium enhancement, serum B-type natriuretic peptide, troponin I, and the impact of treatment on QOL before and 1, 3, and 6 months after receipt of Anth-bC. Results Participants averaged 50 ± 2 (range 19 to 80) years in age, 58% were women, 17% were black, and they each received a range of 50 to 375 mg/m2 of doxorubicin-equivalent chemotherapy. Left ventricular end-systolic volume (48 ± 3 ml to 54 ± 3 ml; p = 0.02), left ventricular strain (-17.7 ± 0.4 to -15.1 ± 0.4; p = 0.0003), pulse wave velocity (6.7 ± 0.5 m/s to 10.1 ± 1 m/s; p = 0.0006), and QOL deterioration (15.4 ± 3.3 to 28.5 ± 3.9; p = 0.008) increased, whereas LVEF (58 ± 1% to 53 ± 1%; p = 0.0002) decreased within 6 months after low to moderate doses of Anth-bC. All findings persisted after accounting for age, gender, race (white/black), doxorubicin-equivalent dose, doxorubicin administration technique, comorbidities associated with CV events, and cancer diagnosis (p = 0.02 to 0.0001 for all). There were no new late gadolinium enhancement findings after 6 months. Conclusions In these study patients, low to moderate doses of Anth-bC were associated with the early development of subclinical abnormalities of cardiac and vascular function that in other populations are associated with the future occurrence of CV events. © 2013 by the American College of Cardiology Foundation.


Melki D.,Section of Cardiology | Lind S.,Karolinska University Hospital | Agewall S.,University of Oslo | Jernberg T.,Section of Cardiology
Clinica Chimica Acta | Year: 2012

The aim was to examine whether high sensitive troponin T (Hs-TnT) is better than conventional troponins to risk stratify chest pain patients, in particular when applying early serial measurements or combining with natriuretic peptides. Samples were obtained on admission and after 2. h in 231 chest pain patients who were followed for a median time of 22. months. Troponin levels were determined by Hs-TnT, conventional TnT (Roche Diagnostics) and troponin I (Beckman Coulter) assays. N-terminal pro B-type natriuretic peptide (NT-proBNP) was determined by the assay from Roche Diagnostics. The combined endpoint was death, MI or heart failure. When predefined decision limits were used, Hs-TnT (14. ng/L), TnT (0.04. μg/L), and TnI (0.06. μg/L) identified 63%, 46%, and 52% of the patients with positive troponin. In those with negative TnT, Hs-TnT identified 36 patients of whom 19% had subsequent events. In those with negative TnI, Hs-TnT identified 26 patients of whom 23% had subsequent events. After adjusting for differences in baseline characteristics, both Hs-TnT and NT-proBNP were independently associated with short-term (3. months) risk of combined endpoint and long-term risk of death or MI. By combining Hs-TnT and NT-proBNP patients could be divided into low-, intermediate- and high-risk groups. © 2012 Elsevier B.V.


Lanahan A.A.,Yale University | Hermans K.,Vesalius Research Center | Claes F.,Vesalius Research Center | Kerley-Hamilton J.S.,Section of Cardiology | And 4 more authors.
Developmental Cell | Year: 2010

VEGF is the key growth factor regulating arterial morphogenesis. However, molecular events involved in this process have not been elucidated. Synectin null mice demonstrate impaired VEGF signaling and a marked reduction in arterial morphogenesis. Here, we show that this occurs due to delayed trafficking of VEGFR2-containing endosomes that exposes internalized VEGFR2 to selective dephosphorylation by PTP1b on Y1175 site. Synectin involvement in VEGFR2 intracellular trafficking requires myosin-VI, and myosin-VI knockout in mice or knockdown in zebrafish phenocopy the synectin null phenotype. Silencing of PTP1b restores VEGFR2 activation and significantly recovers arterial morphogenesis in myosin-VI-/- knockdown zebrafish and synectin-/- mice. We conclude that activation of the VEGF-mediated arterial morphogenesis cascade requires phosphorylation of the VEGFR2 Y1175 site that is dependent on trafficking of internalized VEGFR2 away from the plasma membrane via a synectin-myosin-VI complex. This key event in VEGF signaling occurs at an intracellular site and is regulated by a novel endosomal trafficking-dependent process. © 2010 Elsevier Inc.


Agarwal S.,Oakwood | Cox A.J.,Centers for Diabetes Research and Human Genomics | Herrington D.M.,Section of Cardiology | Jorgensen N.W.,University of Washington | And 4 more authors.
Diabetes Care | Year: 2013

OBJECTIVE-In type 2 diabetesmellitus (T2DM), it remains unclear whether coronary artery calcium (CAC) provides additional information about cardiovascular disease (CVD) mortality beyond the Framingham Risk Score (FRS) factors. RESEARCH DESIGN AND METHODS-A total of 1,123 T2DM participants, ages 34- 86 years, in the Diabetes Heart Study followed up for an average of 7.4 years were separated using baseline computed tomography scans of CAC (0-9, 10-99, 100-299, 300-999, and ≥1,000). Logistic regression was performed to examine the association between CAC and CVD mortality adjusting for FRS. Areas under the curve (AUC) with and without CAC were compared. Net reclassification improvement (NRI) compared FRS (model 1) versus FRS+CAC (model 2) using 7.4-year CVD mortality risk categories 0% to <7%, 7% to <20%, and ≥20%. RESULTS-Overall, 8% of participants died of cardiovascular causes during follow-up. In multivariate analysis, the odds ratios (95%CI) for CVDmortality using CAC 0-9 as the reference group were, CAC 10-99: 2.93 (0.74-19.55); CAC 100-299: 3.17 (0.70-22.22); CAC 300-999: 4.41(1.15-29.00); and CAC≥1,000: 11.23 (3.24-71.00). AUC (95%CI)without CACwas 0.70 (0.67-0.73), AUC with CAC was 0.75 (0.72-0.78), and NRI was 0.13 (0.07-0.19). CONCLUSIONS-In T2DM, CAC predicts CVD mortality and meaningfully reclassifies participants, suggesting clinical utility as a risk stratification tool in a population already at increased CVD risk. © 2013 by the American Diabetes Association.


Marsboom G.,Section of Cardiology | Toth P.T.,Section of Cardiology | Ryan J.J.,Section of Cardiology | Hong Z.,Section of Cardiology | And 11 more authors.
Circulation Research | Year: 2012

Rationale: Pulmonary arterial hypertension (PAH) is a lethal syndrome characterized by pulmonary vascular obstruction caused, in part, by pulmonary artery smooth muscle cell (PASMC) hyperproliferation. Mitochondrial fragmentation and normoxic activation of hypoxia-inducible factor-1α (HIF-1α) have been observed in PAH PASMCs; however, their relationship and relevance to the development of PAH are unknown. Dynamin-related protein-1 (DRP1) is a GTPase that, when activated by kinases that phosphorylate serine 616, causes mitochondrial fission. It is, however, unknown whether mitochondrial fission is a prerequisite for proliferation. Objective: We hypothesize that DRP1 activation is responsible for increased mitochondrial fission in PAH PASMCs and that DRP1 inhibition may slow proliferation and have therapeutic potential. Methods and Results: Experiments were conducted using human control and PAH lungs (n=5) and PASMCs in culture. Parallel experiments were performed in rat lung sections and PASMCs and in rodent PAH models induced by the HIF-1α activator, cobalt, chronic hypoxia, and monocrotaline. HIF-1α activation in human PAH leads to mitochondrial fission by cyclin B1/CDK1-dependent phosphorylation of DRP1 at serine 616. In normal PASMCs, HIF-1α activation by CoCl2 or desferrioxamine causes DRP1-mediated fission. HIF-1α inhibition reduces DRP1 activation, prevents fission, and reduces PASMC proliferation. Both the DRP1 inhibitor Mdivi-1 and siDRP1 prevent mitotic fission and arrest PAH PASMCs at the G2/M interphase. Mdivi-1 is antiproliferative in human PAH PASMCs and in rodent models. Mdivi-1 improves exercise capacity, right ventricular function, and hemodynamics in experimental PAH. Conclusions: DRP-1-mediated mitotic fission is a cell-cycle checkpoint that can be therapeutically targeted in hyperproliferative disorders such as PAH. © 2012 American Heart Association, Inc.


Alboni P.,Section of Cardiology | Holz A.,Section of Cardiology | Brignole M.,Arrhythmologic Center
Heart | Year: 2013

Vagally mediated atrioventricular (AV) block is defined as a paroxysmal AV block, localised within the AV node, associated with slowing of the sinus rate. All types of second-degree AV block, including pseudo-Mobitz II block, and complete AV block, may be present. Most of the patients have normal AV conduction. Differential diagnosis with intrinsic AV block is based on the behaviour of the sinus rate. Vagally mediated AV block is benign; it can be recorded as an asymptomatic or symptomatic event (syncope/presyncope). Syncope due to this form of AV block should be diagnosed and managed as neurally mediated syncope. When this block is fortuitously recorded in asymptomatic patients, pacemaker implantation is not indicated.


Alboni P.,Section of Cardiology
Heart | Year: 2015

For some decades, after the introduction of the head-up tilt test into clinical practice, the clinical presentation of vasovagal syncope (VVS) has been classified as typical (or classical) and atypical (or non-classical). Some clinical features and recent data suggest that even unexplained falls and syncope during sleeping hours may be possible clinical presentations of VVS. In recent studies, tilt testing and carotid sinus massage by means of the 'method of symptoms' were performed in one group of patients with unexplained falls and in another group with unexplained syncope ( presence of prodromal symptoms). Overall, tilt testing and carotid sinus massage displayed a high positivity rate in the group of patients with unexplained falls (about 60%), which was similar to that of the unexplained syncope group. These new data seem to indicate that some unexplained falls could be cases of atypical VVS/carotid sinus syncope with retrograde amnesia. Some clinical features suggest that syncope during sleeping hours is a form of VVS with a different clinical presentation: high prevalence of autonomic prodromes, of diurnal episodes of typical VVS and speci fic phobias, and of positive tilt testing with severe cardioinhibition.


Bowman M.H.,Section of Cardiology | Wilk J.,Section of Cardiology | Heydemann A.,Section of Cardiology | Kim G.,Section of Cardiology | And 5 more authors.
Circulation Research | Year: 2010

RATIONALE: S100A12 is a small calcium binding protein that is a ligand of RAGE (receptor for advanced glycation end products). RAGE has been extensively implicated in inflammatory states such as atherosclerosis, but the role of S100A12 as its ligand is less clear. OBJECTIVE: To test the role of S100A12 in vascular inflammation, we generated and analyzed mice expressing human S100A12 in vascular smooth muscle under control of the smooth muscle 22α promoter because S100A12 is not present in mice. METHODS AND RESULTS: Transgenic mice displayed pathological vascular remodeling with aberrant thickening of the aortic media, disarray of elastic fibers, and increased collagen deposition, together with increased latent matrix metalloproteinase-2 protein and reduction in smooth muscle stress fibers leading to a progressive dilatation of the aorta. In primary aortic smooth muscle cell cultures, we found that S100A12 mediates increased interleukin-6 production, activation of transforming growth factor β pathways and increased metabolic activity with enhanced oxidative stress. To correlate our findings to human aortic aneurysmal disease, we examined S100A12 expression in aortic tissue from patients with thoracic aortic aneurysm and found increased S100A12 expression in vascular smooth muscle cells. CONCLUSIONS: S100A12 expression is sufficient to activate pathogenic pathways through the modulation of oxidative stress, inflammation and vascular remodeling in vivo.


Bowman M.A.H.,Section of Cardiology | Gawdzik J.,Section of Cardiology | Bukhari U.,Section of Cardiology | Husain A.N.,University of Chicago | And 4 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2011

Objective-: The proinflammatory cytokine S100A12 is associated with coronary atherosclerotic plaque rupture. We previously generated transgenic mice with vascular smooth muscle-targeted expression of human S100A12 and found that these mice developed aortic aneurysmal dilation of the thoracic aorta. In the current study, we tested the hypothesis that S100A12 expressed in vascular smooth muscle in atherosclerosis-prone apolipoprotein E (ApoE)-null mice would accelerate atherosclerosis. Methods and results-: ApoE-null mice with or without the S100A12 transgene were analyzed. We found a 1.4-fold increase in atherosclerotic plaque size and more specifically a large increase in calcified plaque area (45% versus 7% of innominate artery plaques and 18% versus 10% of aortic root plaques) in S100A12/ApoE-null mice compared with wild-type/ApoE-null littermates. Expression of bone morphogenic protein and other osteoblastic genes was increased in aorta and cultured vascular smooth muscle, and importantly, these changes in gene expression preceded the development of vascular calcification in S100A12/ApoE-null mice. Accelerated atherosclerosis and vascular calcification were mediated, at least in part, by oxidative stress because inhibition of NADPH oxidase attenuated S100A12-mediated osteogenesis in cultured vascular smooth muscle cells. S100A12 transgenic mice in the wild-type background (ApoE+/+) showed minimal vascular calcification, suggesting that S100A12 requires a proinflammatory/proatherosclerotic environment to induce osteoblastic differentiation and vascular calcification. Conclusion-: Vascular smooth muscle S100A12 accelerates atherosclerosis and augments atherosclerosis-triggered osteogenesis, reminiscent of features associated with plaque instability. © 2011 American Heart Association, Inc.


Patel V.N.,U.S. National Institutes of Health | Lombaert I.M.A.,U.S. National Institutes of Health | Cowherd S.N.,U.S. National Institutes of Health | Shworak N.W.,Section of Cardiology | And 3 more authors.
Developmental Cell | Year: 2014

The exquisite control of growth factor function by heparan sulfate (HS) is dictated by tremendous structural heterogeneity of sulfated modifications. How specific HS structures control growth factor-dependent progenitor expansion during organogenesis is unknown. We isolated KIT+ progenitors from fetal salivary glands during a stage of rapid progenitor expansion and profiled HS biosynthetic enzyme expression. Enzymes generating a specific type of 3-. O-sulfated-HS (3-. O-HS) are enriched, and fibroblast growth factor 10 (FGF10)/FGF receptor 2b (FGFR2b) signaling directly regulates their expression. Bioengineered 3-. O-HS binds FGFR2b and stabilizes FGF10/FGFR2b complexes in a receptor- and growth factor-specific manner. Rapid autocrine feedback increases 3-. O-HS, KIT, and progenitor expansion. Knockdown of multiple Hs3st isoforms limits fetal progenitor expansion but is rescued with bioengineered 3-. O-HS, which also increases adult progenitor expansion. Altering specific 3-. O-sulfated epitopes provides a mechanism to rapidly respond to FGFR2b signaling and control progenitor expansion. 3-. O-HS may expand KIT+ progenitors invitro for regenerative therapy. © 2014 Elsevier Inc.

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