Section of Cardiology
Section of Cardiology
Angeli F.,Section of Cardiology |
Verdecchia P.,Hospital of Assisi |
Pascucci C.,University of Perugia |
Poltronieri C.,Section of Cardiology |
Reboldi G.,University of Perugia
Expert Opinion on Drug Metabolism and Toxicology | Year: 2013
Introduction: Azilsartan medoxomil is a newly approved angiotensin-receptor blocker for the management of hypertension. It is a prodrug that is quickly hydrolyzed to the active moiety azilsartan, a potent and highly selective angiotensin-receptor blocker with estimated bioavailability of ∼ 60%. This new agent induces a potent and long-lasting antihypertensive effect. The effective therapeutic antihypertensive dosages of azilsartan medoxomil in humans vary from 40 to 80 mg/day. Areas covered: The authors review the results of clinical trials published in journals indexed in Medline, Scopus and Google Scholar. Primarily the authors discuss articles that analyze the safety and efficacy of azilsartan in lowering blood pressure. Expert opinion: Clinical trials have demonstrated that azilsartan is superior to other angiotensin-receptor blockers in lowering blood pressure. However, the clinical blood pressure trials of azilsartan published to date have been mainly conducted in patients without serious comorbidities and it is not clear if azilsartan has advantages over other angiotensin-receptor blockers in the treatment of these types of hypertensive patients. In addition, it remains to be determined whether the specific pharmacologic and pharmacokinetic characteristics of azilsartan will have a clinically significant impact on long-term cardiovascular outcomes. © 2013 Informa UK, Ltd.
Landstrom A.P.,Section of Cardiology |
Landstrom A.P.,Cardiovascular Research Institute |
Dobrev D.,University of Duisburg - Essen |
Wehrens X.H.T.,Cardiovascular Research Institute |
Wehrens X.H.T.,Baylor College of Medicine
Circulation Research | Year: 2017
There has been a significant progress in our understanding of the molecular mechanisms by which calcium (Ca 2+) ions mediate various types of cardiac arrhythmias. A growing list of inherited gene defects can cause potentially lethal cardiac arrhythmia syndromes, including catecholaminergic polymorphic ventricular tachycardia, congenital long QT syndrome, and hypertrophic cardiomyopathy. In addition, acquired deficits of multiple Ca 2+ -handling proteins can contribute to the pathogenesis of arrhythmias in patients with various types of heart disease. In this review article, we will first review the key role of Ca 2+ in normal cardiac function - in particular, excitation-contraction coupling and normal electric rhythms. The functional involvement of Ca 2+ in distinct arrhythmia mechanisms will be discussed, followed by various inherited arrhythmia syndromes caused by mutations in Ca 2+ -handling proteins. Finally, we will discuss how changes in the expression of regulation of Ca 2+ channels and transporters can cause acquired arrhythmias, and how these mechanisms might be targeted for therapeutic purposes. © 2017 American Heart Association, Inc.
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.
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.