bluuebunny/crossref_metadata_2025 huggingface dataset:
Common Carotid Intima-Media Thickness and Arterial Stiffness
Authors: Simons Petra C. G. , Algra Ale , Bots Michiel L. , Grobbee Diederick E. , van der Graaf Yolanda
Published: June 2012

Background
—Common carotid intima-media thickness (IMT) and distensibility are markers of structural and functional vessel wall properties. Both parameters have been found in population-based studies to be associated with cardiovascular risk factors and prevalent cardiovascular disease. We investigated cross-sectionally whether IMT and distensibility are associated with cardiovascular risk in patients who already have vascular disease or atherosclerotic risk factors and evaluated the diagnostic ability of IMT and distensibility to discriminate between low- and high-risk patients.

Methods and Results
—IMT and distensibility (change of diameter) of the left and right common carotid arteries were measured in the first 570 patients (537 for distensibility) enrolled in the Second Manifestations of ARTerial disease (SMART) study, a cohort study among patients with a manifestation of vascular disease or cardiovascular risk factors. Three risk scores were used to classify each patient’s vascular risk. Areas under the curve (AUCs) of receiver-operating characteristic curves were calculated for IMT and distensibility after the patients were dichotomized on the median of the risk scores as the outcome. Risk scores increased nearly linearly with increasing IMT and decreasing distensibility. The AUCs for IMT predicting high-risk patients were 0.77, 0.73, and 0.77 based on the 3 risk scores. The AUCs for distensibility were 0.65, 0.62, and 0.66.

Conclusions
—Common carotid IMT and distensibility are clear markers of cardiovascular risk in patients who already have vascular disease or atherosclerotic risk factors. IMT appears to discriminate between low- and high-risk patients better than distensibility.
Previous Cytomegalovirus Infection and Risk of Coronary Thrombotic Events After Stent Placement
Authors: Neumann Franz-Josef , Kastrati Adnan , Miethke Thomas , Pogatsa-Murray Gisela , Seyfarth Melchior , Schömig Albert
Published: June 2012

Background
—Cytomegalovirus (CMV) infection induces upregulation of tissue factor and loss of anticoagulants, including thrombomodulin, prostacyclin, and tissue plasminogen activator. CMV infection may thereby increase the procoagulant properties of coronary artery plaques. This prospective study investigated the effect of previous CMV infection on the early hazard of coronary stent placement.

Methods and Results
—In 551 consecutive patients with successful coronary stent placement, we determined CMV IgG titers. The end point was the composite rate of death, nonfatal Q-wave myocardial infarction, and urgent reintervention during 30-day follow-up. The study population represented the entire spectrum of coronary stenting; an acute coronary syndrome was present in 50% of the patients. A positive CMV IgG titer (≥1/230) was found in 340 patients (62%). Of these, 10 reached the end point during 30-day follow-up (2 deaths, 4 infarctions, 4 urgent reinterventions). In the group with negative CMV titer, thrombotic events did not occur (
P
=0.014 versus group with positive CMV titers). After correction for pertinent covariables, a significant relation between positive CMV titer and the 30-day end point prevailed (
P
<0.001).

Conclusions
—Previous CMV infection may increase the risk of coronary thrombotic events after stent placement.
Assessment of QT Interval and QT Dispersion for Prediction of All-Cause and Cardiovascular Mortality in American Indians
Authors: Okin Peter M. , Devereux Richard B. , Howard Barbara V. , Fabsitz Richard R. , Lee Elisa T. , Welty Thomas K.
Published: June 2012

Background
—Both a prolonged QT interval and increased QT interval dispersion (QTD) have been proposed as surface ECG markers of vulnerability to ventricular arrhythmias and potential predictors of mortality.

Methods and Results
—The predictive values of QT prolongation and QTD were assessed in 1839 participants in the Strong Heart Study, a prospective study of cardiovascular disease in American Indians. ECGs were acquired at 250 Hz; QT intervals were measured by computer in all 12 leads and corrected for heart rate (QTc) by use of Bazett’s formula. QTD was calculated as the difference between the maximum and minimum QTc. After a mean follow-up of 3.7±0.9 years, there were 188 deaths from all causes, including 55 cardiovascular deaths. In univariate Cox analyses, prolonged QTc and increased QTD were significant predictors of all-cause mortality (χ
2
=53.0,
P
<0.0001; χ
2
=11.3,
P
=0.0008) and cardiovascular mortality (χ
2
=14.7,
P
=0.0001; χ
2
=26.5,
P
<0.0001). In multivariate Cox regression analyses controlling for risk factors, QTc remained a strong predictor of all-cause mortality (χ
2
=16.5,
P
<0.0001) and a weaker predictor of cardiovascular mortality (χ
2
=5.8,
P
=0.016); QTD remained a significant predictor of cardiovascular mortality only (χ
2
=12.5,
P
=0.0004).

Conclusions
—These findings support the value of computerized measurements of QTc and QTD in noninvasive risk stratification and suggest that these surface ECG variables may reflect different underlying abnormalities of ventricular repolarization.
Angiotensin II Has Multiple Profibrotic Effects in Human Cardiac Fibroblasts
Authors: Kawano Hiroaki , Do Yung S. , Kawano Yasuko , Starnes Vaughn , Barr Mark , Law Ronald E. , Hsueh Willa A.
Published: June 2012

Background
—Angiotensin II (Ang II) is implicated in cardiac remodeling and is increasingly recognized for its profibrotic activity.

Methods and Results
—Because little is known about the direct cellular effects of Ang II on human cardiac fibroblasts, we isolated fibroblasts from ventricles of explanted human hearts and added Ang II (100 nmol/L) to determine its role in growth, extracellular matrix accumulation, and adhesion. To assess which Ang II receptor is involved, Ang II was added in the presence of irbesartan (10 μmol/L), a specific AT
1
receptor antagonist; PD 123319 (10 μmol/L), a specific AT
2
receptor antagonist, or divalinil (100 nmol/L), an AT
4
receptor inhibitor. In human ventricles (n=13), message levels of atrial natriuretic peptide and AT
1
receptor were inversely correlated, which suggests a decrease in AT
1
receptor expression with progressive heart failure. Northern analysis and fluorescence-activated cell sorting demonstrated AT
1
receptor in cultured human cardiac fibroblasts. Ang II increased mitogen-activated protein kinase activity and in DNA synthesis (5-fold,
P
<0.01) stimulated a 2-fold increase in transforming growth factor-β
1
(
P
<0.05) mRNA levels at 2 hours and a 2-fold increase in laminin (
P
<0.05) and fibronectin (
P
<0.05) mRNA levels at 24 hours. Ang II also enhanced plasminogen activator inhibitor-1 expression, which inhibits metalloproteinases that degrade the extracellular matrix. All of these effects were inhibited by irbesartan but not PD 123319 or divalinil. In addition, Ang II increased cardiac fibroblast attachment to collagens I and III, which was associated with an increase in focal adhesion kinase activity.

Conclusions
—Activation of the AT
1
receptor in human heart promotes fibrosis. Ang II plays a novel role in stimulation of plasminogen activator inhibitor-1 expression and adhesion of cardiac fibroblasts to collagen.
The Cardiac Fas (APO-1/CD95) Receptor/Fas Ligand System
Authors: Wollert Kai C. , Heineke Jörg , Westermann Jürgen , Lüdde Mark , Fiedler Beate , Zierhut Wolfgang , Laurent Didier , Bauer Manuel K. A. , Schulze-Osthoff Klaus , Drexler Helmut
Published: June 2012

Background
—Fas (APO-1/CD95) is a transmembrane receptor belonging to the tumor necrosis factor receptor superfamily. Cross-linking of Fas by Fas ligand (FasL), a tumor necrosis factor-α–related cytokine, promotes apoptosis and/or transcription factor activation in a highly cell-type–specific manner. The biological consequences of Fas activation in cardiomyocytes and the regulation of Fas and FasL abundance in the myocardium in vivo remain largely unknown.

Methods and Results
—As shown by immunohistochemistry, Fas was expressed on the sarcolemma of cardiomyocytes in left ventricular tissue sections. Moreover, FasL was constitutively expressed in the myocardium and in isolated cardiomyocytes, as revealed by reverse transcription polymerase chain reaction and Western blotting. Left ventricular abundance of Fas but not FasL was upregulated in a rat model of compensated volume-overload hypertrophy and was closely related to diastolic but not systolic wall stress as determined by MRI. Cardiomyocyte apoptosis was not enhanced in volume-overload hypertrophy despite the increased expression of Fas and the presence of FasL in the myocardium. Moreover, injection of mice with an agonistic anti-Fas antibody promoted hepatocyte but not cardiomyocyte apoptosis in vivo. Stimulation of isolated cardiomyocytes with recombinant FasL promoted an activation of the transcription factor AP-1 as shown by electrophoretic mobility shift assays but did not induce cell death.

Conclusions
—Fas and FasL are constitutively expressed in the myocardium and in cardiomyocytes. Myocardial expression of Fas is closely related to diastolic loading conditions in vivo. Signaling pathways emanating from Fas are coupled to an activation of the transcription factor AP-1 in cardiomyocytes.
A Comparison of the Framingham Risk Index, Coronary Artery Calcification, and Culprit Plaque Morphology in Sudden Cardiac Death
Authors: Taylor Allen J. , Burke Allen P. , O’Malley Patrick G. , Farb Andrew , Malcom Gray T. , Smialek John , Virmani Renu
Published: June 2012

Background
—Neither clinical prediction models nor noninvasive imaging tests that detect coronary artery calcification identify all patients who experience acute coronary events. Variations in culprit plaque morphology may account for these inaccuracies.

Methods and Results
—We compared the 10-year Framingham risk index, histologic coronary calcification, and culprit plaque morphology in 79 consecutive adults with sudden cardiac death. There was a modest relationship between the Framingham risk index and the extent of histologic coronary calcification (
r
=0.35,
P
=0.002). Agreement in risk classification between the histologic calcification score and the Framingham risk index occurred in 50 of 79 cases (63.3%,
P
=0.039). Either a focus of coronary artery calcification ≥40 μmol/L (62% of cases) or a Framingham risk index score ≥ average risk for age (62% of cases) were present in 66 of 79 (83.5%) cases. Cases with plaque erosion (n=22) had significantly less coronary calcification (
P
=0.003) and lower Framingham risk index (
P
=0.001) scores than stable (n=27) or ruptured (n=30) plaques. Fourteen of 22 (63.6%) cases of plaque erosion were classified as low risk by both the Framingham risk index and the histologic calcification score.

Conclusions
—The prediction of sudden cardiac death using the Framingham risk index and the measurement of coronary calcification are distinct methods of assessing risk for sudden cardiac death. Excessive reliance on either method alone will produce errors in risk classification, particularly for patients at risk of plaque erosion, but their combination may be complementary.
Noninvasive Detection of Myocardial Ischemia From Perfusion Reserve Based on Cardiovascular Magnetic Resonance
Authors: Al-Saadi Nidal , Nagel Eike , Gross Michael , Bornstedt Axel , Schnackenburg Bernhard , Klein Christoph , Klimek Waldemar , Oswald Helmut , Fleck Eckart
Published: June 2012

Background
—Myocardial perfusion reserve can be noninvasively assessed with cardiovascular MR. In this study, the diagnostic accuracy of this technique for the detection of significant coronary artery stenosis was evaluated.

Methods and Results
—In 15 patients with single-vessel coronary artery disease and 5 patients without significant coronary artery disease, the signal intensity–time curves of the first pass of a gadolinium-DTPA bolus injected through a central vein catheter were evaluated before and after dipyridamole infusion to validate the technique. A linear fit was used to determine the upslope, and a cutoff value for the differentiation between the myocardium supplied by stenotic and nonstenotic coronary arteries was defined. The diagnostic accuracy was then examined prospectively in 34 patients with coronary artery disease and was compared with coronary angiography. A significant difference in myocardial perfusion reserve between ischemic and normal myocardial segments (1.08±0.23 and 2.33±0.41;
P
<0.001) was found that resulted in a cutoff value of 1.5 (mean minus 2 SD of normal segments). In the prospective analysis, sensitivity, specificity, and diagnostic accuracy for the detection of coronary artery stenosis (≥75%) were 90%, 83%, and 87%, respectively. Interobserver and intraobserver variabilities for the linear fit were low (
r
=0.96 and 0.99).

Conclusions
—MR first-pass perfusion measurements yielded a high diagnostic accuracy for the detection of coronary artery disease. Myocardial perfusion reserve can be easily and reproducibly determined by a linear fit of the upslope of the signal intensity–time curves.
Assessment of Nonuniformity of Transmural Myocardial Velocities by Color-Coded Tissue Doppler Imaging
Authors: Derumeaux Geneviève , Ovize Michel , Loufoua Joseph , Pontier Gérard , André-Fouet Xavier , Cribier Alain
Published: June 2012

Background
—Transmural myocardial contractile performance is nonuniform across the different layers of the left ventricular wall. We evaluated the accuracy of color M-mode tissue Doppler imaging (TDI) to assess the transmural distribution of myocardial velocities and to quantify the severity of dysfunction induced by acute ischemia and reperfusion in the inner and outer myocardial layers.

Methods and Results
—Thirteen open-chest dogs underwent 15 minutes of left anterior descending coronary artery occlusion followed by 120 minutes of reperfusion. M-mode TDI was obtained from an epicardial short-axis view. Systolic velocities were calculated within endocardium and epicardium of the anterior and posterior walls. Regional myocardial blood flow was assessed by radioactive microspheres. Segment shortening was measured by sonomicrometry in endocardium and epicardium of both the anterior and posterior walls. At baseline, endocardial velocities were higher than epicardial velocities, resulting in an inner/outer myocardial velocity gradient. Ischemia caused a significant and comparable reduction in endocardial and epicardial systolic velocities in the anterior wall with the disappearance of the velocity gradient. Systolic velocities significantly correlated with segment shortening in both endocardium and epicardium during ischemia and reperfusion. In the first minutes after reflow, endocardial velocities showed a greater improvement than epicardial velocities, and the velocity gradient resumed although to a limited extent, indicative of stunning.

Conclusions
—TDI is an accurate method to assess the nonuniformity of transmural velocities and may be a promising new tool for quantifying ischemia-induced regional myocardial dysfunction.
Pharmacokinetic Evaluation of Triiodothyronine Supplementation in Children After Modified Fontan Procedure
Authors: Mainwaring Richard D. , Capparelli Edmund , Schell Kenneth , Acosta Mark , Nelson Jerald C.
Published: June 2012

Background
—Triiodothyronine (T
3
) supplementation may be a useful adjunct in the management of patients after cardiopulmonary bypass. Limited data are available regarding the use and pharmacokinetics of T
3
in children. The present study was performed to evaluate T
3
pharmacokinetics in a cohort of children undergoing the modified Fontan procedure.

Methods and Results
—A total of 28 patients were enrolled in this randomized, prospective study. The patients were divided into 4 groups: 1 group received a placebo and 3 groups received intravenous T
3
at dosages of 0.4, 0.6, and 0.8 μg/kg, respectively. All 28 patients survived their operative procedures. Two patients developed low cardiac output, and 3 patients had pleural effusions. The median length of hospital stay was 7 days. The mean free T
3
level was 316±67 pg/dL after then administration of a placebo. Patients who received T
3
had mean peak free T
3
levels of 972±88, 1351±299, and 1869±281 pg/dL for the dosages of 0.4, 0.6, and 0.8 μg/kg, respectively. The calculated half-life of T
3
was 7 hours.

Conclusions
—The half-life of intravenous T
3
in children is approximately one-third of that reported for adults. These results provide a framework for studying the efficacy of T
3
supplementation in children undergoing open-heart surgery.
Influence of Postangioplasty β-Irradiation on Endothelial Function in Porcine Coronary Arteries
Authors: Thorin Eric , Meerkin David , Bertrand Olivier F. , Paiement Patrice , Joyal Michel , Bonan Raoul
Published: June 2012

Background
—Postangioplasty (PTCA) intracoronary radiation therapy (ICRT) has been demonstrated to limit restenosis. The consequences of these procedures on coronary reactivity are unknown.

Methods and Results
—Porcine coronary arteries were studied after PTCA immediately (n=5) and 6 weeks (n=5) after ICRT (n=5 and 5, respectively), after combined PTCA+ICRT (n=5 and 7, respectively), and after no intervention (n=11). A 3-cm-long source train of Sr/Y
90
was used in vivo to deliver 16 Gy at a depth of 2 mm from the source center, as used in clinical trials. Arterial rings were mounted on myographs to record isometric tension. After achieving steady-state contraction to depolarizing physiological solution containing 40 mmol/L KCl, measured baseline tension was significantly elevated immediately after all interventions. It returned to normal levels 6 weeks after PTCA and ICRT alone but was significantly reduced if combined. Active contractions induced by 40 mmol/L KCl were maintained after combined therapy both immediately after and at 6 weeks. In these depolarizing conditions, nitric oxide–dependent relaxation to substance P was trivial after PTCA+ICRT and reduced after ICRT, whereas in the presence of physiological solution and
N
ω
-nitro-
l
-arginine, substance P–induced relaxation was reduced after PTCA and abolished after PTCA+ICRT 6 weeks after intervention. In rings without endothelium, the relaxation mediated by sodium nitroprusside (0.1 μmol/L) was reduced immediately after PTCA and at 6 weeks.

Conclusions
—PTCA+ICRT altered the passive mechanical properties of porcine coronary arterial wall. Furthermore, at 6 weeks, receptor-operated release of endothelium-derived nitric oxide and endothelium-derived hyperpolarizing factor was reduced by ICRT and PTCA alone, respectively, and was prevented by their combination.
Transfection of Antisense
p53
Tumor Suppressor Gene Oligodeoxynucleotides Into Rat Carotid Artery Results in Abnormal Growth of Vascular Smooth Muscle Cells
Authors: Matsushita Hidetsugu , Morishita Ryuichi , Aoki Motokuni , Tomita Naruya , Taniyama Yoshiaki , Nakagami Hironori , Shimozato Takashi , Higaki Jitsuo , Kaneda Yasufumi , Ogihara Toshio
Published: June 2012

Background
—Although loss of activity of an antioncogene, the
p53
tumor suppressor gene product, has been postulated in the pathogenesis of human restenosis, little is known about the role of
p53
in the regulation of vascular smooth muscle cell (VSMC) growth. In this study, to clarify the role of
p53
in the pathogenesis of restenosis, we examined transfection of antisense
p53
oligodeoxynucleotides (ODN) into VSMC in vitro and rat carotid artery in vivo.

Methods and Results
—The specificity of antisense
p53
ODN was confirmed by a significant decrease in
p53
protein. Transfection of antisense
p53
ODN into VSMC resulted in a significant increase in DNA synthesis and cell number as compared with sense and scrambled ODN (
P
<0.01). Importantly, transfection of antisense
p53
ODN into rat intact carotid artery resulted in a significant increase in the ratio of neointima to medial area at 2 and 4 weeks after transfection, accompanied by a significant decrease in
p53
protein (
P
<0.01). Moreover, cotransfection of wild-type
p53
plasmid completely abolished neointimal formation induced by antisense
p53
ODN. The sustained effect of a single antisense ODN administration was confirmed by the kinetics of ODN in the vessel wall with the use of FITC-labeled ODN.

Conclusions
—Overall, the present study demonstrated that loss of
p53
by antisense
p53
ODN resulted in an abnormal VSMC growth in vitro and in vivo. These results demonstrated the potential contribution of
p53
to the pathogenesis of restenosis.
Hyperhomocysteinemia Increases Risk of Death, Especially in Type 2 Diabetes
Authors: Hoogeveen Ellen K. , Kostense Pieter J. , Jakobs Cornelis , Dekker Jacqueline M. , Nijpels Giel , Heine Robert J. , Bouter Lex M. , Stehouwer Coen D. A.
Published: June 2012

Background
—A high serum total homocysteine (tHcy) concentration is a risk factor for death, but the strength of the relation in patients with type 2 (non–insulin-dependent) diabetes mellitus compared with nondiabetic subjects is not known. A cross-sectional study suggested that the association between tHcy and cardiovascular disease is stronger in diabetic than in nondiabetic subjects. We therefore prospectively investigated the combined effect of hyperhomocysteinemia and type 2 diabetes on mortality.

Methods and Results
—Between October 1, 1989, and December 31, 1991, serum was saved from 2484 men and women, 50 to 75 years of age, who were randomly selected from the town of Hoorn, The Netherlands. Fasting serum tHcy concentration was measured in 171 subjects who died (cases; 76 of cardiovascular disease) and in a stratified random sample of 640 survivors (control subjects). Mortality risks were calculated over 5 years of follow-up by means of logistic regression. The prevalence of hyperhomocysteinemia (tHcy >14 μmol/L) was 25.8%. After adjustment for major cardiovascular risk factors, serum albumin, and HbA
1c
, the odds ratio (95% CI) for 5-year mortality was 1.56 (1.07 to 2.30) for hyperhomocysteinemia and 1.26 (1.02 to 1.55) per 5-μmol/L increment of tHcy. The odds ratio for 5-year mortality for hyperhomocysteinemia was 1.34 (0.87 to 2.06) in nondiabetic subjects and 2.51 (1.07 to 5.91) in diabetic subjects (
P
=0.08 for interaction).

Conclusions
—Hyperhomocysteinemia is related to 5-year mortality independent of other major risk factors and appears to be a stronger (1.9-fold) risk factor for mortality in type 2 diabetic patients than in nondiabetic subjects.
Predictive Power of Increased QT Dispersion in Ventricular Extrasystoles and in Sinus Beats for Risk Stratification After Myocardial Infarction
Authors: Dąbrowski Andrzej , Kramarz Elżbieta , Piotrowicz Ryszard , Kubik Leszek
Published: June 2012

Background
—QT dispersion, commonly measured in sinus beats (QTd-S), can also be calculated in premature ventricular beats (QTd-V). To date, no studies have addressed the relation between these 2 variables.

Methods and Results
—In 148 patients with remote myocardial infarction and premature ventricular beats on a routine ECG, QT dispersion, defined as the difference between the maximum and the minimum QT interval across the 12-lead ECG, was calculated separately for the ventricular extrasystole and the preceding sinus beat. In the total group of patients, QTd-V was greater than QTd-S (83±33 versus 74±34 ms, respectively;
P
=0.001). During a follow-up period of 35±17 months, arrhythmic events (sustained ventricular tachycardia, ventricular fibrillation, or sudden death) were noted in 30 patients. A QTd-V of ≥100 ms was a stronger univariate marker of arrhythmic events than was a QTd-S of ≥100 ms, and multivariate analysis selected only prolonged QTd-V (hazard ratio 3.81, 95% CI 2.2 to 11.2) and low ejection fraction (hazard ratio 3.05, 95% CI 1.6 to 7.6) as independent predictors of arrhythmic events.

Conclusions
—The magnitude of QTd-V was greater than that of QTd-S in the total group of patients. Prolonged QTd-V is associated with a significantly increased risk for arrhythmic events in postinfarction patients, and the prognostic significance of QTd-V exceeds that of QTd-S.
Serum Carboxy-Terminal Propeptide of Procollagen Type I Is a Marker of Myocardial Fibrosis in Hypertensive Heart Disease
Authors: Querejeta Ramón , Varo Nerea , López Begoña , Larman Mariano , Artiñano Edurne , Etayo Juan C. , Ubago José L. Martínez , Gutierrez-Stampa Marian , Emparanza José I. , Gil María J. , Monreal Ignacio , Mindán Javier Pardo , Díez Javier
Published: June 2012

Background
—This study was designed to investigate whether the serum concentration of the carboxy-terminal propeptide of procollagen type I (PIP), a marker of collagen type I synthesis, is related to myocardial fibrosis in hypertensive patients.

Methods and Results
—The study was performed in 26 patients with essential hypertension in which ischemic cardiomyopathy was excluded after a complete medical workup. Right septal endomyocardial biopsies were performed in hypertensive patients to quantify collagen content. Collagen volume fraction (CVF) was determined on picrosirius red–stained sections with an automated image analysis system. The serum concentration of PIP was measured by specific radioimmunoassay. Compared with normotensives, both serum PIP and CVF were increased (
P
<0.001) in hypertensives. A direct correlation was found between CVF and serum PIP (
r
=0.471,
P
<0.02) in all hypertensives. Histological analysis revealed the presence of 2 subgroups of patients: 8 with severe fibrosis and 18 with nonsevere fibrosis. Serum PIP was higher (
P
<0.05) in patients with severe fibrosis than in patients with nonsevere fibrosis. Using receiver operating characteristic curves, we observed that a cutoff of 127 μg/L for PIP provided 78% specificity and 75% sensitivity for predicting severe fibrosis with a relative risk of 4.80 (95% CI, 1.19 to 19.30).

Conclusions
—These results show a strong correlation between myocardial collagen content and the serum concentration of PIP in essential hypertension. Although preliminary, these findings suggest that the determination of PIP may be an easy and reliable method for the screening and diagnosis of severe myocardial fibrosis associated with arterial hypertension.
Prognostic Impact of Coronary Vasodilator Dysfunction on Adverse Long-Term Outcome of Coronary Heart Disease
Authors: Schächinger Volker , Britten Martina B. , Zeiher Andreas M.
Published: June 2012

Background
—Endothelial vasodilator dysfunction is a characteristic feature of patients at risk for coronary atherosclerosis. Therefore, we prospectively investigated whether coronary endothelial dysfunction predicts disease progression and cardiovascular event rates.

Methods and Results
—Coronary vasoreactivity was assessed in 147 patients using the endothelium-dependent dilator acetylcholine, sympathetic activation by cold pressor testing, dilator responses to increased blood flow, and dilation in response to nitroglycerin. Cardiovascular events (cardiovascular death, unstable angina, myocardial infarction, percutaneous transluminal coronary angioplasty, coronary bypass grafting, ischemic stroke, or peripheral artery revascularization) served as outcome variables over a median follow-up period of 7.7 years. Patients suffering from cardiovascular events during follow-up (n=16) had significantly increased vasoconstrictor responses to acetylcholine infusion (
P
=0.009) and cold pressor testing (
P
=0.002), as well as significantly blunted vasodilator responses to increased blood flow (
P
<0.001) and the intracoronary injection of nitroglycerin (
P
=0.001). Impaired endothelial and endothelium-independent coronary vasoreactivity were associated with a significantly higher incidence of cardiovascular events by Kaplan-Meier analysis. By multivariate analysis, all tests of coronary vasoreactivity were significant, independent predictors of a poor prognosis, even after adjustment for traditional cardiovascular risk factors or the presence of atherosclerosis itself.

Conclusions
—Coronary endothelial vasodilator dysfunction predicts long-term atherosclerotic disease progression and cardiovascular event rates. Thus, the assessment of coronary endothelial vasoreactivity can provide pivotal information as both a diagnostic and prognostic tool in patients at risk for coronary heart disease.
Frequency and Clinical Implications of Fluid Dynamically Significant Diffuse Coronary Artery Disease Manifest as Graded, Longitudinal, Base-to-Apex Myocardial Perfusion Abnormalities by Noninvasive Positron Emission Tomography
Authors: Gould K. Lance , Nakagawa Yuko , Nakagawa Keiichi , Sdringola Stefano , Hess Mary Jane , Haynie Mary , Parker Neal , Mullani Nizar , Kirkeeide Richard
Published: June 2012

Background
—Diffuse coronary atherosclerosis is the substrate for plaque rupture and coronary events. Therefore, in patients with mild arteriographic coronary artery disease without significant segmental dipyridamole-induced myocardial perfusion defects, we tested the hypothesis that fluid dynamically significant diffuse coronary artery narrowing is frequently manifest as a graded, longitudinal, base-to-apex myocardial perfusion abnormality by noninvasive PET.

Methods and Results
—In this study, 1001 patients with documented coronary artery disease by coronary arteriography showing any visible coronary artery narrowing underwent rest-dipyridamole PET perfusion imaging. Quantitative severity of dipyridamole-induced, circumscribed, segmental PET perfusion defects was objectively measured by automated software as the minimum quadrant average relative activity indicating localized flow limiting stenoses. Quantitative severity of the graded, longitudinal, base-to-apex myocardial perfusion gradient indicating fluid dynamic effects of diffuse coronary artery narrowing was objectively measured by automated software as the spatial slope of relative activity along the cardiac longitudinal axis.

Conclusions
—In patients with mild arteriographic disease without statistically significant dipyridamole-induced segmental myocardial perfusion defects caused by flow-limiting stenoses compared with normal control subjects, there was a graded, longitudinal, base-to-apex myocardial perfusion gradient significantly different from normal control subjects (
P
=0.001) that was also observed for moderate to severe dipyridamole-induced segmental perfusion defects (
P
=0.0001), indicating diffuse disease underlying segmental perfusion defects; 43% of patients with or without segmental perfusion defects demonstrated graded, longitudinal, base-to-apex perfusion abnormalities beyond ±2 SD of normal control subjects, indicating diffuse coronary arterial narrowing by noninvasive PET perfusion imaging.
Nitric Oxide Modulates Expression of Cell Cycle Regulatory Proteins
Authors: Tanner Felix C. , Meier Peter , Greutert Helen , Champion Claudine , Nabel Elizabeth G. , Lüscher Thomas F.
Published: June 2012

Background
—We examined the effect of NO on the proliferation and cell cycle regulation of human aortic vascular smooth muscle cells (VSMCs).

Methods and Results
—The NO donor diethylenetriamineNONOate (10
−5
to 10
−3
mol/L) inhibited proliferation in response to 10% fetal calf serum (FCS) and 100 ng/mL platelet-derived growth factor-BB in a concentration-dependent manner. This effect was not observed with disintegrated diethylenetriamineNONOate or with the parent compound, diethylenetriamine. Adenoviral transfection of endothelial NO synthase (NOS) inhibited proliferation in response to FCS, which was prevented with
N
G
-nitro-
l
-arginine methyl ester. NOS overexpression did not inhibit proliferation in response to platelet-derived growth factor, although the transfection efficiency and protein expression were similar to those of FCS-stimulated cells. Nitrate release was selectively enhanced from FCS-treated cells, indicating that NOS was activated by FCS only. NO caused G
1
cell cycle arrest. Cytotoxicity was determined with trypan blue exclusion, and apoptosis was assessed with DNA fragmentation. Cyclin-dependent kinase 2 expression level, threonine phosphorylation, and kinase activity were inhibited. Cyclin A expression was blunted, whereas cyclin E remained unchanged. p21 expression was induced, and p27 remained unaltered. The effect on cyclin A and p21 started within 6 hours and preceded the changes in cell cycle distribution. Proliferation in response to 10% FCS was barely inhibited with 8-bromo-cGMP (10
−3
mol/L) but was blunted with both forskolin and 8-bromo-cAMP. Proliferation in response to 2% FCS was inhibited with 8-bromo-cGMP, but it did not mimic the cell cycle effects of NO.

Conclusions
—NO inhibits VSMC proliferation by specifically changing the expression and activity of cell cycle regulatory proteins, which may occur independent of cGMP. Adenoviral overexpression of endothelial NOS represents a cytostatic strategy for gene therapy of vascular disease.
Anger Proneness Predicts Coronary Heart Disease Risk
Authors: Williams Janice E. , Paton Catherine C. , Siegler Ilene C. , Eigenbrodt Marsha L. , Nieto F. Javier , Tyroler Herman A.
Published: June 2012

Background
—Increased research attention is being paid to the negative impact of anger on coronary heart disease (CHD).

Methods and Results
—This study examined prospectively the association between trait anger and the risk of combined CHD (acute myocardial infarction [MI]/fatal CHD, silent MI, or cardiac revascularization procedures) and of “hard” events (acute MI/fatal CHD). Participants were 12 986 black and white men and women enrolled in the Atherosclerosis Risk In Communities study. In the entire cohort, individuals with high trait anger, compared with their low anger counterparts, were at increased risk of CHD in both event categories. The multivariate-adjusted hazard ratio (HR) (95% CI) was 1.54 (95% CI 1.10 to 2.16) for combined CHD and 1.75 (95% CI 1.17 to 2.64) for “hard” events. Heterogeneity of effect was observed by hypertensive status. Among normotensive individuals, the risk of combined CHD and of “hard” events increased monotonically with increasing levels of trait anger. The multivariate-adjusted HR of CHD for high versus low anger was 2.20 (95% CI 1.36 to 3.55) and for moderate versus low anger was 1.32 (95% CI 0.94 to 1.84). For “hard” events, the multivariate-adjusted HRs were 2.69 (95% CI 1.48 to 4.90) and 1.35 (95% CI 0.87 to 2.10), respectively. No statistically significant association between trait anger and incident CHD risk was observed among hypertensive individuals.

Conclusions
—Proneness to anger places normotensive middle-aged men and women at significant risk for CHD morbidity and death independent of the established biological risk factors.
Deletion Allele of Angiotensin-Converting Enzyme Gene Increases Risk of Essential Hypertension in Japanese Men
Authors: Higaki Jitsuo , Baba Shunroku , Katsuya Tomohiro , Sato Noriyuki , Ishikawa Kazuhiko , Mannami Toshihumi , Ogata Jun , Ogihara Toshio
Published: June 2012

Background
—The Framingham Study recently revealed that the homozygous deletion polymorphism of the angiotensin-converting enzyme gene (
ACE DD
) is associated with increased risk for essential hypertension in a male-specific manner. However, this association has not been confirmed in races other than whites.

Methods and Results
—Using a large number of Japanese subjects (n=5014) that were randomly selected from the general population (the Suita Study), we examined the association between
ACE DD
and hypertension. The frequency of
DD
(17.1%) in hypertensive men was significantly higher (
P
<0.0015) than that (11.8%) in other mildly hypertensive or normotensive men, and the estimated odds prevalence for hypertension (
DD
vs
II
) was 1.75 (95% CI 1.21 to 2.53). In contrast, no significant association was confirmed in women (OR 1.17, 95% CI 0.79 to 1.72).

Conclusions
—Despite the lower frequency of the
DD
genotype in Japanese than in whites, the
ACE
gene polymorphism was associated with increased risk for hypertension, suggesting that this polymorphism is a mild but certain genetic risk factor for essential hypertension in men.
Oral
l
-Arginine in Patients With Coronary Artery Disease on Medical Management
Authors: Blum Arnon , Hathaway Londa , Mincemoyer Rita , Schenke William H. , Kirby Martha , Csako Gyorgy , Waclawiw Myron A. , Panza Julio A. , Cannon Richard O.
Published: June 2012

Background
—Vascular nitric oxide (NO) bioavailability is reduced in patients with coronary artery disease (CAD). We investigated whether oral
l
-arginine, the substrate for NO synthesis, improves homeostatic functions of the vascular endothelium in patients maintained on appropriate medical therapy and thus might be useful as adjunctive therapy.

Methods and Results
—Thirty CAD patients (29 men; age, 67±8 years) on appropriate medical management were randomly assigned to
l
-arginine (9 g) or placebo daily for 1 month, with crossover to the alternate therapy after 1 month off therapy, in a double-blind study. Nitrogen oxides in serum (as an index of endothelial NO release), flow-mediated brachial artery dilation (as an index of vascular NO bioactivity), and serum cell adhesion molecules (as an index of NO-regulated markers of inflammation) were measured at the end of each treatment period.
l
-Arginine significantly increased arginine levels in plasma (130±53 versus 70±17 μmol/L,
P
<0.001) compared with placebo. However, there was no effect of
l
-arginine on nitrogen oxides (19.3±7.9 versus 18.6±6.7 μmol/L,
P
=0.546), on flow-mediated dilation of the brachial artery (11.9±6.3% versus 11.4±7.9%,
P
=0.742), or on the cell adhesion molecules E-selectin (47.8±15.2 versus 47.2±14.4 ng/mL,
P
=0.601), intercellular adhesion molecule-1 (250±57 versus 249±57 ng/mL,
P
=0.862), and vascular cell adhesion molecule-1 (567±124 versus 574±135 ng/mL,
P
=0.473).

Conclusions
—Oral
l
-arginine therapy does not improve NO bioavailability in CAD patients on appropriate medical management and thus may not benefit this group of patients.
Increased Diastolic Chamber Stiffness During Demand Ischemia
Authors: Varma Niraj , Eberli Franz R. , Apstein Carl S.
Published: June 2012

Background
—Increased diastolic chamber stiffness (↑DCS) during angina (demand ischemia) has been postulated to be generated by increased diastolic myocyte calcium concentration.

Methods and Results
—We reproduced demand ischemia in isolated isovolumically contracting red-cell–perfused rabbit hearts by imposing pacing tachycardia during global low coronary blood flow (32% of baseline). This increased lactate production without increasing oxygen consumption and resulted in ↑DCS (isovolumic left ventricular end-diastolic pressure [LVEDP] increased 10 mm Hg,
P
<0.001, n=38). To determine the mechanism of ↑DCS, we assessed responses to a quick-stretch-release maneuver (QSR), in which the intraventricular balloon was rapidly inflated and deflated to achieve a 3% circumferential muscle fiber length change. QSR was first validated as an effective method of discriminating between calcium-driven and rigor-mediated ↑DCS. QSR imposed during demand ischemia when DCS had increased (LVEDP pretachycardia versus posttachycardia, 15±1 versus 27±2 mm Hg,
P
<0.001, n=6) reduced DCS to pretachycardia values (LVEDP post-QSR, 15±1 mm Hg,
P
<0.001), ie, elicited a response characteristic of rigor, without any component of calcium-generated tension.

Conclusions
—A rigor force, possibly resulting from high-energy phosphate depletion and/or an increase in ADP, appears to be the primary mechanism underlying increased DCS in this model of global LV demand ischemia.
Prediction of 1-Year Survival After Thrombolysis for Acute Myocardial Infarction in the Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries Trial
Authors: Califf Robert M. , Pieper Karen S. , Lee Kerry L. , Van de Werf Frans , Simes R. John , Armstrong Paul W. , Topol Eric J.
Published: June 2012

Background
—When a patient survives thrombolysis for acute myocardial infarction, little information from large studies exists from which to estimate prognosis during follow-up visits.

Methods and Results
—Baseline, in-hospital, and later survival data were collected from 41 021 patients enrolled in Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries, a randomized trial of 4 thrombolytic-heparin regimens with standard aspirin and β-blockade. Cox proportional hazards models were developed to predict 1-year survival in 30-day survivors (n=37 869) from baseline clinical and ECG factors and in-hospital factors; a combined model then was developed (C-index 0.800). The model was simplified into a nomogram to predict individual outcomes (C-index 0.754). Factors reflecting demographics (advanced age, lighter weight), larger infarctions (higher Killip class, lower blood pressure, faster heart rate, longer QRS duration), cardiac risk (smoking, hypertension, prior cerebrovascular disease), and arrhythmia were important predictors of death between 30 days and 1 year. Black race was associated with a substantial increase in risk after considering other factors. Revascularization was associated with reduced risk between 30 days and 1 year.

Conclusions
—When evaluating a patient who has survived acute infarction treated with thrombolysis, clinicians can estimate the likelihood of survival from factors easily measured during admission. Although many risk factors clearly relate to age, left ventricular dysfunction, or clinical instability, black race is an unexplained risk factor requiring further examination.
Circulating Adhesion Molecules in Humans
Authors: Marfella Raffaele , Esposito Katherine , Giunta Riccardo , Coppola Giuseppe , De Angelis Lorenita , Farzati Bartolomeo , Paolisso Giuseppe , Giugliano Dario
Published: June 2012

Background
—We assessed the role of glucose and insulin in the regulation of circulating levels of soluble intercellular adhesion molecule-1 (sICAM-1) and vascular adhesion molecule-1 (sVCAM-1) in normal subjects and in patients with type 2 diabetes.

Methods and Results
—Plasma glucose concentrations were acutely raised in 10 normal subjects and 10 newly diagnosed, complication-free type 2 diabetic patients and maintained at 15 mmol/L for 2 hours. In normal subjects, plasma sICAM-1, but not sVCAM-1, levels rose significantly (
P
<0.01) at 1 hour and returned to basal values at 2 hours. In another study, octreotide was infused during the hyperglycemic clamp to block the release of endogenous insulin; this prevented the late fall of plasma sICAM-l levels observed in under control clamp conditions. The diabetic patients had plasma sICAM-1 levels significantly higher (
P
<0.01) than those of the control subjects; plasma sVCAM-1 levels were similar. Both sICAM-l and sVCAM-1 concentrations did not change significantly during the control hyperglycemic clamp; however, octreotide infusion increased plasma sICAM-1 levels, which remained significantly (
P
<0.05) above baseline during the whole clamp. In an additional 10 type 2 diabetic patients, overnight euglycemia (plasma glucose 5.5 mmol/L) obtained with the aid of an artificial pancreas or supplementation with l-arginine (10 g PO for 30 days), the natural precursor of NO, normalized the increased plasma sICAM-1 levels.

Conclusions
—Acute hyperglycemia increases circulating sICAM-1 levels in normal subjects, whereas the correction of hyperglycemia with insulin or l-arginine supplementation restored to normal levels the increased plasma sICAM-1 levels of type 2 diabetic patients.
Impact of Diabetes on Cardiac Structure and Function
Authors: Devereux Richard B. , Roman Mary J. , Paranicas Mary , O’Grady Michael J. , Lee Elisa T. , Welty Thomas K. , Fabsitz Richard R. , Robbins David , Rhoades Everett R. , Howard Barbara V.
Published: June 2012

Background
—Whether diabetes mellitus (DM) adversely affects left ventricular (LV) structure and function independently of increases in body mass index (BMI) and blood pressure is controversial.

Methods and Results
—Echocardiography was used in the Strong Heart Study, a study of cardiovascular disease in American Indians, to compare LV measurements between 1810 participants with DM and 944 with normal glucose tolerance. Participants with DM were older (mean age, 60 versus 59 years), had higher BMI (32.4 versus 28.9 kg/m
2
) and systolic blood pressure (133 versus 124 mm Hg), and were more likely to be female, to be on antihypertensive treatment, and to live in Arizona (all
P
<0.001). In analyses adjusted for covariates, women and men with DM had higher LV mass and wall thicknesses and lower LV fractional shortening, midwall shortening, and stress-corrected midwall shortening (all
P
<0.002). Pulse pressure/stroke volume, a measure of arterial stiffness, was higher in participants with DM (
P
<0.001 independent of confounders).

Conclusions
—Non–insulin-dependent DM has independent adverse cardiac effects, including increased LV mass and wall thicknesses, reduced LV systolic chamber and myocardial function, and increased arterial stiffness. These findings identify adverse cardiovascular effects of DM, independent of associated increases in BMI and arterial pressure, that may contribute to cardiovascular events in diabetic individuals.
Hypotension and Resistance to Lipopolysaccharide-Induced Shock in Transgenic Mice Overexpressing Adrenomedullin in Their Vasculature
Authors: Shindo Takayuki , Kurihara Hiroki , Maemura Koji , Kurihara Yukiko , Kuwaki Tomoyuki , Izumida Taro , Minamino Naoto , Ju Ki-Hwan , Morita Hiroyuki , Oh-hashi Yoshio , Kumada Mamoru , Kangawa Kenji , Nagai Ryozo , Yazaki Yoshio
Published: June 2012

Background
—Adrenomedullin (AM) is a vasodilating peptide involved in the regulation of circulatory homeostasis and in the pathophysiology of certain cardiovascular diseases. To determine the extent to which chronic AM overproduction affects circulatory physiology under normal and pathological conditions, we used a preproendothelin-1 promoter to establish transgenic mouse lines overexpressing AM in their vasculature.

Methods and Results
—Transgenic mice overexpressing AM mainly in vascular endothelial and smooth muscle cells exhibited significantly lower blood pressure (BP) and higher plasma cGMP levels than their wild-type littermates. Blockade of NO synthase with
N
G
-monomethyl-
l
-arginine elevated BP to a greater degree in AM transgenic mice, offsetting the BP difference between the 2 groups. Despite their lower basal BP, administration of bacterial lipopolysaccharide elicited smaller declines in BP and less severe organ damage in AM transgenic mice than in wild-type mice. Furthermore, the 24-hour survival rate after induction of lipopolysaccharide shock was significantly higher in the transgenic mice.

Conclusions
—A chronic increase in vascular AM production reduces BP at least in part via an NO-dependent pathway. In addition, smaller responses to LPS in transgenic mice suggest that AM is protective against the circulatory collapse, organ damage, and mortality characteristic of endotoxic shock.