bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of the Preaxillary Flora in Pacemaker Infections
Authors: Da Costa Antoine , Lelièvre Hervé , PhaD  , Kirkorian Gilbert , Célard Marie , Chevalier Philippe , Vandenesch François , Etienne Jerome , Touboul Paul
Published: June 2012

Background
—Infection remains a severe complication after pacemaker implantation. The purpose of our prospective study was to evaluate the role of the local bacteriologic flora in its occurrence.

Methods and Results
—Specimens were collected at the site of implantation for culture from the skin and the pocket before and after insertion in a consecutive series of patients who underwent elective permanent pacemaker implantation. Microorganisms isolated both at the time of insertion and of any potentially infective complication were compared by using conventional speciation and ribotyping. There were 103 patients (67 men and 36 women) whose age ranged from 16 to 93 years (mean±SD, 67±15). At the time of pacemaker implantation, a total of 267 isolates were identified. The majority (85%) were staphylococci. During a mean follow-up of 16.5 months (range, 1 to 24), infection occurred in four patients (3.9%). In two of them, an isolate of
Staphylococcus schleiferi
was recognized by molecular method as identical to the one previously found in the pacemaker pocket. In one patient,
Staphylococcus aureus
, an organism that was absent at the time of pacemaker insertion, was isolated. In another patient, a
Staphylococcus epidermidis
was identified both at the time of pacemaker insertion and when erosion occurred; however, their antibiotic resistance profiles were different.

Conclusions
—This study strongly supports the hypothesis that pacemaker-related infections are mainly due to local contamination during implantation.
S schleiferi
appears to play an underestimated role in infectious colonization of implanted biomaterials and should be regarded as an important opportunistic pathogen.
Left Ventricular Geometry and Severe Left Ventricular Hypertrophy in Children and Adolescents With Essential Hypertension
Authors: Daniels Stephen R. , Loggie Jennifer M. H. , Khoury Philip , Kimball Thomas R.
Published: June 2012

Background
—Left ventricular (LV) hypertrophy has been established as an independent risk factor for cardiovascular disease in adults. Recent research has refined this relationship by determining a cutpoint of 51 g/m
2.7
for LV mass index indicative of increased risk and defining LV geometric patterns that are associated with increased risk. The purpose of this study was to evaluate severe LV hypertrophy and LV geometry in children and adolescents with essential hypertension.

Methods and Results
—A cross-sectional study of young patients (n=130) with persistent blood pressure elevation above the 90th percentile was conducted. Nineteen patients (14%) had LV mass greater than the 99th percentile; 11 of these were also above the adult cutpoint of 51 g/m
2.7
. Males, subjects with greater body mass index, and those who had lower heart rate at maximum exercise were at significantly (
P
<.05) higher risk of severe LV hypertrophy. In addition, 22 patients (17%) had concentric LV hypertrophy, a geometric pattern that is associated with increased risk of cardiovascular disease in adults. Seven patients had LV mass index above the cutpoint and concentric hypertrophy. No consistent significant determinants of LV geometry were identified in these children and adolescents with hypertension.

Conclusions
—Severe LV hypertrophy and abnormal LV geometry are relatively prevalent in young patients with essential hypertension. These findings suggest that these patients may be at risk for future cardiovascular disease and underscore the importance of recognition and treatment of blood pressure elevation in children and adolescents. Weight loss is an important component of therapy in young patients with essential hypertension who are overweight.
Plasma N-Terminal Pro–Brain Natriuretic Peptide and Adrenomedullin
Authors: Richards A. Mark , Nicholls M. Gary , Yandle Tim G. , Frampton Chris , Espiner Eric A. , Turner John G. , Buttimore Rona C. , Lainchbury John G. , Elliott John M. , Ikram Hamid , Crozier Ian G. , Smyth David W.
Published: June 2012

Background
—Newly discovered circulating peptides, N-terminal pro–brain natriuretic peptide (N-BNP) and adrenomedullin (ADM), were examined for prediction of cardiac function and prognosis and compared with previously reported markers in 121 patients with myocardial infarction.

Methods and Results
—The association between radionuclide left ventricular ejection fraction (LVEF) and N-BNP at 2 to 4 days (
r
=−.63,
P
<.0001) and 3 to 5 months (
r
=−.58,
P
<.0001) after infarction was comparable to that for C-terminal BNP and far stronger than for ADM (
r
=−.26,
P
<.01), N-terminal atrial natriuretic peptide (N-ANP), C-terminal ANP, cGMP, or plasma catecholamine concentrations. For prediction of death over 24 months of follow-up, an early postinfarction N-BNP level ≥160 pmol/L had sensitivity, specificity, positive predictive value, and negative predictive values of 91%, 72%, 39%, and 97%, respectively, and was superior to any other neurohormone measured and to LVEF. Only 1 of 21 deaths occurred in a patient with an N-BNP level below the group median (Kaplan-Meier survival analysis,
P
<.00001). For prediction of heart failure (left ventricular failure), plasma N-BNP ≥ 145 pmol/L had sensitivity (85%) and negative predictive value (91%) comparable to the other cardiac peptides and was superior to ADM, plasma catecholamines, and LVEF. By multivariate analysis, N-BNP but not ADM provided predictive information for death and left ventricular failure independent of patient age, sex, LVEF, levels of other hormones, and previous history of heart failure, myocardial infarction, hypertension, or diabetes.

Conclusions
—Plasma N-BNP measured 2 to 4 days after myocardial infarction independently predicted left ventricular function and 2-year survival. Stratification of patients into low- and high-risk groups can be facilitated by plasma N-BNP or BNP measurements, and one of these could reasonably be included in the routine clinical workup of patients after myocardial infarction.
Pressure Overload Induces Cardiac Hypertrophy in Angiotensin II Type 1A Receptor Knockout Mice
Authors: Harada Koichiro , Komuro Issei , Shiojima Ichiro , Hayashi Doubun , Kudoh Sumiyo , Mizuno Takehiko , Kijima Kazuhisa , Matsubara Hiroaki , Sugaya Takeshi , Murakami Kazuo , Yazaki Yoshio
Published: June 2012

Background
—Many studies have suggested that the renin-angiotensin system plays an important role in the development of pressure overload–induced cardiac hypertrophy. Moreover, it has been reported that pressure overload–induced cardiac hypertrophy is completely prevented by ACE inhibitors in vivo and that the stored angiotensin II (Ang II) is released from cardiac myocytes in response to mechanical stretch and induces cardiomyocyte hypertrophy through the Ang II type 1 receptor (AT
1
) in vitro. These results suggest that the AT
1
-mediated signaling is critical for the development of mechanical stress–induced cardiac hypertrophy.

Methods and Results
—To determine whether AT
1
-mediated signaling is indispensable for the development of pressure overload–induced cardiac hypertrophy, pressure overload was produced by constricting the abdominal aorta of AT
1A
knockout (KO) mice. Quantitative reverse transcriptase–polymerase chain reaction revealed that the cardiac AT
1
(probably AT
1B
) mRNA levels in AT
1A
KO mice were <10% of those of wild-type (WT) mice and were not affected by pressure overload. Chronic treatment with subpressor doses of Ang II increased left ventricular mass in WT mice but not in KO mice. Pressure overload, however, fully induced cardiac hypertrophy in KO as well as WT mice. There were no significant differences between WT and KO mice in expression levels of fetal-type cardiac genes, in the left ventricular wall thickness and systolic function as revealed by the transthoracic echocardiogram, or in the histological changes such as myocyte hypertrophy and fibrosis.

Conclusions
—AT
1
-mediated Ang II signaling is not essential for the development of pressure overload–induced cardiac hypertrophy.
Family History as a Risk Factor for Primary Cardiac Arrest
Authors: Friedlander Yechiel , Siscovick David S. , Weinmann Sheila , Austin Melissa A. , Psaty Bruce M. , Lemaitre Rozenn N. , Arbogast Patrick , Raghunathan T. E. , Cobb Leonard A.
Published: June 2012

Background
—The hypothesis that a family history of myocardial infarction (MI) or primary cardiac arrest (PCA) is an independent risk factor for primary cardiac arrest was examined in a population-based case-control study. In addition, we investigated whether recognized risk factors account for the familial aggregation of these cardiovascular events.

Methods and Results
—PCA cases, 25 to 74 years old, attended by paramedics during the period 1988 to 1994 and population-based control subjects matched for age and sex were identified from the community by random digit dialing. All subjects were free of recognized clinical heart disease and major comorbidity. A detailed history of MI and PCA in first-degree relatives was collected in interviews with the spouses of case and control subjects by trained interviewers using a standardized questionnaire. For each familial relationship, there was a higher rate of MI or primary cardiac arrest (MI/PCA) in relatives of case compared with relatives of control subjects. Overall, the rate of MI/PCA among first-degree relatives of cardiac arrest patients was almost 50% higher than that in first-degree relatives of control subjects (rate ratio [RR]=1.46; 95% CI=1.23 to 1.72). In a multivariate logistic model, family history of MI/PCA was associated with PCA (RR=1.57; 95% CI=1.27 to 1.95) even after adjustment for other common risk factors.

Conclusions
—Family history of MI or PCA is positively associated with the risk of primary cardiac arrest. This association is mostly independent of familial aggregation of other common risk factors.
Personality, Disease Severity, and the Risk of Long-term Cardiac Events in Patients With a Decreased Ejection Fraction After Myocardial Infarction
Authors: Denollet Johan , Brutsaert Dirk L.
Published: June 2012

Background
—Patients with myocardial infarction (MI) with a decreased left ventricular ejection fraction (LVEF) have a poor prognosis, but the role of emotional stress in prognosis is not known. We hypothesized that emotional stress in these patients (1) is unrelated to the severity of cardiac disorder, (2) predicts cardiac events, and (3) is a function of basic personality traits.

Methods and Results
—Eighty-seven patients with MI (age, 41 to 69 years) with an LVEF of ≤50% underwent psychological assessment at baseline. Patients and their families were contacted after 6 to 10 years (mean, 7.9 years); cardiac events were defined as cardiac death or nonfatal MI. Emotional distress was unrelated to the severity of cardiac disorder. At follow-up, 21 patients had experienced a cardiac event (13 fatal events). These events were related to LVEF of ≤30%, poor exercise tolerance, previous MI, anxiety, anger, and depression (all
P
≤.02). Patients with a distressed personality (type D; ie, the tendency to suppress negative emotions) were more likely to experience an event over time compared with non–type D patients (
P
=.00005). Cox proportional hazards analysis yielded LVEF of ≤30% (relative risk, 3.0; 95% confidence interval, 1.2 to 7.7;
P
=.02) and type D (relative risk, 4.7; 95% confidence interval, 1.9 to 11.8;
P
=.001) as independent predictors. Anxiety, anger, and depression did not add to the predictive power of type D; these negative emotions were hightly correlated and reflected the personality domain of negative affectivity.

Conclusions
—Personality influences the clinical course of patients with a decreased LVEF. Emotional distress in these patients is unrelated to disease severity but reflects individual differences in personality. Clinical trials should take a broad view of the target of intervention; assessment of LVEF and personality may identify patients at risk.
Different Proliferative Properties of Smooth Muscle Cells of Human Arterial and Venous Bypass Vessels
Authors: Yang Zhihong , Oemar Barry S. , Carrel Thiery , Kipfer Beat , Julmy Friedgard , Lüscher Thomas F.
Published: June 2012

Background
—Internal mammary artery (IMA) bypass grafts have a higher patency than saphenous vein (SV) grafts. Intimal hyperplasia of SV grafts is due to smooth muscle cell (SMC) proliferation and migration. We hypothesized that different SMC growth activity exists in IMA and SV, which may explain the different patencies of arterial and venous grafts.

Methods and Results
—SMCs were isolated from IMA and SV by explant culture and stimulated with serum or platelet-derived growth factor-BB (PDGF-BB). Cell growth was analyzed by explant outgrowth rate,
3
H-thymidine incorporation, or cell counting. PDGF receptor expression and autophosphorylation, regulation of mitogen-activated protein kinases (MAPKs), and cyclin-dependent kinase inhibitors (p27
Kip1
and p21
Cip1
) were analyzed by molecular techniques. SMC outgrowth from explants by serum (20%) over a 20-day period was more pronounced in SV (37±5%) than in IMA (4±3%;
P
<.001) of the same patients. Serum (10%) increased cell number more rapidly in SV (2×10
4
/well to 18±4×10
4
/well;
P
<.05) than in IMA (2×10
4
/well to 9±4×10
4
/well;
P
<.05) over an 8-day period. PDGF-BB (0.01 to 10 ng/mL) stimulated
3
H-thymidine incorporation (1347±470% above control levels) and increased cell number in SV (2×10
4
/well to 5±1×10
4
/well;
P
<.05) but not in IMA. PDGF α- and β-receptors were similarly expressed and were activated in both SV and IMA. PDGF-BB induced a similar MAPK activation (kinetics and maximal activity) in both SV and IMA cells but increased MAPK protein level only in SV. Furthermore, PDGF-BB markedly downregulated the cell cycle inhibitor p27
Kip1
in SV, but this was much less pronounced in IMA.

Conclusions
—SMCs from SVs exhibit enhanced proliferation compared with IMA in spite of functional growth factor receptor expression and MAPK activation. However, PDGF increased MAPK protein level only in SV and downregulated cell cycle inhibitor (p27
Kip1
) more potently in SV than in IMA. This may explain the resistance to growth stimuli of IMA SMCs and may contribute to the longer patency of arterial versus venous grafts.
Remodeling of In-Stent Neointima, Which Became Thinner and Transparent Over 3 Years
Authors: Asakura Masanori , Ueda Yasunori , Nanto Shinsuke , Hirayama Atsushi , Adachi Takayoshi , Kitakaze Masafumi , Hori Masatsugu , Kodama Kazuhisa
Published: June 2012

Background
—Recently, it has been reported that the luminal diameter shows phasic changes after stenting: the progression of luminal narrowing followed by its regression. To elucidate the mechanisms involved in the phasic changes in luminal diameter after stenting, we examined the changes in neointimal thickness and the appearance of neointima by a series of angiographic and angioscopic observations for 3 years after stent implantation.

Methods and Results
—In 12 patients who received a Wiktor coronary stent, serial angiographic and angioscopic examinations were performed immediately, 2 to 4 weeks, 3 months, 6 months, and 3 years after the stenting without repetition of angioplasty. Neointimal thickness was determined by angiography as the difference between stent and luminal diameters. The angioscopic appearance of neointima over the stent was classified as transparent or nontransparent according to the visibility of the majority of the stent. Neointimal thickness increased significantly at 3 months (0.75±0.32 mm) without further changes at 6 months (0.74±0.32 mm). Thereafter, however, it decreased significantly over 3 years (0.51±0.26 mm). The angioscopic appearance was classified as transparent in 8 patients (100%) immediately after stenting, 6 patients (100%) at 2 to 4 weeks, 2 patients (17%) at 3 months, 2 patients (20%) at 6 months, and 7 patients (58%) at 3 years.

Conclusions
—The neointima became thick and nontransparent until 6 months and then became thin and transparent by 3 years. We conclude that neointimal remodeling exists after stenting and plays a major role in the alteration of coronary luminal diameter after stenting.
Gene for Arrhythmogenic Right Ventricular Cardiomyopathy With Diffuse Nonepidermolytic Palmoplantar Keratoderma and Woolly Hair (Naxos Disease) Maps to 17q21
Authors: Coonar Aman S. , Protonotarios Nikos , Tsatsopoulou Adalena , Needham Edward W.A. , Houlston Richard S. , Cliff Sandeep , Otter Mark I. , Murday Victoria A. , Mattu Raj K. , McKenna William J.
Published: June 2012

Background
—Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart muscle disease of unknown etiology that causes arrhythmias, heart failure, and sudden death. Diagnosis can be difficult, and this hampers investigation of its molecular basis. Forms of ARVC in which gene penetrance and disease expression are greater should facilitate genetic study. We undertook a clinical and genetic investigation of Naxos disease, originally described by Protonotarios in 1986. This disease constitutes the triad of ARVC, diffuse nonepidermolytic palmoplantar keratoderma, and woolly hair.

Methods and Results
—We evaluated the population of Naxos, Greece, to identify probands, which was followed by family screening. Twenty-one affected persons from 9 families of 150 persons were identified. Linkage analysis was performed with microsatellite markers. The disease locus mapped to 17q21. A peak 2-point LOD score of 3.62 at θ=0.0 was found with a marker within intron 4 of the keratin 9 gene, a member of the type I (acidic) keratin family. A preserved homozygous disease haplotype was identified. Haplotype analysis delimited the disease interval.

Conclusions
—Hair and skin abnormalities were found to be reliable markers of subsequent heart disease. This suggests the presence of a single mutant gene with novel cardiac, skin, and hair function or two or more tightly linked disease genes. Recessive inheritance of Naxos disease and a founder effect were demonstrated. Identification of a fully informative genetic marker linked to the disease and uncommon in the background population may be of use as a test to identify disease gene carriers.
Estrogen Modulates AT
1
Receptor Gene Expression In Vitro and In Vivo
Authors: Nickenig Georg , Bäumer Anselm T. , Grohè Christian , Kahlert Stefan , Strehlow Kerstin , Rosenkranz Stephan , Stäblein Alexander , Beckers Frank , Smits Jos F. M. , Daemen Mat J. A. P. , Vetter Hans , Böhm Michael
Published: June 2012

Background
—The AT
1
receptor has been implicated in the pathogenesis of hypertension and atherosclerosis. Estrogen deficiency is also associated with cardiovascular diseases. Therefore, we examined the AT
1
receptor gene expression in ovariectomized rats with and without estrogen replacement therapy and the influence of estrogen on AT
1
receptor expression in cultured vascular smooth muscle cells.

Methods and Results
—Rat aortic tissue was examined 5 weeks after ovariectomy. In one group, estrogen (1.7 mg estradiol) was administered during the 5-week period. Functional experiments assessed angiotensin II–induced contraction of aortic rings. AT
1
receptor mRNA levels were measured by quantitative polymerase chain reaction and Northern blotting. AT
1
receptor density was assessed by radioligand binding assays. These techniques were also applied in cultured vascular smooth muscle cells. The efficacy of angiotensin II on vasoconstriction was significantly increased in aortas from ovariectomized rats. As assessed by radioligand binding assays, AT
1
receptor density was increased to 160% without changes in receptor affinity during estrogen deficiency. AT
1
receptor mRNA levels were consistently increased to 187% in ovariectomized rats compared with sham-operated animals. Estrogen substitution therapy in ovariectomized rats reversed this AT
1
receptor overexpression. To explore the underlying mechanisms, the direct influence of estradiol on AT
1
receptor expression was investigated in VSMCs. Estradiol (1 μmol/L) led to a time-dependent downregulation of AT
1
receptor mRNA, with a maximum of 33.3% at 12 hours. There was a correlative decrease in AT
1
receptor density.

Conclusions
—This novel observation of estrogen-induced downregulation of AT
1
receptor expression could explain the association of estrogen deficiency with hypertension and atherosclerosis, because activation of the AT
1
receptor plays a key role in the regulation of blood pressure, fluid homeostasis, and vascular cell growth.
Inducible Nitric Oxide Synthase Expression in Smooth Muscle Cells and Macrophages of Human Transplant Coronary Artery Disease
Authors: Ravalli Stefano , Albala Arline , Ming Ming , Szabolcs Matthias , Barbone Alessandro , Michler Robert E. , Cannon Paul J.
Published: June 2012

Background
—The inducible isoform of the nitric oxide synthase (iNOS) produces large amounts of nitric oxide in response to cytokine stimulation. Previous investigations have demonstrated iNOS expression in the setting of acute and chronic rejection in experimental cardiac transplant models. The goal of this study was to investigate whether iNOS is upregulated in human transplant coronary artery disease (TCAD), a major cause of late mortality after cardiac transplantation.

Methods and Results
—We studied 15 patients with TCAD and 10 with normal coronary arteries. In situ hybridization and immunohistochemistry were used in tissue sections to localize iNOS mRNA and protein, respectively. The presence of peroxynitrite was indirectly assessed by immunostaining with an anti-nitrotyrosine antibody. Normal coronary arteries had no evidence of iNOS expression. In contrast, 30 of 36 coronary artery segments with TCAD (83%) were immunostained by the iNOS antibody. The presence of iNOS mRNA was demonstrated in these vessels by in situ hybridization. Specific cell markers identified iNOS-positive cells as neointimal macrophages and smooth muscle cells. Nitrotyrosine immunoreactivity colocalized with iNOS expression in arteries with TCAD, distributed in macrophages and smooth muscle cells.

Conclusions
—iNOS mRNA and protein are expressed in human arteries with TCAD, where they are associated with extensive nitration of protein tyrosines. These findings indicate that the high-output nitric oxide pathway and possibly the oxidant peroxynitrite might be involved in the process leading to the development of TCAD.
Postrepolarization Refractoriness Versus Conduction Slowing Caused by Class I Antiarrhythmic Drugs
Authors: Kirchhof Paulus F. , Fabritz C. Larissa , Franz Michael R.
Published: June 2012

Background
—Conduction block may be both antiarrhythmic and proarrhythmic. Drug-induced postrepolarization refractoriness (PRR) may prevent premature excitation and tachyarrhythmia induction. The effects of propafenone and procainamide on these parameters, and their antiarrhythmic or proarrhythmic consequences, were investigated.

Methods and Results
—In 11 isolated Langendorff-perfused rabbit hearts, monophasic action potentials (MAPs) were recorded simultaneously from six to seven different right and left ventricular sites, along with a volume-conducted ECG. All recordings were used to discern ventricular tachycardia (VT) or ventricular fibrillation (VF) induced by repetitive extrastimulation (S2-S5) or 10-second burst stimulation at 25 to 200 Hz at baseline and after addition of procainamide (20 μmol/L) or propafenone (1 μmol/L) to the perfusate. MAPs were analyzed for action potential duration at 90% repolarization (APD
90
), conduction times (CT) between the pacing site and the other MAPs, and PRR (effective refractory period−APD
90
=PRR) and related to the induction of VT or VF. During steady-state pacing, procainamide and propafenone prolonged APD
90
by 12% and 14%, respectively. Procainamide slowed mean CT by 40% during S2-S5 pacing, whereas propafenone slowed mean CT by up to 400% (
P
<0.001 versus baseline and procainamide). Wavelength was not changed significantly by procainamide but was shortened fourfold by propafenone at S5. Both drugs produced PRR, which was associated with a 70% decrease in VF inducibility with procainamide and elimination of VF with propafenone. Despite this protection from VF, monomorphic VT was induced with propafenone in 57% of burst stimulations.

Conclusions
—Drug-induced PRR protects against VF induction. Propafenone promotes slow monomorphic VT, probably by use-dependent conduction slowing and wavelength shortening.
5-Methyltetrahydrofolate, the Active Form of Folic Acid, Restores Endothelial Function in Familial Hypercholesterolemia
Authors: Verhaar Marianne C. , Wever Robert M. F. , Kastelein John J. P. , van Dam Thea , Koomans Hein A. , Rabelink Ton J.
Published: June 2012

Background
—Impaired nitric oxide (NO) activity is an early event in the pathogenesis of cardiovascular disease, resulting from either reduced NO formation or increased NO degradation. Administration of tetrahydrobiopterin (BH
4
), an essential cofactor for NO production, could restore NO activity in familial hypercholesterolemia (FH). Because folates have been suggested to stimulate endogenous BH
4
regeneration, we hypothesized that administration of 5-methyltetrahydrofolate (5-MTHF, the active circulating form of folate) might improve NO formation in FH.

Methods and Results
—We studied the effects of 5-MTHF on NO bioavailability in vivo in 10 patients with FH and 10 matched control subjects by venous occlusion plethysmography, using serotonin and nitroprusside as endothelium-dependent and -independent vasodilators. In vitro, we investigated the effect of 5-MTHF on NO production by recombinant endothelial NO synthase (eNOS) by use of [
3
H]arginine to [
3
H]citrulline conversion. We also studied the effects of 5-MTHF on superoxide generation by eNOS and xanthine oxidase (XO) by use of lucigenin chemiluminescence. The impaired endothelium-dependent vasodilation in FH (63% versus 90% in control subjects) could be reversed by coinfusion of 5-MTHF (117% vasodilation), whereas 5-MTHF had no significant effect on endothelium-dependent vasodilation in control subjects. 5-MTHF did not influence basal forearm vasomotion or endothelium-independent vasodilation. 5-MTHF had no direct effect on in vitro NO production by eNOS. However, we did observe a dose-dependent reduction in both eNOS- and XO-induced superoxide generation.

Conclusions
—These results show that the active form of folic acid restores in vivo endothelial function in FH. It is suggested from our in vitro experiments that this effect is due to reduced catabolism of NO.
Platelet Activation With Unfractionated Heparin at Therapeutic Concentrations and Comparisons With a Low-Molecular-Weight Heparin and With a Direct Thrombin Inhibitor
Authors: Xiao Zihui , Théroux Pierre
Published: June 2012

Background
—The growing use of heparin in acute thrombotic disorders, coupled with the availability of many new antithrombotic agents, emphasizes the need for adequate characterization of the platelet effects of the various anticoagulants. Controversial platelet effects have been reported with heparin (eg, enhanced platelet activation in vitro with high doses and no such effect in vivo at therapeutic doses). This study examined platelet receptor activation and platelet aggregation at therapeutic concentrations of unfractionated heparin (UFH), of enoxaparin, a low-molecular-weight heparin, and of argatroban, a direct thrombin inhibitor.

Methods and Results
—Platelet P-selectin (CD62) and activated GP IIb/IIIa (PAC-1) expression on platelet membrane was quantified in whole blood as well as platelet aggregation in platelet-rich plasma in 43 patients with unstable angina before and during treatment with UFH or enoxaparin. Studies were also carried out in blood of seven normal volunteers after addition ex vivo of UFH (0.25 U/mL), enoxaparin (0.25 U/mL), argatroban (1 ng/mL), and normal saline. UFH in patients with unstable angina increased the percentage of circulating platelets positive to PAC-1 from 2.7±1.7% to 4.4±3.4% (
P
<.05) and to CD62 from 1.6±0.9% to 2.7±1.5% (
P
<.01). Platelets were also hyperresponsive to stimulation with ADP and with the thrombin-receptor agonist peptide. Aggregation to ADP increased from 6.8±4.6% to 11.2±7.0% and to TRAP from 5.2±3.5% to 11.1±6.0% (
P
<.001). The addition of UFH to blood of normal volunteers resulted also in activation of GP IIb/IIIa receptors, expression of P-selectin, and enhanced platelet aggregation. Enoxaparin had only minor effects on platelet activation in vivo and ex vivo, and argatroban, evaluated ex vivo, had no detectable effects.

Conclusions
—Therapeutic concentrations of UFH are associated with platelet activation.
Vitamin C Improves Endothelial Function of Conduit Arteries in Patients With Chronic Heart Failure
Authors: Hornig Burkhard , Arakawa Naoshi , Kohler Christoph , Drexler Helmut
Published: June 2012

Background
—Chronic heart failure (CHF) is associated with endothelial dysfunction including impaired endothelium-mediated, flow-dependent dilation (FDD). There is evidence for increased radical formation in CHF, raising the possibility that nitric oxide is inactivated by radicals, thereby impairing endothelial function. To test this hypothesis, we determined the effect of the antioxidant vitamin C on FDD in patients with CHF.

Methods and Results
—High-resolution ultrasound and Doppler was used to measure radial artery diameter and blood flow in 15 patients with CHF and 8 healthy volunteers. Vascular effects of vitamin C (25 mg/min IA) and placebo were determined at rest and during reactive hyperemia (causing endothelium-mediated dilation) before and after intra-arterial infusion of
N
-monomethyl-
l
-arginine (L-NMMA) to inhibit endothelial synthesis of nitric oxide. Vitamin C restored FDD in patients with heart failure after acute intra-arterial administration (13.2±1.7% versus 8.2±1.0%;
P
<.01) and after 4 weeks of oral therapy (11.9±0.9% versus 8.2±1.0%;
P
<.05). In particular, the portion of FDD mediated by nitric oxide (ie, inhibited by L-NMMA) was increased after acute as well as after chronic treatment (CHF baseline: 4.2±0.7%; acute: 9.1±1.3%; chronic: 7.3±1.2%; normal subjects: 8.9±0.8%;
P
<.01).

Conclusions
—Vitamin C improves FDD in patients with CHF as the result of increased availability of nitric oxide. This observation supports the concept that endothelial dysfunction in patients with CHF is, at least in part, due to accelerated degradation of nitric oxide by radicals.
Non–Q-Wave Versus Q-Wave Myocardial Infarction After Thrombolytic Therapy
Authors: Goodman Shaun G. , Langer Anatoly , Ross Allan M. , Wildermann Nancy M. , Barbagelata Alejandro , Sgarbossa Elena B. , Wagner Galen S. , Granger Christopher B. , Califf Robert M. , Topol Eric J. , Simoons Maarten L. , Armstrong Paul W.
Published: June 2012

Background
—Although the stratification of patients with myocardial infarction into ECG subsets based on the presence or absence of new Q waves has important clinical and prognostic utility, systematic evaluation of the impact of thrombolytic therapy on the subsequent development and prognosis of non–Q-wave infarction has been limited to date.

Methods and Results
—We examined 12-lead ECG, coronary anatomy, left ventricular function, and mortality among 2046 patients with ST-segment elevation infarction from the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries angiographic subset to gain further insight into the pathophysiology and prognosis of Q- versus non–Q-wave infarction in the thrombolytic era. Non–Q-wave infarction developed in 409 patients (20%) after thrombolytic therapy. Compared with Q-wave patients, non–Q-wave patients were more likely to present with lesser ST-segment elevation in a nonanterior location. The infarct-related artery in non–Q-wave patients was more likely to be nonanterior (67% versus 58%,
P
=.012) and distally located (33% versus 39%,
P
=.021). Early (90-minute, 77% versus 65%,
P
=.001) and complete (54% versus 44%,
P
<.001) infarct-related artery patency was greater among the non–Q-wave group. Non–Q-wave patients had better global (ejection fraction, 66% versus 57%;
P
<.0001) and regional left ventricular function (10 versus 24 abnormal chords,
P
=.0001). In-hospital, 30-day, 1-year, and 2-year (6.3% versus 10.1%,
P
=.02) mortality rates were lower among non–Q-wave patients.

Conclusions
—The excellent prognosis among the subgroup of patients who develop non–Q-wave infarction after thrombolysis is related to early, complete, and sustained infarct-related artery patency with resultant limitation of left ventricular infarction and dysfunction.
Influence of Pregnancy on the Risk for Cardiac Events in Patients With Hereditary Long QT Syndrome
Authors: Rashba Eric J. , Zareba Wojciech , Moss Arthur J. , Hall W. Jackson , Robinson Jennifer , Locati Emanuela H. , Schwartz Peter J. , Andrews Mark
Published: June 2012

Background
—The effects of pregnancy on women with the hereditary long QT syndrome are currently unknown. The appropriate medical management of pregnant patients with the long QT syndrome has not been established.

Methods and Results
—The study was a retrospective analysis of the 422 women (111 probands affected with the long QT syndrome and 311 first-degree relatives) enrolled in the long QT syndrome registry who had one or more pregnancies. The first-degree relatives were classified as affected (QTc >0.47), borderline (QTc=0.45 to 0.47), and unaffected (QTc <0.45). Cardiac events were defined as the combined incidence of long QT syndrome–related death, aborted cardiac arrest, and syncope. The incidence of cardiac events was compared during equal prepregnancy, pregnancy, and postpartum intervals (40 weeks each). Multivariate logistic regression analysis was performed by use of a mixed-effects model to identify independent predictors of cardiac events among probands. The pregnancy and postpartum intervals were not associated with cardiac events among first-degree relatives. The postpartum interval was independently associated with cardiac events among probands (odds ratio [OR], 40.8; 95% confidence interval [CI], 3.1 to 540;
P
=.01); the pregnancy interval was not associated with cardiac events. Treatment with β-adrenergic blockers was independently associated with a decrease in the risk for cardiac events among probands (OR, 0.023; 95% CI, 0.001 to 0.44;
P
=.01).

Conclusions
—The postpartum interval is associated with a significant increase in risk for cardiac events among probands with the long QT syndrome but not among first-degree relatives. Prophylactic treatment with β-adrenergic blockers should be continued during the pregnancy and postpartum intervals in probands with the long QT syndrome.
Prediction of Indications for Valve Replacement Among Asymptomatic or Minimally Symptomatic Patients With Chronic Aortic Regurgitation and Normal Left Ventricular Performance
Authors: Borer Jeffrey S. , Hochreiter Clare , Herrold Edmond McM. , Supino Phyllis , Aschermann Michael , Wencker Detlef , Devereux Richard B. , Roman Mary J. , Szulc Massimiliano , Kligfield Paul , Isom O. Wayne
Published: June 2012

Background
—Optimal criteria for valve replacement are unclear in asymptomatic/minimally symptomatic patients with aortic regurgitation (AR) and normal left ventricular (LV) performance at rest. Moreover, previous studies have not assessed the prognostic capacity of load-adjusted LV performance (“contractility”) variables, which may be fundamentally related to clinical state. Therefore, 18 years ago, we set out to test prospectively the hypothesis that objective noninvasive measures of LV size and performance and, specifically, of load-adjusted variables, assessed at rest and during exercise (ex), could predict the development of currently accepted indications for operation for AR.

Methods and Results
—Clinical variables and measures of LV size, performance, and end-systolic wall stress (ESS) were assessed annually in 104 patients by radionuclide cineangiography at rest and maximal ex and by echocardiography at rest; ESS was derived during ex. During an average 7.3-year follow-up among patients who had not been operated on, 39 of 104 patients either died suddenly (n=4) or developed operable symptoms only (n=22) or subnormal LV performance with or without symptoms (n=13) (progression rate=6.2%/y). By multivariate Cox model analysis, change (Δ) in LV ejection fraction (EF) from rest to ex, normalized for ΔESS from rest to ex (ΔLVEF-ΔESS index), was the strongest predictor of progression to any end point or to sudden cardiac death alone. Unadjusted ΔLVEF was almost as efficient. Symptom status modified prediction on the basis of the ΔLVEF-ΔESS index. The population tercile at highest risk by ΔLVEF-ΔESS progressed to end points at a rate of 13.3%/y, and the lowest-risk tercile progressed at 1.8%/y.

Conclusions
—Currently accepted symptom and LV performance indications for valve replacement, as well as sudden cardiac death, can be predicted in asymptomatic/minimally symptomatic patients with AR by load-adjusted ΔLVEF-ΔESS index, which includes data obtained during exercise.
Amlodipine Releases Nitric Oxide From Canine Coronary Microvessels
Authors: Zhang Xiaoping , Hintze Thomas H.
Published: June 2012

Background
—Recent studies suggest that amlodipine may reduce mortality in patients with heart failure, especially those with dilated cardiomyopathy. In general, drugs that release NO, such as organic nitrates and ACE inhibitors, have been shown to be of substantial benefit in the treatment of heart failure.

Methods and Results
—We hypothesized that a portion of the beneficial actions of amlodipine may involve the release or action of NO. Coronary microvessels were isolated from the heart of normal dogs and incubated with increasing doses of the calcium channel blockers nifedipine, diltiazem, and amlodipine or the ACE inhibitors enalaprilat and ramiprilat. Neither nifedipine nor diltiazem increased nitrite production at any dose studied. In marked contrast, amlodipine caused a dose-dependent increase in nitrite production from 74±5 to 130±8 pmol/mg (by 85±21%,10
−5
mol/L,
P
<.05) that was similar in magnitude to that of either of the ACE inhibitors. Amlodipine also increased nitrite production in large coronary arteries and in aorta.
N
ω
-Nitro-
l
-arginine methyl ester, HOE-140, and dichloroisocoumarin essentially abolished the increase in nitrite production, indicating that (1) nitrite production reflected NO formation, (2) nitrite production was dependent on stimulation of the kinin
2
receptor, and (3) nitrite production is most likely secondary to the formation of local kinins.

Conclusions
—Thus, unlike nifedipine and diltiazem, amlodipine releases NO from blood vessels.
Prognostic Significance of Microvascular Obstruction by Magnetic Resonance Imaging in Patients With Acute Myocardial Infarction
Authors: Wu Katherine C. , Zerhouni Elias A. , Judd Robert M. , Lugo-Olivieri Carlos H. , Barouch Lili A. , Schulman Steven P. , Blumenthal Roger S. , Lima João A. C.
Published: June 2012

Background
—The extent of microvascular obstruction during acute coronary occlusion may determine the eventual magnitude of myocardial damage and thus, patient prognosis after infarction. By contrast-enhanced MRI, regions of profound microvascular obstruction at the infarct core are hypoenhanced and correspond to greater myocardial damage acutely. We investigated whether profound microvascular obstruction after infarction predicts 2-year cardiovascular morbidity and mortality.

Methods and Results
—Forty-four patients underwent MRI 10±6 days after infarction. Microvascular obstruction was defined as hypoenhancement seen 1 to 2 minutes after contrast injection. Infarct size was assessed as percent left ventricular mass hyperenhanced 5 to 10 minutes after contrast. Patients were followed clinically for 16±5 months. Seventeen patients returned 6 months after infarction for repeat MRI. Patients with microvascular obstruction (n=11) had more cardiovascular events than those without (45% versus 9%;
P
=.016). In fact, microvascular status predicted occurrence of cardiovascular complications (χ
2
=6.46,
P
<.01). The risk of adverse events increased with infarct extent (30%, 43%, and 71% for small [n=10], midsized [n=14], and large [n=14] infarcts,
P
<.05). Even after infarct size was controlled for, the presence of microvascular obstruction remained a prognostic marker of postinfarction complications (χ
2
=5.17,
P
<.05). Among those returning for follow-up imaging, the presence of microvascular obstruction was associated with fibrous scar formation (χ
2
=10.0,
P
<.01) and left ventricular remodeling (
P
<.05).

Conclusions
—After infarction, MRI-determined microvascular obstruction predicts more frequent cardiovascular complications. In addition, infarct size determined by MRI also relates directly to long-term prognosis in patients with acute myocardial infarction. Moreover, microvascular status remains a strong prognostic marker even after control for infarct size.
Relation of Seizures After Cardiac Surgery in Early Infancy to Neurodevelopmental Outcome
Authors: Rappaport Leonard A. , Wypij David , Bellinger David C. , Helmers Sandra L. , Holmes Gregory L. , Barnes Patrick D. , Wernovsky Gil , Kuban Karl C. K. , Jonas Richard A. , Newburger Jane W.
Published: June 2012

Background
—The outcome of infants who have transient seizures after open heart surgery has not been studied. Using the database of the Boston Circulatory Arrest Study involving 171 children with D-transposition of the great arteries, we explored the relationship between early postoperative clinical and EEG seizures and neurodevelopmental outcomes at ages 1 and 21/2 years.

Methods and Results
—At 1 year, children returned for developmental and neurological evaluations and MRI. Parent-completed developmental questionnaires were collected at 2 1/2 years of age. At 1 year, children with early postoperative seizures had lower Psychomotor Development Index (motor function) scores (clinical seizures: 12.9 mean difference [MD]; 95% confidence interval [CI], 2.2 to 23.6;
P
=.02; EEG seizures: 13.3 MD; 95% CI, 6.8 to 19.7;
P
<.001). Mental Developmental Index scores of children with clinical or EEG seizures were also lower, but the differences were not statistically significant. Infants with seizures were more likely to have an abnormal neurological examination (clinical seizures: 78% versus 31%;
P
=.008; EEG seizures: 58% versus 34%;
P
=.04). Children with EEG seizures were more likely to have MRI abnormalities (43% versus 13%,
P
=.002). At age 21/2, children with EEG seizures had lower scores in several areas of function.

Conclusions
—In infants undergoing the arterial switch operation for correction of D-transposition of the great arteries, transient postoperative clinical and EEG seizures were associated with worse neurodevelopmental outcomes at ages 1 and 2 1/2 years as well as neurological and MRI abnormalities at 1 year of age. The occurrence of such seizures may provide an early sign of brain injury with neurological and developmental sequelae.
Effects of Recombinant Apolipoprotein A-I
Milano
on Aortic Atherosclerosis in Apolipoprotein E–Deficient Mice
Authors: Shah Prediman K. , Nilsson Jan , Kaul Sanjay , Fishbein Michael C. , Ageland Hans , Hamsten Anders , Johansson Jan , Karpe Frederick , Cercek Bojan
Published: June 2012

Background
—We previously reported marked inhibitory effects of recombinant apolipoprotein (apo) A-I
Milano
/phospholipid complex (A-I
Milano
/PC) on neointimal lesions in balloon-injured iliofemoral arteries of hypercholesterolemic rabbits. In this study, we tested the hypothesis that apo A-I
Milano
/PC would inhibit aortic atherosclerosis in apo E–deficient mice.

Methods and Results
—Thirty-five apo E–deficient mice fed a high-cholesterol diet were included in the study. Control mice were killed at 20 (n=8) or 25 (n=7) weeks. Treated mice received 18 injections of either 40 mg/kg apo A-I
Milano
/PC (n=15) or PC only (n=5) intravenously every other day from 20 weeks until death at 25 weeks. Aortic atherosclerosis was identified with Sudan IV staining. Lipid and macrophage contents of the aortic sinus plaques were measured after oil-red O and Mac-1 antibody staining, respectively, and quantified with computed morphometry. In control mice, from 20 to 25 weeks, aortic atherosclerosis increased by 59% (11±1% versus 17±5% of the aortic surface,
P
=.002), and lipid content increased by 45% (22±8% versus 32±6% of plaque area,
P
=.02) without a significant change in macrophage content (10.8±2% versus 13.2±6%). Compared with 20-week-old untreated control mice, PC only–treated mice at 25 weeks demonstrated a 32% increase in aortic atherosclerosis (11±1% versus 15±4%,
P
=.01) and an increase in lipid content (22±8% versus 47±3%,
P
<.0001) without a change in macrophage content (10.8±2% versus 11±2%). In comparison with 20-week-old untreated control mice, 25-week-old apo A-I
Milano
/PC–treated mice demonstrated no increase in aortic atherosclerosis (11±1% versus 10±4%,
P
=NS), a 40% reduction in lipid content (22±8% versus 13±8%,
P
=.01), and a 46% reduction in macrophage content (10.8±2% versus 5.8±2.9%;
P
=.03). Serum cholesterol levels were markedly elevated in all groups and did not change significantly with apo A-I
Milano
/PC or PC only. In vitro, apo A-I
Milano
/PC stimulated cholesterol efflux from cholesterol-loaded FU5AH hepatoma cell lines in a dose-dependent manner, whereas PC only or PC-free apo A-I
Milano
had no effect.

Conclusions
—Recombinant A-I
Milano
/PC prevented progression of aortic atherosclerosis and reduced lipid and macrophage content of plaques in apo E–deficient mice despite severe hypercholesterolemia. Thus, A-I
Milano
/PC may have a role in inhibiting progression and promoting stabilization of atherosclerosis.
Impact of Atrial Fibrillation on the Risk of Death
Authors: Benjamin Emelia J. , Wolf Philip A. , D’Agostino Ralph B. , Silbershatz Halit , Kannel William B. , Levy Daniel
Published: June 2012

Background
—Atrial fibrillation (AF) causes substantial morbidity. It is uncertain whether AF is associated with excess mortality independent of associated cardiac conditions and risk factors.

Methods and Results
—We examined the mortality of subjects 55 to 94 years of age who developed AF during 40 years of follow-up of the original Framingham Heart Study cohort. Of the original 5209 subjects, 296 men and 325 women (mean ages, 74 and 76 years, respectively) developed AF and met eligibility criteria. By pooled logistic regression, after adjustment for age, hypertension, smoking, diabetes, left ventricular hypertrophy, myocardial infarction, congestive heart failure, valvular heart disease, and stroke or transient ischemic attack, AF was associated with an OR for death of 1.5 (95% CI, 1.2 to 1.8) in men and 1.9 (95% CI, 1.5 to 2.2) in women. The risk of mortality conferred by AF did not significantly vary by age. However, there was a significant AF-sex interaction: AF diminished the female advantage in survival. In secondary multivariate analyses, in subjects free of valvular heart disease and preexisting cardiovascular disease, AF remained significantly associated with excess mortality, with about a doubling of mortality in both sexes.

Conclusions
—In subjects from the original cohort of the Framingham Heart Study, AF was associated with a 1.5- to 1.9-fold mortality risk after adjustment for the preexisting cardiovascular conditions with which AF was related. The decreased survival seen with AF was present in men and women and across a wide range of ages.