bluuebunny/crossref_metadata_2025 huggingface dataset:
Red Wine Inhibits Monocyte Chemotactic Protein-1 Expression and Modestly Reduces Neointimal Hyperplasia After Balloon Injury in Cholesterol-Fed Rabbits
Authors: Feng An-Ning , Chen Yuh-Lien , Chen Ya-Ting , Ding Yaw-Zon , Lin Shing-Jong
Published: June 2012

Background
—Wine consumption decreases the risk of myocardial infarction. Intimal hyperplasia contributes to restenosis after angioplasty. Local ethanol delivery inhibits intimal hyperplasia after balloon injury in rabbit iliac and pig coronary arteries. The effects of wine consumption on intimal response and monocyte chemotactic protein-1 (MCP-1) expression were studied in cholesterol-fed rabbits.

Methods and Results
—Male rabbits were fed a 2% cholesterol diet together with red wine (12.5% vol, 5 mL/kg body wt per day; n=7), white wine (13.3% vol, 5 mL/kg body wt per day; n=7), or no wine as a control (n=8) for 6 weeks. A balloon injury of the abdominal aorta was performed at the end of the third week. Abdominal aortas were harvested at the end of 6 weeks. Neointimal hyperplasia was measured morphometrically. MCP-1 expression was determined by Northern blot, in situ hybridization, and immunohistochemistry. Rabbits fed red wine had significantly less neointimal hyperplasia than did control rabbits (intima/media area ratio 0.59±0.05 [red wine group] versus 0.79±0.07 [control group],
P
<0.05). However, rabbits fed white wine showed a trend (but not significant) toward less intimal response compared with control rabbits (intima/media area ratio 0.65±0.04 [white wine group] versus 0.79±0.07 [control group],
P
=0.165). Both red wine and white wine significantly reduced MCP-1 mRNA and protein expression in the aorta.

Conclusions
—Long-term consumption of red wine and white wine inhibits MCP-1 expression, and in the small number of animals studied, red wine modestly reduces neointimal hyperplasia. Since red wine exhibits higher antioxidant capacity than does white wine, the decreased intimal response might be partly attributed to its antioxidant effects.
Subtype Specific Regulation of Human Vascular α
1
-Adrenergic Receptors by Vessel Bed and Age
Authors: Rudner Xiaowen L. , Berkowitz Dan E. , Booth John V. , Funk Bonita L. , Cozart Kelli L. , D’Amico Elizabeth B. , El-Moalem Habib , Page Stella O. , Richardson Charlene D. , Winters Bradford , Marucci Leo , Schwinn Debra A.
Published: June 2012

Background
—α
1
-adrenergic receptors (α
1
ARs) regulate blood pressure, regional vascular resistance, and venous capacitance; the exact subtype (α
1a
, α
1b
, α
1 d
) mediating these effects is unknown and varies with species studied. In order to understand mechanisms underlying cardiovascular responses to acute stress and chronic catecholamine exposure (as seen with aging), we tested two hypotheses: (1) human α
1
AR subtype expression differs with vascular bed, and (2) age influences human vascular α
1
AR subtype expression.

Methods and Results
—Five hundred vessels from 384 patients were examined for α
1
AR subtype distribution at mRNA and protein levels (RNase protection assays, ligand binding, contraction assays). Overall vessel α
1
AR density is 16±2.3fmol/mg total protein. α
1a
AR predominates in arteries at mRNA (
P
<0.001) and protein (
P
<0.05) levels; all 3 subtypes are present in veins. Furthermore, α
1
AR mRNA subtype expression varies with vessel bed (α
1a
higher in splanchnic versus central arteries,
P
<0.05); competition analysis (selected vessels) and functional assays demonstrate α
1a
and α
1b
-mediated mammary artery contraction. Overall α
1
AR expression doubles with age (<55 versus ≥65 years) in mammary artery (no change in saphenous vein), accompanied by increased α
1b
>α
1a
expression (
P
≤0.001).

Conclusions
—Human vascular α
1
AR subtype distribution differs from animal models, varies with vessel bed, correlates with contraction in mammary artery, and is modulated by aging. These findings provide potential novel targets for therapeutic intervention in many clinical settings.
Long-Term Follow-Up of Patients With Long-QT Syndrome Treated With β-Blockers and Continuous Pacing
Authors: Dorostkar Parvin C. , Eldar Michael , Belhassen Bernard , Scheinman Melvin M.
Published: June 2012

Background
—The long-QT syndrome is associated with sudden cardiac death. Combination of β-blocker and pacing therapy has been proposed for treatment of drug-resistant patients. The purpose of this study was to summarize our long-term experience with combined therapy in patients with long-QT syndrome.

Methods and Results
—A total of 37 patients with idiopathic long-QT syndrome were treated with combined therapy consisting of continuous cardiac pacing and maximally tolerated β-blocker therapy and followed up for 6.3±4.6 years (mean±SD). The group consisted of 32 female and 5 male patients with a mean age of 31.6 years. The mean paced rate was 82±7 bpm (range, 60 to 100 bpm). On follow-up, recurrent symptoms caused by pacemaker malfunction were documented in 3 patients. Four patients died during the follow-up period: 2 adolescents stopped β-blocker therapy, 1 patient died suddenly while treated with combined therapy, and 1 patient died of unrelated causes. In addition, 3 patients had resuscitated cardiac arrest while on combined therapy, and 1 patient had repeated, appropriate implantable cardioverter-defibrillator discharges on follow-up.

Conclusions
—Because 28 of 37 patients remain without symptoms with β-blocker therapy and continuous pacing, combined therapy appears to provide reasonable, long-term control for this high-risk group. However, the incidence of sudden death and aborted sudden death (24% in all patients and 17% in compliant patients) strongly suggests the use of a “back-up” defibrillator, particularly in noncompliant adolescent patients. Implantable cardioverter-defibrillator therapy, however, may be associated with recurrent shocks in susceptible patients.
Systemic Administration of Calmodulin Antagonist W-7 or Protein Kinase A Inhibitor H-8 Prevents Torsade de Pointes in Rabbits
Authors: Mazur Alexander , Roden Dan M. , Anderson Mark E.
Published: June 2012

Background
—The ventricular arrhythmia torsade de pointes (TdP) occurs after QT interval prolongation and is associated with sudden cardiac death. The afterdepolarizations that initiate TdP are facilitated by protein kinase A and the multifunctional Ca
2+
/calmodulin-dependent protein kinase II (CaM kinase).

Methods and Results
—In this study, we evaluated the feasibility of suppression of TdP through systemic therapy with kinase inhibitory agents in an established animal model. Under control conditions, TdP was inducible in 6 of 8 rabbits. CaM kinase blockade with the calmodulin antagonist W-7 reduced TdP in a dose-dependent fashion (4 of 7 inducible at 25 μmol/kg and 1 of 7 inducible at 50 μmol/kg). Increased intracellular Ca
2+
has been implicated in the genesis of afterdepolarizations, but pretreatment with high-dose W-7 did not prevent TdP in response to the L-type Ca
2+
channel agonist BAY K 8644 (300 nmol/kg), suggesting that CaM kinase–independent activation of L-type Ca
2+
current was not affected by W-7. Compared with control animals, W-7 reduced TdP inducibility without shortening the QT interval, increasing heart rate, or reducing the blood pressure. The protein kinase A antagonist H-8 also caused a dose-dependent reduction in TdP inducibility (5 of 6 at 1 μmol/kg, 4 of 6 at 5 μmol/kg, and 0 of 6 at 10 μmol/kg), but unlike W-7, H-8 did so by shortening the QT interval.

Conclusions
—These findings show that the acute systemic application of W-7 and H-8 is hemodynamically tolerated and indicate that kinase inhibition may be a viable antiarrhythmic strategy.
Abnormal Coronary Flow Velocity Reserve After Coronary Artery Stenting in Patients
Authors: Kern Morton J. , Puri Sanjeev , Bach Richard G. , Donohue Thomas J. , Dupouy Patrick , Caracciolo Eugene A. , Craig W. Randall , Aguirre Frank , Aptecar Eduardo , Wolford Thomas L. , Mechem Carol J. , Dubois-Rande Jean-Luc
Published: June 2012

Background
—Absolute coronary flow velocity reserve (CVR) after stenting may remain abnormal as a result of several different mechanisms. Relative CVR (rCVR=CVR
target
/CVR
reference
) theoretically normalizes for global microcirculatory disturbances and facilitates interpretation of abnormal CVR.

Methods and Results
—To characterize potential mechanisms of poststent physiology, CVR was measured using a Doppler-tipped angioplasty guidewire in 55 patients before and after angioplasty, after stenting, and in an angiographically normal reference vessel. For the group, the percent diameter stenosis decreased from 75±13% to 40±18% after angioplasty and to 10±9% (all
P
<0.05) after stent placement. After angioplasty, CVR increased from 1.63±0.71 to 1.89±0.55 (
P
<0.05) and after stent placement, to 2.48±0.75 (
P
<0.05 versus pre- and postangioplasty). After angioplasty, rCVR increased from 0.64±0.26 to 0.75±0.23 and after stent placement to 1.00±0.34. In 17 patients with CVR
stent
≤2.0, increased basal coronary flow, rather than attenuated hyperemia, was responsible in large part for the lower CVR
stent
compared with patients having CVR
stent
>2.0. In 8 patients with CVR
stent
<2.0, a normal rCVR supported global microvascular disease. The subgroup of 9 patients with CVR
stent
<2.0 and abnormal rCVR (16% of the studied patients) may require a pressure-derived fractional flow reserve to differentiate persistent obstruction from diffuse atherosclerotic disease or microvascular stunning.

Conclusions
—Although a majority of patients after stenting normalize CVR for the individual circulation (ie, normal CVR or normal rCVR), in those with impaired CVR
stent
, the analysis of coronary flow dynamics suggests several different physiological mechanisms. Additional assessment may be required to fully characterize the physiological result for such patients to exclude remediable luminal abnormalities.
Cavotricuspid Isthmus Mapping to Assess Bidirectional Block During Common Atrial Flutter Radiofrequency Ablation
Authors: Chen Jian , Christian de Chillou  , Basiouny Tarek , Sadoul Nicolas , Filho Jorge Da Silva , Magnin-Poull Isabelle , Messier Marc , Aliot Etienne
Published: June 2012

Background
—We sought to compare published methods to an alternative approach ascertaining cavotricuspid isthmus (CTI) block during atrial flutter ablation.

Methods and Results
—In 39 consecutive patients who underwent an atrial flutter ablation procedure, a 24-pole mapping catheter was positioned so that 2 adjacent dipoles were bracketing the targeted CTI line of block (LOB), with proximal dipoles lateral to the LOB and distal dipoles in the coronary sinus. Two pacing sites were lateral (positions A and B) and 2 were septal (positions C and D) to the LOB, with locations A and D closest to the LOB. A resulting CTI block was accepted when 3 criteria were fulfilled: (1) complete reversal of the right atrial depolarization on the 24-pole catheter when pacing in the coronary sinus, (2) conduction delays from A to D greater than from B to D, and (3) conduction delays from D to A greater than from C to A. A successful CTI block was obtained in all patients. Before CTI block was obtained, a progressive CTI conduction delay was observed in 11 patients (28.2%). During the procedure, the 3 criteria defined above were either all present or all absent.

Conclusions
—This study establishes that reversal of the atrial depolarization sequence up to the LOB is a definitive and mandatory criteria of successful atrial flutter ablation.
Interactive Effect of Heart Rate and Muscle Sympathetic Nerve Activity on Blood Pressure
Authors: Narkiewicz Krzysztof , Somers Virend K.
Published: June 2012

Background
—Sympathetic traffic to the peripheral vasculature and sympathetic discharge to the heart have complementary effects on blood pressure. Although faster heart rates have been linked to higher blood pressures, the relationship between muscle sympathetic nerve activity (MSNA) and long-term regulation of blood pressure is not clear. We tested the hypothesis that MSNA and heart rate are linked to blood pressure levels in normotensive subjects.

Methods and Results
—We studied normal young male (n=120) and female (n=48) subjects subdivided according to tertiles of heart rate and MSNA distributions. Systolic, diastolic, and pulse pressures were significantly different across the heart rate tertiles in male subjects, with the highest blood pressure values in the upper tertile of heart rate. No significant differences in blood pressure across the tertiles of MSNA were found. The relationship between MSNA and blood pressure, however, was affected by heart rate. MSNA did not influence blood pressure in the first and second heart rate tertiles. However, within the upper heart rate tertile, subjects with higher levels of MSNA had significantly higher systolic (
P
=0.02) and pulse (
P
=0.004) pressures than subjects with lower levels of MSNA. In female subjects, blood pressure was not different across the tertiles of heart rate or MSNA.

Conclusions
—MSNA and heart rate have interactive effects on systolic blood pressure and pulse pressure in normotensive male but not female subjects. No relationship between MSNA and blood pressure or pulse pressure is evident in subjects with slower heart rate. In male subjects with faster heart rates, higher levels of MSNA are associated with higher systolic and pulse pressures.
Inhibition of the Na
+
/H
+
Exchanger Confers Greater Cardioprotection Against 90 Minutes of Myocardial Ischemia Than Ischemic Preconditioning in Dogs
Authors: Gumina Richard J. , Buerger Erich , Eickmeier Christian , Moore Jeannine , Daemmgen Juergen , Gross Garrett J.
Published: June 2012

Background
—This study compared the efficacy of ischemic preconditioning (IPC) and sodium-hydrogen exchanger (NHE)-1 inhibition to reduce infarct size (IS) induced by a 90-minute ischemic insult and examined the interaction between NHE-1 inhibition and IPC.

Methods and Results
—In a canine infarct model, either IPC, produced by 1 or four 5-minute coronary artery occlusions, or the specific NHE-1 inhibitor BIIB 513, 0.75 or 3.0 mg/kg, was administered 15 minutes before either a 60- or 90-minute coronary artery occlusion followed by 3 hours of reperfusion. IS was determined by TTC staining and expressed as a percentage of the area at risk (IS/AAR). Although both IPC and BIIB 513 at 0.75 mg/kg produced comparable and significant reductions in IS/AAR in the 60-minute occlusion model, insignificant reductions in IS/AAR were observed in the 90-minute occlusion model. However, BIIB 513 at 3.0 mg/kg markedly reduced IS in both models (
P
<0.05). Next, to examine the interaction between NHE-1 blockade and IPC, BIIB 0.75 mg/kg was administered either before IPC or during the washout phase of IPC before 90 minutes of coronary artery occlusion. Both combinations resulted in a greater-than-additive reduction in IS/AAR (
P
<0.05).

Conclusions
—These data demonstrate that although IPC and NHE-1 inhibition provide comparable protection against 60 minutes of myocardial ischemia, NHE-1 inhibition is more efficacious than IPC at protecting against a 90-minute ischemic insult. Furthermore, the combination of NHE-1 inhibition and IPC produces a greater-than-additive reduction in IS/AAR, suggesting either that NHE activity limits the efficacy of IPC or that different mechanisms are involved in the cardioprotective effect of IPC and NHE-1 inhibition.
Induction of Electrical Heterogeneity Impairs Ventricular Defibrillation
Authors: Ujhelyi Michael R. , Sims J. Jason , Miller Allison Winecoff
Published: June 2012

Background
—This study determined whether dispersion of conduction velocity, refractoriness, or excitability increases biphasic shock defibrillation energy requirements (DERs).

Methods and Results
—Twenty-four swine were instrumented with a mid-LAD perfusion catheter for regional infusion of lidocaine 0.75 mg · kg
−1
· h
−1
(n=7), low-dose
d
-sotalol (0.16 mg · kg
−1
· h
−1
) (n=4), high-dose
d
-sotalol (0.5 mg · kg
−1
· h
−1
) (n=6), or saline (n=7). Effective refractory periods (ERPs) were determined at 5 myocardial sites, and regional conduction velocity was determined in LAD-perfused and -nonperfused regions. Regional lidocaine infusion increased DER values by 84% (
P
=0.008) and slowed conduction velocity by 23% to 35% (
P
<0.01) but did not affect ERP. Conversely, regional low- and high-dose
d
-sotalol infusion did not alter DER values or conduction velocity but increased regional ERP by 14% to 17% (
P
<0.001). Regional lidocaine increased conduction velocity dispersion by 100% to 200% (
P
=0.01) but did not change ERP dispersion, whereas
d
-sotalol increased ERP dispersion by 140% (
P
<0.001) without affecting conduction velocity dispersion. Lidocaine infusion induced ventricular fibrillation (VF) in 6 of 7 animals, whereas regional
d
-sotalol was not proarrhythmic. Regional infusion of lidocaine and
d
-sotalol prolonged VF cycle length by 23% to 41% (
P
<0.05) in the perfused region and increased VF cycle length dispersion by 85% to 240% (
P
<0.05). Both agents increased pacing threshold (excitability) in the perfused region by 93% to 116% (
P
<0.05).

Conclusions
—Regional conduction velocity slowing increased DER values, which was probably a result of spatial dispersion of conduction velocity. Increasing refractory period dispersion without changing conduction velocity did not alter DFT values. Thus, dispersion of conduction velocity may be a more likely regulator of defibrillation efficacy than dispersion of refractoriness.
Enhanced Sympathetic and Ventilatory Responses to Central Chemoreflex Activation in Heart Failure
Authors: Narkiewicz Krzysztof , Pesek Catherine A. , van de Borne Philippe J. H. , Kato Masahiko , Somers Virend K.
Published: June 2012

Background
—Sympathetic activation and respiratory abnormalities may each be implicated in the pathophysiology of congestive heart failure (CHF). Chemoreflexes are an important mechanism regulating both sympathetic drive and breathing. We therefore tested the hypothesis that chemoreflex function is altered in CHF.

Methods and Results
—We compared ventilatory, sympathetic, heart rate, and blood pressure responses to hypoxia, hypercapnia, and the cold pressor test in 9 patients with CHF and 9 control subjects matched for age and body mass index. Baseline muscle sympathetic nerve activity (MSNA) was higher in the patients with CHF compared with control subjects (47±8 versus 23±3 bursts per minute,
P
<0.01). During hypercapnia, patients with CHF had greater increases in minute ventilation (6.7±1.4 versus 2.7±0.9 L/min,
P
=0.03) and heart rate (7.0±2.1 versus 0.6±1.2 bpm,
P
=0.02). Despite higher ventilation, which inhibits sympathetic activity, the MSNA increase in patients with CHF was also greater than that in control subjects (58±12% versus 21±9%,
P
=0.03). Ventilatory, autonomic, and blood pressure responses to hypoxia and the cold pressor test in CHF patients were not different from those in control subjects.

Conclusions
—Chronic heart failure is characterized by a selective potentiation of ventilatory and sympathetic responses to central chemoreceptor activation by hypercapnia.
Left Atrial Relaxation and Left Ventricular Systolic Function Determine Left Atrial Reservoir Function
Authors: Barbier Paolo , Solomon Steven B. , Schiller Nelson B. , Glantz Stanton A.
Published: June 2012

Background
—Determinants of left atrial (LA) reservoir function and its influence on left ventricular (LV) function have not been quantified.

Methods and Results
—In an open-pericardium, paced (70 and 90 bpm) pig model of LV regional ischemia (left anterior descending coronary constriction), with high-fidelity LV, LA, and RV pressure recordings, we obtained the LA area with 2D automated border detection echocardiography, LA pressure-area loops, and Doppler transmitral flow. We calculated LV τ, LA relaxation (a−x pressure difference divided by time, normalized by a pressure), and stiffness (slope between x and v pressure points of v loop). Determinants of total LA reservoir (maximum−minimum area, cm
2
) were identified by multiple regression analysis. Different mean rates of LA area increase identified 2 consecutive (early rapid and late slow) reservoir phases. During ischemia, LV long-axis shortening (LAS, LV base systolic descent) and LA reservoir area change decreased (7.3±0.3 [SEM] versus 5.6±0.3 cm
2
,
P
<0.001) and LA stiffness increased (1.6±0.3 versus 3.1±0.3 mm Hg/cm
2
,
P
=0.009). Early reservoir area change depended on LA mean ejection rate (LA area at ECG P wave minus minimum area divided by time; multiple regression coefficient=0.9;
P
<0.001) and relaxation (coefficient=4.9 cm
2
×ms/s;
P
<0.001). Late reservoir area change depended on LAS (coefficient=8 cm/s;
P
<0.001). Total reservoir filling depended on LA stiffness (coefficient=−0.31 cm
4
/mm Hg;
P
=0.001) and cardiac output (coefficient=0.001 cm
2
×min/L;
P
=0.002). The strongest predictor of cardiac output was LA reservoir filling (coefficient=301 L/min×cm
2
;
P
<0.001). The v loop area was determined by cardiac output, LV ejection time, τ, and early transmitral flow.

Conclusions
—Two (early and late) reservoir phases are determined by LA contraction and relaxation and LV base descent. Acute LV regional ischemia increases LA stiffness and impairs LA reservoir function by reducing LV base descent.
Adenovirus-Mediated Overexpression of Tissue Inhibitor of Metalloproteinase-1 Reduces Atherosclerotic Lesions in Apolipoprotein E–Deficient Mice
Authors: Rouis M. , Adamy C. , Duverger N. , Lesnik P. , Horellou P. , Moreau M. , Emmanuel F. , Caillaud J. M. , Laplaud P. M. , Dachet C. , Chapman M. J.
Published: June 2012

Background
—To define the role of metalloproteinases (MMPs) in the development of lipid-rich atherosclerotic lesions in relation to the balance between proteolytic and antiproteolytic activities, we investigated the impact of adenovirus-mediated elevation in the circulating levels of human tissue inhibitor of MMP (TIMP-1) in atherosclerosis-susceptible apolipoprotein E–deficient (apoE
−/−
) mice.

Methods and Results
—Infusion of apoE
−/−
mice fed a lipid-rich diet with rAd.RSV.TIMP-1 (1×10
11
viral particles) resulted in high hepatic expression of TIMP-1. At 2 weeks after injection, plasma TIMP-1 levels ranged from 7 to 24 μg/mL (mean 14.8±6.8). Marked overexpression of TIMP-1 was transient, with levels of TIMP-1 decreasing to 2.5 to 8 μg/mL (mean 4.3±2.1) at 4 weeks. Plasma lipid and lipoprotein levels in mice treated with rAd.RSV.TIMP-1 were similar to those treated with rAd.RSV.βGal. However, rAd.RSV.TIMP-1–infused mice displayed a marked reduction (≈32%;
P
<0.05) in mean lesion area per section (512±121 μm
2
×10
3
; n=12 sections from 4 animals) as compared with rAd.RSV.βGal-infused mice (750±182 μm
2
×10
3
; n=12 sections from 4 animals). Similarly, marked reduction in macrophage deposition as well as MMP-2, MMP-3, and MMP-13 antigens was observed.

Conclusions
—Histological and immunohistologic analyses of atherosclerotic lesions revealed increases in collagen, elastin, and smooth muscle α-actin content in mice treated with rAd.RSV.TIMP-1. These qualitative and quantitative features were the consequence of TIMP-1 infiltration from plasma to arterial intima, as immunohistochemical analyses revealed an abundance of TIMP-1 specifically in lesions of rAd.RSV.TIMP-1–treated mice.
Ischemic Preconditioning in Humans
Authors: Tomai Fabrizio , Crea Filippo , Chiariello Luigi , Gioffrè Pier A.
Published: June 2012

Abstract
—Ischemic preconditioning, a powerful form of endogenous protection against myocardial infarction, has been demonstrated in several animal species and, recently, in isolated human cardiomyocytes. For both logistic and ethical reasons, no clinical study can meet the strict conditions of experimental studies on preconditioning with infarct size as the end-point. Nevertheless, the demonstration of adaptation to ischemia observed during in vitro studies on human atrial trabeculae, in patients in the setting of coronary bypass surgery, and in the setting of coronary angioplasty in the absence of collateral vessel recruitment strongly suggests that ischemic preconditioning occurs in humans. This notion is further supported by the observation that in these human models, the adaptation to ischemia is influenced by drugs acting on K
ATP
channels and on purinergic and α-adrenergic receptors, similar to what is observed in accepted experimental models of ischemic preconditioning. This important form of myocardial endogenous protection may also play a role in the warm-up phenomenon and in mediating the beneficial effects of preinfarction angina. The demonstration of ischemic preconditioning in humans and the identification of some of its mediators suggests that in patients at high risk for myocardial infarction, drugs known to block this endogenous form of protection should be used with caution, whereas drugs known to elicit preconditioning might have a relevant therapeutic role.
Preferential Impairment of Nitric Oxide–Mediated Endothelium-Dependent Relaxation in Human Cervical Arteries After Irradiation
Authors: Sugihara Tsuneki , Hattori Yuichi , Yamamoto Yuhei , Qi Fazhi , Ichikawa Ryoichi , Sato Atsushi , Liu Ming-Yue , Abe Kazuhiro , Kanno Morio
Published: June 2012

Background
—Vascular abnormalities are a major cause of postoperative complications in irradiated tissues. Endothelial cell dysfunction characterized by diminished endothelium-dependent relaxation may be involved. We examined the endothelium-dependent relaxation and morphology of the endothelium in irradiated human cervical arteries.

Methods and Results
—Irradiated arteries were taken from the neck region of patients who had radiation therapy. Arteries from patients who did not receive radiation therapy were used as controls. Endothelium-dependent relaxation to acetylcholine and A23187 was impaired in irradiated arteries. Norepinephrine-induced contraction and sodium nitroprusside–induced relaxation were unchanged. In control arteries,
N
ω
-nitro-
l
-arginine and indomethacin each caused a partial inhibition of endothelium-dependent relaxation. In irradiated arteries, the impaired endothelium-dependent relaxation was unaffected by these agents, but it was abolished by high K
+
. Acetylcholine produced similar degrees of hyperpolarization in control and irradiated arteries. Immunohistochemical examination for endothelial nitric oxide synthase indicated no expression in the endothelium of irradiated arteries. Electron scanning microscopy showed morphologically intact endothelial cells in irradiated arteries.

Conclusions
—In irradiated human cervical arteries, the nitric oxide– and prostacyclin-mediated endothelium-dependent relaxation, but not endothelium-derived hyperpolarizing factor–mediated relaxation, are specifically impaired, without significant morphological damage of the endothelium. The impaired nitric oxide–mediated relaxation was associated with a lack of endothelial nitric oxide synthase expression. Our results suggest the importance of impaired endothelial function in irradiated human blood vessels, which may partly explain the development of vascular stenosis and poor surgical wound healing in irradiated tissues.
Flavopiridol Inhibits Smooth Muscle Cell Proliferation In Vitro and Neointimal Formation In Vivo After Carotid Injury in the Rat
Authors: Ruef Johannes , Meshel Adam S. , Hu Zhaoyong , Horaist Chris , Ballinger Carol A. , Thompson Larry J. , Subbarao Vijay D. , Dumont Jennifer A. , Patterson Cam
Published: June 2012

Background
—Smooth muscle cell (SMC) proliferation is a critical component of neointimal formation in many models of vascular injury and in human lesions as well. Cell-cycle inhibition by gene transfer techniques can block SMC proliferation and lesion formation in animal models, although these methods are not yet applicable to the treatment of human disease. Flavopiridol is a recently identified, potent, orally available cyclin-dependent kinase inhibitor.

Methods and Results
—Using human aortic SMCs, we found that flavopiridol in concentrations as low as 75 nmol/L resulted in nearly complete inhibition of basic fibroblast growth factor–induced and thrombin-induced proliferation. At this dose, flavopiridol inhibited cyclin-dependent kinase activity, as measured by histone H1 phosphorylation, but had no effect on mitogen-activated protein kinase activation. Induction of the cell cycle–related proteins cyclin D1, proliferating cell nuclear antigen, and phosphorylated retinoblastoma protein was also blocked by flavopiridol. Flavopiridol had no effect on cellular viability. To test whether flavopiridol had a similar activity in vivo when administered orally, we examined neointimal formation in rat carotid arteries after balloon injury. Flavopiridol 5 mg/kg reduced neointimal area by 35% and 39% at 7 and 14 days, respectively, after injury.

Conclusions
—Flavopiridol inhibits SMC growth in vitro and in vivo. Its oral availability and selectivity for cyclin-dependent kinases make it a potential therapeutic tool in the treatment of SMC-rich vascular lesions.
Prospective Study of Markers of Hemostatic Function With Risk of Ischemic Stroke
Authors: Folsom Aaron R. , Rosamond Wayne D. , Shahar Eyal , Cooper Lawton S. , Aleksic Nena , Nieto F. Javier , Rasmussen Mandy L. , Wu Kenneth K.
Published: June 2012

Background
—Several markers of hemostatic function and inflammation have been associated with increased risk of coronary heart disease, but prospective evidence for their role in ischemic stroke is scant.

Methods and Results
—The Atherosclerosis Risk in Communities (ARIC) Study measured several of these markers in more than 14 700 participants 45 to 64 years old who were free of cardiovascular disease and were followed up for 6 to 9 years for occurrence of ischemic stroke (n=191). There was no apparent association between ischemic stroke incidence and factor VIIc, antithrombin III, platelet count, or activated partial thromboplastin time. After adjustment for multiple cardiovascular risk factors, von Willebrand factor, factor VIIIc, fibrinogen, and white blood cell count were positively associated and protein C was negatively but nonsignificantly associated with ischemic stroke incidence in regression analyses based on either continuous variables or fourths of the variable distributions. The adjusted relative risk (and 95% CI) for ischemic stroke in those in the highest versus lowest fourth were: von Willebrand factor, 1.71 (1.1 to 2.7); factor VIIIc, 1.93 (1.2 to 3.1); white blood cell count, 1.50 (0.9 to 2.4); fibrinogen, 1.26 (0.8 to 2.0); and protein C, 0.65 (0.4 to 1.0).

Conclusions
—This study offers modest support for the hypothesis that some markers of hemostatic function and inflammation can identify groups of middle-aged adults at increased risk of stroke. These factors may play a role in the pathogenesis of ischemic stroke.
Increased Lipoprotein(a) Is an Important Risk Factor for Venous Thromboembolism in Childhood
Authors: Nowak-Göttl Ulrike , Junker Ralf , Hartmeier Marion , Koch Hans-Georg , Münchow Nicole , Assmann Gerd , von Eckardstein Arnold
Published: June 2012

Background
—Serum levels of lipoprotein(a) [Lp(a)] are determined largely by genetic variation in the gene encoding for apolipoprotein(a) [apo(a)], the specific protein component of Lp(a) that is very homologous to plasminogen. High plasma levels of Lp(a) increase the risk for premature atherosclerotic vessel diseases. We investigated the little-characterized role of Lp(a) as a risk factor for venous thromboembolic diseases, alone and in conjunction with established thrombophilic risk factors of proteins regulating blood coagulation and fibrinolysis.

Methods and Results
—Serum levels of Lp(a) and lipids, protein C, protein S, and antithrombin, as well as the size of apo(a) isoforms and the presence of the factor V:Q
506
mutation, were determined in 186 consecutively admitted children from neonates to 18 years old with a history of venous thrombosis and in 186 age- and disease-matched control subjects. Children with a history of venous thrombosis had a significantly higher median Lp(a) level (19 versus 4.4 mg/dL) than control subjects. The risk for thromboembolic events in children with Lp(a) levels in the upper quartile, ie, >30 mg/dL, was 7.2 (95% CI, 3.7 to 14.5). The size of apo(a) isoforms was inversely related to Lp(a) levels and to the risk for thromboembolic events. Compared with the highest quartile of the apo(a) size distribution, the lowest quartile was associated with a risk of 8.2. In addition, multivariate statistical analysis gives evidence that the factor V:Q
506
mutation (OR/CI, 2.8/1.6 to 4.9), protein C (OR/CI, 6.5/2.1 to 19), and antithrombin deficiency (OR/CI, 10.4/1.2 to 90) were independent risk factors of childhood venous thrombosis. Coincidence of elevated Lp(a) with factor V:Q
506
mutation or deficiencies of protein C or antithrombin further increased the risk for thromboembolic events to 8.4.

Conclusions
—Lp(a) >30 mg/dL is a risk factor for venous thromboembolism in childhood. Lp(a) measurements should be included in the screening of causal factors in children with venous thromboembolic events.
Acute Right Ventricular Dilatation in Response to Ischemia Significantly Impairs Left Ventricular Systolic Performance
Authors: Brookes Carl , Ravn Hanne , White Paul , Moeldrup Ulla , Oldershaw Paul , Redington Andrew
Published: June 2012

Background
—Right ventricular (RV) dilatation that occurs as a consequence of RV infarction is thought to produce hemodynamic instability by reducing left ventricular (LV) preload and compliance. We hypothesized that these geometric changes may also adversely affect LV systolic performance.

Methods and Results
—Twelve 40-kg pigs were studied. Integrated conductance catheters and micromanometers were placed in both the LV and RV to allow simultaneous recordings of pressure and volume and derivation of indices of contractile function. RV ischemia was induced by balloon occlusion of the proximal right coronary artery (RCA) under 3 conditions: 1) with the pericardium intact, 2) with the pericardium intact and inotropic support, and 3) with the pericardium wide open. With an intact pericardium, RCA occlusion produced a decrease in LV end-diastolic volume associated with a marked decline in the contractile function. With the pericardium open, the same ischemic insult resulted in both LV and RV dilatation, which produced a significantly smaller negative effect on cardiac output (
P
=0.03), LV systolic pressure (
P
=0.02), LV preload-recruitable stroke work (
P
<0.01), and LV end-systolic pressure-volume relations (
P
<0.01). Similarly, administration of dobutamine during RCA occlusion decreased the ventricular volume changes and produced a relative improvement in LV contractile performance.

Conclusions
—The hemodynamic compromise seen in association with acute RV dilatation within an intact pericardium is partly attributable to impaired LV systolic performance and cannot be wholly ascribed to changes in LV preload or compliance.
Is 8-mm More Effective Than 4-mm Tip Electrode Catheter for Ablation of Typical Atrial Flutter?
Authors: Tsai Chin-Feng , Tai Ching-Tai , Yu Wen-Chung , Chen Yi-Jen , Hsieh Ming-Hsiung , Chiang Chern-En , Ding Yu-An , Chang Mau-Song , Chen Shih-Ann
Published: June 2012

Background
—The prospective, randomized study comparing 4- with 8-mm tip electrodes for radiofrequency linear ablation of typical atrial flutter is not available.

Methods and Results
—A total of 104 consecutive patients with typical atrial flutter were randomly assigned to undergo radiofrequency linear ablation using a 4- (Group I, n=54) or 8-mm tip electrode (Group II, n=50) catheter (temperature-control model, preset 70°C). If complete bidirectional isthmus block could not be achieved after 5 pulses, the ablation catheter was changed to the other type; the maximal radiofrequency pulse number was limited to <10 pulses. Complete or incomplete isthmus conduction block was assessed by activation sequence in a multielectrode Halo catheter during low lateral right atrial and proximal coronary sinus pacing. Before shifting to the other catheter type, the 8-mm electrode catheter achieved higher complete isthmus block rate (92% versus 67%,
P
<0.05) with fewer pulses (2±1 versus 3±1,
P
<0.05), shorter procedure time (24±15 versus 31±12 minutes,
P
<0.05), and shorter fluoroscopic time (14±10 versus 23±15 minutes,
P
<0.05). After 5 failed ablation pulses, 12 (67%) of 18 patients in group I attained complete isthmus block by using an 8-mm tip catheter, but none of 4 patients in group II achieved complete block by changing to a 4-mm tip catheter.

Conclusions
—The 8-mm tip electrodes are more effective than the standard 4-mm length electrodes in linear ablation for typical atrial flutter. This clinical benefit may be of particular value for some patients with broad and/or thick isthmus.
Late Coronary Occlusion After Intracoronary Brachytherapy
Authors: Costa Marco A. , Sabaté Manel , van der Giessen Wim J. , Kay I. Patrick , Cervinka Pavel , Ligthart Jurgen M. R. , Serrano Pedro , Coen Veronique L. M. A. , Levendag Peter C. , Serruys Patrick W.
Published: June 2012

Background
—Intracoronary brachytherapy appears to be a promising technology to prevent restenosis. Presently, limited data are available regarding the late safety of this therapeutic modality. The aim of the study was to determine the incidence of late (>1 month) thrombosis after PTCA and radiotherapy.

Methods and Results
—From April 1997 to March 1999, we successfully treated 108 patients with PTCA followed by intracoronary β-radiation. Ninety-one patients have completed at least 2 months of clinical follow-up. Of these patients, 6.6% (6 patients) presented with sudden thrombotic events confirmed by angiography 2 to 15 months after intervention (2 balloon angioplasty and 4 stent). Some factors (overlapping stents, unhealed dissection) may have triggered the thrombosis process, but the timing of the event is extremely unusual. Therefore, the effect of radiation on delaying the healing process and maintaining a thrombogenic coronary surface is proposed as the most plausible mechanism to explain such late events.

Conclusions
—Late and sudden thrombosis after PTCA followed by intracoronary radiotherapy is a new phenomenon in interventional cardiology.
Increased Carotid Intimal-Medial Thickness and Coronary Calcification Are Related in Young and Middle-Aged Adults
Authors: Davis Patricia H. , Dawson Jeffrey D. , Mahoney Larry T. , Lauer Ronald M.
Published: June 2012

Background
—Increased carotid intimal-medial thickness (IMT) and coronary artery calcification (CAC) are used as 2 markers of early atherosclerosis. Our objectives were to assess whether increased IMT and CAC are related and to determine the relationship between cardiovascular risk factors and carotid IMT in young adults.

Methods and Results
—A sample of 182 men and 136 women aged 33 to 42 years living in Muscatine, Iowa, underwent B-mode carotid ultrasound to determine the mean of 12 measurements of maximal carotid IMT. CAC was defined as calcification in the proximal coronary arteries in ≥3 contiguous pixels with a density of ≥130 HU. The mean IMT was 0.788 mm (SD 0.127) for men and 0.720 mm (SD 0.105) for women. CAC was present in 27% of men and 14% of women and was significantly associated with IMT in men (
P
<0.025) and women (
P
<0.005). With multivariate analysis, after adjustment for age, significant risk factors for carotid IMT were LDL cholesterol (
P
<0.001) and pack-years of smoking (
P
<0.05) in men and LDL cholesterol (
P
<0.001) and systolic blood pressure (
P
<0.01) in women. These risk factors remained significant after CAC was included in the multivariate model.

Conclusions
—There is an association between increased carotid IMT and CAC and between cardiovascular risk factors and increased IMT in young adults. Carotid IMT may provide information in addition to CAC that can be used to identify young adults with premature atherosclerosis.
Brief Myocardial Ischemia Attenuates Platelet Thrombosis in Remote, Damaged, and Stenotic Carotid Arteries
Authors: Hata Katsuya , Whittaker Peter , Kloner Robert A. , Przyklenk Karin
Published: June 2012

Background
—Brief antecedent periods of coronary artery occlusion improve subsequent vessel patency in damaged and stenotic coronary arteries via release of adenosine from ischemic/reperfused myocardium and resultant adenosine receptor stimulation. However, the site of receptor stimulation—circulating blood-borne elements (ie, platelets) versus vessel-wall components of the culprit artery—remains unclear. If platelet adenosine receptors are involved, then the benefits of brief coronary occlusion (1) should be manifested systemically and improve patency at a remote site and (2) should be inhibited by an antagonist of adenosine A
2
receptors, whereas, in contrast, (3) brief vascular occlusion not associated with appreciable adenosine release should be ineffective in improving vessel patency.

Methods and Results
—In Protocol 1, anesthetized rabbits received 5 minutes of transient coronary occlusion, 5 minutes of transient bilateral carotid occlusion (purported to cause negligible adenosine release from the brain), or no intervention. All rabbits then underwent injury plus stenosis of the left carotid artery, resulting in repeated cyclic variations in carotid blood flow (CFVs). Carotid patency during the initial 2 hours after stenosis (assessed by quantifying the nadir of the CFVs and area of the flow-time profile) was significantly enhanced with antecedent coronary—but not carotid—occlusion versus controls. In Protocol 2, improvement in carotid patency after brief coronary occlusion was corroborated in anesthetized dogs. However, the benefits of brief coronary occlusion were abrogated by the A
2
/A
1
antagonist CGS 15943.

Conclusions
—Brief antecedent coronary artery occlusion enhanced vessel patency in remote, damaged, and stenotic carotid arteries, largely due to adenosine receptor stimulation on circulating elements.
Antibody Blockade of Thrombospondin Accelerates Reendothelialization and Reduces Neointima Formation in Balloon-Injured Rat Carotid Artery
Authors: Chen Donghui , Asahara Takayuki , Krasinski Kevin , Witzenbichler Bernhard , Yang Jihong , Magner Meredith , Kearney Marianne , Frazier William A. , Isner Jeffrey M. , Andrés Vicente
Published: June 2012

Background
—Remodeling of the extracellular matrix plays an important role during the pathogenesis of atherosclerosis and restenosis. The matrix glycoprotein thrombospondin-1 (TSP1) inhibits endothelial cell proliferation and migration in vitro. In contrast, TSP1 facilitates the growth and migration of cultured vascular smooth muscle cells. Accordingly, we investigated the hypothesis that administration of anti-TSP1 antibody could facilitate reendothelialization and inhibit neointimal thickening in balloon-injured rat carotid artery.

Methods and Results
—Sprague-Dawley rats were subjected to left common carotid artery denudation, after which arteries were treated with C6.7 anti-TSP1 or control antibody. Evans blue dye staining 2 weeks after injury disclosed significantly increased reendothelialization in arteries treated with C6.7 antibody compared with the control group, and this effect was associated with increased number of proliferating cell nuclear antigen–positive endothelial cells. In contrast, treatment with C6.7 antibody decreased the number of proliferating cell nuclear antigen–positive vascular smooth muscle cells in the injured arterial wall. Neointimal thickening was correspondingly attenuated to a statistically significant degree in arteries receiving C6.7 antibody versus the control group at both the 2-week and 4-week time points.

Conclusions
—Intra-arterial delivery of antibody against TSP1 facilitated reendothelialization and reduced neointimal lesion formation after balloon denudation.
Angiotensin II Induces LOX-1, the Human Endothelial Receptor for Oxidized Low-Density Lipoprotein
Authors: Morawietz Henning , Rueckschloss Uwe , Niemann Bernd , Duerrschmidt Nicole , Galle Jan , Hakim Kavous , Zerkowski Hans-Reinhard , Sawamura Tatsuya , Holtz Juergen
Published: June 2012

Background
—Oxidatively modified LDL (oxLDL) plays an important role in the development of atherosclerosis. OxLDL effects, eg, foam cell formation, are mediated in part by the classic scavenger receptor, whereas other effects may involve the recently cloned endothelial oxLDL receptor, LOX-1 (lectinlike oxLDL receptor-1), which is distinct from macrophage scavenger receptors. Because the regulation of LOX-1 must still be defined, we investigated whether LOX-1 is regulated by the potentially proatherosclerotic stimulant angiotensin II (Ang II).

Methods and Results
—Using competitive reverse transcription–polymerase chain reaction (RT-PCR), we quantified mRNA expression of LOX-1 in primary cultures of human umbilical vein endothelial cells (HUVECs). After treatment with Ang II for 3 hours (1 nmol/L to 1 μmol/L), LOX-1 mRNA was concentration-dependently induced (from 6.9±1.4 to 23.1±5.5 relative units [RU] by 1 μmol/L Ang II;
P
<0.05). The angiotensin II type 1 (AT
1
) receptor antagonist losartan prevented this induction. Incubation of HUVECs with Ang II (100 nmol/L, 3 hours) induced LOX-1 protein expression (212±21% of control level;
P
<0.01) and uptake of 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI)-labeled oxLDL (209±17% of control level;
P
<0.05) by an AT
1
-dependent pathway, reaching its maximum after 24 hours (680±89%;
P
<0.05). In internal mammary artery biopsy samples from patients with or without ACE inhibitor treatment before coronary artery bypass surgery, LOX-1 mRNA was downregulated by ACE inhibition (6.4±2.0 versus 19.3±5.9 RU; n=12 each;
P
<0.05).

Conclusions
—We conclude that LOX-1 is regulated by Ang II in vitro and in vivo, that induction of LOX-1 is mediated by the AT
1
receptor, and that repression of LOX-1 by long-term ACE inhibitor treatment may contribute to the antiatherosclerotic potential of this therapy.
Mononuclear Cell Adherence to Cultured Endothelium Is Enhanced by Hypertension and Insulin Resistance in Healthy Nondiabetic Volunteers
Authors: Chen N.-G. , Abbasi F. , Lamendola C. , McLaughlin T. , Cooke J. P. , Tsao P. S. , Reaven G. M.
Published: June 2012

Background
—This study was initiated to compare the adherence to cultured endothelial cells of mononuclear cells isolated from normotensive and hypertensive individuals.

Methods and Results
—Mononuclear cell binding to endothelium was greater in patients with hypertension (32±1 versus 25±2;
P
<0.001) than in normal volunteers. There was a significant relationship (
r
=0.42,
P
<0.01) between mononuclear cell binding and mean arterial pressure, independent of differences in age, sex, and body mass index. A significant relationship also existed between insulin resistance (estimated by the steady-state plasma glucose concentration during the insulin suppression test) and mononuclear cell binding in both the normotensive (
r
=0.86,
P
<0.001) and hypertensive (
r
=0.74,
P
<0.001) groups. Furthermore, multiple regression analysis demonstrated an independent relationship (
P
<0.001) between mononuclear cell binding and both steady-state plasma glucose and hypertensive status.

Conclusions
—These results indicate that both hypertension and insulin resistance lead to changes in mononuclear cells that increase their adherence to cultured endothelial cells.