bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of von Willebrand Factor Binding to Platelet GP Ib by a Fractionated Aurintricarboxylic Acid Prevents Restenosis After Vascular Injury in Hamster Carotid Artery
Authors: Matsuno Hiroyuki , Kozawa Osamu , Niwa Masayuki , Uematsu Toshihiko
Published: June 2012

Background
Aurintricarboxylic acid (ATA) prevents von Willebrand factor binding to platelet glycoprotein (GP) Ib, with higher-molecular-weight ATA more effective than the lower-molecular-weight compound. We investigated the effects of high-molecular-weight ATA (
M
r
=7500), obtained by fractionating commercial ATA, in the injured hamster carotid artery.

Methods and Results
Platelet aggregation was induced in vitro with ADP (2.5 μmol/L) or botrocetin (5 μg/mL) in hamster platelet-rich plasma. IC
50
values were 348.6±22.4 and 8.2±3.2 μg/mL, respectively. The endothelium of hamster carotid artery was denuded with a modified catheter. Continuous administration of high-molecular-weight ATA (10, 30, and 100 μg·kg
−1
·h
−1
) with an infusion pump produced antithrombotic effects in a dose-dependent manner, as evaluated by prolongation of time to occlusion. Neointima formation was observed 2 weeks after catheterization, and proliferating smooth muscle cells (SMCs) were identified by the thymidine analogue 5-bromo-2-deoxy-uridine (BrdU). Continuous treatment with the compound (100 μg·kg
−1
·h
−1
) with a 2ML1 Alzet infusion pump resulted in a reduction of neointimal area by 38.0±8.8% and decreased the BrdU index on days 1 and 7 significantly. DNA synthesis in DDT1MF2 hamster SMCs was also decreased by the compound in a dose-dependent manner. In histological observation, the process of endothelial healing was improved by this treatment with the compound.

Conclusions
Inhibition of platelet adhesion by von Willebrand factor binding to platelet GP Ib by high-molecular-weight ATA results in the prevention of thrombus formation and the suppression of neointima lesion. In addition, high-molecular-weight ATA has an inhibitory effect on SMC proliferation. This inhibition of both platelet adhesion and SMC proliferation markedly reduced vascular stenosis.
Basal Release of Nitric Oxide Augments the Frank-Starling Response in the Isolated Heart
Authors: Prendergast Bernard D. , Sagach Vadim F. , Shah Ajay M.
Published: June 2012

Background
The Frank-Starling response contributes to the regulation of cardiac output. The major underlying subcellular mechanism is a length-dependent change in myofilament responsiveness to Ca
2+
. Recent studies indicate that nitric oxide decreases myofilament responsiveness to Ca
2+
and modulates myocardial relaxation and left ventricular (LV) diastolic function. We therefore investigated the interaction between nitric oxide and the Frank-Starling response.

Methods and Results
Isolated ejecting guinea pig hearts (constant afterload and heart rate) were studied before and after interventions. Elevation of filling pressure from 10 to 20 cm H
2
O increased cardiac output, LV end-diastolic pressure (LVEDP), and peak LV pressure (LVP
max
). In the presence of
N
G
-monomethyl-
l
-arginine (L-NMMA, 10 μmol/L; n=10) or free hemoglobin (1 μmol/L; n=8), preload-induced increases in cardiac output were significantly attenuated but baseline cardiac output was unaffected. The effects of L-NMMA were inhibited in the presence of excess
l
-arginine (100 μmol/L; n=6). These changes were not attributable to alterations in coronary flow. Prostaglandin F
2α
(0.01 μmol/L; n=6), which reduced coronary flow, failed to alter the cardiac output response to preload elevation. The exogenous nitric oxide donor sodium nitroprusside (1 μmol/L; n=6) reduced cardiac output at the lowest preload but not at higher preloads. LVEDP was elevated after L-NMMA and hemoglobin but reduced after sodium nitroprusside.

Conclusions
Basal intracardiac production of nitric oxide significantly augments preload-induced rises in cardiac output in the isolated ejecting guinea pig heart. The mechanism appears to be unrelated to changes in coronary flow and may involve direct effects of nitric oxide on myocardial diastolic and/or systolic function.
Regression of Left Ventricular Hypertrophy With Captopril Restores Normal Ventricular Action Potential Duration, Dispersion of Refractoriness, and Vulnerability to Inducible Ventricular Fibrillation
Authors: Rials Seth J. , Wu Ying , Xu Xiaoping , Filart Roland A. , Marinchak Roger A. , Kowey Peter R.
Published: June 2012

Background
Left ventricular hypertrophy (LVH) is associated with multiple cellular electrophysiological abnormalities, susceptibility to ventricular arrhythmias, and an increased risk of sudden death. Several pharmacological therapies have been shown to produce regression of hypertrophy, but the value of regression is unclear. The present study examines whether pharmacological regression of LVH has effects on the susceptibility to ventricular arrhythmia or the cellular electrophysiological abnormalities of LVH.

Methods and Results
Rabbits underwent unilateral renal artery banding and contralateral nephrectomy to induce LVH or were placed in the control group. Both groups were studied 3 months later by in vivo and in vitro electrophysiological techniques. Banded rabbits had increased mean arterial pressure, increased left ventricular weight and wall thickness, increased dispersion of refractoriness, and lower ventricular fibrillation thresholds than control rabbits. Action potential duration and cell capacitance were also greater in the banded group. Additional rabbits were treated beginning 3 months after banding with either captopril (5 mg·kg
−1
·d
−1
) or vehicle added to their diet for an additional 3 months. These rabbits and age-matched controls were then studied by in vivo and in vitro electrophysiological techniques. In banded rabbits that received vehicle and were studied 6 months after banding, increased dispersion of refractoriness, a lower ventricular fibrillation threshold, and action potential prolongation persisted and were unchanged from animals studied 3 months after banding. Captopril, started 3 months after banding, caused regression of hypertrophy and normalization of the in vivo and in vitro electrophysiological abnormalities. Addition of captopril to the tissue bath during in vitro electrophysiological study showed no effect on cells from control or banded rabbits.

Conclusions
Pharmacological regression of LVH with captopril normalizes the in vivo and in vitro electrophysiological abnormalities of ventricular hypertrophy and reduces the vulnerability to ventricular fibrillation in a renovascular model of LVH.
Simvastatin Reduces Graft Vessel Disease and Mortality After Heart Transplantation
Authors: Wenke Klaus , Meiser Bruno , Thiery Joachim , Nagel Dorothea , von Scheidt Wolfgang , Steinbeck Gerhard , Seidel Dietrich , Reichart Bruno
Published: June 2012

Background
Accelerated graft vessel disease (GVD) represents the most serious long-term complication of heart transplantation. A possible cause underlying this progressive coronary vascular disease is believed to be post-transplantation hypercholesterolemia.

Methods and Results
In a 4-year prospective randomized study with heart transplant recipients, the efficacy of primary antihypercholesterolemic therapy with simvastatin was compared with that of general dietary therapy. The aim of the treatment was to maintain post-transplantation LDL-cholesterol levels at <120 mg/dL. Seventy-two heart transplant recipients receiving standard triple immunosuppression were randomly assigned to an active-treatment group (low-cholesterol diet and simvastatin, n=35) or a control group (general dietary measures, n=37). In the course of 4 years after transplantation, the simvastatin group had significantly lower LDL-cholesterol concentrations than the control group (mean±SD, 115±14 versus 156±17 mg/dL,
P
=.002), a significantly better long-term survival (88.6% versus 70.3%,
P
=.05), and a lower incidence of GVD in the coronary angiographic findings (16.6% versus 42.3%,
P
=.045). The incidence of graft rejections did not differ between the two groups, although there was a tendency toward a lower number of serious rejections in the simvastatin group (2.8% versus 13.5%,
P
=.1). Intracoronary ultrasound performed after 4 years in a subgroup of 27 patients (simvastatin, 10; control, 17) showed less intimal thickening in patients with LDL-cholesterol levels of <110 mg/dL (170±84 versus 370±171 μm,
P
=.04) and a lower intimal index (13.8±7.1% versus 27.9±12.1%,
P
=.04).

Conclusions
In comparison with dietary measures alone, the combination of a low-cholesterol diet and simvastatin after heart transplantation led to a significant reduction in cholesterol levels, a significantly higher long-term survival rate, and a lower incidence of GVD.
Common Carotid Intima-Media Thickness and Risk of Stroke and Myocardial Infarction
Authors: Bots Michiel L. , Hoes Arno W. , Koudstaal Peter J. , Hofman Albert , Grobbee Diederick E.
Published: June 2012

Background
Noninvasive assessment of intima-media thickness (IMT) is widely used in observational studies and trials as an intermediate or proxy end point for cardiovascular disease. However, data showing that IMT predicts cardiovascular disease are limited. We studied whether common carotid IMT is related to future stroke and myocardial infarction.

Methods and Results
We used a nested case-control approach among 7983 subjects aged ≥55 years participating in the Rotterdam Study. At baseline (March 1990 through July 1993), ultrasound images of the common carotid artery were stored on videotape. Determination of incident myocardial infarction and stroke was predominantly based on hospital discharge records. Analysis (logistic regression) was based on 98 myocardial infarctions and 95 strokes that were registered before December 31, 1994. IMT was measured from videotape for all case subjects and a sample of 1373 subjects who remained free from myocardial infarction and stroke during follow-up. The mean duration of follow-up was 2.7 years. Results were adjusted for age and sex. Stroke risk increased gradually with increasing IMT. The odds ratio for stroke per standard deviation increase (0.163 mm) was 1.41 (95% CI, 1.25 to 1.82). For myocardial infarction, an odds ratio of 1.43 (95% CI, 1.16 to 1.78) was found. When subjects with a previous myocardial infarction or stroke were excluded, odds ratios were 1.57 (95% CI, 1.27 to 1.94) for stroke and 1.51 (95% CI, 1.18 to 1.92) for myocardial infarction. Additional adjustment for several cardiovascular risk factors attenuated these associations: 1.34 (95% CI, 1.08 to 1.67) and 1.25 (95% CI, 0.98 to 1.58), respectively.

Conclusions
The present study, based on a short follow-up period, provides evidence that an increased common carotid IMT is associated with future cerebrovascular and cardiovascular events.
Troponin I Phosphorylation in the Normal and Failing Adult Human Heart
Authors: Bodor Geza S. , Oakeley Annette E. , Allen Paul D. , Crimmins Dan L. , Ladenson Jack H. , Anderson Page A. W.
Published: June 2012

Background
In the failing human heart myofibrillar calcium sensitivity of tension development is greater and maximal myofibrillar ATPase activity is less than in the normal heart. Phosphorylation of the cardiac troponin I (cTnI)–specific NH
2
-terminus decreases myofilament sensitivity to calcium, while phosphorylation of other cTnI sites decreases maximal myofibrillar ATPase activity.

Methods and Results
We examined cTnI phosphorylation in left ventricular myocardium collected from failing hearts at the time of transplant (n=20) and normal hearts from trauma victims (n=24). The relative amounts of actin, tropomyosin, and TnI did not differ between failing and normal myocardium. Using Western blot analysis with a monoclonal antibody (MAb) that recognizes the striated muscle TnI isoforms, we confirmed that the adult human heart expresses only cTnI. A cTnI-specific MAb recognized two bands of cTnI, designated cTnI
1
and cTnI
2
, while a MAb whose epitope is located in the cTnI-specific NH
2
-terminus recognized only cTnI
1
. Alkaline phosphatase decreased the relative amount of cTnI
1
, while protein kinase A and protein kinase C increased cTnI
1
. The percentage of cTnI made up of cTnI
1
, the phosphorylated form of TnI, is greater in the normal than the failing human heart (
P
<.001).

Conclusions
This phosphorylation difference could underlie the reported greater myofibrillar calcium sensitivity of failing myocardium. The functional consequence of this difference may be an adaptive or maladaptive response to the lower and longer calcium concentration transient of the failing heart, eg, enhancing force development or producing ventricular diastolic dysfunction.
Class Ia Antiarrhythmic Drug Cibenzoline
Authors: Hamada Mareomi , Shigematsu Yuji , Ikeda Shuntaro , Hara Yuji , Okayama Hideki , Kodama Koji , Ochi Takaaki , Hiwada Kunio
Published: June 2012

Background
The class Ia antiarrhythmic drug disopyramide relieves the outflow tract obstruction of hypertrophic obstructive cardiomyopathy (HOCM). Disopyramide, however, has several adverse effects, such as dysuria and thirst, resulting from its anticholinergic activity. A new class Ia antiarrhythmic drug, cibenzoline, has little anticholinergic activity. The aim of this study is to elucidate whether cibenzoline attenuates left ventricular pressure gradient (LVPG) in patients with HOCM.

Methods and Results
Ten patients with HOCM (mean age, 59±12 years) participated in this study. LVPG and left ventricular functions were measured before and 2 hours after administration of a single oral dose of 150 or 200 mg cibenzoline. LVPG decreased from 123±60 to 39±33 mm Hg (
P
=.0026). The E/A ratio in transmitral Doppler flow increased from 1.20±0.84 to 2.00±1.72 (
P
=.029). Isovolumic relaxation time increased from 73±16 to 101±23 ms (
P
=.0026). Left ventricular diastolic dimension remained unchanged, but left ventricular systolic dimension enlarged significantly, from 21.6±2.4 to 26.2±3.3 mm (
P
=.0004). Fractional shortening decreased from 47.6±6.1% to 34.6±8.8% (
P
=.0007). Left ventricular ejection time index decreased significantly, and preejection period index increased in all the patients. Decreased LVPG remained maintained even in the long-term treatment with cibenzoline.

Conclusions
These results indicate that cibenzoline can markedly attenuate LVPG in patients with HOCM. A decrease in myocardial contractility seems to be closely related to a marked decrease in LVPG.
Ischemic Preconditioning Decreases Apoptosis in Rat Hearts In Vivo
Authors: Piot Christophe A. , Padmanaban Devi , Ursell Philip C. , Sievers Richard E. , Wolfe Christopher L.
Published: June 2012

Background
Previous studies have demonstrated that ischemic preconditioning prevents lethal cell injury and, as a consequence, limits infarct size in rat heart. Although both apoptosis and necrosis have been shown to contribute to myocardial cell death after myocardial ischemia and reperfusion, the ability of ischemic preconditioning to prevent programmed cell death remains unknown.

Methods and Results
To test the hypothesis that ischemic preconditioning reduces irreversible ischemic injury in part by decreasing apoptosis, rats that underwent ischemic preconditioning and controls were subjected to 30 minutes of left coronary artery occlusion followed by 180 minutes of reperfusion. Ischemic preconditioning was achieved by five 5-minute cycles of ischemia, each followed by 5 minutes of reperfusion. Infarct size, determined by dual staining with triphenyltetrazolium chloride and phthalocyanine blue dye, was significantly reduced in preconditioned compared with nonpreconditioned rats (11.4±1.4% versus 58.7±1.4%; n=20 in each group;
P
<.001; infarct size/risk area). Genomic DNA from preconditioned hearts showed little or no oligonucleosome-sized fragments (200-bp multiples), whereas genomic DNA from nonpreconditioned hearts showed a typical nucleosome fragmentation. The TUNEL assay localized fewer and sparsely stained nuclei within the infarct zone of ischemic preconditioned hearts compared with nonpreconditioned hearts. Consistent with these findings, the number of cytosolic histone–associated low-molecular-weight DNA fragments was significantly decreased in preconditioned hearts compared with controls (0.17±0.02 versus 1.07±0.09 U; n=10 in each group;
P
<.001; absorbance 405 nm/490 nm).

Conclusions
This study suggests that ischemic preconditioning reduces irreversible ischemic injury in part by decreasing apoptosis after prolonged ischemia and reperfusion.
Estrogen Restores Endothelial Cell Function in an Experimental Model of Vascular Injury
Authors: White C. Roger , Shelton Jonathan , Chen Shi-Juan , Darley-Usmar Victor , Allen Leslie , Nabors Cheryl , Sanders Paul W. , Chen Yiu-Fai , Oparil Suzanne
Published: June 2012

Background
It has been suggested that reendothelialization of damaged blood vessels protects against the vascular injury response. The goal of the present study was to determine whether estrogen restores endothelial cell function in balloon-injured rat carotid arteries.

Methods and Results
Ten-week-old male and female Sprague-Dawley rats with intact gonads underwent balloon injury to the right common carotid artery. Female rats were randomized to receive either daily subcutaneous injections of 17β-estradiol (17β-E
2
; 20 μg · kg
−1
· d
−1
) or vehicle over the course of the study. Vessel morphology was assessed 2 weeks after injury. Significant neointima formation was observed in vehicle-treated males. This response was blunted in vehicle-treated and 17β-E
2
–supplemented females. Intima-to-media ratios were 1.28±0.23 (males), 0.72±0.07 (vehicle-treated females), and 0.49±0.07 (17β-E
2
–supplemented females). To test whether reductions in neointimal lesion formation were related to the functional reendothelialization of the damaged vessel, endothelium-dependent relaxation was tested in isolated ring segments from the three experimental groups. Vessels were precontracted with phenylephrine followed by cumulative administration of acetylcholine, an endothelium-dependent vasodilator. Maximum relaxation to acetylcholine was 8.13±1.70% (males), 22.06±4.36% (vehicle-treated females), and 46.47±3.48% (17β-E
2
–supplemented females). The enhanced endothelium-dependent relaxation of rings from 17β-E
2
–supplemented females correlated with reduced neointimal proliferation in this group. The concentration of nitric oxide metabolites in plasma correlated positively with plasma 17β-E
2
concentration.

Conclusions
These results suggest that estrogen protects against neointimal injury in the balloon-injured rat, at least in part, by facilitating the reendothelialization of the damaged vessel.
Radiofrequency Catheter Ablation of the Atria Eliminates Pacing-Induced Sustained Atrial Fibrillation and Reduces Connexin 43 in Dogs
Authors: Elvan Arif , Huang Xiao-di , Pressler Milton L. , Zipes Douglas P.
Published: June 2012

Background
We assessed the effects of radiofrequency catheter ablation (RFCA) of the atrial epicardium on pacing-induced sustained atrial fibrillation (AF) and the expression and distribution of the intercellular gap junction protein connexin 43 (Cx43) in dogs.

Methods and Results
In 12 mongrel dogs, after creation of complete AV block and implantation of a ventricular inhibited pacemaker, a high-rate pulse generator (20 to 30 Hz to induce AF) was implanted in the neck, connected to a right atrial endocardial pacing lead, and used to pace the atrium for 10 to 14 weeks. In group 1 (n=9 dogs), corrected sinus node recovery time (CSNRT), P-wave duration, 24-hour Holter ECG, maximal heart rate (MHR) in response to isoproterenol, and intrinsic heart rate (IHR) after atropine (0.04 mg/kg) and propranolol were measured before and after atrial pacing and RFCA. Group 2 dogs were used to assess the effect of chronic AF alone on Cx43 expression and distribution. All group 1 dogs developed sustained (>24 hours) AF. Right-sided RFCA of the atria eliminated the sustained AF in 5 dogs, but both right and left atrial RFCA was required to abolish sustained AF in the other 4 dogs. After RFCA restored sinus rhythm, CSNRT and P-wave duration were prolonged and MHR and IHR were decreased. Chronic rapid atrial pacing (group 2) increased the expression of Cx43, which was absent in ablated areas and markedly depressed in viable atrial myocytes near the ablation zones (group 1).

Conclusions
Rapid atrial pacing for long time periods induced sustained AF that can be eliminated by linear right and left atrial lesions created with RFCA, with preservation of sinus rhythm and atrial contractile function. Chronic AF increased the expression and distribution of gap junction protein Cx43, which became reduced in ablated and nearby nonablated areas.
Active Serum Vitamin D Levels Are Inversely Correlated With Coronary Calcification
Authors: Watson Karol E. , Abrolat Marla L. , Malone Lonzetta L. , Hoeg Jeffrey M. , Doherty Terry , Detrano Robert , Demer Linda L.
Published: June 2012

Background
Arterial calcification is a common feature of atherosclerosis, occurring in >90% of angiographically significant lesions. Recent evidence from this and other studies suggests that development of atherosclerotic calcification is similar to osteogenesis; thus, we undertook the current investigation on the potential role of osteoregulatory factors in arterial calcification.

Methods and Results
We studied two human populations (173 subjects) at high and moderate risk for coronary heart disease and assessed them for associations between vascular calcification and serum levels of the osteoregulatory molecules osteocalcin, parathyroid hormone, and 1α,25-dihydroxyvitamin D
3
(1,25-vitamin D). Our results revealed that 1,25-vitamin D levels are inversely correlated with the extent of vascular calcification in both groups. No correlations were found between extent of calcification and levels of osteocalcin or parathyroid hormone.

Conclusions
These data suggest a possible role for vitamin D in the development of vascular calcification. Vitamin D is also known to be important in bone mineralization; thus, 1,25-vitamin D may be one factor to explain the long observed association between osteoporosis and vascular calcification.
Long-term Outcome in Acute Myocardial Infarction Patients Admitted to Hospitals With and Without On-site Cardiac Catheterization Facilities
Authors: Every Nathan R. , Parsons Lori S. , Fihn Stephan D. , Larson Eric B. , Maynard Charles , Hallstrom Alfred P. , Martin Jenny S. , Weaver W. Douglas , Investigators for the MITI
Published: June 2012

Background
Previous studies have documented the strong association between availability of on-site cardiac catheterization facilities and increased use of coronary angiography in patients with acute myocardial infarction (AMI). Although these studies have shown little influence of the availability of catheterization labs on hospital mortality, no long-term follow-up has been reported.

Methods and Results
From a cohort of 12 331 AMI patients admitted to 19 Seattle area hospitals, we compared long-term outcome in 7985 patients admitted to hospitals with and 4346 patients admitted to hospitals without on-site catheterization labs. During the index hospitalization, patients admitted to hospitals with on-site catheterization were more likely to undergo coronary angiography (67.1% versus 39.3%,
P
<.0001), coronary angioplasty (32.5% versus 13.2%,
P
<.0001), or coronary bypass surgery (12.5% versus 9.5%,
P
<.0001). At 3-year follow-up, patients admitted to hospitals with on-site catheterization labs were more likely to undergo postdischarge angiography (19.2% versus 15.2%,
P
=.0001) and coronary angioplasty (11.6% versus 8.2%,
P
<.0001). This was associated with approximately $2500.00 per patient in higher cumulative costs. Despite this higher rate of procedure use, there was no association between admission to a hospital with on-site catheterization facilities and lower long-term mortality (multivariate hazard ratio, 1.0; 95% CI, 0.93 to 1.1., the hazard being associated with admission to hospitals with on-site catheterization facilities).

Conclusions
In an urban area with unconstrained patient transfer mechanisms and high overall cardiac procedure use rates, AMI patients admitted to hospitals without on-site catheterization facilities were managed with fewer procedures during hospitalization and follow-up. This more conservative treatment approach was not associated with any observed increase in long-term mortality.
Acute Myocardial Infarction Detected in the 12-Lead ECG by Artificial Neural Networks
Authors: Hedén Bo , Öhlin Hans , Rittner Ralf , Edenbrandt Lars
Published: June 2012

Background
The 12-lead ECG, together with patient history and clinical findings, remains the most important method for early diagnosis of acute myocardial infarction. Automated interpretation of ECG is widely used as decision support for less experienced physicians. Recent reports have demonstrated that artificial neural networks can be used to improve selected aspects of conventional rule-based interpretation programs. The purpose of this study was to detect acute myocardial infarction in the 12-lead ECG with artificial neural networks.

Methods and Results
A total of 1120 ECGs from patients with acute myocardial infarction and 10 452 control ECGs, recorded at an emergency department with computerized ECGs, were studied. Artificial neural networks were trained to detect acute myocardial infarction by use of measurements from the 12 ST-T segments of each ECG, together with the correct diagnosis. After this training process, the performance of the neural networks was compared with that of a widely used ECG interpretation program and the classification of an experienced cardiologist. The neural networks showed higher sensitivities and discriminant power than both the interpretation program and cardiologist. The sensitivity of the neural networks was 15.5% (95% confidence interval [CI], 12.4 to 18.6) higher than that of the interpretation program compared at a specificity of 95.4% (
P
<.00001) and 10.5% (95% CI, 7.2 to 13.6) higher than the cardiologist at a specificity of 86.3% (
P
<.00001).

Conclusions
Artificial neural networks can be used to improve automated ECG interpretation for acute myocardial infarction. The networks may be useful as decision support even for the experienced ECG readers.
Association Between Plasma Total Homocysteine and Parental History of Cardiovascular Disease in Children With Familial Hypercholesterolemia
Authors: Tonstad Serena , Refsum Helga , Ueland Per Magne
Published: June 2012

Background
Recently, we reported a relation between plasma total homocysteine (tHcy) in children and cardiovascular disease (CVD) in their male relatives, suggesting that tHcy may partly explain the increased risk related to a family history of CVD. Because individuals with familial hyperlipidemias have an exceptionally high risk of premature CVD, we explored the relationship between tHcy and parental history of CVD in children with familial hypercholesterolemia (FH).

Methods and Results
Study subjects were 91 boys and 64 girls (age range, 7 to 17 years) with FH who were treated with a standard lipid-lowering diet at a tertiary care lipid clinic. We conducted a cross-sectional analysis of demographics, the diet, tHcy level, presence of the C677T mutation in the methylenetetrahydrofolate reductase gene (a common genetic cause of elevated tHcy) in children, and the prevalence of parental CVD. tHcy increased after puberty and was inversely related to parental educational level. Intakes of folate, vitamin C, and fruits and vegetables were inversely associated with tHcy, as were serum folate and vitamin B
12
(Spearman’s ρ, −0.2 to −0.4;
P
<.05). tHcy was increased in children whose parent with FH had experienced CVD compared with children without parental CVD (median [interquartile range], 6.6 [5.3, 8.0] μmol/L versus 5.6 [4.7, 6.8] μmol/L;
P
=.01). This difference remained significant in multivariate regression analysis. Homozygosity for the C677T mutation was associated with a higher tHcy level and tended to be more frequent in the group with than in the group without a parental history of CVD (18% versus 8%;
P
=.07).

Conclusions
These findings suggest that a moderately elevated tHcy level may partly account for the contribution of the family history to risk of CVD in FH. Dietary recommendations for FH should include nutrients that affect homocysteine metabolism.
Vitronectin Receptor (α
v
β
3
) Mediates Platelet Adhesion to the Luminal Aspect of Endothelial Cells
Authors: Gawaz Meinrad , Neumann Franz-Josef , Dickfeld Timm , Reininger Armin , Adelsberger Helmut , Gebhardt Adrian , Schömig Albert
Published: June 2012

Background
Platelet interaction with endothelium plays an important role in the pathophysiology of coronary microcirculation. We assessed the role of the vitronectin receptor (integrin α
v
β
3
) in platelet/endothelium adhesion.

Methods and Results
We investigated the effect on platelet/endothelium adhesion of plasma obtained from patients with acute myocardial infarction during reperfusion (before and 8, 24, 48, and 72 hours and 5 to 7 days after direct angioplasty) and with pretreatment with α-thrombin (2 U/mL) and recombinant human interleukin-1β. Platelet/endothelium adhesion was significantly enhanced by ≈20% after pretreatment of endothelium with patient plasma for 4 hours (
P
<.05) compared with endothelium treated with pooled control plasma. Plasma-induced platelet/endothelium adhesion was, in part, RGD peptide dependent. Pretreatment of endothelial cells with α-thrombin or recombinant human interleukin-1β enhanced platelet/endothelium adhesion and surface expression of α
v
β
3
on the luminal aspect of endothelium (
P
<.05). The adhesion of platelets, isolated platelet microparticles, and Chinese hamster ovary cells bearing human recombinant α
IIb
β
3
(platelet glycoprotein IIb-IIIa) to activated endothelial cells was inhibited by antiadhesive peptides GRGDSP and c(RGDfV) and monoclonal antibodies 4F10, LM609, and 7E3.

Conclusions
The expression of vitronectin receptor exposed on the luminal aspect of activated endothelium is enhanced and mediates platelet/endothelium adhesion. Vitronectin receptor–mediated platelet attachment to activated endothelium during reperfusion may contribute to reperfusion injury and could be a target for antiadhesive therapy.
Early Surgery in Patients With Mitral Regurgitation Due to Flail Leaflets
Authors: Ling Lieng H. , Enriquez-Sarano Maurice , Seward James B. , Orszulak Thomas A. , Schaff Hartzell V. , Bailey Kent R. , Tajik A. Jamil , Frye Robert L.
Published: June 2012

Background
The optimal timing for surgery in patients with mitral regurgitation is disputed. Because of the frequency of left ventricular dysfunction, which is difficult to predict, early surgery has been recommended, but its potential benefits have not been demonstrated.

Methods and Results
The outcomes of 221 patients (mean age, 65±13 years; 71% males) with flail leaflets diagnosed with two-dimensional echocardiography between 1980 and 1989 who were eligible for operation were analyzed. Group I comprised 63 patients who had early mitral valve surgery (within 1 month after diagnosis). Group II comprised 158 patients initially treated conservatively (80 of whom were operated on later). Group I patients were younger (
P
=.009), had more symptoms (
P
<.0001), and were more frequently in atrial fibrillation (
P
=.023) than group II patients. There was no difference in ejection fraction between the groups. The early surgery strategy was followed by an improved overall survival rate (
P=
.028) and a lower incidence of cardiovascular deaths (
P
=.025), congestive heart failure (
P
=.046), and new chronic atrial fibrillation (
P
=.032), as confirmed by multivariate analysis (adjusted risk ratios of 0.31, 0.18, 0.38, and 0.05, respectively; all
P<
.02).

Conclusions
In patients with mitral regurgitation due to flail leaflets, the strategy of early surgery versus conservative management is associated with an improved long-term survival rate, decreased cardiac mortality, and decreased morbidity after diagnosis. This outcome advantage suggests that early surgery is a reasonable treatment option to be considered in low-risk candidates with repairable valves and severe mitral regurgitation.
Circulating Microemboli in Patients After Aortic Valve Replacement With Pulmonary Autografts and Mechanical Valve Prostheses
Authors: Nötzold Axel , Droste Dirk W. , Hagedorn Gunnar , Berndt Suliko , Kaps Manfred , Graf Bernhard , Sievers Hans H.
Published: June 2012

Background
The pulmonary autograft procedure (Ross) is now considered the gold standard for aortic valve replacement. One of its advantages is the freedom from macroemboli without anticoagulation. Whether this holds true for circulating microemboli, detectable as high-intensity transient Doppler signals (HITS), has not yet been verified.

Methods and Results
We investigated 8 patients (2 women, 6 men; mean age, 50.6±17.9 years) after the Ross procedure, 9 patients (3 women, 6 men; mean age, 67.2±9.46 years) after aortic valve replacement with a mechanical valve prosthesis, and 12 young healthy volunteers by unilateral 1-hour recording of the middle cerebral artery on digital audio tape. Patients with extracranial carotid artery disease were excluded by color duplex sonography. During the off-line evaluation, the investigator was not aware of any patient details. No HITS were detected in healthy volunteers (95% confidence interval [CI], 0% to 26.46%). After the Ross procedure, 1 patient had 11 and 1 patient had 1 HITS (95% CI, 3.19% to 65.09%). All recipients of mechanical valves had HITS, ranging from 2 to 84 per hour (95% CI, 66.7% to 100%). Significantly more recipients of mechanical valves exhibited HITS than recipients of pulmonary autografts (
P
<.05) or control subjects (
P
<.05).

Conclusions
In contrast to mechanical valves, pulmonary autografts are seldom the source of microemboli, confirming the pulmonary autograft as the superior substitute for aortic valve replacement.
Cardiac Risk of Noncardiac Surgery
Authors: Eagle Kim A. , Rihal Charanjit S. , Mickel Mary C. , Holmes David R. , Foster Eric D. , Gersh Bernard J. , Investigators for the CASS , Program University of Michigan Heart Care
Published: June 2012

Background
The influence of prior coronary artery bypass surgery (CABG) versus medical therapy for reducing the risk of postoperative cardiac complications after noncardiac surgery continues to be debated. To further clarify this controversy we studied 24 959 participants in the Coronary Artery Surgery Study (CASS) database with suspected coronary disease by identifying those who required noncardiac surgery during more than 10 years of follow-up.

Methods and Results
CASS registry enrollees were either treated with CABG or medical therapy after initial entry. During follow-up, patients who required noncardiac operations were evaluated for hospital death or out-of-hospital death within 30 days of noncardiac surgery and nonfatal postoperative myocardial infarction (MI). At a mean follow-up of 4.1 years, 3368 patients underwent noncardiac surgery, with abdominal (36%), urologic (21%), orthopedic (15%), and vascular being most common. Abdominal, vascular, thoracic, and head and neck surgery each had a combined MI/death rate among patients with nonrevascularized coronary disease >4%. Among 1961 patients undergoing higher-risk surgery, prior CABG was associated with fewer postoperative deaths (1.7% versus 3.3%,
P
=.03) and MIs (0.8% versus 2.7%,
P
=.002) compared with medically managed coronary disease. Contrariwise, 1297 patients undergoing urologic, orthopedic, breast, and skin operations had mortality of <1% regardless of prior coronary treatment. Prior CABG was most protective in patients with advanced angina and/or multivessel coronary artery disease.

Conclusions
In patients with known coronary artery disease, noncardiac surgeries involving the thorax, abdomen, vasculature, and head and neck are associated with the highest cardiac risk, which is reduced among patients with prior CABG.
Angiotensin II–Induced Hypertension Increases Heme Oxygenase-1 Expression in Rat Aorta
Authors: Ishizaka Nobukazu , De León Héctor , Bech Laursen Jørn , Fukui Toshiki , Wilcox Josiah N. , De Keulenaer Gilles , Griendling Kathy K. , Alexander R. Wayne
Published: June 2012

Background
We investigated the in vivo effects of angiotensin (Ang) II–induced hypertension on heme oxygenase (HO) mRNA and protein expression, activity, and localization in rat aortas.

Methods and Results
Infusion of Ang II (0.7 mg · kg
−1
· d
−1
) increased HO-1 mRNA levels to 169±31%, 251±47%, 339±26%, and 370±74% of the control level at 1, 3, 5, and 7 days after operation, respectively. The HO-1 protein level at 7 days was markedly upregulated, as was HO activity. Treatment with either losartan (25 mg · kg
−1
· d
−1
) or hydralazine (15 mg · kg
−1
· d
−1
), both of which prevented the Ang II–induced hypertension, blocked HO-1 mRNA upregulation. Norepinephrine infusion (2.8 mg · kg
−1
· d
−1
) produced a degree of hypertension and degree of HO-1 mRNA upregulation similar to those of Ang II infusion, which was again blocked by treatment with hydralazine (382±18% and 150±30% of the control level, respectively). Immunohistochemical analysis demonstrated that HO-1 is expressed in medial smooth muscle and adventitial cells in normotensive rat aortas, and this is markedly increased in adventitial and endothelial cells in Ang II–induced hypertensive rat aortas. In contrast, HO-2 protein expression was not changed in hypertensive rat aortas.

Conclusions
These findings indicate that HO-1 is upregulated in hypertensive rat aortas, apparently by mechanisms unique to Ang II and by hemodynamic stress.
Role of Endogenous Endothelin in Chronic Heart Failure
Authors: Mulder Paul , Richard Vincent , Derumeaux Geneviève , Hogie Manuela , Henry Jean Paul , Lallemand Françoise , Compagnon Patricia , Macé Bertrand , Comoy Etienne , Letac Brice , Thuillez Christian
Published: June 2012

Background
Plasma levels of the vasoconstrictor peptide endothelin (ET) are increased in chronic heart failure (CHF), and ET levels are a major predictor of mortality in this disease. Thus, ET may play a deleterious role in CHF. The purpose of this study was to assess the effects of chronic treatment with the ET receptor antagonist bosentan in a rat model of CHF.

Methods and Results
Rats were subjected to coronary artery ligation and were treated for 2 or 9 months with placebo or bosentan (30 or 100 mg · kg
−1
· d
−1
). Bosentan 100 mg · kg
−1
markedly increased survival (after 9 months: untreated, 47%; bosentan, 65%;
P
<.01). Throughout the 9-month treatment period, bosentan significantly reduced arterial pressure and heart rate. After 2 or 9 months of treatment, the ET antagonist reduced central venous pressure and left ventricular (LV) end-diastolic pressure as well as plasma catecholamines, urinary cGMP, and LV ventricular collagen density. Bosentan also reduced LV dilatation (evidenced at 2 months by a shift in the pressure/volume relationship ex vivo). Echocardiographic studies performed after 2 months showed that the ET antagonist reduced hypertrophy and increased contractility of the noninfarcted LV wall. The lower dose of bosentan (30 mg · kg
−1
), which had no major hemodynamic or structural effects, also had no effect on survival.

Conclusions
Long-term treatment with an ET antagonist markedly increases survival in this rat model of CHF. This increase in survival is associated with decreases in both preload and afterload and an increase in cardiac output as well as decreased LV hypertrophy, LV dilatation, and cardiac fibrosis. Thus, chronic treatment with ET antagonists such as bosentan might be beneficial in human CHF and might increase long-term survival in this disease.
Beneficial Hemodynamic and Renal Effects of Adrenomedullin in an Ovine Model of Heart Failure
Authors: Rademaker M. T. , Charles C. J. , Lewis L. K. , Yandle T. G. , Cooper G. J. S. , Coy D. H. , Richards A. M. , Nicholls M. G.
Published: June 2012

Background
Adrenomedullin is a recently discovered endogenous peptide with hypotensive and natriuretic actions in normal animals. Circulating and ventricular adrenomedullin are elevated in congestive heart failure, suggesting a possible role in the pathophysiology of this disease. No studies have previously examined the effects of adrenomedullin in heart failure.

Methods and Results
Eight sheep with pacing-induced heart failure received human adrenomedullin(1-52) at 10 and 100 ng · kg
−1
· min
−1
IV for 90 minutes each. Compared with vehicle control data, adrenomedullin increased plasma cAMP (high dose,
P
<.05) in association with dose-dependent falls in calculated peripheral resistance (13 mm Hg · L
−1
· min
−1
,
P
<.001), mean arterial pressure (9 mm Hg,
P
<.001), and left atrial pressure (5 mm Hg,
P
<.001) and increases in cardiac output (0.5 L/min,
P
<.001). Adrenomedullin increased urine sodium (threefold,
P
<.05), creatinine (
P
<.05) and cAMP excretion (
P
<.01), creatinine clearance (
P
<.05), and renal production of cAMP (
P
<.05), whereas urine output was maintained during infusion and raised after infusion (
P
<.05). Adrenomedullin reduced plasma aldosterone levels (
P
<.05), whereas plasma atrial and brain natriuretic peptide concentrations were unchanged during infusion and rose after infusion (
P
<.01 and
P
<.05, respectively). Plasma catecholamine, cortisol, renin, calcium, and glucose concentrations were not significantly altered.

Conclusions
Adrenomedullin reduced ventricular preload and afterload and improved cardiac output in sheep with congestive heart failure. Despite the clear fall in arterial pressure, adrenomedullin increased creatinine clearance and sodium excretion and maintained urine output. These results imply an important pathophysiological role for adrenomedullin in the regulation of pressure and volume in heart failure and raise the possibility of a new therapeutic approach to this disease.
Sodium Channel Block With Mexiletine Is Effective in Reducing Dispersion of Repolarization and Preventing Torsade de Pointes in LQT2 and LQT3 Models of the Long-QT Syndrome
Authors: Shimizu Wataru , Antzelevitch Charles
Published: June 2012

Background
This study examines the contribution of transmural heterogeneity of transmembrane activity to phenotypic T-wave patterns and the effects of pacing and of sodium channel block under conditions mimicking
HERG
and
SCN5A
defects linked to the congenital long-QT syndrome (LQTS).

Methods and Results
A transmural ECG and transmembrane action potentials from epicardial, M, and endocardial or Purkinje cells were simultaneously recorded in an arterially perfused wedge of canine left ventricle.
d
-Sotalol was used to mimic LQT2, whereas ATX-II mimicked LQT3.
d
-Sotalol caused a preferential prolongation of the M cell action potential duration (APD
90
, 291±14 to 354±35 ms), giving rise to broad and sometimes low-amplitude bifurcated T waves and an increased transmural dispersion of repolarization (TDR, 51±15 to 72±17 ms). QT interval increased from 320±13 to 385±37 ms. ATX-II produced a preferential prolongation of the M cell APD
90
(280±25 to 609±49 ms) and caused a marked delay in the onset of the T wave and a sharp rise in TDR (40±5 to 168±40 ms). QT-, APD
90
-, and dispersion-rate relations were much steeper in the ATX-II than in the
d
-sotalol model. Mexiletine (2 to 20 μmol/L) dose-dependently abbreviated the QT interval and APD
90
of all cell types, more in the ATX-II than in the
d
-sotalol model, but decreased TDR equally in the two models. Mexiletine 2 to 5 μmol/L totally suppressed spontaneous torsade de pointes (TdP) and reduced the vulnerable window during which single extrastimuli could induce TdP in both models. Higher concentrations of mexiletine (10 to 20 μmol/L) totally suppressed stimulation-induced TdP.

Conclusions
Our results suggest that although pacing and sodium channel block are very effective in abbreviating the QT interval and TDR in LQT3, these therapeutic approaches may also be valuable in reducing the incidence of arrhythmogenesis in LQT2.
Cardiac Allograft Vasculopathy
Authors: Weis Michael , von Scheidt Wolfgang
Published: June 2012

Abstract
Cardiac allograft vasculopathy (CAV) remains a troublesome long-term complication of heart transplantation. It is manifested by a unique and unusually accelerated form of coronary disease affecting both intramural and epicardial coronary arteries and veins. CAV is characterized by vascular injury induced by a variety of noxious stimuli, including the immune system response to the allograft, ischemia-reperfusion injury, viral infection, immunosuppressive drugs, and classic risk factors such as hyperlipidemia, insulin resistance, and hypertension. The obstructive vascular lesions are thought to progress through repetitive endothelial injury followed by repair response. The role of major histocompatibility complex donor-recipient differences in the pathogenesis of CAV has not yet been completely elucidated. Intracoronary ultrasound studies reveal a dual morphology with donor-transmitted or de novo focal, noncircumferential plaques in proximal segments and/or a diffuse, concentric pattern observed in distal segments. A lack of correlation between microvascular and epicardial vessel disease suggests discordant manifestations and progression of CAV. Apoptosis and loss of functional vascular remodeling have to be considered as important mediators of clinically relevant CAV. Strategies for blocking T-cell costimulation and expression of adhesion molecules may help prevent chronic rejection in clinical transplantation. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and antiproliferative drugs may slow progression of CAV by various effects. Methods to augment endogenous nitric oxide bioavailability as well as newer immunosuppressive regimens may be protective. Balloon angioplasty has a limited role in the treatment of focal lesions. Experiences with coronary stenting, coronary artery bypass grafting, and transmyocardial laser revascularization are limited. Retransplantation has a worse outcome than initial transplantation.
Intravascular Ultrasound–Guided Percutaneous Fenestration of the Intimal Flap in the Dissected Aorta
Authors: Chavan A. , Hausmann D. , Dresler C. , Rosenthal H. , Jaeger K. , Haverich A. , Borst H. G. , Galanski M.
Published: June 2012

Background
Aortic dissection with branch obstruction is associated with high morbidity and mortality. Fenestration of the dissection flap to relieve distal vessel ischemia is at present largely performed surgically. The surgical mortality and morbidity are high, because most patients are poor candidates for anesthesia or surgery.

Methods and Results
Nine percutaneous fenestrations (one with additional stenting of the infrarenal true aortic lumen) were performed under local anesthesia in seven patients with aortic dissection. The presenting symptoms were abdominal angina or claudication. By the transfemoral approach, the intimal flap was initially punctured with a needle-catheter combination through which a guidewire was placed across the dissection flap. The fenestration was carried out with a balloon catheter introduced over the guidewire. The procedure was performed under on-line guidance with intravascular ultrasound imaging. The procedure was performed successfully and without complications in all patients. After intervention, symptoms resolved in all seven patients.

Conclusions
Intravascular ultrasound–guided percutaneous fenestration of the intimal flap in symptomatic aortic dissections with distal vessel involvement is a technically feasible and safe procedure that can effectively relieve the patient’s symptoms.