bluuebunny/crossref_metadata_2025 huggingface dataset:
Angiotensin-Converting Enzyme DD Genotype and Cardiovascular Disease in Heterozygous Familial Hypercholesterolemia
Authors: O’Malley Jean P. , BS  , Maslen Cheryl L. , Illingworth D. Roger
Published: June 2012

Background
—Controversy exists as to whether the deletion/deletion genotype (DD) of the ACE gene polymorphism increases the risk of myocardial infarction (MI). Studies have suggested that the ACE DD genotype is associated with increased plaque instability. We hypothesized that the ACE DD genotype may increase the risk of myocardial infarction and coronary heart disease (CHD) in patients with heterozygous familial hypercholesterolemia (FH) or familial defective apolipoprotein B-100 (FDB) who, as a group, are at high risk of having lipid-rich plaques in their coronary arteries.

Methods and Results
—We determined the ACE genotypes and incidence of MI or surgical intervention for CHD in 213 adult patients with heterozygous FH or FDB. The incidence of MI in 35 male patients who carried the ACE DD genotype was 2.5 times that observed in male patients with the II or DI genotypes, and the incidence of CHD in male patients with the DD genotype was 2.2 times higher than in those who had ACE DI+II. The potential effects of ACE genotype on CHD could not be directly compared in female patients because of a disparity in the smoking history of the genotypic groups. From logistic regression analysis, the estimated odds ratio associated with the ACE DD genotype was 2.57 for MI and 2.21 for CHD adjusted for age, sex, and smoking history.

Conclusions
—The ACE DD genotype is associated with an increased risk of MI and CHD in patients with heterozygous FH or FDB. Determination of the ACE genotype in asymptomatic FH and FDB patients provides an additional means to identify those patients at greatest risk for the premature development of CHD.
Effects of Procainamide on Wave-Front Dynamics During Ventricular Fibrillation in Open-Chest Dogs
Authors: Kwan Yvonne Y. , Fan Wei , Hough Dustan , Lee John J. , Fishbein Michael C. , Karagueuzian Hrayr S. , Chen Peng-Sheng
Published: June 2012

Background
—There is increasing evidence that both functional reentrant wave fronts and multiple wavelets are present during ventricular fibrillation (VF). However, the effects of procainamide on the characteristics of activation waves during VF are poorly understood.

Methods and Results
—Seven dogs were studied; six underwent subendocardial chemical ablation procedures. A plaque with 317 to 480 bipolar electrodes was sutured to the right ventricular free wall, and the patterns of activation were registered with a computerized mapping system. VF was electrically induced, and the patterns of activation were registered at baseline and during procainamide infusion (serum concentration, 9.3±1.9 μg/mL). Among the six dogs that had their subendocardium ablated, reentrant wave fronts were present in 6 of the 108 runs of VF at baseline and in 6 of the 100 runs of VF during procainamide infusion. By analyzing the wave fronts, we found that the cycle length, refractory period, conduction velocity, and wavelength at baseline were 101±9 ms, 54±5 ms, 0.93±0.21 mm/ms, and 51±16 mm, respectively, and during procainamide infusion, values became 125±11 ms (
P
<.001), 119±7 ms (
P
<.001), 0.42±0.02 mm/ms (
P
<.001), and 50±4 mm (
P
=.8), respectively. The vast majority of the activation waves do not form organized reentry. These activation waves broke up more frequently at baseline than during procainamide administration. The number of activation waves was 7.25±1.39 s
−1
· cm
−2
at baseline and 4.45±1.80 s
−1
· cm
−2
during procainamide administration (
P
<.001). The dog without subendocardial ablation had similar results.

Conclusions
—Procainamide decreases the number of wavelets during VF by preventing spontaneous wave breaks. This represents a novel mechanism of antiarrhythmic drug action.
Prediction of Coronary Heart Disease Using Risk Factor Categories
Authors: Wilson Peter W. F. , D’Agostino Ralph B. , Levy Daniel , Belanger Albert M. , Silbershatz Halit , Kannel William B.
Published: June 2012

Background
—The objective of this study was to examine the association of Joint National Committee (JNC-V) blood pressure and National Cholesterol Education Program (NCEP) cholesterol categories with coronary heart disease (CHD) risk, to incorporate them into coronary prediction algorithms, and to compare the discrimination properties of this approach with other noncategorical prediction functions.

Methods and Results
—This work was designed as a prospective, single-center study in the setting of a community-based cohort. The patients were 2489 men and 2856 women 30 to 74 years old at baseline with 12 years of follow-up. During the 12 years of follow-up, a total of 383 men and 227 women developed CHD, which was significantly associated with categories of blood pressure, total cholesterol, LDL cholesterol, and HDL cholesterol (all
P
<.001). Sex-specific prediction equations were formulated to predict CHD risk according to age, diabetes, smoking, JNC-V blood pressure categories, and NCEP total cholesterol and LDL cholesterol categories. The accuracy of this categorical approach was found to be comparable to CHD prediction when the continuous variables themselves were used. After adjustment for other factors, ≈28% of CHD events in men and 29% in women were attributable to blood pressure levels that exceeded high normal (≥130/85). The corresponding multivariable-adjusted attributable risk percent associated with elevated total cholesterol (≥200 mg/dL) was 27% in men and 34% in women.

Conclusions
—Recommended guidelines of blood pressure, total cholesterol, and LDL cholesterol effectively predict CHD risk in a middle-aged white population sample. A simple coronary disease prediction algorithm was developed using categorical variables, which allows physicians to predict multivariate CHD risk in patients without overt CHD.
Tracking of Left Ventricular Mass in Children: Race and Sex Comparisons
Authors: Schieken Richard M. , Schwartz Pamela F. , Goble Monica M.
Published: June 2012

Background
—Increased left ventricular (LV) mass is a predictor of cardiovascular disease in adults. The mechanism(s) for these observations are not fully understood.

Methods and Results
—We repeatedly studied a biracial sample of children from ages 11 through 17 years. At visits 1 through 5, height, weight, and pubertal stage were determined. Blood pressure and heart rate were measured. M-mode and two-dimensional echocardiograms were performed with a 3.5-MHz transducer with the subject in the supine position. LV mass was calculated. Repeated-measures analysis using a mixed modeling approach was performed for LV mass. At all ages, boys had greater LV mass than girls. For the population as a whole, we found significant tracking correlations for LV mass between each interval of measurement and throughout the entire period of examination. The tracking correlation for the entire sample from visit 1 through visit 5 was
r
=.41. The LV mass in white children tracked from the youngest to the oldest. Black children tracked similarly from ages 1 to 15 years, but tracking was not significant across the widest interval, visit 1 through visit 5. Racial differences were found in the interactions of systolic blood pressure and heart rate, which magnified the differences in LV mass. During adolescence, LV mass tracks significantly in both black and white children.

Conclusions
—Interactive effects such as weight, blood pressure, and heart rate magnify sex and race differences in LV mass.
Glutathione-Related Antioxidant Defenses in Human Atherosclerotic Plaques
Authors: Lapenna Domenico , de Gioia Sergio , Ciofani Giuliano , Mezzetti Andrea , Ucchino Sante , Calafiore Antonio M. , Napolitano Antonio M. , Di Ilio Carmine , Cuccurullo Franco
Published: June 2012

Background
—Oxidative stress, resulting from an antioxidant/prooxidant imbalance, seems to be crucial in atherogenesis. Recent evidence has emerged, however, of a surprisingly high content of low-molecular-weight antioxidants in human atherosclerotic plaques, although other antioxidant systems have not been investigated in these lesions.

Methods and Results
—We studied glutathione-related antioxidant defenses (which play a key role in tissue antioxidant protection) in carotid atherosclerotic plaques of 13 patients subjected to endarterectomy and in normal internal mammary arteries of 13 patients undergoing coronary artery bypass surgery. Selenium-dependent glutathione peroxidase activity was undetectable in the plaques of 7 patients; the other 6 patients with plaques showed a mean enzymatic activity ≈3.5-fold lower than that of mammary arteries. Glutathione reductase activity was also markedly lower in the plaques than in the arteries. Glutathione transferase instead had comparable activity in the two tissues. Remarkably, 5 of the 7 patients with an undetectable selenium-dependent glutathione peroxidase activity but none of the 6 with a detectable one were characterized by multivascular atherosclerotic involvement (3 patients) or stenosis of the contralateral carotid artery (2 patients).

Conclusions
—A weak glutathione-related enzymatic antioxidant shield is present in human atherosclerotic lesions. Although the cause of this phenomenon remains to be determined, the present data suggest that a specific antioxidant/prooxidant imbalance operative in the vascular wall may be involved in atherogenic processes in humans.
Noninvasive In Vivo Clot Dissolution Without a Thrombolytic Drug
Authors: Birnbaum Yochai , Luo Huai , Nagai Tomoo , Fishbein Michael C. , Peterson Thomas M. , Li Shouping , Kricsfeld David , Porter Thomas R. , Siegel Robert J.
Published: June 2012

Background
—Previous in vivo studies have shown that microbubbles not only enhance the effectiveness of thrombolytic agents in the presence of ultrasound but may also augment clot dissolution without thrombolytic drugs.

Methods and Results
—The objective of this study was to examine the efficacy of arterial clot disruption by a noninvasive, nonlytic approach with intravenous administration of perfluorocarbon-exposed sonicated dextrose albumin (PESDA) and transcutaneous delivery of ultrasound alone. Pairs of iliofemoral arteries in 10 rabbits were randomized to receive transcutaneous ultrasound treatment or no ultrasound treatment after an acute artery thrombotic occlusion and intravenous PESDA infusion. Five arteries from 3 additional rabbits served as controls (ultrasound alone). All 10 iliofemoral arteries treated with PESDA+ultrasound were recanalized by angiography after ultrasound treatment. None of the 10 contralateral arteries treated with PESDA alone and none of the 5 arteries treated with ultrasound alone were patent after 1 hour.
d
-Dimer levels did not change after intravenous PESDA+ultrasound–mediated reperfusion.

Conclusions
—In vivo arterial clot dissolution can be achieved with intravenous microbubbles and transcutaneous ultrasound delivery alone. This technique has potential for clinical application in patients with acute arterial and venous thrombotic occlusions.
Prospective Study of Hyperhomocysteinemia as an Adverse Cardiovascular Risk Factor in End-Stage Renal Disease
Authors: Moustapha Ali , Naso Arabi , Nahlawi Maher , Gupta Anjan , Arheart Kristopher L. , Jacobsen Donald W. , Robinson Killian , Dennis Vincent W.
Published: June 2012

Background
—Retrospective and case-control studies show that hyperhomocysteinemia is an independent risk factor for atherosclerosis in patients with end-stage renal disease. We studied prospectively the association between total homocysteine and cardiovascular outcomes.

Methods and Results
—In all, 167 patients (93 men, 74 women; mean age, 56.3±14.7 years) were followed for a mean duration of 17.4±6.4 months. Cardiovascular events and causes of mortality were related to total homocysteine values and other cardiovascular risk factors. Cox regression analysis was used to identify the independent predictors for cardiovascular events and mortality. Fifty-five patients (33%) developed cardiovascular events and 31 (19%) died, 12 (8%) of cardiovascular causes. Total plasma homocysteine values ranged between 7.9 and 315.0 μmol/L. Levels were higher in patients who had cardiovascular events or died of cardiovascular causes (43.0±48.6 versus 26.9±14.9 μmol/L,
P
=.02). The relative risk (RR) for cardiovascular events, including death, increased 1% per μmol/L increase in total homocysteine concentration (RR, 1.01; CI, 1.00 to 1.01;
P
=.01).

Conclusions
—These prospective observations confirm that hyperhomocysteinemia is an independent risk factor for cardiovascular morbidity and mortality in end-stage renal disease, with an increased RR of 1% per μmol/L increase in total homocysteine concentration. Interventional studies are needed to evaluate the possible effects of modifying this risk factor in these patients.
Mutation of the Gene for
I
sK Associated With Both Jervell and Lange-Nielsen and Romano-Ward Forms of Long-QT Syndrome
Authors: Duggal Priya , Vesely Mark R. , Wattanasirichaigoon Duangrurdee , Villafane Juan , Kaushik Vineet , Beggs Alan H.
Published: June 2012

Background
—Long-QT syndrome (LQTS) is a disorder of ventricular repolarization characterized by a prolonged QT interval, syncope, seizures, and sudden death. Recently, three forms of LQTS have been shown to result from mutations in potassium or sodium ion channel genes:
KVLQT1
for LQT1,
HERG
for LQT2, and
SCN5A
for LQT3.
I
sK, an apparent potassium channel subunit encoded by
KCNE1
on chromosome 21, regulates both KVLQT1 and HERG. This relationship makes
KCNE1
a likely candidate gene, because mutations of these genes are known to cause both the autosomal dominant Romano-Ward and recessive Jervell and Lange-Nielsen (JLN) forms of LQTS.

Methods and Results
—We screened 84 unrelated patients with Romano-Ward and 4 with JLN for possible mutations in
KCNE1
. We identified one homozygous mutation in a JLN patient that results in the nonconservative substitution of Asn for Asp at amino acid 76. The patient is congenitally deaf-mute, with recurrent syncopal events and a greatly prolonged QT
c
interval. The proband’s mother and half-sister are both heterozygous for this mutation. Remarkably, both these family members have prolonged QT
c
intervals and would have been classified as Romano-Ward patients if not for the proband’s diagnosis of JLN. This mutation was not identified in more than 100 control individuals.

Conclusions
—These data provide strong evidence that
KCNE1
mutations represent a fifth LQTS locus (LQT5). Further functional analysis, as well as the identification of more LQTS patients with
KCNE1
mutations, will be important to confirm the role of
I
sK in LQTS.
Block of the Rapid Component of the Delayed Rectifier Potassium Current by the Prokinetic Agent Cisapride Underlies Drug-Related Lengthening of the QT Interval
Authors: Drolet Benoit , Khalifa Majed , Daleau Pascal , Hamelin Bettina A. , Turgeon Jacques
Published: June 2012

Background
—Lengthening of the QT interval and torsades de pointes resulting in cardiac arrests and deaths have been noticed during treatment with cisapride, a newly developed gastrointestinal prokinetic agent. The rapid (
I
Kr
) and slow (
I
Ks
) components of the delayed rectifier current (
I
K
) are candidate ionic currents to explain cisapride-related toxicity because of their role in repolarization of cardiac ventricular myocytes. Our objectives were to (1) characterize effects of cisapride on two major time-dependent outward potassium currents involved in the repolarization of cardiac ventricular myocytes,
I
Kr
and
I
Ks
, and (2) determine action potential–prolonging effects of cisapride on isolated hearts.

Methods and Results
—A first set of experiments was performed in isolated guinea pig ventricular myocytes with the whole-cell configuration of the patch-clamp technique. Cells were held at −40 mV while time-dependent outward currents were elicited by depolarizing pulses lasting either 250 ms (
I
K250
) or 5000 ms (
I
K5000
). Effects of cisapride on the
I
Kr
component were assessed by measurement of time-dependent activating currents elicited by short pulses (250 ms;
I
K250
) to low depolarizing potentials (−20, −10, and 0 mV). Time-dependent activating currents elicited by long pulses (5000 ms;
I
K5000
) to positive potentials (>+30 mV) were recorded to assess effects of the drug on the
I
Ks
component. A second set of experiments was conducted in isolated guinea pig hearts buffer-perfused in the Langendorff mode to assess effects of the drug on monophasic action potential duration measured at 90% repolarization (MAPD
90
). Hearts were exposed to cisapride 100 nmol/L at decremental pacing cycle lengths of 250, 225, 200, 175, and 150 ms to determine reverse frequency-dependent effects of the drug. Overall, 112 myocytes were exposed to seven concentrations of cisapride (10 nmol/L to 10 μmol/L). Cisapride inhibited
I
Kr
, the major time-dependent outward current elicited by short pulses (
I
K250
) to low depolarizing potentials, in a concentration-dependent manner with an IC
50
of 15 nmol/L (therapeutic levels, 50 to 200 nmol/L). Conversely, block of
I
Ks
by the drug was less potent (estimated IC
50
>10 μmol/L). In isolated hearts (n=9 experiments), cisapride 100 nmol/L increased MAPD
90
by 23±3 (
P
<.05) at a basic cycle length of 250 ms but by only 7±1 ms (
P
<.05) at a basic cycle length of 150 ms.

Conclusions
—Block of
I
Kr
gives an explanation to lengthening of cardiac repolarization observed in isolated guinea pig hearts. Potent block of
I
Kr
is also likely to underlie prolongation of the QT interval observed in patients receiving clinically recommended doses of cisapride as well as severe cardiac toxicity (torsades de pointes) observed in patients with increased plasma concentrations of the drug.
C-Reactive Protein Adds to the Predictive Value of Total and HDL Cholesterol in Determining Risk of First Myocardial Infarction
Authors: Ridker Paul M. , Glynn Robert J. , Hennekens Charles H.
Published: June 2012

Background
—C-reactive protein (CRP) is a sensitive marker of inflammation, and elevated levels have been associated with future risk of myocardial infarction (MI). However, whether measurement of CRP adds to the predictive value of total cholesterol (TC) and HDL cholesterol (HDL-C) in determining risk is uncertain.

Methods and Results
—Among 14 916 apparently healthy men participating in the Physicians’ Health Study, baseline levels of CRP, TC, and HDL-C were measured among 245 study subjects who subsequently developed a first MI (cases) and among 372 subjects who remained free of cardiovascular disease during an average follow-up period of 9 years (controls). In univariate analyses, high baseline levels of CRP, TC, and TC:HDL-C ratio were each associated with significantly increased risks of future MI (all
P
values <0.001). In multivariate analyses, models incorporating CRP and lipid parameters provided a significantly better method to predict risk than did models using lipids alone (all likelihood ratio test
P
values <0.003). For example, relative risks of future MI among those with high levels of both CRP and TC (RR=5.0,
P
=0.0001) were greater than the product of the individual risks associated with isolated elevations of either CRP (RR=1.5) or TC (RR=2.3). In stratified analyses, baseline CRP level was predictive of risk for those with low as well as high levels of TC and the TC:HDL-C ratio. These findings were virtually identical in analyses limited to nonsmokers and after control for other cardiovascular risk factors.

Conclusions
—In prospective data from a large cohort of apparently healthy men, baseline CRP level added to the predictive value of lipid parameters in determining risk of first MI.
The Cost-effectiveness of Automatic Implantable Cardiac Defibrillators:
Authors: Mushlin Alvin I. , Hall W. Jackson , Zwanziger Jack , Gajary Elizabeth , Andrews Mark , Marron Rebecca , Zou Kelly H. , Moss Arthur J.
Published: June 2012

Background
—The recently reported Multicenter Automatic Defibrillator Implantation Trial (MADIT) showed improved survival in selected asymptomatic patients with coronary disease and nonsustained ventricular tachycardia. The economic consequences of defibrillator management in this patient population are unknown.

Methods and Results
—Patients were followed up to quantify their use of healthcare services, including hospitalizations, physician visits, medications, laboratory tests, and procedures, during the trial. The costs of these services, including the costs of the defibrillator, were determined in patients randomized to defibrillator and nondefibrillator therapy. Incremental cost-effectiveness ratios were calculated by relating these costs to the increased survival associated with the use of the defibrillator. The average survival for the defibrillator group over a 4-year period was 3.66 years compared with 2.80 years for conventionally treated patients. Accumulated net costs were $97 560 for the defibrillator group compared with $75 980 for individuals treated with medications alone. The resulting incremental cost-effectiveness ratio of $27 000 per life-year saved compares favorably with other cardiac interventions. Sensitivity analyses showed that the incremental cost-effectiveness ratio would be reduced to ≈$23 000 per life-year saved if transvenous defibrillators were used instead of the older devices, which required thoracic surgery for implantation.

Conclusions
—An implanted cardiac defibrillator is cost-effective in selected individuals at high risk for ventricular arrhythmias.
Induction of Plasminogen Activator Inhibitor Type 1 and Type 1 Collagen Expression in Rat Cardiac Microvascular Endothelial Cells by Interleukin-1 and Its Dependence on Oxygen-Centered Free Radicals
Authors: Okada Hitoshi , Woodcock-Mitchell Janet , Mitchell John , Sakamoto Tomohiro , Marutsuka Kousuke , Sobel Burton E. , Fujii Satoshi
Published: June 2012

Background
—Ischemia with or without reperfusion induces the release of diverse products from monocytes, including cytokines such as interleukin-1 (IL-1). To determine whether these phenomena modulate fibrinolysis and potentially exacerbate impairment of the macrocirculation, microcirculation, or both, we characterized the effects of IL-1 on the expression of fibrinolytic system and matrix proteins in rat cardiac microvascular endothelial cells (CMECs).

Methods and Results
—Confluent CMECs were exposed to IL-1 in serum-free medium for 24 hours, and cell-conditioned medium was assayed for plasminogen activator inhibitor type 1 (PAI-1), the primary physiological inhibitor of plasminogen activators, and for type 1 collagen with Western blotting. IL-1 (2 ng/mL) specifically increased the accumulation of PAI-1 (4.4±0.6-fold; mean±SD; n=9) without affecting tissue plasminogen activator (t-PA) or urokinase plasminogen activator (u-PA) levels, which remained unchanged. IL-1 increased the accumulation of collagen in conditioned media by 3.5±0.7-fold (n=6). Conversely, the accumulation of both PAI-1 and collagen induced by IL-1 was inhibited with an IL-1 receptor antagonist (200 ng/mL; n=6) and with cycloheximide (10 μg/mL; n=6), implying that protein synthesis was a requirement for the effect. To determine whether the IL-1 effect was mediated by induction of oxygen-centered free radical production, known to be induced by IL-1, we exposed the cells to the hydroxyl radical scavenger tetramethylthiourea (10 mmol/L) and observed abolition of the IL-1–induced increase in the expression of PAI-1 and collagen (n=6). Conversely, superoxides (generated with 10 mU/mL xanthine oxidase plus 0.6 mmol/L hypoxanthine, and 100 μmol/L hydrogen peroxide) induced the accumulation of PAI-1 and collagen (n=6). IL-1 (1 μg/kg body wt) and lipopolysaccharide (50 μg/kg body wt) administered in vivo increased PAI-1 protein in rat hearts as detected with Western blotting and PAI-1 immunostaining of rat heart microvessels, indicating the effects delineated in vitro were paralleled by effects in vivo.

Conclusions
—These results indicate that IL-1–induced oxygen-centered free radicals stimulate elaboration of PAI-1 and collagen by CMECs. Accordingly, microvascularly mediated inhibition of fibrinolysis may predispose to the persistence of microvascular thrombi, thereby contributing to impaired microcirculatory function, the no-reflow phenomenon, and cardiac dysfunction after ischemia and reperfusion.
Intracoronary Infusion of Reduced Glutathione Improves Endothelial Vasomotor Response to Acetylcholine in Human Coronary Circulation
Authors: Kugiyama Kiyotaka , Ohgushi Masamichi , Motoyama Takeshi , Hirashima Osamu , Soejima Hirofumi , Misumi Kenji , Yoshimura Michihiro , Ogawa Hisao , Sugiyama Seigo , Yasue Hirofumi
Published: June 2012

Background
—Oxygen free radicals have been shown to cause endothelial vasomotor dysfunction. This study examined the effect of reduced glutathione (GSH), an antioxidant, on human coronary circulation.

Methods and Results
—Responses of epicardial diameter and blood flow of the left anterior descending coronary artery to intracoronary infusion of acetylcholine (ACh, 50 μg/min) were measured by quantitative coronary angiography and Doppler flow-wire technique, respectively, before and during combined intracoronary infusion of GSH (50 mg/min) or saline in 26 subjects with no significant coronary stenosis. GSH infusion suppressed the constrictor response of epicardial diameter to ACh and enhanced the increase in blood flow response to ACh. Furthermore, GSH potentiated the coronary dilator effect of nitroglycerin. A beneficial effect of GSH on the epicardial diameter response to ACh was observed in a subgroup of subjects with ≥1 coronary risk factors but not in a subgroup without risk factors. Saline infusion did not have any effects.

Conclusions
—The results indicate that GSH improved coronary endothelial vasomotor function, particularly in subjects with coronary risk factors, and it potentiated the vasodilator effect of nitroglycerin in human coronary arteries.
Myocyte Recovery After Mechanical Circulatory Support in Humans With End-Stage Heart Failure
Authors: Dipla Konstantina , Mattiello Julian A. , Jeevanandam Valluvan , Houser Steven R. , Margulies Kenneth B.
Published: June 2012

Background
—The failing myocardium is characterized by decreased force production, slowed relaxation, and depressed responses to β-adrenergic stimulation. In some heart failure patients, heart function is so poor that a left ventricular assist device (LVAD) is inserted as a bridge to transplantation. In the present research, we investigated whether circulatory support with an LVAD influenced the functional properties of myocytes from the failing heart.

Methods and Results
—Myocytes were isolated from human explanted failing hearts (HF-myocytes) and failing hearts with antecedent LVAD support (HF-LVAD-myocytes). Studies of myocyte function indicated that the magnitude of contraction was greater (9.6±0.7% versus 6.9±0.5% shortening), the time to peak contraction was significantly abbreviated (0.37±0.01 versus 0.75±0.04 seconds), and the time to 50% relaxation was reduced (0.55±0.02 versus 1.45±0.11 seconds) in the HF-LVAD-myocytes compared with the HF-myocytes (
P
<0.05). The HF-LVAD-myocytes had larger contractions than the HF-myocytes at all frequencies of stimulation tested. The negative force-frequency relationship of the HF-myocytes was improved in HF-LVAD-myocytes but was not reversed. Responses to β-adrenergic stimulation (by isoproterenol) were greater in HF-LVAD-myocytes versus HF-myocytes.

Conclusions
—The results of the study strongly support the idea that circulatory support with an LVAD improves myocyte contractile properties and increases β-adrenergic responsiveness.
Interlesion Dependence of the Risk for Restenosis in Patients With Coronary Stent Placement in Multiple Lesions
Authors: Kastrati Adnan , Schömig Albert , Elezi Shpend , Schühlen Helmut , Wilhelm Manfred , Dirschinger Josef
Published: June 2012

Background
—Little is known about the behavior with regard to restenosis of multiple lesions within the same patient treated with intracoronary stenting. Our objective was to test the hypothesis that there is an intrapatient dependence of restenosis between lesions.

Methods and Results
—Quantitative analysis was carried out on angiograms obtained before, immediately after, and at 6 months after coronary stent placement in 1734 lesions in 1244 patients. We used a specialized logistic regression that not only accounts for intraclass correlation but also quantifies it in the form of odds ratio (OR) as the change in risk of a lesion to develop restenosis if another companion lesion had restenosis. The model was based on 23 patient- and lesion-related variables with binary restenosis (diameter stenosis ≥50%) as end point. The overall restenosis rate was 27.5%: 24.4% for single-lesion, 28.6% for double-lesion, and 33.8% for ≥3-lesion interventions. After adjustment for the influence of significant factors (hypercholesterolemia, systemic arterial hypertension, diabetes mellitus, previous PTCA, ostial lesion, location in left anterior descending coronary artery, number of stents placed, vessel size, stenosis severity, balloon-to-vessel ratio, and final result), the analysis found a significant intrapatient correlation, OR 2.5 (1.8 to 3.6). This means that in patients with multilesion interventions, the risk of a lesion to develop restenosis is 2.5 times higher if a companion lesion has restenosis, independently of the presence or absence of analyzed patient risk factors (eg, diabetes).

Conclusions
—This study demonstrates that there is a dependence of restenosis between coronary lesions in patients who undergo a multilesion intervention. The likelihood of restenosis for a lesion is higher when another companion lesion has also developed restenosis. Other, as yet unidentified patient factors may be the source of this intrapatient correlation of restenosis.
Differential Leukotriene Constrictor Responses in Human Atherosclerotic Coronary Arteries
Authors: Allen Sean , Dashwood Michael , Morrison Karen , Yacoub Magdi
Published: June 2012

Background
—Leukotrienes are a class of biologically active lipids that have potent effects on the heart. To assess their role in coronary artery disease, we compared the contractile responses of leukotriene C
4
(LTC
4
) and leukotriene D
4
(LTD
4
) and their binding activity in both atherosclerotic and nonatherosclerotic human coronary arteries. We also studied expression of the enzymes that control their formation to understand how the 5-lipoxygenase (5-LO) pathway is activated in the coronary arteries.

Methods and Results
—The capacity of leukotrienes to affect coronary vessel tone and the influence of atherosclerosis was tested in organ baths. Leukotriene receptors were examined by autoradiography, and antibody binding to the various enzymes responsible for their formation was assessed by use of immunocytochemistry. Nonatherosclerotic coronary artery ring segments were unresponsive to LTC
4
and LTD
4
. In contrast, LTC
4
and LTD
4
induced concentration-dependent contractions in atherosclerotic coronary arteries. Specific [
3
H]-LTC
4
but not LTD
4
binding to atherosclerotic coronary artery was evident, with no evidence of specific binding of [
3
H]-leukotrienes to nonatherosclerotic coronary artery. High-resolution autoradiography identified specific [
3
H]-LTC
4
binding sites to smooth muscle cell and to regions of intimal proliferation and plaque. Cells showing positive antibody binding to 5-LO, FLAP (5-lipoxygenase activating protein), and leukotriene A
4
hydrolase were also present in the coronary arteries and had a similar distribution to macrophages.

Conclusions
—Atherosclerosis is associated with a specific leukotriene receptor(s) capable of inducing hyperreactivity of human epicardial coronary arteries in response to LTC
4
and LTD
4
.
Lipid Lowering by Diet Reduces Matrix Metalloproteinase Activity and Increases Collagen Content of Rabbit Atheroma
Authors: Aikawa Masanori , Rabkin Elena , Okada Yoshikatsu , Voglic Sami J. , Clinton Steven K. , Brinckerhoff Constance E. , Sukhova Galina K. , Libby Peter
Published: June 2012

Background
—Proteolytic enzyme activity in lipid-rich atheroma may promote plaque rupture and precipitate acute coronary syndromes. This study tested the hypothesis that lipid lowering stabilizes plaques by reducing proteolytic activity.

Methods and Results
—We produced experimental atheroma in 33 rabbits by balloon injury and an atherogenic diet (0.3% cholesterol and 4.7% coconut oil) for 4 months. At that time, 15 rabbits were killed (baseline group). The remaining animals were divided into two groups: a hyperlipemic group continued to consume a cholesterol-enriched diet (0.05% to 0.2%) for 16 more months (n=5) and a lipid-lowering group consumed a purified chow diet with no added cholesterol or fat for 8 (n=3) or 16 months (n=10). Macrophage accumulation and interstitial collagenase (matrix metalloproteinase-1, MMP-1) expression in the lesion were measured by quantitative image analysis of standardized sections of immunostained aortas. Baseline lesions expressed high levels of MMP-1 and contained many macrophages. These features of plaque instability persisted in the hyperlipemic group. However, the lipid-lowering group showed progressive reduction in both macrophage content and MMP-1 immunoreactivity with time. Aortic rings of the baseline and hyperlipemic groups elaborated gelatinolytic, caseinolytic, and elastinolytic activity attributable to MMP-2, MMP-3, or MMP-9, monitored by SDS-PAGE zymography. Proteolytic activity decreased markedly in the lipid-lowering group. Aortic content of interstitial collagen, determined by sirius red staining, increased in the lipid-lowering group compared with the baseline or continued hyperlipemic groups, indicating that lipid lowering reinforced the fibrous skeleton of the atheroma.

Conclusions
—These results establish a mechanism by which lipid lowering may stabilize vulnerable plaques by reduced expression and activity of enzymes that degrade the arterial extracellular matrix and render atheroma less susceptible to disruption and thrombosis by favoring collagen accumulation in the fibrous cap.
Mitochondrial ATP-Dependent Potassium Channels
Authors: Liu Yongge , Sato Toshiaki , O’Rourke Brian , Marban Eduardo
Published: June 2012

Background
—Brief interruptions of coronary blood flow paradoxically protect the heart from subsequent prolonged ischemia. The basis of such endogenous cardioprotection, known as “ischemic preconditioning,” remains uncertain. Pharmacological evidence has implicated ATP-dependent potassium (K
ATP
) channels in the mechanism of preconditioning; however, the effects of sarcolemmal K
ATP
channels on excitability cannot account for the protection.

Methods and Results
—We simultaneously measured flavoprotein fluorescence, an index of mitochondrial redox state, and sarcolemmal K
ATP
currents in intact rabbit ventricular myocytes. Our results show that diazoxide, a K
ATP
channel opener, selectively activates mitochondrial K
ATP
channels. Diazoxide induced reversible oxidation of flavoproteins with an EC
50
of 27 μmol/L but did not activate sarcolemmal K
ATP
channels. The subcellular site of diazoxide action is further localized to mitochondria by confocal imaging of fluorescence arising from flavoproteins and tetramethylrhodamine ethyl ester. In a cellular model of simulated ischemia, inclusion of diazoxide decreased the rate of cell death to about half of that in controls. Both the redox changes and protection are inhibited by the K
ATP
channel blocker 5-hydroxydecanoic acid.

Conclusions
—Our results demonstrate that diazoxide targets mitochondrial but not sarcolemmal K
ATP
channels and imply that mitochondrial K
ATP
channels may mediate the protection from K
ATP
channel openers.
Effects of Tumor Necrosis Factor Gene Polymorphisms on Patients With Congestive Heart Failure
Authors: Kubota Toru , McNamara Dennis M. , Wang Jue J. , Trost Mary , McTiernan Charles F. , Mann Douglas L. , Feldman Arthur M.
Published: June 2012

Background
—Tumor necrosis factor-α (TNF-α) is known to be elevated in patients with congestive heart failure (CHF). Two biallelic polymorphisms have been identified in the TNF gene locus: one in the promoter region of TNF-α (TNFA1/2), and the other in the first intron of TNF-β (TNFB1/2). Both TNFA2 and TNFB2 alleles are associated with high TNF-α production in vitro and susceptibility to inflammatory diseases. Given the importance of TNF-α in the pathogenesis of CHF, we studied the prevalence of TNF gene polymorphisms in CHF patients and the correlation of genotypes to in vivo TNF-α levels.

Methods and Results
—TNFA and TNFB genotypes were determined by the polymerase chain reaction–restriction fragment length polymorphism technique. There were no differences in the TNF allele frequencies between CHF (n=229; TNFA1/2=0.84/0.16, TNFB1/2=0.33/0.67) and control subjects (n=139; TNFA1/2=0.84/0.16, TNFB1/2=0.32/0.68). In 211 patients with CHF, circulating levels of TNF-α and the soluble receptors type I and type II were measured by ELISA: 6.18±3.59 pg/mL, 1768±761 pg/mL, and 4484±1750 pg/mL, respectively. There were no correlations between TNFA or TNFB genotypes and circulating levels of TNF-α or its soluble receptors in the CHF patients.

Conclusions
—Despite their association with other inflammatory diseases, neither TNFA nor TNFB polymorphisms are related to the presence of CHF or the elevation of circulating TNF-α. Thus, other factors may be more important in determining the circulating levels of TNF-α in CHF.
Differential Effects of Interleukin-1 Receptor Antagonist and Tumor Necrosis Factor Binding Protein on Fatty-Streak Formation in Apolipoprotein E–Deficient Mice
Authors: Elhage R. , Maret A. , Pieraggi M.-T. , Thiers J. C. , Arnal J. F. , Bayard F.
Published: June 2012

Background
—The cytokines interleukin 1 (IL-1) and tumor necrosis factor (TNF) are secreted by the different cell populations of the vascular wall and have been suggested to promote atherosclerosis.

Methods and Results
—Their respective roles in fatty-streak formation in apolipoprotein E–deficient mice were investigated by use of IL-1 receptor antagonist and TNF binding protein. Estradiol-17β was used as a positive control. Blocking TNF seemed to be active in female animals but not in males. IL-1 receptor antagonist was as effective as or more effective than estradiol in both sexes.

Conclusions
—IL-1 plays a crucial role in the initial step of the atherosclerotic process in this animal model, and blocking the activity of this cytokine should be considered as a therapeutic possibility.
Hydrogen Peroxide Induces Intracellular Calcium Oscillations in Human Aortic Endothelial Cells
Authors: Hu Qinghua , Corda Stefano , Zweier Jay L. , Capogrossi Maurizio C. , Ziegelstein Roy C.
Published: June 2012

Background
—Because the vascular endothelium is exposed to oxidant stress resulting from ischemia/reperfusion and from the products of polymorphonuclear leukocytes or monocytes, studies were performed to examine the effect of hydrogen peroxide (1 μmol/L to 10 mmol/L) on endothelial Ca
2+
signaling.

Methods and Results
—At low concentrations (1 to 10 μmol/L), hydrogen peroxide did not affect intracellular Ca
2+
concentration in subconfluent, indo 1–loaded human aortic endothelial monolayers. At a concentration of 100 μmol/L hydrogen peroxide, intracellular free Ca
2+
gradually increased from 125.3±6.8 to 286.3±19.9 nmol/L over 4.2±0.9 minutes before repetitive Ca
2+
oscillations were observed, consisting of an initial large, transient spike of ≈1 μmol/L followed by several spikes of decreasing amplitudes at a frequency of 0.7±0.1 min
−1
over 12.0±1.1 minutes. After these oscillations, intracellular Ca
2+
reached a plateau of 543.4±64.0 nmol/L, which was maintained above baseline levels for >5 minutes and then partially reversible on washout of hydrogen peroxide in most monolayers. Intracellular Ca
2+
oscillations were typically observed when monolayers were exposed to 100 to 500 μmol/L hydrogen peroxide. Higher concentrations of hydrogen peroxide (1 and 10 mmol/L) increased intracellular Ca
2+
but only rarely (2 of 6 monolayers at 1 mmol/L) or never (at 10 mmol/L) stimulated intracellular Ca
2+
oscillations. Removal of Ca
2+
from the buffer either before hydrogen peroxide stimulation or during an established response did not block intracellular Ca
2+
oscillations in response to 100 μmol/L hydrogen peroxide, but prior depletion of an intracellular Ca
2+
store with either caffeine, histamine, or thapsigargin abolished Ca
2+
oscillations.

Conclusions
—Hydrogen peroxide induces concentration-dependent intracellular Ca
2+
oscillations in human endothelial cells, which results from release of an endoplasmic reticulum Ca
2+
store. Because oxidant production appears to occur in the micromolar range in the postischemic/anoxic endothelium and is associated with impaired endothelium-dependent relaxation, the effects of micromolar concentrations of hydrogen peroxide on endothelial Ca
2+
signaling described in the present study may be important in the pathogenesis of postischemic endothelial dysfunction.
‘Optimal’ Directional Coronary Atherectomy
Authors: Simonton Charles A. , Leon Martin B. , Baim Donald S. , Hinohara Tomoaki , Kent Kenneth M. , Bersin Robert M. , Wilson B. Hadley , Mintz Gary S. , Fitzgerald Peter J. , Yock Paul G. , Popma Jeffrey J. , Ho Kalon K. L. , Cutlip Donald E. , Senerchia Cynthia , Kuntz Richard E.
Published: June 2012

Background
—Previous clinical trials of directional coronary atherectomy (DCA) have failed to show significant improvement in early or late outcomes compared with balloon angioplasty (PTCA). The present study tested the hypothesis that more aggressive “optimal” atherectomy could be performed safely to produce larger initial lumen diameters and a lower late restenosis rate.

Methods and Results
—The present study was a prospective multicenter registry of consecutive patients undergoing optimal DCA of de novo or restenotic lesions in 3.0- to 4.5-mm native coronary arteries. Optimal DCA was defined as using a 7F atherectomy device and adjunctive PTCA if necessary to achieve a <15% residual stenosis. Six-month angiographic and 1-year clinical follow-up was planned in all patients. A total of 199 patients with 213 lesions met eligibility criteria for enrollment. Short-term procedural success was achieved in 97.5%, with a major complication rate (death, emergency bypass surgery, or Q-wave myocardial infarction [MI]) of 2.5%. There were no early deaths. Non–Q-wave MI (CK-MB >3 times normal) occurred in 14% of patients. Mean reference vessel diameter was 3.28 mm. Mean diameter stenosis was reduced from 63.5% to a final stenosis of 7%. Late 1-year clinical follow-up revealed one cardiac death and a target lesion revascularization rate of 17.8%. The angiographic restenosis rate at 6 months was 28.9%, with the major predictor of restenosis being a smaller postprocedure lumen diameter.

Conclusions
—Optimal DCA produced a low residual percent diameter stenosis and a lower restenosis rate than seen in previous trials without an increase in early or late major adverse events.
Erythrocyte Promotion of Platelet Reactivity Decreases the Effectiveness of Aspirin as an Antithrombotic Therapeutic Modality
Authors: Valles Juana , Santos M. Teresa , Aznar Justo , Osa Ana , Lago Aida , Cosin Juan , Sanchez Elena , Broekman M. Johan , Marcus Aaron J.
Published: June 2012

Background
—Aspirin (acetylsalicylic acid, ASA) is widely used for secondary prevention of ischemic vascular events, although its protection only occurs in 25% of patients. We previously demonstrated that platelet reactivity is enhanced by a prothrombotic effect of erythrocytes in a thromboxane-independent manner. This diminishes the antithrombotic therapeutic potential of ASA. Recent data from our laboratory indicate that the prothrombotic effect of erythrocytes also contains an ASA-sensitive component. In accordance with this observation, intermittent treatment with high-dose ASA reduced the prothrombotic effects of erythrocytes ex vivo in healthy volunteers. In the present study, the effects of platelet-erythrocyte interactions were evaluated ex vivo in 82 patients with vascular disease: 62 patients with ischemic heart disease treated with 200 mg ASA/d and 20 patients with ischemic stroke treated with 300 mg ASA/d.

Methods and Results
—Platelet activation (release reaction) and platelet recruitment (fluid-phase proaggregatory activity of cell-free releasates from activated platelets) were assessed after collagen stimulation (1 μg/mL) of platelets, platelet-erythrocyte mixtures, or whole blood. Platelet thromboxane A
2
synthesis was inhibited by >94% by ASA administration in all patients. Importantly, platelet recruitment followed one of three distinct patterns. In group A (n=32; 39%), platelet recruitment was blocked by ASA both in the presence and absence of erythrocytes. In group B (n=37; 45%), recruitment was abolished when platelets were evaluated alone but continued in the presence of erythrocytes, indicating a suboptimal effect of ASA on erythrocytes of this patient group. In group C (n=13; 16%), detectable recruitment in stimulated platelets alone persisted and was markedly enhanced by the presence of erythrocytes.

Conclusions
—In two thirds of a group of patients with vascular disease, 200 to 300 mg ASA was insufficient to block platelet reactivity in the presence of erythrocytes despite abolishing thromboxane A
2
synthesis. Platelet activation in the presence of erythrocytes can induce the release reaction and generate biologically active products that recruit additional platelets into a developing thrombus. Insufficient blockade of this proaggregatory property of erythrocytes can lead to development of additional ischemic complications.
Plasma Concentration of C-Reactive Protein and Risk of Developing Peripheral Vascular Disease
Authors: Ridker Paul M. , Cushman Mary , Stampfer Meir J. , Tracy Russell P. , Hennekens Charles H.
Published: June 2012

Background
—Among apparently healthy men, elevated levels of C-reactive protein (CRP), a marker for systemic inflammation, predict risk of myocardial infarction and thromboembolic stroke. Whether increased levels of CRP are also associated with the development of symptomatic peripheral arterial disease (PAD) is unknown.

Methods and Results
—Using a prospective, nested, case-control design, we measured baseline levels of CRP in 144 apparently healthy men participating in the Physicians’ Health Study who subsequently developed symptomatic PAD (intermittent claudication or need for revascularization) and in an equal number of control subjects matched on the basis of age and smoking habit who remained free of vascular disease during a follow-up period of 60 months. Median CRP levels at baseline were significantly higher among those who subsequently developed PAD (1.34 versus 0.99 mg/L;
P
=.04). Furthermore, the risks of developing PAD increased significantly with each increasing quartile of baseline CRP concentration such that relative risks of PAD from lowest (referent) to highest quartile of CRP were 1.0, 1.3, 2.0, and 2.1 (
P
trend
=.02). Compared with those with no clinical evidence of disease, the subgroup of case patients who required revascularization had the highest baseline CRP levels (median=1.75 mg/L;
P
=.04); relative risks from lowest to highest quartile of CRP for this end point were 1.0, 1.8, 3.8, and 4.1 (
P
trend
=.02). Risk estimates were similar after additional control for body mass index, hypercholesterolemia, hypertension, diabetes, and a family history of premature atherosclerosis.

Conclusions
—These prospective data indicate that among apparently healthy men, baseline levels of CRP predict future risk of developing symptomatic PAD and thus provide further support for the hypothesis that chronic inflammation is important in the pathogenesis of atherothrombosis.