bluuebunny/crossref_metadata_2025 huggingface dataset:
Remodeling of Carotid Artery Is Associated With Increased Expression of Matrix Metalloproteinases in Mouse Blood Flow Cessation Model
Authors: Godin Denis , Ivan Eugen , Johnson Chad , Magid Richard , Galis Zorina S.
Published: June 2012

Background
—The matrix-degrading activity of matrix metalloproteinases (MMPs), required for cell migration and general tissue reshaping, is thought essential for pathological arterial remodeling in atherosclerosis and restenosis.

Methods and Results
—We triggered remodeling of the carotid artery in C57BL/6 mice by blood flow cessation to study the relationship with gelatinases MMP-9 and MMP-2. Ligated and contralateral carotid arteries from ligated and sham-operated mice were harvested fresh, for biochemical analyses, or were perfusion-fixed, for histological studies, at 0, 1, 3, 7, 14, and 28 days after ligation. An early statistically significant (
P
<0.01) 4- to 5-fold increase in MMP-9 expression detected by SDS-PAGE zymography and Western blotting in tissue homogenates of ligated carotid arteries 1 day after flow cessation was maintained through day 7, after which expression gradually fell. Maximal MMP-9 levels were higher than MMP-2 levels, which became significantly increased 7 days after ligation. Proliferating cells, identified by bromodeoxyuridine incorporation, were detectable at day 1 in the adventitia and subsequently throughout the wall. Neointima was visible in 3-day specimens of ligated arteries. Suggested by morphology and predicted by theoretical considerations, maximal MMP-9 expression coincided with cell migration into the neointima, supporting its enabling role. Morphological measurements also demonstrated positive lumen remodeling up to 7 days after ligation.

Conclusions
—MMP-9 induction is associated with the formation of intimal hyperplasia and does not require frank mechanical injury. Our data also show that a significant increase in MMP-9 expression preceded the positive geometrical remodeling of arteries, suggesting a potentially beneficial role for this matrix-degrading enzyme.
Enhanced Efficacy of Eptifibatide Administration in Patients With Acute Coronary Syndrome Requiring In-Hospital Coronary Artery Bypass Grafting
Authors: Marso Steven P. , Bhatt Deepak L. , Roe Matthew T. , Houghtaling Penny L. , Labinaz Marino , Kleiman Neal S. , Dyke Cornelius , Simmoons Maarten L. , Califf Robert M. , Harrington Robert A. , Topol Eric J.
Published: June 2012

Background
—Patients with a recent episode of non–ST-segment elevation acute coronary syndrome before CABG have higher rates of operative morbidity and mortality than patients with stable coronary syndromes. The efficacy of administering eptifibatide to these patients undergoing in-hospital CABG is unknown.

Methods and Results
—The Platelet Glycoprotein IIb-IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial randomized 10 948 patients to receive either eptifibatide or placebo. There were 1558 study participants who underwent in-hospital CABG: 692 received placebo, and 866 received eptifibatide. The main substudy analysis end point was death or myocardial infarction (MI) rates at the 6-month follow-up. The 30-day death or MI rates were 30.8% and 26.1% for the placebo and eptifibatide groups, respectively (
P
=0.041). The benefit of eptifibatide administration persisted through 6-months of follow-up (32.7% versus 27.6% for placebo versus eptifibatide, respectively;
P
=0.029). There was a greater reduction in the 6-month death or MI rate for patients who received eptifibatide within 72 hours of CABG (33.6% versus 23.8%;
P
=0.002) compared with the >72-hour group (31.6% versus 32%;
P
=1.0). The incidence of major bleeding was 56.6% for placebo-treated patients versus 58.2% for eptifibatide-treated patients (
P
=0.7).

Conclusions
—Eptifibatide administration in patients undergoing in-hospital CABG with a recent episode of a non–ST-segment elevation acute coronary syndrome results in a significant reduction in death or MI that is evident at 7 days and persists through the 6-month follow-up without a significant increase in perioperative bleeding rates.
Left Ventricular or Biventricular Pacing Improves Cardiac Function at Diminished Energy Cost in Patients With Dilated Cardiomyopathy and Left Bundle-Branch Block
Authors: Nelson Gregory S. , Berger Ronald D. , Fetics Barry J. , Talbot Maurice , Spinelli Julio C. , Hare Joshua M. , Kass David A.
Published: June 2012

Background
—Left ventricular or biventricular pacing/stimulation can acutely improve systolic function in patients with dilated cardiomyopathy (DCM) and intraventricular conduction delay by resynchronizing contraction. Most heart failure therapies directly enhancing systolic function do so while concomitantly increasing myocardial oxygen consumption (MVO
2
). We hypothesized that pacing/stimulation, in contrast, incurs systolic benefits without raising energy demand.

Methods and Results
—Ten DCM patients with left bundle-branch block (ejection fraction 20±3%, QRS duration179±3 ms, mean±SEM) underwent cardiac catheterization to measure ventricular and aortic pressure, coronary blood flow, arterial–coronary sinus oxygen difference (ΔAVO
2
), and MV̇O
2
. Data were measured under sinus rhythm or with left ventricular or biventricular pacing/stimulation at the same heart rate. These results were then contrasted to intravenous dobutamine (n=7) titrated to match systolic changes during LV pacing. Systolic function rose quickly and substantially from LV pacing (18±4% rise in arterial pulse pressure, which correlates with cardiac output, and 43±6% increase in dP/dt
max
; both
P
<0.01). However, ΔAVO
2
and MV̇O
2
declined −4±2% and −8±6.5%, respectively (both
P
<0.05). Similar results were obtained with biventricular activation. In contrast, dobutamine raised dP/dt
max
37±6%, accompanied by a 22±11% rise in per-beat MV̇O
2
(
P
<0.05 versus pacing).

Conclusions
—Ventricular resynchronization by left ventricular or biventricular pacing/stimulation in DCM patients with left bundle-branch block acutely enhances systolic function while modestly lowering energy cost. This should prove valuable for treating DCM patients with basal dyssynchrony.
Sympathetic Activation by Sildenafil
Authors: Phillips Bradley G. , Kato Masahiko , Pesek Catherine A. , Winnicki Mikolaj , Narkiewicz Krzysztof , Davison Diane , Somers Virend K.
Published: June 2012

Background
—Sildenafil citrate is an effective and widely prescribed therapy for erectile dysfunction. Little is known about the effects of sildenafil on neural control of the circulation or about the effects of sildenafil on neurocirculatory stress responses.

Methods and Results
—We studied 14 normal volunteers (age 32±7 years) who were randomized in a double-blind crossover fashion to receive a single oral dose of sildenafil 100 mg or placebo on 2 separate study days. Blood pressure, heart rate, forearm vascular resistance, muscle sympathetic nerve activity, and plasma catecholamines were measured at baseline and at 30 and 60 minutes after sildenafil and after placebo administration. The effects of sildenafil and placebo on neural and circulatory responses to stressful stimuli (sustained handgrip, maximal forearm ischemia, mental stress, and the cold pressor test) were also evaluated. Blood pressure, heart rate, and forearm vascular resistance after sildenafil and placebo were similar. However, muscle sympathetic nerve activity increased strikingly after sildenafil (by 141±26%, mean±SEM) compared with placebo (3±8%) (
P
=0.006); plasma norepinephrine levels also increased by 31±5% after sildenafil administration (
P
=0.004). Sympathetic nerve traffic during mental, physical, and cold stresses was 2- to 8-fold higher after sildenafil than with placebo (
P
<0.05).

Conclusions
—Sildenafil causes a marked increase in sympathetic activation, evident both at rest and during stressful stimuli. Sympathetic activation by sildenafil may have implications for understanding cardiovascular events associated with sildenafil use.
Prostacyclin Analogues Differentially Inhibit Growth of Distal and Proximal Human Pulmonary Artery Smooth Muscle Cells
Authors: Wharton John , Davie Neil , Upton Paul D. , Yacoub Magdi H. , Polak Julia M. , Morrell Nicholas W.
Published: June 2012

Background
—Prostacyclin has proved to be a beneficial treatment for patients with severe pulmonary hypertension. We postulated that the response may reflect, at least in part, inhibition of pulmonary artery smooth muscle cell (PASMC) growth.

Methods and Results
—Human PASMCs were derived from distal (<1-mm external diameter, n=8) and proximal (>8-mm external diameter, n=12) pulmonary arteries obtained at transplant surgery and pneumonectomy. The effects of the stable prostacyclin analogues on [
methyl
-
3
H]thymidine incorporation and cell proliferation were investigated by using immunohistochemically characterized cells. Distal cells proliferated faster than did proximal PASMCs and displayed a distinct sensitivity to cicaprost and iloprost. Both analogues inhibited thymidine uptake over 24 hours (20% to 60%,
P
<0.001; n=8) and abolished stimulation of DNA synthesis by platelet-derived growth factor-BB (10 ng/mL) in distal but not proximal cells. The inhibitory effect of cicaprost was mimicked by isoproterenol (10
−5
mol/L), forskolin (10
−5
mol/L), and dibutyryl cAMP (5×10
−4
mol/L) and was potentiated by the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (5×10
−5
mol/L). Cicaprost (10
−10
to 10
−6
mol/L) inhibited the proliferation of PASMCs, which had been stimulated with either platelet-derived growth factor-BB or serum, and increased cAMP production. These effects were potentiated by 3-isobutyl-1-methylxanthine and attenuated by the adenylyl cyclase inhibitor 2′,5′-dideoxyadenosine (10
−5
to 10
−4
mol/L).

Conclusions
—Cicaprost and iloprost inhibit DNA synthesis and proliferation to a greater extent in distal compared with proximal human PASMCs, acting at least in part via a cAMP-dependent mechanism. The results are consistent with the hypothesis that prostacyclin analogues inhibit vascular remodeling in pulmonary hypertension and demonstrate heterogeneity among human PASMCs.
Sildenafil (Viagra) Prolongs Cardiac Repolarization by Blocking the Rapid Component of the Delayed Rectifier Potassium Current
Authors: Geelen Peter , Drolet Benoit , Rail Jimmy , Bérubé Jocelyn , Daleau Pascal , Rousseau Guy , Cardinal René , O’Hara Gilles E. , Turgeon Jacques
Published: June 2012

Background
—Several cases of unexpected death have been reported with sildenafil in patients predisposed to ischemic cardiac events. Although acute episodes of ischemia could account for some of these deaths, we hypothesized that sildenafil may have unsuspected electrophysiological effects predisposing some patients to proarrhythmia.

Methods and Results
—Studies were undertaken in 10 isolated guinea pig hearts that demonstrated prolongation of cardiac repolarization in a reverse use-dependent manner by sildenafil 30 μmol/L. Action potential duration increased 15% from baseline 117±3 to 134±2 ms with sildenafil during pacing at 250 ms cycle length, whereas a 6% increase from 99±2 to 105±2 ms was seen with pacing at 150 ms cycle length. Experiments in human
ether-a-go-go
–related gene (HERG)–transfected HEK293 cells (n=30) demonstrated concentration-dependent block of the rapid component (I
Kr
) of the delayed rectifier potassium current: activating current was 50% decreased at 100 μmol/L. This effect was confirmed using HERG-transfected Chinese hamster ovary (CHO) cells, which exhibit no endogenous I
K
-like current.

Conclusions
—Sildenafil possesses direct cardiac electrophysiological effects similar to class III antiarrhythmic drugs. These effects are observed at concentrations that may be found in conditions of impaired drug elimination such as renal or hepatic insufficiency, during coadministration of another CYP3A substrate/inhibitor, or after drug overdose and offer a new potential explanation for sudden death during sildenafil treatment.
Clinical Significance of Abnormal Electrocardiographic Patterns in Trained Athletes
Authors: Pelliccia Antonio , Maron Barry J. , Culasso Franco , Di Paolo Fernando M. , Spataro Antonio , Biffi Alessandro , Caselli Giovanni , Piovano Paola
Published: June 2012

Background
—The prevalence, clinical significance, and determinants of abnormal ECG patterns in trained athletes remain largely unresolved.

Methods and Results
—We compared ECG patterns with cardiac morphology (as assessed by echocardiography) in 1005 consecutive athletes (aged 24±6 years; 75% male) who were participating in 38 sporting disciplines. ECG patterns were distinctly abnormal in 145 athletes (14%), mildly abnormal in 257 (26%), and normal or with minor alterations in 603 (60%). Structural cardiovascular abnormalities were identified in only 53 athletes (5%). Larger cardiac dimensions were associated with abnormal ECG patterns: left ventricular end-diastolic cavity dimensions were 56.0±5.6, 55.4±5.7, and 53.7±5.7 mm (
P
<0.001) and maximum wall thicknesses were 10.1±1.4, 9.8±1.3, and 9.3±1.4 mm (
P
<0.001) in distinctly abnormal, mildly abnormal, and normal ECGs, respectively. Abnormal ECGs were also most associated with male sex, younger age (<20 years), and endurance sports (cycling, rowing/canoeing, and cross-country skiing). A subset of athletes (5% of the 1005) showed particularly abnormal or bizarre ECG patterns, but no evidence of structural cardiovascular abnormalities or an increase in cardiac dimensions.

Conclusions
—Most athletes (60%) in this large cohort had ECGs that were completely normal or showed only minor alterations. A variety of abnormal ECG patterns occurred in 40%; this was usually indicative of physiological cardiac remodeling. A small but important subgroup of athletes without cardiac morphological changes showed striking ECG abnormalities that suggested cardiovascular disease; however, these changes were likely an innocent consequence of long-term, intense athletic training and, therefore, another component of athlete heart syndrome. Such false-positive ECGs represent a potential limitation to routine ECG testing as part of preparticipation screening.
Common Carotid Artery Intima-Media Thickness and Brain Infarction
Authors: Touboul Pierre-Jean , Elbaz Alexis , Koller Cornelia , Lucas Christian , Adraï Valérie , Chédru François , Amarenco Pierre , Investigators for the GÉNIC
Published: June 2012

Background
—The use of intima-media thickness (IMT) as an outcome measure in observational studies and intervention trials relies on the view that it reflects early stages of atherosclerosis and cardiovascular risk. There is little knowledge concerning the relation between IMT and brain infarction (BI).

Methods and Results
—We investigated the relation of IMT with BI and its subtypes in 470 cases and 463 controls. Cases with BI proven by MRI were consecutively recruited and classified into subtypes by cause of BI. Controls were recruited among individuals hospitalized at the same institutions and matched for age, sex, and center. IMT was measured at the far wall of both common carotid arteries (CCA) using an automatic detection system. Adventitia-to-adventitia diameters and CCA-IMT were measured on transverse views; lumen diameter was computed using these measures. Mean (±SEM) CCA-IMT was higher in cases (0.797±0.006 mm) than in controls (0.735±0.006 mm;
P
<0.0001). This difference remained after adjustment for lumen diameter and when analyses were restricted to subjects free of previous cardiovascular or cerebrovascular history. The difference in CCA-IMT between cases and controls was significant in the main subtypes. The risk of BI increased continuously with increasing CCA-IMT. The odds ratio per SD increase (0.150 mm) was 1.82 (95% confidence interval, 1.54 to 2.15); adjustment for cardiovascular risk factors slightly attenuated this relation (odds ratio, 1.73; 95% confidence interval, 1.45 to 2.07).

Conclusions
—An increased CCA-IMT was associated with BI, both overall and in the main subtypes. An increased IMT may help select patients at high risk for BI.
Effect of Coumarins Started Before Coronary Angioplasty on Acute Complications and Long-Term Follow-Up
Authors: Berg Jurriën M. ten , Kelder Johannes C. , Suttorp Maarten Jan , Mast E. Gijs , Bal Egbert , Ernst Sjef M. P. G. , Verheugt Freek W. A. , Plokker H. W. Thijs
Published: June 2012

Background
—Coronary angioplasty frequently creates a thrombogenic surface, with subsequent mural thrombosis that may lead to acute complications and possibly stimulates the development of restenosis. Whether coumarins can prevent these complications is unclear. The objective of this open, randomized trial was to assess the clinical effect of coumarins started before coronary angioplasty and continued for 6 months.

Methods and Results
—Before coronary angioplasty, 530 patients were randomly assigned to aspirin plus coumarins and 528 patients to aspirin alone. At the start of the angioplasty, the mean international normalized ratio was 2.7±1.1; during follow-up, it was 3.0±1.1. At 30 days, the composite end point of death, myocardial infarction, target-lesion revascularization, and stroke was observed in 18 patients (3.4%) treated with aspirin plus coumarin compared with 34 patients (6.4%) treated with aspirin alone (relative risk, 0.53; 95% CI, 0.30 to 0.92). At 1 year, these figures were 14.3% and 20.3%, respectively (relative risk, 0.71; 95% CI, 0.54 to 0.93). The incidence of major bleeding and false aneurysm during hospitalization was 3.2% and 1.0%, respectively (relative risk, 3.39; 95% CI, 1.26 to 9.11). The benefit of coumarins was observed in both stented and nonstented patients.

Conclusions
—Coumarins in addition to aspirin started before PTCA and continued for 6 months was more effective than aspirin alone in the prevention of acute and late complications after coronary angioplasty. This benefit was accompanied by a small but significant increase in bleeding complications.
Targeting Patients Undergoing Angioplasty for Thrombus Inhibition
Authors: Weintraub William S. , Thompson Trevor D. , Culler Steven , Boccuzzi Stephen J. , Becker Edmund R. , Kosinski Andrzej S. , Mahoney Elizabeth
Published: June 2012

Background
—In recent clinical trials, glycoprotein IIb/IIIa blockers have demonstrated effectiveness in preventing adverse events after angioplasty in high-risk patients. However, uncertainty exists regarding the cost-effective selection of patients to receive antiplatelet therapy.

Methods and Results
—All 4962 patients at Emory University Hospitals who underwent coronary intervention procedures (n=6062) from 1993 to 1995 were studied. Multivariate models to predict death and the composite of death, Q-wave and non-Q-wave myocardial infarction, and emergency additional revascularization were developed. Hospital costs and professional costs were determined. A cost-effectiveness analysis with therapy targeted to high-risk patients was performed. If patients with a >5% probability of events received antiplatelet therapy that reduced events by 24% and cost $1000, 40.1% of patients would receive therapy; complications would be reduced from 6.39% to 5.37%, and cost would increase $261 from $10 343 to $10 604, or $25 504 per event prevented. The marginal cost per event prevented by moving from a 7% to a 5% probability of an event cutoff would be $57 799.

Conclusions
—For high-risk patients, there may be cost savings; for low-risk patients, therapy may not be cost effective; and for patients in the midrange (between 5% and 7% probability of an adverse event), events may be prevented at an acceptable level of cost.
Deletion of a 5-cM Region at Chromosome 8p23 Is Associated With a Spectrum of Congenital Heart Defects
Authors: Giglio Sabrina , Graw Sharon L. , Gimelli Giorgio , Pirola Barbara , Varone Paolo , Voullaire Lucille , Lerzo Franco , Rossi Elena , Dellavecchia Claudia , Bonaglia Maria Clara , Digilio Maria Cristina , Giannotti Aldo , Marino Bruno , Carrozzo Romeo , Korenberg Julie R. , Danesino Cesare , Sujansky Eva , Dallapiccola Bruno , Zuffardi Orsetta
Published: June 2012

Background
—Cytogenetic evidence suggests that the haploinsufficiency of ≥1 gene located in 8p23 behaves as a dominant mutation, impairing heart differentiation and leading to a wide spectrum of congenital heart defects (CHDs), including conotruncal lesions, atrial septal defects, atrioventricular canal defects, and pulmonary valve stenosis. An 8p heart-defect–critical region was delineated, and the zinc finger transcription factor GATA4 was considered a likely candidate for these defects. We narrowed this region and excluded a major role of GATA4 in these CHDs.

Methods and Results
—We studied 12 patients (7 had CHD and 5 did not) with distal 8p deletions from 9 families by defining their chromosome rearrangements at the molecular level by fluorescent in situ hybridization and short-tandem repeat analysis. Subjects with 8p deletions distal to D8S1706, at ≈10 cM from the 8p telomere, did not have CHD, whereas subjects with a deletion that included the more proximal region suffered from the spectrum of heart defects reported in patients with 8p distal deletions. The 5-cM critical region is flanked distally by D8S1706 and WI-8327, both at ≈10 cM, and proximally by D8S1825, at 15 cM. Neither GATA4 nor angiopoietin-2 (ANGPT2; a gene in 8p23 involved in blood vessel formation) were found to be deleted in some of the critical patients. We also found that CHDs are not related to the parental origin of deletion.

Conclusions
—Haploinsufficiency for a gene between WI-8327 and D8S1825 is critical for heart development. A causal relationship does not seem to exist between GATA4 and ANGPT2 haploinsufficiency and CHDs.
Cardioprotective Mechanism of Ischemic Preconditioning Is Impaired by Postinfarct Ventricular Remodeling Through Angiotensin II Type 1 Receptor Activation
Authors: Miki Takayuki , Miura Tetsuji , Tsuchida Akihito , Nakano Atsushi , Hasegawa Tohru , Fukuma Takayuki , Shimamoto Kazuaki
Published: June 2012

Background
—Activation of protein kinase C–linked receptors and subsequent opening of the mitochondrial ATP-sensitive K
+
(mitoK
ATP
) channel are crucial in preconditioning (PC). This study examined whether postinfarct ventricular remodeling interferes with the PC mechanism.

Methods and Results
—Two weeks before isolation of hearts, rabbits underwent a sham operation or coronary ligation (COL) to induce remodeling. Isolated buffer-perfused hearts were subjected to 30-minute global ischemia/2-hour reperfusion, and infarct size was expressed as a percentage of the left ventricle (%I/LV), from which the scarred infarct by COL was excluded. Although %I/LV was similar in sham-operated and remodeled hearts (52.9±6.5% versus 45.8±5.2%), PC with 2 episodes of 5-minute ischemia protected sham-operated but not remodeled hearts (%I/LV=18.1±2.5% versus 54.8±2.9%,
P
<0.05). Infusion of valsartan (10 mg · kg
−
1
· d
−
1
), an angiotensin II type 1 (AT
1
) receptor blocker, for 2 weeks after COL prevented the ventricular remodeling and preserved the response to PC (%I/LV=27.4±3.8%), although valsartan alone did not change %I/LV. Diazoxide, a mitoK
ATP
channel opener, protected both sham-operated and remodeled hearts (%I/LV=14.1±3.1% and 8.3±3.6%).

Conclusions
—The myocardium remodeled after infarction is refractory to PC, which is probably due to interruption of cellular signaling by PC upstream of mitoK
ATP
channels. An AT
1
receptor blocker is beneficial not only for suppression of ventricular remodeling but also for preservation of the PC mechanism.
Noninvasive In Vivo Human Coronary Artery Lumen and Wall Imaging Using Black-Blood Magnetic Resonance Imaging
Authors: Fayad Zahi A. , Fuster Valentin , Fallon John T. , Jayasundera Timothy , Worthley Stephen G. , Helft Gerard , Aguinaldo J. Gilberto , Badimon Juan J. , Sharma Samin K.
Published: June 2012

Background
—High-resolution MRI has the potential to noninvasively image the human coronary artery wall and define the degree and nature of coronary artery disease. Coronary artery imaging by MR has been limited by artifacts related to blood flow and motion and by low spatial resolution.

Methods and Results
—We used a noninvasive black-blood (BB) MRI (BB-MR) method, free of motion and blood-flow artifacts, for high-resolution (down to 0.46 mm in-plane resolution and 3-mm slice thickness) imaging of the coronary artery lumen and wall. In vivo BB-MR of both normal and atherosclerotic human coronary arteries was performed in 13 subjects: 8 normal subjects and 5 patients with coronary artery disease. The average coronary wall thickness for each cross-sectional image was 0.75±0.17 mm (range, 0.55 to 1.0 mm) in the normal subjects. MR images of coronary arteries in patients with ≥40% stenosis as assessed by x-ray angiography showed localized wall thickness of 4.38±0.71 mm (range, 3.30 to 5.73 mm). The difference in maximum wall thickness between the normal subjects and patients was statistically significant (
P
<0.0001).

Conclusions
—In vivo high-spatial-resolution BB-MR provides a unique new method to noninvasively image and assess the morphological features of human coronary arteries. This may allow the identification of atherosclerotic disease before it is symptomatic. Further studies are necessary to identify the different plaque components and to assess lesions in asymptomatic patients and their outcomes.
Adenovirus-Mediated VEGF
121
Gene Transfer Stimulates Angiogenesis in Normoperfused Skeletal Muscle and Preserves Tissue Perfusion After Induction of Ischemia
Authors: Gowdak Luis Henrique W. , Poliakova Lioubov , Wang Xiaotong , Kovesdi Imre , Fishbein Kenneth W. , Zacheo Antonella , Palumbo Roberta , Straino Stefania , Emanueli Costanza , Marrocco-Trischitta Massimiliano , Lakatta Edward G. , Anversa Piero , Spencer Richard G. S. , Talan Mark , Capogrossi Maurizio C.
Published: June 2012

Background
—Administration of angiogenic factors stimulates neovascularization in ischemic tissues. However, there is no evidence that angiogenesis can be induced in normoperfused skeletal muscles. We tested the hypothesis that adenovirus-mediated intramuscular (IM) gene transfer of the 121-amino-acid form of vascular endothelial growth factor (AdCMV.VEGF
121
) could stimulate neovascularization in nonischemic skeletal muscle and consequently attenuate the hemodynamic deficit secondary to surgically induced ischemia.

Methods and Results
—Rabbits and rats received IM injections of AdCMV.VEGF
121
, AdCMV.Null, or saline in the thigh, 4 weeks (rabbits) or 2 weeks (rats) before femoral artery removal in the injected limb. In unoperated rats, at the site of injection of AdCMV.VEGF
121
, we found 96% and 29% increases in length density of arterioles and capillaries, respectively. Increased tissue perfusion (TP) to the ischemic limb in the AdCMV.VEGF
121
group was documented, as early as day 1 after surgery, by improved blood flow to the ischemic gastrocnemius muscle measured by radioactive microspheres (AdCMV.VEGF
121
=5.69±0.40, AdCMV.Null=2.97±0.50, and saline=2.78±0.43 mL · min
−
1
· 100 g
−
1
,
P
<0.001), more angiographically recognizable collateral vessels (angioscore) (AdCMV.VEGF
121
=50.58±1.48, AdCMV.Null=29.08±4.22, saline=11.83±1.90,
P
<0.0001), and improvement of the bioenergetic reserve of the gastrocnemius muscle as assessed by
31
P NMR spectroscopy. Follow-up studies showed that superior TP to the ischemic limb in the AdCMV.VEGF
121
group persisted until it was equalized by spontaneous collateral vessel development in untreated animals.

Conclusions
—IM administration of AdCMV.VEGF
121
stimulates angiogenesis in normoperfused skeletal muscles, and the newly formed vessels preserve TP after induction of ischemia.
Fas-Mediated Apoptosis in Adriamycin-Induced Cardiomyopathy in Rats
Authors: Nakamura Tsuneyuki , Ueda Yoshimichi , Juan Yang , Katsuda Shogo , Takahashi Hiroaki , Koh Eikan
Published: June 2012

Background
—The precise molecular mechanism of Adriamycin-induced cardiomyopathy (ADR-CM) is still unknown. We address the demonstration of apoptotic myocardial cell death and the apoptosis-inducing molecules in ADR-CM induced in rats.

Methods and Results
—Until 8 weeks after the first administration of ADR, there was no increase in the number of labeled cells by terminal deoxynucleotidyl transferase assay (TUNEL method). Apoptotic indices increased significantly at weeks 9 and 10 in hearts of the ADR-treated group but not in those of the control group (0.42±0.12% versus 0.10±0.02% and 0.86±0.11% versus 0.09±0.04% at weeks 9 and 10, respectively). DNA ladder formation was also observed in the myocardial tissues during the late stages of the ADR-CM of rats. There was no significant difference in expression of
p53
gene between the ADR group and the control group at either the message or the protein level. An overexpression of Fas antigen was shown in myocardial cells of ADR-treated hearts at weeks 9 and 10 by both Western blotting and immunofluorescent staining. Furthermore, we confirmed that neutralization of anti–Fas ligand antibody inhibited ADR-induced apoptosis.

Conclusions
—Apoptotic cell death was observed in the hearts of ADR-CM rats, and the number of apoptotic myocardial cells increased with the deterioration of morphological findings and cardiac function, indicating that apoptosis may be an important mechanism of loss of myocardial cells and cardiac dysfunction in ADR-CM. Apoptosis in ADR-CM rats is not p53-dependent but rather is executed through a Fas-mediated pathway.
Arrhythmogenic Mechanism of an LQT-3 Mutation of the Human Heart Na
+
Channel α-Subunit
Authors: Wehrens X. H. T. , Abriel H. , Cabo C. , Benhorin J. , Kass R. S.
Published: June 2012

Background
—D1790G, a mutation of
SCN5A
, the gene that encodes the human Na
+
channel α-subunit, is linked to 1 form of the congenital long-QT syndrome (LQT-3). In contrast to other LQT-3–linked
SCN5A
mutations, D1790G does not promote sustained Na
+
channel activity but instead alters the kinetics and voltage-dependence of the inactivated state.

Methods and Results
—We modeled the cardiac ventricular action potential (AP) using parameters and techniques described by Luo and Rudy as our control. On this background, we modified only the properties of the voltage-gated Na
+
channel according to our patch-clamp analysis of D1790G channels. Our results indicate that D1790G-induced changes in Na
+
channel activity prolong APs in a steeply heart rate–dependent manner not directly due to changes in Na
+
entry through mutant channels but instead to alterations in the balance of net plateau currents by modulation of calcium-sensitive exchange and ion channel currents.

Conclusions
—We conclude that the D1790G mutation of the Na
+
channel α-subunit can prolong the cardiac ventricular AP despite the absence of mutation-induced sustained Na
+
channel current. This prolongation is calcium-dependent, is enhanced at slow heart rates, and at sufficiently slow heart rate triggers arrhythmogenic early afterdepolarizations.
Characterization of Plaque Components With Intravascular Ultrasound Elastography in Human Femoral and Coronary Arteries In Vitro
Authors: de Korte Chris L. , Pasterkamp Gerard , van der Steen Anton F. W. , Woutman Hein A. , Bom Nicolaas
Published: June 2012

Background
—The composition of plaque is a major determinant of coronary-related clinical syndromes. Intravascular ultrasound (IVUS) elastography has proven to be a technique capable of reflecting the mechanical properties of phantom material and the femoral arterial wall. The aim of this study was to investigate the capability of intravascular elastography to characterize different plaque components.

Methods and Results
—Diseased human femoral (n=9) and coronary (n=4) arteries were studied in vitro. At each location (n=45), 2 IVUS images were acquired at different intraluminal pressures (80 and 100 mm Hg). With the use of cross-correlation analysis on the high-frequency (radiofrequency) ultrasound signal, the local strain in the tissue was determined. The strain was color-coded and plotted as an additional image to the IVUS echogram. The visualized segments were stained on the presence of collagen, smooth muscle cells, and macrophages. Matching of elastographic data and histology were performed with the use of the IVUS echogram. The cross sections were segmented in regions (n=125) that were based on the strain value on the elastogram. The dominant plaque types in these regions (fibrous, fibro-fatty, or fatty) were obtained from histology and correlated with the average strain and echo intensity. The strain for the 3 plaque types as determined by histology differed significantly (
P
=0.0002). This difference was mainly evident between fibrous and fatty tissue (
P
=0.0004). The plaque types did not reveal echo-intensity differences in the IVUS echogram (
P
=0.882).

Conclusions
—Different strain values are found between fibrous, fibro-fatty, and fatty plaque components, indicating the potential of intravascular elastography to distinguish different plaque morphologies.
Double-Blind Study of the Safety of Clopidogrel With and Without a Loading Dose in Combination With Aspirin Compared With Ticlopidine in Combination With Aspirin After Coronary Stenting
Authors: Bertrand Michel E. , Rupprecht Hans-Jürgen , Urban Philip , Gershlick Anthony H. , Investigators for the CLASSICS
Published: June 2012

Background
—Combination therapy with the ADP receptor antagonist ticlopidine plus aspirin has emerged as standard care after coronary stenting. Clopidogrel, a new ADP receptor antagonist, has greater molar potency than ticlopidine and better safety/tolerability.

Methods and Results
—Patients (n=1020) were randomized after successful stent placement and initiated on a 28-day regimen of either (1) 300-mg clopidogrel loading dose and 325 mg/d aspirin on day 1, followed by 75 mg/d clopidogrel and 325 mg/d aspirin; (2) 75 mg/d clopidogrel and 325 mg/d aspirin; or (3) 250 mg BID ticlopidine and 325 mg/d aspirin. The primary end point consisted of major peripheral or bleeding complications, neutropenia, thrombocytopenia, or early discontinuation of study drug as the result of a noncardiac adverse event during the study-drug treatment period. The primary end point occurred in 9.1% of patients (n=31) in the ticlopidine group and 4.6% of patients (n=31) in the combined clopidogrel group (relative risk 0.50; 95% CI 0.31 to 0.81;
P
=0.005). Overall rates of major adverse cardiac events (cardiac death, myocardial infarction, target lesion revascularization) were low and comparable between treatment groups (0.9% with ticlopidine, 1.5% with 75 mg/d clopidogrel, 1.2% with the clopidogrel loading dose;
P
=NS for all comparisons).

Conclusions
—The safety/tolerability of clopidogrel (plus aspirin) is superior to that of ticlopidine (plus aspirin) (
P
=0.005). The 300-mg loading dose was well tolerated, notably with no increased risk of bleeding. Secondary end point data are consistent with the hypothesis that clopidogrel and ticlopidine have comparable efficacy with regard to cardiac events after successful stenting.
PTX3, A Prototypical Long Pentraxin, Is an Early Indicator of Acute Myocardial Infarction in Humans
Authors: Peri Giuseppe , Introna Martino , Corradi Domenico , Iacuitti Giuseppe , Signorini Stefano , Avanzini Fausto , Pizzetti Fabrizio , Maggioni Aldo P. , Moccetti Tiziano , Metra Marco , Cas Livio Dei , Ghezzi Pietro , Sipe Jean D. , Re Gianpietro , Olivetti Giorgio , Mantovani Alberto , Latini Roberto
Published: June 2012

Background
—Inflammation is an important component of ischemic heart disease. PTX3 is a long pentraxin whose expression is induced by cytokines in endothelial cells, mononuclear phagocytes, and myocardium. The possibility that PTX3 is altered in patients with acute myocardial infarction (AMI) has not yet been tested.

Methods and Results
—Blood samples were collected from 37 patients admitted to the coronary care unit (CCU) with symptoms of AMI. PTX3 plasma concentrations, as measured by ELISA, higher than the mean+2 SD of age-matched controls (2.01 ng/mL) were found in 27 patients within the first 24 hours of CCU admission. PTX3 peaked at 7.5 hours after CCU admission, and mean peak concentration was 6.94±11.26 ng/mL. Plasma concentrations of PTX3 returned to normal in all but 3 patients at hospital discharge and were unrelated to AMI site or extent, Killip class at entry, hours from symptom onset, and thrombolysis. C-reactive protein peaked in plasma at 24 hours after CCU admission, much later than PTX3 (
P
<0.001). Patients >64 years old and women had significantly higher PTX3 concentrations at 24 hours (
P
<0.05). PTX3 was detected by immunohistochemistry in normal but not in necrotic myocytes.

Conclusions
—PTX3 is present in the intact myocardium, increases in the blood of patients with AMI, and disappears from damaged myocytes. We suggest that PTX3 is an early indicator of myocyte irreversible injury in ischemic cardiomyopathy.
Clinical Features of Hypertrophic Cardiomyopathy Caused by a Lys183 Deletion Mutation in the Cardiac Troponin I Gene
Authors: Kokado Hiromasa , Shimizu Masami , Yoshio Hiroyuki , Ino Hidekazu , Okeie Kazuyasu , Emoto Yorito , Matsuyama Toru , Yamaguchi Masato , Yasuda Toshihiko , Fujino Noboru , Ito Hideki , Mabuchi Hiroshi
Published: June 2012

Background
—Mutations that cause hypertrophic cardiomyopathy (HCM) have been identified in 9 genes that code proteins in the sarcomere. Previous reports have demonstrated that cardiac troponin I (cTnI) gene mutations may account for familial HCM; however, the clinical characteristics and prognosis of patients with HCM caused by cTnI gene mutations are not known.

Methods and Results
—We analyzed cTnI gene mutations in 130 unrelated probands with HCM and their families to clarify the genotype-phenotype correlations. We identified 25 individuals in 7 families with a Lys183 deletion (Lys183 del) mutation in exon 7 of the cTnI gene. The disease penetrance in subjects aged >20 years was 88% by echocardiography and 96% by ECG. Sudden death occurred in 7 individuals of 4 families at any age. Overall, 7 (43.8%) of 16 individuals aged >40 years had left ventricular systolic dysfunction, and 3 (18.8%) displayed dilated cardiomyopathy-like features. Of affected individuals, 4 of 5 individuals aged >40 years followed by echocardiography showed septal thinning and decreased fractional shortening during >5 years of follow-up.

Conclusions
—The Lys183 del mutation in the cTnI gene in patients with HCM is associated with variable clinical features and outcomes. HCM caused by the Lys183 del mutation has a significant disease penetrance. This mutation is associated with sudden death at any age and dilated cardiomyopathy-like features in those aged >40 years. However, it remains unclear whether screening of families with HCM for this mutation will be useful in patient management and counseling.
Specific Cellular Features of Atheroma Associated With Development of Neointima After Carotid Endarterectomy
Authors: Pauletto Paolo , Puato Massimo , Faggin Elisabetta , Santipolo Nicoletta , Pagliara Valeria , Zoleo Miranda , Deriu Giovanni Paolo , Grego Franco , Plebani Mario , Sartore Saverio , Bon Gabriele Bittolo , Heymes Christophe , Samuel Jeane-Lise , Pessina Achille Cesare
Published: June 2012

Background
—The purpose of this study was to investigate whether some cellular and molecular features of tissue retrieved at carotid endarterectomy are associated with the extent of neointima formation at ultrasound follow-up.

Methods and Results
—One hundred fifty patients were studied. Endarterectomy specimens were tested by immunocytochemistry with the use of (1) monoclonal antibodies that identify smooth muscle cells (SMCs) and fetal-type SMCs on the basis of smooth muscle and nonmuscle myosin content, (2) the anti-macrophage HAM 56, and (3) the anti-lymphocyte CD45RO. The maximum intima-media thickness (M-IMT) of the revascularized vessel was assessed by the use of B-mode ultrasonography 6 months after surgery. The M-IMT values were related positively to the number of SMCs (
r
=0.534,
P
<0.0005) and negatively to that of macrophages and lymphocytes (
r
=−0.428,
P
<0.0005, and −0.538,
P
=0.001, respectively). Patients were classified as class 1 (M-IMT ≤1.0 mm), class 2 (1.01.3 mm). An abundance of SMCs, mostly of fetal type, was found in the plaque of class 3 patients, whereas lesions from class 1 patients were rich in macrophages and lymphocytes. In the multivariate analysis, factors related to M-IMT were the number of SMCs and the percentage of fetal-type SMCs present in the plaque.

Conclusions
—Although the classic risk factors did not play a role, an abundance of SMCs and a scarcity of macrophages characterized the primary lesion of patients in whom neointima developed after surgery. In patients in whom neointima did not develop, lesions were rich in macrophages and lymphocytes. This approach can be useful in defining patients at risk of restenosis.
CC Chemokine I-309 Is the Principal Monocyte Chemoattractant Induced by Apolipoprotein(a) in Human Vascular Endothelial Cells
Authors: Haque Nasreen S. , Zhang Xiaoxia , French Deborah L. , Li Jihong , Poon Michael , Fallon John T. , Gabel Brent R. , Taubman Mark B. , Koschinsky Marlys , Harpel Peter C.
Published: June 2012

Background
—Lipoprotein(a) [Lp(a)] is a risk factor for atherosclerosis; however, the mechanisms are unclear. We previously reported that Lp(a) stimulated human vascular endothelial cells to produce monocyte chemotactic activity. The apolipoprotein(a) [apo(a)] portion of Lp(a) was the active moiety.

Methods and Results
—We now describe the identification of the chemotactic activity as being due to the CC chemokine I-309. The carboxy-terminal domain of apo(a) containing 6 type-4 kringles (types 5 to 10), kringle V, and the protease domain was demonstrated to contain the I-309–inducing portion. Polyclonal and monoclonal anti–I-309 antibodies as well as an antibody against a portion of the extracellular domain of CCR8, the I-309 receptor, inhibited the increase in monocyte chemotactic activity induced by apo(a). I-309 antisense oligonucleotides also inhibited the induction of endothelial monocyte chemotactic activity by apo(a). I-309 mRNA was identified in human umbilical vein endothelial cells. Apo(a) induced an increase in I-309 protein in the endothelial cytoplasm and in the conditioned medium. Immunohistochemical studies have identified I-309 in endothelium, macrophages, and extracellular areas of human atherosclerotic plaques and have found that I-309 colocalized with apo(a).

Conclusions
—These data establish that I-309 is responsible for the monocyte chemotactic activity induced in human umbilical vein endothelial cells by Lp(a). The identification of the endothelial cell as a source for I-309 suggests that this chemokine may participate in vessel wall biology. Our data also suggest that I-309 may play a role in mediating the effects of Lp(a) in atherosclerosis.
Adenosine Primes the Opening of Mitochondrial ATP-Sensitive Potassium Channels
Authors: Sato Toshiaki , Sasaki Norihito , O’Rourke Brian , Marbán Eduardo
Published: June 2012

Background
—Adenosine can initiate ischemic preconditioning, and mitochondrial ATP-sensitive potassium (K
ATP
) channels have emerged as the likely effectors. We sought to determine the mechanistic interactions between these 2 observations.

Methods and Results
—The mitochondrial flavoprotein oxidation induced by diazoxide (100 μmol/L) was used to quantify mitochondrial K
ATP
channel activity in intact rabbit ventricular myocytes. Adenosine (100 μmol/L) increased mitochondrial K
ATP
channel activity and abbreviated the latency to mitochondrial K
ATP
channel opening. These potentiating effects were entirely prevented by the adenosine receptor antagonist 8-(
p
-sulfophenyl)-theophylline (100 μmol/L) or by the protein kinase C inhibitor polymyxin B (50 μmol/L). The effects of adenosine and diazoxide reflected mitochondrial K
ATP
channel activation, because they could be blocked by the mitochondrial K
ATP
channel blocker 5-hydroxydecanoate (500 μmol/L). In a cellular model of simulated ischemia, adenosine mitigated cell injury; this cardioprotective effect was blocked by 5-hydroxydecanoate but not by the surface-selective K
ATP
channel blocker HMR1098. Moreover, adenosine augmented the cardioprotective effect of diazoxide. A quantitative model of mitochondrial K
ATP
channel gating reproduced the major experimental findings.

Conclusions
—Our results support the hypothesis that adenosine receptor activation primes the opening of mitochondrial K
ATP
channels in a protein kinase C–dependent manner. The findings provide tangible links among various key elements in the preconditioning cascade.
Infections, Immunity, and Atherosclerosis
Authors: Mayr Manuel , Kiechl Stefan , Willeit Johann , Wick Georg , Xu Qingbo
Published: June 2012

Background
—Atherogenesis involves inflammatory processes in which infections are incriminated as possible contributors.

Methods and Results
—We evaluated cardiovascular risk factors as well as seropositivity to
Chlamydia pneumoniae
,
Helicobacter pylori
, and cytomegalovirus in a population-based study. A significant association between prevalence and severity of atherosclerosis in carotid and femoral arteries and IgA antibodies to
C pneumoniae
was demonstrated that was not substantially altered after adjustment for established risk factors. For anti
–H pylori
IgG antibodies, significant correlations to vascular disease were restricted to low social status and lesions in carotid arteries. In addition, the study design allowed us to monitor lesion progression over time. In this prospective analysis,
C pneumoniae
seropositivity emerged as a significant risk predictor. Antibody titers against cytomegalovirus were not a marker for prevalence or incidence of atherosclerosis in this population. Further infection parameters added to the predictive value of chlamydial serology in risk assessment: Mean odds ratios for the prevalence of carotid atherosclerosis were 4.2 and 6.3 for seropositive subjects with elevated C-reactive protein levels and clinical evidence for chronic respiratory infection, respectively. For subjects with all 3 infection parameters, the odds ratio of carotid atherosclerosis reached 10.3 (
P
<0.0001). Concomitantly, serum antibodies to mycobacterial heat-shock protein 65 (mHSP65) correlated with seropositivity to
C pneumoniae
and
H pylori
but not to cytomegalovirus.

Conclusions
—This prospective population-based study provides strong evidence for a potential atherogenic role of persistent bacterial infection, especially
C pneumoniae,
as indicated by serological and clinical data and demonstrates a correlation between immune reactions to mHSP65 and bacterial infections in atherogenesis.