bluuebunny/crossref_metadata_2025 huggingface dataset:
Left Ventricular Remodeling in Transgenic Mice With Cardiac Restricted Overexpression of Tumor Necrosis Factor
Authors: Sivasubramanian Natarajan , Coker Mytsi L. , Kurrelmeyer Karla M. , MacLellan William R. , DeMayo Francesco J. , Spinale Francis G. , Mann Douglas L.
Published: September 2007

Background

The mechanisms responsible for tumor necrosis factor (TNF)–induced LV structural remodeling in the adult heart are not known.

Methods and Results

We generated a line of transgenic mice (MHCsTNF) with cardiac restricted overexpression of TNF that develop progressive LV dilation/remodeling from 4 to 12 weeks of age. During the early phases of LV structural remodeling, there was a significant increase in total matrix metalloproteinase (MMP) activity that corresponded to a decrease in total myocardial fibrillar collagen content. As the MHCsTNF mice aged, there was a significant decrease in total MMP zymographic activity that was accompanied by an increase in total fibrillar collagen content. The changes in total MMP activity and myocardial fibrillar collagen content were related to a time- dependent increase in myocardial tissue inhibitor of metalloproteinases (TIMP)-1 levels, resulting in a significant time-dependent decrease in the MMP activity/TIMP level ratio in the MHCsTNF mice. To determine a possible mechanism for the increase in myocardial fibrosis, we also measured levels of TGF-β
1
and TGF-β
2
protein levels, which were shown to be significantly elevated in the hearts of the MHCsTNF mice.

Conclusions

Our results suggest that progressive time-dependent changes in the balance between MMP activity and TIMP activity are responsible, at least in part, for the spectrum of TNF-induced changes in the myofibrillar collagen content that occur during LV structural remodeling in the MHCsTNF mice.
Maternal Energy Stores and Diet Composition During Pregnancy Program Adolescent Blood Pressure
Authors: Adair Linda S. , Kuzawa Christopher W. , Borja Judith
Published: September 2007

Background

Fetal undernutrition is hypothesized to program blood pressure (BP) later in life. Human epidemiological studies that use birth weight as a proxy for fetal malnutrition fail to identify specific aspects of maternal nutrition responsible for programming.

Methods and Results

We examined how maternal nutrition during pregnancy and infant birth weight relate to systolic and diastolic BP (SBP and DBP) in 2026 Filipino adolescents. Data were collected prospectively during the Cebu (Philippines) Longitudinal Health and Nutrition Survey. Women were assessed at ≈30 weeks gestation, and children were followed from birth through adolescence. Regression models were used to examine how the mothers’ total energy intake, percentage of energy from protein and fat, triceps skinfold thickness during pregnancy, and infant birth weight relate to adolescent BP, controlling for current age, height, and body mass index and other potential confounders. Maternal triceps skinfold thickness was significantly inversely related to SBP among boys and to DBP in boys and girls. Maternal nutrition variables attenuated but did not eliminate an inverse birth weight–SBP relationship in boys. SBP was significantly inversely related to the mothers’ percent of dietary energy from protein in boys. Among girls, SBP and DBP were inversely related to the mothers’ percentage of calories from fat. There was no evidence of confounding of these relationships by current diet, maturation status, physical activity, or socioeconomic status.

Conclusions

Maternal diet composition and energy stores in the form of subcutaneous fat have long-term effects on offspring BP in adolescence.
Gating-Dependent Mechanisms for Flecainide Action inSCN5A-Linked Arrhythmia Syndromes
Authors: Viswanathan Prakash C. , Bezzina Connie R. , George Alfred L. , Roden Dan M. , Wilde Arthur A.M. , Balser Jeffrey R.
Published: September 2007

Background—Mutations in the cardiac sodium (Na) channel gene (SCN5A) give rise to the congenital long-QT syndrome (LQT3) and the Brugada syndrome. Na channel blockade by antiarrhythmic drugs improves the QT interval prolongation in LQT3 but worsens the Brugada syndrome ST-segment elevation. Although Na channel blockade has been proposed as a treatment for LQT3, flecainide also evokes “Brugada-like” ST-segment elevation in LQT3 patients. Here, we examine how Na channel inactivation gating defects in LQT3 and Brugada syndrome elicit proarrhythmic sensitivity to flecainide.

Methods and Results—We measured whole-cell Na current (INa) from tsA-201 cells transfected with ΔKPQ, a LQT3 mutation, and 1795insD, a mutation that provokes both the LQT3 and Brugada syndromes. The 1795insD and ΔKPQ channels both exhibited modified inactivation gating (from the closed state), thus potentiating tonicINablock. Flecainide (1 μmol/L) tonic block was only 16.8±3.0% for wild type but was 58.0±6.0% for 1795insD (P<0.01) and 39.4±8.0% (P<0.05) for ΔKPQ. In addition, the 1795insD mutation delayed recovery from inactivation by enhancing intermediate inactivation, with a 4-fold delay in recovery from use-dependent flecainide block.

Conclusions—We have linked 2 inactivation gating defects (“closed-state” fast inactivation and intermediate inactivation) to flecainide sensitivity in patients carrying LQT3 and Brugada syndrome mutations. These results provide a mechanistic rationale for predicting proarrhythmic sensitivity to flecainide based on the identification of specificSCN5Ainactivation gating defects.
Different Patterns of Interatrial Conduction in Clockwise and Counterclockwise Atrial Flutter
Authors: Marine Joseph E. , Korley Victoria J. , Obioha-Ngwu Ogundu , Chen Jane , Zimetbaum Peter , Papageorgiou Panos , Milliez Paul , Josephson Mark E.
Published: September 2007

Background

—

The terms counterclockwise (CC) and clockwise (C) atrial flutter (Afl) are used to describe right atrial activation around the tricuspid valve in the left anterior oblique view. The manner in which the left atrium is activated, as reflected by coronary sinus (CS) recordings, has not been systematically evaluated.

Methods and Results

—

Nine patients with both CC and C Afl underwent electrophysiological study with CS recordings during both rhythms with the use of a decapolar catheter with the tip placed in the distal CS. Patterns of CS activation during each type of Afl as well as during during sinus rhythm were categorized into 1 of 3 patterns: sequential proximal-to-distal, sequential distal-to-proximal, and fused, indicating activation from different directions. In 7 of 9 patients, the pattern of CS activation in CC Afl and C Afl differed, with a proximal-to-distal pattern in CC Afl and a fused pattern in C Afl. In 2 patients, pacing the high right atrial septum near the presumed site of Bachmann’s bundle in sinus rhythm showed a similar fused pattern of CS activation.

Conclusions

—

These results demonstrate different patterns of CS activation in CC Afl and C Afl in the majority of patients and are consistent with a model in which the left atrium is activated predominantly over Bachmann’s bundle during C Afl and over the CS os in CC Afl. These findings may have implications for maintenance of Afl, interpretation of flutter wave morphology on surface ECG, and left atrial mechanical function in Afl.
Transmural Extent of Acute Myocardial Infarction Predicts Long-Term Improvement in Contractile Function
Authors: Choi Kelly M. , Kim Raymond J. , Gubernikoff George , Vargas John D. , Parker Michelle , Judd Robert M.
Published: September 2007

Background

—

Previous animal studies have demonstrated that the transmural extent of acute myocardial infarction defined by contrast-enhanced MRI (ceMRI) relates to early restoration of flow and future improvements in contractile function. We tested the hypothesis that ceMRI would have similar predictive value in humans.

Methods and Results

—

Twenty-four patients who presented with their first myocardial infarction and were successfully revascularized underwent cine and ceMRI of their heart within 7 days (scan 1) of the peak MB band of creatine kinase. Cine MRI was repeated 8 to 12 weeks later (scan 2). The transmural extent of infarction on scan 1 and wall thickening on both scans were determined using a 72-segment model. A total of 524 of 1571 segments (33%) were dysfunctional on scan 1. Improvement in segmental contractile function on scan 2 was inversely related to the transmural extent of infarction on scan 1 (
P
=0.001). Improvement in global contractile function, as assessed by ejection fraction and mean wall thickening score, was not predicted by peak creatine kinase-MB (
P
=0.66) or by total infarct size, as defined by MRI (
P
=0.70). The best predictor of global improvement was the extent of dysfunctional myocardium that was not infarcted or had infarction comprising <25% of left ventricular wall thickness (
P
<0.005 for ejection fraction,
P
<0.001 for mean wall thickening score).

Conclusion

—

In patients with acute myocardial infarction, the transmural extent of infarction defined by ceMRI predicts improvement in contractile function.
Significance of Chymase-Dependent Angiotensin II–Forming Pathway in the Development of Vascular Proliferation
Authors: Nishimoto Masayoshi , Takai Shinji , Kim Shokei , Jin Denan , Yuda Atsushi , Sakaguchi Masato , Yamada Mayumi , Sawada Yoshihide , Kondo Keiichiro , Asada Kunio , Iwao Hiroshi , Sasaki Shinjiro , Miyazaki Mizuo
Published: September 2007

BackgroundVascular tissues of humans and dogs contain chymase as an angiotensin II–forming enzyme. In this study, we investigated whether chymase-dependent angiotensin II formation plays a crucial role in the development of vascular proliferation in dog grafted veins.

Methods and ResultsThe right external jugular vein of dogs was grafted to the ipsilateral carotid artery. As a control group, the right external jugular veins in dogs that had not received grafts were used. In the chymase inhibitor–treated group, the vein was infiltrated with 10 μmol/L Suc-Val-Pro-PheP(OPh)2and was grafted to the carotid artery. In the placebo-treated group, ACE activity in the grafted veins was significantly lower than that in the control veins up to 7 days after the operation, whereas chymase activity was increased significantly. After 7 days, the mRNA levels of collagen I, collagen III, and fibronectin, all of which are induced by an increase of angiotensin II action, were significantly increased in the grafted veins, and the intima-media ratio of the grafted veins was also increased. In the chymase inhibitor–treated group, the chymase activity in the grafted veins 7 days after the operation was suppressed to 12.1%. The elevated mRNA levels of fibronectin, collagen I, and collagen III in the grafted veins were significantly suppressed by treatment with the chymase inhibitor, and the intima-media ratio was also decreased significantly.

ConclusionsWe demonstrate for the first time that chymase-dependent angiotensin II formation plays an important role in the development of vascular proliferation in the grafted veins.
Chronic Administration of Ghrelin Improves Left Ventricular Dysfunction and Attenuates Development of Cardiac Cachexia in Rats With Heart Failure
Authors: Nagaya Noritoshi , Uematsu Masaaki , Kojima Masayasu , Ikeda Yoshihiko , Yoshihara Fumiki , Shimizu Wataru , Hosoda Hiroshi , Hirota Yuki , Ishida Hideyuki , Mori Hidezo , Kangawa Kenji
Published: September 2007

Background
—

Ghrelin is a novel growth hormone (GH)–releasing peptide that may also induce vasodilation and stimulate feeding through GH-independent mechanisms. We investigated whether ghrelin improves left ventricular (LV) dysfunction and attenuates cardiac cachexia in rats with chronic heart failure (CHF).

Methods and Results
—

Ligation of the left coronary artery or sham operation was performed; 4 weeks after surgery, rat ghrelin (100 μg/kg SC BID) or saline was administered for 3 weeks. Echocardiography and cardiac catheterization were performed. Serum GH and insulin-like growth factor-1 were significantly higher in both CHF and sham rats treated with ghrelin than in those given placebo (
P
<0.05 for both). CHF rats given placebo showed an impaired increase in body weight compared with sham rats given placebo (
P
<0.05). CHF rats treated with ghrelin, however, showed a significantly greater increase in body weight than those given placebo (+10% versus +3%,
P
<0.05). They showed significantly higher cardiac output (315±49 versus 266±31 mL · min
−1
· kg
−1
,
P
<0.05) and LV dP/dt
max
(5738±908 versus 4363±973 mm Hg/s,
P
<0.05) than CHF rats given placebo. Ghrelin increased diastolic thickness of the noninfarcted posterior wall, inhibited LV enlargement, and increased LV fractional shortening in CHF rats (from 15±3% to 19±3%,
P
<0.05).

Conclusions
—

Chronic subcutaneous administration of ghrelin improved LV dysfunction and attenuated the development of LV remodeling and cardiac cachexia in rats with CHF.
Effects of Once-Daily Angiotensin-Converting Enzyme Inhibition and Calcium Channel Blockade-Based Antihypertensive Treatment Regimens on Left Ventricular Hypertrophy and Diastolic Filling in Hypertension
Authors: Devereux Richard B. , Palmieri Vittorio , Sharpe Norman , De Quattro Vincent , Bella Jonathan N. , de Simone Giovanni , Walker J. Findlay , Hahn Rebecca T. , Dahlöf Björn
Published: September 2007

Background

The Prospective Randomized Enalapril Study Evaluating Regression of Ventricular Enlargement (PRESERVE) study was designed to test whether enalapril achieves greater left ventricular (LV) mass reduction than does a nifedipine gastrointestinal treatment system by a prognostically meaningful degree on a population basis (10 g/m
2
).

Methods and Results

An ethnically diverse population of 303 men and women with essential hypertension and increased LV mass at screening echocardiography were enrolled at clinical centers on 4 continents and studied by echocardiography at baseline and after 6- and 12-month randomized therapy. Clinical examination and blinded echocardiogram readings 48 weeks after study entry in an intention-to-treat analysis of 113 enalapril-treated and 122 nifedipine-treated patients revealed similar reductions in systolic/diastolic pressure (−22/12 versus −21/13 mm Hg) and LV mass index (−15 versus −17g/m
2
, both
P
>0.20). No significant between-treatment difference was detected in population subsets defined by monotherapy treatment, sex, age, race, or severity of baseline hypertrophy. Similarly, there was no between-treatment difference in change in velocities of early diastolic or atrial phase transmitral blood flow. More enalapril-treated than nifedipine-treated patients required supplemental treatment with hydrochlorothiazide (59% versus 34%,
P
<0.001) but not atenolol (27% versus 22%, NS).

Conclusions

Once-daily antihypertensive treatment with enalapril or long-acting nifedipine, plus adjunctive hydrochlorothiazide and atenolol when needed to control blood pressure, both had moderately beneficial and statistically indistinguishable effects on regression of LV hypertrophy.
Attenuated Myocardial Vasodilator Response in Patients With Hypertensive Hypertrophy Revealed by Oxygenation-Dependent Magnetic Resonance Imaging
Authors: Beache Garth M. , Herzka Daniel A. , Boxerman Jerrold L. , Post Wendy S. , Gupta Sandeep N. , Faranesh Anthony Z. , Solaiyappan Meiyappan , Bottomley Paul A. , Weiss James L. , Shapiro Edward P. , Hill Martha N.
Published: September 2007

Background

Oxygen (O
2
) homeostasis is central to myocardial tissue functioning, and increased O
2
demand is thought to be satisfied by a vasodilatory mechanism that results in increased blood and O
2
delivery. We applied blood oxygenation level–dependent (BOLD) MRI in conjunction with vasodilatory stress to index the ability to augment intramyocardial oxygenation in hypertensive hypertrophy, the primary cause of heart failure.

Methods and Results

Nine healthy controls and 10 hypertensive subjects with moderate-to-severe hypertrophy underwent imaging on a 1.5 T clinical scanner. The dipyridamole-induced change in the apparent transverse relaxation rate, R2*, which correlates with hemoglobin oxygenation, was −5.4±2.2 s
−1
(95% CI, −4.0 to −6.8 s
−1
) in controls compared with −1.7±1.4 s
−1
(95% CI, −0.8 to −2.6 s
−1
) in hypertensive patients (
P
=0.0003).

Conclusions

Patients with hypertensive hypertrophy demonstrate an impaired ability to increase intramyocardial oxygenation during vasodilatory stress, as indexed by BOLD MRI. The capacity to image vascular function with BOLD MRI may advance the understanding of the development of ventricular dysfunction in hypertension.
Circulating Cell Adhesion Molecules and Death in Patients With Coronary Artery Disease
Authors: Blankenberg Stefan , Rupprecht Hans J. , Bickel Christoph , Peetz Dirk , Hafner Gerd , Tiret Laurence , Meyer Jürgen ,   for the AtheroGene Investigators
Published: September 2007

Background

—Vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1, and E-selectin mediate adhesion and transmigration of leukocytes to the vascular endothelial wall and may promote plaque growth and instability. In a prospective study, we evaluated the effect of soluble adhesion molecules on the risk of future cardiovascular events among patients with angiographically documented coronary artery disease (CAD).

Methods and Results

—We obtained baseline samples from a prospective cohort of 1246 patients with CAD. Besides various markers of inflammation, soluble VCAM-1 (sVCAM-1), sICAM-1, and sE-selectin were determined. Follow-up information on cardiovascular events was obtained (mean, 2.7; maximum, 4.1 years). Independently higher levels of sVCAM-1 (1932 versus 1128 ng/mL;
P
<0.0001), sICAM-1 (353 versus 287 ng/mL;
P
=0.015), and sE-selectin (81 versus 63 ng/mL;
P
=0.003) were observed in patients with future death from cardiovascular causes. In a multivariate model, fatal risk was 2.1-fold (1.1 to 4.0) higher in patients within the top quartile of baseline sVCAM-1 concentrations compared with lower quartiles. This association was present independent of general inflammatory response as reflected by low or high C-reactive protein (hs-CRP) levels. In a model that simultaneously controlled for all inflammatory and soluble adhesion markers determined, only sVCAM-1 remained independently significant for future fatal cardiovascular events, with a 2.8-fold increase in risk (
P
=0.003).

Conclusions

—Soluble adhesion molecules sVCAM-1, sICAM-1, and sE-selectin were significantly related to future death from cardiovascular causes among patients with documented CAD. Especially sVCAM-1 added to the predictive value of classic risk factors and hs-CRP in determining the risk of future cardiovascular death.
Randomized Comparison of Coronary Stent Implantation Under Ultrasound or Angiographic Guidance to Reduce Stent Restenosis (OPTICUS Study)
Authors: Mudra Harald , di Mario Carlo , de Jaegere Peter , Figulla Hans Reiner , Macaya Carlos , Zahn Ralf , Wennerblom Bertil , Rutsch Wolfgang , Voudris Vasilj , Regar Evelyn , Henneke Karl-Heinz , Schächinger Volker , Zeiher Andreas ,   for the OPTICUS (OPTimization with ICUS to reduce stent restenosis) Study Investigators
Published: September 2007

Background
—

Observational studies in selected patients have shown remarkably low restenosis rates after ultrasound-guided stent implantation. However, it is unknown whether this implantation strategy improves long-term angiographic and clinical outcome in routine clinical practice.

Methods and Results
—

A total of 550 patients with a symptomatic coronary lesion or silent ischemia were randomly assigned to either ultrasound-guided or angiography-guided implantation of ≤2 tubular stents. The primary end points were angiographic dichotomous restenosis rate, minimal lumen diameter, and percent diameter stenosis after 6 months as determined by quantitative coronary angiography. Secondary end points were the occurrence rates of major adverse cardiac events (death, myocardial infarction, coronary bypass surgery, and repeat percutaneous intervention) after 6 and 12 months of follow-up. At 6 months, repeat angiography revealed no significant differences between the groups with ultrasound- or angiography-guided stent implantation with respect to dichotomous restenosis rate (24.5% versus 22.8%,
P
=0.68), minimal lumen diameter (1.95±0.72 mm versus 1.91±0.68 mm,
P
=0.52), and percent diameter stenosis (34.8±20.6% versus 36.8±19.6%,
P
=0.29), respectively. At 12 months, neither major adverse cardiac events (relative risk, 1.07; 95% CI 0.75 to 1.52;
P
=0.71) nor repeat percutaneous interventions (relative risk 1.04; 95% CI 0.64 to 1.67;
P
=0.87) were reduced in the ultrasound-guided group.

Conclusions
—

This study does not support the routine use of ultrasound guidance for coronary stenting. Angiography-guided optimization of tubular stents can be performed with comparable angiographic and clinical long-term results.
Alcohol Consumption and Hemostatic Factors
Authors: Mukamal Kenneth J. , Jadhav Praveen P. , D’Agostino Ralph B. , Massaro Joseph M. , Mittleman Murray A. , Lipinska Izabella , Sutherland Patrice A. , Matheney Travis , Levy Daniel , Wilson Peter W.F. , Ellison R. Curtis , Silbershatz Halit , Muller James E. , Tofler Geoffrey H.
Published: September 2007

Background
—

Moderate alcohol consumers have lower rates of cardiovascular disease than abstainers. One proposed mechanism is a beneficial effect on hemostatic parameters, but previous studies have provided conflicting results.

Methods and Results
—

We measured levels of fibrinogen, plasma viscosity, von Willebrand factor, factor VII, plasminogen activator inhibitor antigen-1, and tissue plasminogen activator antigen in a cross-sectional analysis of 3223 adults free of cardiovascular disease enrolled in the Framingham Offspring Study. We assessed their alcohol consumption with a standardized questionnaire. Light-to-moderate alcohol consumption was associated with lower levels of fibrinogen, plasma viscosity, von Willebrand factor, and factor VII. This association was most pronounced for consumers of 3 to 7 drinks weekly for viscosity and 7 to 21 drinks weekly for the other hemostatic measures. Alcohol intake of 7 to 21 drinks weekly or more was associated with impaired fibrinolytic potential, reflected by higher levels of plasminogen activator inhibitor antigen-1 and tissue plasminogen activator antigen. Wine drinkers had lower plasminogen activator inhibitor antigen-1 levels than other drinkers, particularly at 3 to 21 drinks weekly, but beverage type did not otherwise consistently affect the results.

Conclusions
—

Light-to-moderate alcohol consumption is associated with lower levels of coagulatory factors, but higher intake is associated with impaired fibrinolytic potential. These findings are consistent with the hypothesis that a balance between hemostatic and fibrinolytic activity may contribute to the complex relation of alcohol use with coronary heart disease.
Gap Junction Blockers Decrease Defibrillation Thresholds Without Changes in Ventricular Refractoriness in Isolated Rabbit Hearts
Authors: Qi Xiangqian , Varma Pryamvada , Newman David , Dorian Paul
Published: September 2007

Background

The maintenance and termination of reentry arrhythmias are determined by tissue properties such as refractoriness and conduction velocity. Although the effects of Na
+
and K
+
channel block on electrophysiological properties and defibrillation threshold (DFT) have been studied, little is known about the effect of gap junction blockers on defibrillation and tissue electrophysiological properties.

Methods and Results

Triplicate DFTs (volts) were obtained before and 15 minutes after 4 μmol/L 16-doxyl-stearic acid (16-DSA, n=8), 1 mmol/L 1-heptanol (n=12) (both gap junction blockers), 3 μg/mL lidocaine (a sodium channel blocker) (n=8), and respective controls (n=27) in isolated perfused rabbit hearts. DFT decreased after 16-DSA (23±14%,
P
<0.01) and 1-heptanol (21±16%,
P
<0.01) but increased after lidocaine (26±28%,
P
<0.05). Ventricular fibrillation cycle length (VFCL) and QRS duration increased after all 3 agents, by 36±19% and 44±16% (16-DSA), 87±42% and 49±15% (heptanol), and 57±20% and 43±26% (lidocaine), respectively (all
P
<0.01). Spatially averaged temporal VFCL dispersion decreased significantly after all 3 agents, by 47±42% (16-DSA,
P
<0.05), 74±19% (1-heptanol,
P
<0.01), and 82±13% (lidocaine,
P
<0.01), respectively. Ventricular effective refractory period and monophasic action potential duration at 90% repolarization were unchanged after 16-DSA and 1-heptanol (
P
=NS) but increased after lidocaine (16±13%,
P
<0.01, and 6±5%,
P
=NS, respectively). There were no significant changes in DFT or any other electrophysiological variable in control hearts.

Conclusions

Electrical uncoupling by 16-DSA and 1-heptanol significantly lowers DFT and dispersion of VFCL without altering refractoriness; lidocaine, at doses resulting in similar slowing of conduction, increases DFT.
Nitric Oxide Synthase (nNOS) Gene Transfer Modifies Venous Bypass Graft Remodeling
Authors: West Nick E.J. , Qian HuSheng , Guzik Tomasz J. , Black Edward , Cai Shijie , George Samuel E. , Channon Keith M.
Published: September 2007

Background

Pathological vascular remodeling in venous bypass grafts (VGs) results in smooth muscle cell (SMC) intimal hyperplasia and provides the substrate for progressive atherosclerosis, the principal cause of late VG failure. Nitric oxide (NO) bioactivity is reduced in VGs, in association with increased vascular superoxide production, but how these features relate to pathological VG remodeling remains unclear. We used gene transfer of the neuronal isoform of nitric oxide synthase (nNOS) to investigate how increased NO production modulates vascular remodeling in VGs and determined the effects on late VG phenotype.

Methods and Results

New Zealand White rabbits (n=60) underwent jugular-carotid interposition bypass graft surgery with intraoperative adenoviral gene transfer of nNOS or β-galactosidase. Vessels were analyzed after 3 days (early, to investigate acute injury/inflammation) or 28 days (late, to investigate SMC intimal hyperplasia). In early VGs, nNOS gene transfer significantly increased NOS activity and substantially reduced adhesion molecule expression and inflammatory cell infiltration. In late VGs, recombinant nNOS protein was no longer evident, but there were sustained effects on VG remodeling, resulting in a striking reduction in SMC intimal hyperplasia, a more differentiated intimal SMC phenotype, and reduced vascular superoxide production.

Conclusions

Intraoperative nNOS gene transfer has sustained favorable effects on VG remodeling and on the vascular phenotype of mature VGs. These findings suggest that early, transient modification of the response to vascular injury is a powerful approach to modulate VG biology and highlight the potential utility of NOS gene transfer as a therapeutic strategy in VGs.
Unstable Coronary Plaque and Its Relation to Coronary Calcium
Authors: Schmermund Axel , Erbel Raimund
Published: September 2007

Coronary calcium is intimately associated with coronary atherosclerotic plaque development. The use of electron-beam computed tomography (EBCT) for accurate quantitative measurements has led to an increased interest in understanding the clinical importance of coronary calcium, particularly in terms of the ability to identify unstable coronary plaques that underlie the clinical acute coronary syndromes. Histopathologic studies have demonstrated that calcium is a frequent feature of ruptured plaques, but the presence or absence of calcium does not allow for reliable distinction between unstable versus stable plaques. This issue is complicated by the lack of a prospective definition for “unstable.” Plaque rupture is sometimes found in apparently healthy subjects and in patients with clinically stable disease. Coronary atherosclerosis is a coronary systemic disease process. Imaging of coronary calcium, although unable to identify a localized unstable plaque, potentially can identify the more clinically pertinent “unstable patient.” Almost all patients with a recent acute coronary syndrome have measurable coronary calcium because moderate-to-advanced coronary plaque disease is already present, although obstructive disease frequently is not. Prospective studies have demonstrated that extensive coronary calcium detected by EBCT is associated with a significantly increased incidence of subsequent myocardial infarction, need for revascularization, and coronary death. The incremental prognostic value of coronary calcium compared with that of risk factor assessment remains to be fully defined. The occurrence of an acute coronary syndrome is determined by many factors apart from the extent of atherosclerotic plaque disease. Large prospective trials in the general population are needed to define the subgroups that will benefit most from quantitative assessment of coronary calcium.
12/15-Lipoxygenase Gene Disruption Attenuates Atherogenesis in LDL Receptor–Deficient Mice
Authors: George Jacob , Afek Arnon , Shaish Aviv , Levkovitz Hana , Bloom Nira , Cyrus Tillmann , Zhao Lei , Funk Colin D. , Sigal Eliott , Harats Dror
Published: September 2007

Background

Human 15-lipoxygenase (LO) and its murine analogue 12/15-LO are capable of directly oxidizing esterified fatty acids in lipoproteins and phospholipids. Because these oxidized products possess atherogenic properties, it was suggested that LOs may be involved in enhancing atherogenesis. Previous in vivo tests of the role of LOs in atherogenesis animal models, however, have yielded conflicting results.

Methods and Results

Aiming to study the role of the 12/15-LO in murine atherogenesis, we crossed LDL-receptor–deficient mice (LDL-R
−/−
) with 12/15-LO–knockout mice and evaluated plaque formation 3 to 18 weeks after initiation of a high-fat diet. Atherosclerotic lesions were considerably reduced in the LDL-R/12/15-LO–double-knockout mice compared with LDL-R
−/−
mice at 3, 9, 12, and 18 weeks, at the aortic root as well as throughout the aorta. The cellular composition of plaques from mice deficient in 12/15-LO did not differ with respect to macrophage and T-lymphocyte content compared with plaques from 12/15-LO littermates.

Conclusions

12/15-LO plays a dominant role in promoting atherogenesis in LDL-R
−/−
mice.
High-Density Lipoproteins and Endothelial Function
Authors: O’Connell Brian J. , Genest Jacques
Published: September 2007

Elevated plasma levels of HDL cholesterol or apolipoprotein A-I, the major protein moiety of HDL particles, are protective against coronary artery disease. HDL particles remove cholesterol from peripheral cells and transfer it to the liver for bile acid synthesis. The interaction between lipoproteins is not mediated through simple contact between 2 phospholipid membranes but involves specific protein-receptor interactions, charged phospholipid-phospholipid contact, and activation of cellular signaling pathways. These lead to regulation of genes or the modification of proteins involved in vasomotor function, platelet activation, thrombosis and thrombolysis, cell adhesion, apoptosis and cell proliferation, and cellular cholesterol homeostasis.
Effect of Clinical Risk Stratification on Cost-Effectiveness of the Implantable Cardioverter-Defibrillator
Authors: Sheldon Robert , O’Brien Bernie J. , Blackhouse Gordon , Goeree Ron , Mitchell Brent , Klein George , Roberts Robin S. , Gent Michael , Connolly Stuart J. ,   for the Canadian Implantable Defibrillator Study (CIDS) Investigators
Published: September 2007

Background

Three randomized clinical trials showed that implantable cardioverter-defibrillators (ICDs) reduce the risk of death in survivors of ventricular tachyarrhythmias, but the cost per year of life gained is high. A substudy of the Canadian Implantable Defibrillator Study (CIDS) showed that 3 clinical factors, age ≥70 years, left ventricular ejection fraction ≤35%, and New York Heart Association class III, predicted the risk of death and benefit from the ICD. We estimated the extent to which selecting patients for ICD therapy based on these risk factors makes ICD therapy more economically attractive.

Methods and Results

Patients in CIDS were grouped according to whether they had ≥2 of 3 risk factors. Incremental cost-effectiveness of ICD therapy was computed as the ratio of the difference in mean cost to the difference in life expectancy between the 2 groups. Over 6.3 years, the mean cost per patient in the ICD group was Canadian (C) $87 715 versus $38 600 in the amiodarone group (C$1≈US$0.67). Life expectancy for the ICD group was 4.58 years versus 4.35 years for amiodarone, for an incremental cost-effectiveness of ICD therapy of C$213 543 per life-year gained. The cost per life-year gained in patients with ≥2 factors was C$65 195, compared with C$916 659 with <2 risk factors.

Conclusions

The cost-effectiveness of ICD therapy varies by patient risk factor status. The use of ICD therapy in patients who have ≥2 risk factors of age ≥70 years, left ventricular ejection fraction ≤35%, and NYHA class III is C$65 195 to gain a year of life.
Early Outcome After Off-Pump Versus On-Pump Coronary Bypass Surgery
Authors: van Dijk Diederik , Nierich Arno P. , Jansen Erik W.L. , Nathoe Hendrik M. , Suyker Willem J.L. , Diephuis Jan C. , van Boven Wim-Jan , Borst Cornelius , Buskens Erik , Grobbee Diederick E. , Robles de Medina Etienne O. , de Jaegere Peter P.T.
Published: September 2007

Background

The use of cardiopulmonary bypass during coronary artery bypass surgery (CABG) has been associated with substantial morbidity. The recent introduction of cardiac stabilizers facilitates CABG without cardiopulmonary bypass (off-pump CABG), but it is unknown whether cardiac outcome after off-pump surgery is similar to that for the on-pump procedure.

Methods and Results

In a multicenter trial, 281 patients (mean age 61 years, SD 9 years) were randomly assigned to off-pump or on-pump CABG. In-hospital results and cardiac outcome and quality of life after 1 month are presented. Cardiac outcome was defined as survival free of stroke, myocardial infarction, and coronary reintervention. The mean numbers of distal anastomoses per patient were 2.4 (SD 1.0) and 2.6 (SD 1.1) in the off-pump and on-pump groups, respectively. Completeness of revascularization was similar in both groups. Blood products were needed during 3% of the off-pump procedures and 13% of the on-pump procedures (
P
<0.01). Release of creatine kinase muscle-brain isoenzyme was 41% less in the off-pump group (
P
<0.01). Otherwise, no differences in complications were found postoperatively. Off-pump patients were discharged 1 day earlier. At 1 month, operative mortality was zero in both groups, and quality of life had improved similarly. In both groups, 4% of the patients had recurrent angina. The proportions of patients surviving free of cardiovascular events were 93.0% in the off-pump group and 94.2% in the on-pump group (
P
=0.66).

Conclusions

In selected patients, off-pump CABG is safe and yields a short-term cardiac outcome comparable to that of on-pump CABG.
Induction of NAD(P)H Oxidase by Oxidized Low-Density Lipoprotein in Human Endothelial Cells
Authors: Rueckschloss Uwe , Galle Jan , Holtz Juergen , Zerkowski Hans-Reinhard , Morawietz Henning
Published: September 2007

Background

Elevated oxidative stress and superoxide anion formation in vascular cells could promote conversion of LDL to atherogenic oxidized LDL (oxLDL), contributing to endothelial dysfunction and atherosclerosis. As a major source of vascular superoxide anion formation, an endothelial NAD(P)H oxidase, similar to the leukocyte enzyme, has been identified.

Methods and Results

To elucidate functional differences between NAD(P)H oxidases of endothelial cells and leukocytes, DNA sequences of endothelial NAD(P)H oxidase subunits were determined. Gp91phox cDNA sequence showed no difference between the 2 cell types. Endothelial p67phox cDNA sequence revealed 2 known polymorphisms, which do not affect NAD(P)H oxidase function. Next, we analyzed relative mRNA expression of NAD(P)H subunits in human umbilical vein endothelial cells (HUVECs) and leukocytes using a common cRNA standard in competitive reverse transcription–polymerase chain reaction. NAD(P)H oxidase subunits p22phox and p47phox are expressed at a similar level in both cell types, whereas p67phox (2.5%) and gp91phox (1.1%) are expressed at a much lower level in endothelial cells than in leukocytes. Differences of gp91phox expression in leukocytes and HUVECs correlate with differences in superoxide release. Gp91phox mRNA and endothelial superoxide anion formation are induced in response to oxLDL in HUVECs. Furthermore, a lower gp91phox mRNA expression was found in internal mammary artery biopsy samples of patients with coronary artery disease treated with HMG-CoA reductase inhibitors before coronary bypass surgery.

Conclusions

We conclude that oxLDL induces proatherosclerotic NAD(P)H oxidase expression and superoxide anion formation in human endothelial cells and an antioxidative potential of HMG-CoA reductase inhibition via reduction of vascular NAD(P)H oxidase expression.
Peroxisome Proliferator-Activated Receptor γ Activators Inhibit Cardiac Hypertrophy in Cardiac Myocytes
Authors: Yamamoto Keiji , Ohki Ruri , Lee Richard T. , Ikeda Uichi , Shimada Kazuyuki
Published: September 2007

Background

Peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the nuclear receptor superfamily. PPARγ mRNA is present in cardiac myocytes; however, whether PPARγ affects cardiac hypertrophy remains unknown.

Methods and Results

We investigated the effects of PPARγ activators on cardiac hypertrophy in neonatal rat cardiac myocytes. Cyclic 4% biaxial mechanical strain caused enlargement of cardiac myocytes (1.3-fold versus control,
P
<0.0001), but the PPARγ activators troglitazone and 15-deoxy-Δ
12-14
-prostaglandin J
2
(15d-PGJ
2
) (10 μmol/L) inhibited this effect (troglitazone, −72%,
P
<0.0005; 15d-PGJ
2
, −88%,
P
<0.0002). Total cell protein was increased by mechanical strain (control, 164.3 μg/dish; strain, 265.5,
P
<0.0002), and this effect was inhibited by troglitazone and 15d-PGJ
2
(troglitazone, −61%,
P
<0.005; 15d-PGJ
2
, −72%,
P
<0.001). [
3
H]Leucine uptake was also increased by mechanical strain (1.9-fold versus control,
P
<0.002), and this increase was inhibited by troglitazone and 15d-PGJ
2
(troglitazone, −52% at 10 μmol/L,
P
<0.01; 15d-PGJ
2
, −70% at 10 μmol/L,
P
<0.005). An increase in [
3
H]leucine uptake induced by angiotensin II or phenylephrine was significantly inhibited by troglitazone and 15d-PGJ
2
. Mechanical strain induced mRNA expression for brain natriuretic peptide, but PPARγ activators inhibited this induction. Furthermore, PPARγ activators inhibited mechanically induced activation of nuclear factor (NF)-κB. Pyrrolidine dithiocarbamate, an inhibitor of NF-κB activation, inhibited strain-induced [
3
H]leucine uptake (−50% at 100 μmol/L,
P
<0.05).

Conclusions

These results demonstrate that PPARγ activators inhibit cardiac hypertrophy in cardiac myocytes and suggest that PPARγ activators may regulate cardiomyocyte hypertrophy at least partially through the NF-κB pathway.
Angiotensin II Induces Circadian Gene Expression of Clock Genes in Cultured Vascular Smooth Muscle Cells
Authors: Nonaka Hidemi , Emoto Noriaki , Ikeda Koji , Fukuya Hiroyuki , Rohman Mohammad Saifur , Raharjo Sunu Budhi , Yagita Kazuhiro , Okamura Hitoshi , Yokoyama Mitsuhiro
Published: September 2007

BackgroundDaily rhythms of mammalian physiology and endocrinology are regulated by circadian pacemakers. The master circadian pacemaker resides in the suprachiasmatic nucleus, which is located in the hypothalamus of the brain, but circadian oscillators also exist in peripheral tissues. Because many studies have demonstrated apparent circadian variations in the frequency of cardiovascular disorders, it is of great interest to investigate a possible relation between circadian gene expression and cardiovascular function. We examined whether a circadian oscillation system exists in the aorta and/or in cultured vascular smooth muscle cells (VSMCs).

Methods and ResultsThe mRNA levels of clock genes were assayed by northern blot analysis. The mouse aorta showed a clear circadian oscillation in the expression ofmPer2,dbp, andBmal1. Brief treatment of VSMCs with angiotensin II induced a robust increase inmPer2gene expression, followed by a marked reduction inmPer2mRNA levels and subsequent synchronous cycling ofmPer2,dbp, andBmal1mRNAs. The induction ofmPer2in VSMCs by angiotensin II was completely abolished by treatment with CV11947, a specific angiotensin II type1 receptor antagonist.

ConclusionsThe present results demonstrate that the aorta and VSMCs possess a circadian oscillation system which is comparable to that of the suprachiasmatic nucleus and that the circadian gene expression in VSMCs is induced by angiotensin II through the angiotensin II type1 receptor. Our in vitro system will provide a useful tool to further analyze the physiological significance of the peripheral clock in cardiovascular function.
Electrophysiological Effects of Ibutilide in Patients With Accessory Pathways
Authors: Glatter Kathryn A. , Dorostkar Parvin C. , Yang Yanfei , Lee Randall J. , Van Hare George F. , Keung Edmund , Modin Gunnard , Scheinman Melvin M.
Published: September 2007

BackgroundAtrial fibrillation (AF) may cause life-threatening ventricular arrhythmias in patients with Wolff-Parkinson-White syndrome. We prospectively evaluated the effects of ibutilide on the conduction system in patients with accessory pathways (AP).

Methods and ResultsIn part I, we gave ibutilide to 22 patients (18 men, 31±13 years of age) who had AF during electrophysiology study, including 6 pediatric patients ≤18 years of age. Ibutilide terminated AF in 21 of 22 patients (95%) during or 8±5 minutes after infusion and prolonged the shortest preexcited R-R interval during AF. Successful ablation was performed in all patients. In part II, ibutilide was given to 18 patients (14 men, 28±21 years) to assess its effects on the AP and conduction system. Ibutilide prolonged the antegrade atrioventricular node effective refractory period (ERP) (from 252±60 to 303±70 ms;P<0.02). Ibutilide caused transient loss of the delta wave in 1 patient and abolished inducible tachycardia in 2 patients, although retrograde mapping still allowed for successful AP ablation. The antegrade AP ERP prolonged from 275±40 to 320±60 ms (P<0.01), as did the antegrade AP block cycle length; the retrograde AP ERP and block cycle length similarly prolonged with ibutilide. The relative and effective refractory period of the His-Purkinje system increased in 61% of patients after ibutilide. There were no adverse side effects.

ConclusionsWe report the use of ibutilide in terminating AP-mediated AF, including the first report in the pediatric population. Ibutilide prolonged refractoriness of the atrioventricular node, His-Purkinje system, and AP.
Fractional Flow Reserve Compared With Intravascular Ultrasound Guidance for Optimizing Stent Deployment
Authors: Fearon William F. , Luna Jorge , Samady Habib , Powers Eric R. , Feldman Ted , Dib Nabil , Tuzcu E. Murat , Cleman Michael W. , Chou Tony M. , Cohen David J. , Ragosta Michael , Takagi Atsushi , Jeremias Allen , Fitzgerald Peter J. , Yeung Alan C. , Kern Morton J. , Yock Paul G.
Published: September 2007

Background

Determination of fractional flow reserve (FFR) has been proposed as a means to assess stent deployment. In this prospective, multicenter trial, we evaluate the use of FFR to optimize stenting by comparing it with standard intravascular ultrasound (IVUS) criteria.

Methods and Results

Eighty-four stable patients with isolated coronary lesions underwent coronary stent deployment starting at 10 atm and increased serially by 2 atm until the FFR was ≥0.94 or 16 atm was achieved. IVUS was then performed. FFR was measured with a coronary pressure wire with intracoronary adenosine to induce hyperemia. The diagnostic characteristics of an FFR <0.94 to predict suboptimal stent expansion by IVUS, defined in both absolute and relative terms, were calculated. Over a range of IVUS criteria, the highest sensitivity, specificity, and predictive accuracy of FFR were 80%, 30%, and 42%, respectively. Receiver operator characteristic analysis defined an optimal FFR cut point at ≥0.96; at this threshold, the sensitivity, specificity, and predictive accuracy of FFR were 75%, 58%, and 62%, respectively (
P
=0.03 for comparison of predictive accuracy,
P
=0.01 for concordance between FFR and IVUS). The negative predictive value was 88%. Significantly better diagnostic performance was achieved in a subgroup that received higher doses (>30 μg) of intracoronary adenosine during pressure measurements, suggesting that FFR might be overestimated in the other group.

Conclusions

A fractional flow reserve <0.96, measured after stent deployment, predicts a suboptimal result based on validated intravascular ultrasound criteria; however, an FFR ≥0.96 does not reliably predict an optimal stent result. Higher doses of intracoronary adenosine than previously used to measure FFR improve these results.
In Cardiomyocyte Hypoxia, Insulin-Like Growth Factor-I-Induced Antiapoptotic Signaling Requires Phosphatidylinositol-3-OH-Kinase-Dependent and Mitogen-Activated Protein Kinase-Dependent Activation of the Transcription Factor cAMP Response Element-Binding Protein
Authors: Mehrhof Felix B. , Müller Frank- Ulrich , Bergmann Martin W. , Li Peifeng , Wang Yibin , Schmitz Wilhelm , Dietz Rainer , von Harsdorf Rüdiger
Published: September 2007

Background

A variety of pathologic stimuli lead to apoptosis of cardiomyocytes. Survival factors like insulin-like growth factor-I (IGF-I) exert anti-apoptotic effects in the heart. Yet the underlying signaling pathways are poorly understood.

Methods and Results

In a model of hypoxia-induced apoptosis of cultured neonatal cardiomyocytes, IGF-I prevented cell death in a dose-dependent manner. Antiapoptotic signals induced by IGF-I are mediated by more than one signaling pathway, because pharmacological inhibition of the phosphatidylinositol-3-OH-kinase (PI3K) or the mitogen-activated protein kinase kinase (MEK1) signaling pathway both antagonize the protective effect of IGF-I in an additive manner. IGF-I-stimulation was followed by a PI3K-dependent phosphorylation of AKT and BAD and an MEK1-dependent phosphorylation of extracellular signal-regulated kinase (ERK) 1 and ERK2. IGF-I also induced phosphorylation of cAMP response element-binding protein (CREB) in a PI3K- and MEK1-dependent manner. Ectopic overexpression of a dominant-negative mutant of CREB abolished the antiapoptotic effect of IGF-I. Protein levels of the antiapoptotic factor bcl-2 increased after longer periods of IGF-I-stimulation, which could be reversed by pharmacological inhibition of PI3K as well as MEK1 and also by overexpression of dominant-negative CREB.

Conclusions

In summary, our data demonstrate that in cardiomyocytes, the antiapoptotic effect of IGF-I requires both PI3K- and MEK1-dependent pathways leading to the activation of the transcription factor CREB, which then induces the expression of the antiapoptotic factor bcl-2.