bluuebunny/crossref_metadata_2025 huggingface dataset:
Vitamin C Inhibits Endothelial Cell Apoptosis in Congestive Heart Failure
Authors: Rössig Lothar , Hoffmann Jörg , Hugel Bénédicte , Mallat Ziad , Haase Astrid , Freyssinet Jean-Marie , Tedgui Alain , Aicher Alexandra , Zeiher Andreas M. , Dimmeler Stefanie
Published: September 2007

Background

Proinflammatory cytokines like tumor necrosis factor-α and oxidative stress induce apoptotic cell death in endothelial cells (ECs). Systemic inflammation and increased oxidative stress in congestive heart failure (CHF) coincide with enhanced EC apoptosis and the development of endothelial dysfunction. Therefore, we investigated the effects of antioxidative vitamin C therapy on EC apoptosis in CHF patients.

Methods and Results

Vitamin C dose dependently suppressed the induction of EC apoptosis by tumor necrosis factor-α and angiotensin II in vitro as assessed by DNA fragmentation, DAPI nuclear staining, and MTT viability assay. The antiapoptotic effect of vitamin C was associated with reduced cytochrome C release from mitochondria and the inhibition of caspase-9 activity. To assess EC protection by vitamin C in CHF patients, we prospectively randomized CHF patients in a double-blind trial to vitamin C treatment versus placebo. Vitamin C administration to CHF patients markedly reduced plasma levels of circulating apoptotic microparticles to 32±8% of baseline levels, whereas placebo had no effect (87±14%,
P
<0.005). In addition, vitamin C administration suppressed the proapoptotic activity on EC of the serum of CHF patients (
P
<0.001).

Conclusions

Administration of vitamin C to CHF patients suppresses EC apoptosis in vivo, which might contribute to the established functional benefit of vitamin C supplementation on endothelial function.
Cyclooxygenase-1 and -2 Knockout Mice Demonstrate Increased Cardiac Ischemia/Reperfusion Injury but Are Protected by Acute Preconditioning
Authors: Camitta Michael G.W. , Gabel Scott A. , Chulada Patricia , Bradbury J. Alyce , Langenbach Robert , Zeldin Darryl C. , Murphy Elizabeth
Published: September 2007

Background

The purpose of this study was to examine the effects of cyclooxygenase (COX) deficiency on baseline functional characteristics and on recovery of left ventricular developed pressure (LVDP) after 20 minutes of global ischemia and 40 minutes of reperfusion in untreated and preconditioned hearts.

Methods and Results

Compared with hearts from wild-type (WT) and COX-2
−/−
mice, baseline cardiac prostaglandin (PG) E
2
and 6-keto-PGF
1α
levels were significantly decreased in hearts from COX-1
−/−
mice. After ischemia, cardiac PGE
2
levels increased in WT, COX-1
−/−
, and COX-2
−/−
mice (
P
<0.05). Recovery of function (LVDP) after global ischemia in hearts from COX-1
−/−
and COX-2
−/−
mice was significantly less than in WT hearts. Pretreatment of WT mice with indomethacin for 2 days before ischemia significantly decreased LVDP recovery; however, perfusion of WT hearts with indomethacin for 40 minutes before ischemia did not significantly alter LVDP recovery. Postischemic recovery of LVDP in COX-1
−/−
and COX-2
−/−
was unchanged by perfusion with 5 μmol/L PGE
2
, PGD
2
, PGF
2α
, or carboprostacyclin. Hearts from COX-2
−/−
mice showed an increase in ischemic contracture compared with hearts from WT and COX-1
−/−
mice; however, hearts did not differ in intracellular pH, ATP, or inorganic phosphate during ischemia. Ischemic preconditioning significantly improved postischemic LVDP recovery in COX-1
−/−
, COX-2
−/−
, and WT mice.

Conclusions

Genetic disruption or 2-day chemical inhibition of COX-1 and COX-2 decreases recovery of LVDP after ischemia; however, acute perfusion with indomethacin is not detrimental. These data are consistent with protection due to the altered expression of some protein that is modulated by COX or its metabolites.
Hormone Therapy and In-Hospital Survival After Myocardial Infarction in Postmenopausal Women
Authors: Shlipak Michael G. , Angeja Brad G. , Go Alan S. , Frederick Paul D. , Canto John G. , Grady Deborah
Published: September 2007

Background

Although postmenopausal hormone therapy (HRT) commonly is used in hope of preventing coronary heart disease, the effect of HRT on case fatality of myocardial infarction has never been studied. We evaluated HRT as a predictor of survival after MI in postmenopausal women.

Methods and Results

The present study was performed with 114 724 women of age ≥55 years with confirmed myocardial infarction who presented between April 1998 and January 2000 to 1 of 1674 hospitals participating in the National Registry of Myocardial Infarction-3. Presenting characteristics, treatment, and clinical outcome data were obtained by chart review. At time of hospitalization, 7353 (6.4%) women reported current use of HRT, defined as use of estrogen, progestin, or estrogen/progestin for reasons other than contraception. Unadjusted mortality was 7.4% in users of HRT and 16.2% in nonusers (odds ratio 0.41, 95% confidence interval 0.36 to 0.43). After adjustments were made for prior medical history, clinical characteristics, treatments received in-hospital, and likelihood of receiving HRT, HRT remained associated with an improved rate of survival (odds ratio 0.65, 95% confidence interval 0.59 to 0.72). Significant association of HRT with decreased mortality after myocardial infarction was observed in all age strata.

Conclusions

Postmenopausal HRT appears to be associated with reduced mortality after myocardial infarction. This finding could be caused by therapeutic effect of HRT, selection and adherence bias, or some combination of both.
Adverse Hemodynamic Effects of Interrupting Chest Compressions for Rescue Breathing During Cardiopulmonary Resuscitation for Ventricular Fibrillation Cardiac Arrest
Authors: Berg Robert A. , Sanders Arthur B. , Kern Karl B. , Hilwig Ronald W. , Heidenreich Joseph W. , Porter Matthew E. , Ewy Gordon A.
Published: September 2007

Background

Despite improving arterial oxygen saturation and pH, bystander cardiopulmonary resuscitation (CPR) with chest compressions plus rescue breathing (CC+RB) has not improved survival from ventricular fibrillation (VF) compared with chest compressions alone (CC) in numerous animal models and 2 clinical investigations.

Methods and Results

After 3 minutes of untreated VF, 14 swine (32±1 kg) were randomly assigned to receive CC+RB or CC for 12 minutes, followed by advanced cardiac life support. All 14 animals survived 24 hours, 13 with good neurological outcome. For the CC+RB group, the aortic relaxation pressures routinely decreased during the 2 rescue breaths. Therefore, the mean coronary perfusion pressure of the first 2 compressions in each compression cycle was lower than those of the final 2 compressions (14±1 versus 21±2 mm Hg,
P
<0.001). During each minute of CPR, the number of chest compressions was also lower in the CC+RB group (62±1 versus 92±1 compressions,
P
<0.001). Consequently, the integrated coronary perfusion pressure was lower with CC+RB during each minute of CPR (
P
<0.05 for the first 8 minutes). Moreover, at 2 to 5 minutes of CPR, the median left ventricular blood flow by fluorescent microsphere technique was 60 mL · 100 g
−1
· min
−1
with CC+RB versus 96 mL · 100 g
−1
· min
−1
with CC,
P
<0.05. Because the arterial oxygen saturation was higher with CC+RB, the left ventricular myocardial oxygen delivery did not differ.

Conclusions

Interrupting chest compressions for rescue breathing can adversely affect hemodynamics during CPR for VF.
Noninvasive Prediction of Ultimate Infarct Size at the Time of Acute Coronary Occlusion Based on the Extent and Magnitude of Collateral-Derived Myocardial Blood Flow
Authors: Coggins Matthew P. , Sklenar Jiri , Le D. Elizabeth , Wei Kevin , Lindner Jonathan R. , Kaul Sanjiv
Published: September 2007

Background

We hypothesized that by detecting regions with adequate collateral-derived myocardial blood flow (MBF) within the risk area (RA), we could predict ultimate infarct size (IS) at the time of coronary occlusion.

Methods and Results

Group 1 dogs (n=15) underwent coronary occlusion without reperfusion, whereas group 2 dogs (n=6) underwent both occlusion and reperfusion. RA was measured with aortic root injections of microbubbles. Myocardial contrast echocardiography (MCE) was performed with high mechanical index intermittent harmonic imaging at pulsing intervals (PIs) of <1 to 30 cardiac cycles during an intravenous infusion of microbubbles (Sonozoid). MBF was measured with radiolabeled microspheres, and postmortem tissue staining was used to determine IS. Perfusion defect size (PDS) on MCE varied with the PI and was largest at a PI of 2.6±0.4 seconds, where it correlated well with RA (
r
=0.82). PDS was smallest at a PI of ≥10.6±1.5 seconds, where it correlated closely with IS (
r
≥0.92). Areas that underwent necrosis could be identified early after coronary occlusion as having the lowest microvascular flow velocity (β) and MCE-derived MBF (A×β). The results were similar with or without reperfusion. Because of variability in collateral-derived MBF, there was no correlation between RA and ultimate IS (
P
=0.37). The extent of regional dysfunction also correlated poorly with IS (
r
=0.31).

Conclusions

MCE can be used immediately after coronary occlusion to define ultimate IS by measuring the magnitude and spatial extent of collateral-derived residual MBF within the RA. Thus, it could help individualize risk and management in acute myocardial infarction.
Altered Autonomic Support of Arterial Blood Pressure With Age in Healthy Men
Authors: Jones Pamela Parker , Shapiro Linda F. , Keisling Gretchen A. , Jordan Jens , Shannon John R. , Quaife Robert A. , Seals Douglas R.
Published: September 2007

Background

Primary aging is associated with changes in the autonomic nervous system (ANS), but the functional significance of these changes for systemic circulatory control of arterial blood pressure (BP) is unknown. We tested the hypothesis that ANS support of BP is altered in healthy older humans.

Methods and Results

A total of 23 young (aged 24±1 years; systolic/diastolic BP, 126±2/66±1 mm Hg) and 16 older (aged 65±1 years; systolic/diastolic BP, 125±3/62±2 mm Hg) healthy men were studied before and during ganglionic blockade (intravenous trimethaphan). The reduction in mean BP (radial artery catheter) with trimethaphan was almost twice as great in the older men (−33±2 versus −19±2 mm Hg; −40% versus −22% of baseline;
P
<0.01) due to a lack of increase in heart rate (3±2 versus 25±2 bpm;
P
<0.001) and cardiac output (−0.42±0.19 versus 1.01±0.26 L/min;
P
<0.001); the decreases in systemic vascular resistance were not different. The absence of tachycardia in the older men was associated with reduced baseline heart rate variability (HRV,
P
<0.05); the change in heart rate with trimethaphan correlated with the standard deviation of the R-R intervals (HRV
SD R-R interval
;
r
=0.57,
P
<0.001). Among individual subjects (pooled groups), the reductions in mean BP with trimethaphan were most strongly related to measures of sympathetic activity (
r
=0.58 to 0.67,
P
<0.005), change in mean BP with intravenous phenylephrine (
r
=0.57,
P
<0.001), and HRV
SD R-R interval
(
r
=−0.40,
P
<0.01).

Conclusions

ANS support of BP is altered with age in healthy men due to less cardiac vagal inhibition of heart rate and cardiac output. Basal sympathetic activity and α-adrenergic vascular sensitivity are also key physiological correlates of ANS support of BP in healthy men.
Abnormal Epicardial Coronary Resistance in Patients With Diffuse Atherosclerosis but “Normal” Coronary Angiography
Authors: De Bruyne Bernard , Hersbach Ferry , Pijls Nico H.J. , Bartunek Jozef , Bech Jan-Willem , Heyndrickx Guy R. , Gould K. Lance , Wijns William
Published: September 2007

Background

Coronary arteries without focal stenosis at angiography are generally considered non–flow-limiting. However, atherosclerosis is a diffuse process that often remains invisible at angiography. Accordingly, we hypothesized that in patients with coronary artery disease, nonstenotic coronary arteries induce a decrease in pressure along their length due to diffuse coronary atherosclerosis.

Methods and Results

Coronary pressure and fractional flow reserve (FFR), as indices of coronary conductance, were obtained from 37 arteries in 10 individuals without atherosclerosis (group I) and from 106 nonstenotic arteries in 62 patients with arteriographic stenoses in another coronary artery (group II). In group I, the pressure gradient between aorta and distal coronary artery was minimal at rest (1±1 mm Hg) and during maximal hyperemia (3±3 mm Hg). Corresponding values were significantly larger in group II (5±4 mm Hg and 10±8 mm Hg, respectively; both
P
<0.001). The FFR was near unity (0.97±0.02; range, 0.92 to 1) in group I, indicating no resistance to flow in truly normal coronary arteries, but it was significantly lower (0.89±0.08; range, 0.69 to 1) in group II, indicating a higher resistance to flow. In 57% of arteries in group II, FFR was lower than the lowest value in group I. In 8% of arteries in group II, FFR was <0.75, the threshold for inducible ischemia.

Conclusion

Diffuse coronary atherosclerosis without focal stenosis at angiography causes a graded, continuous pressure fall along arterial length. This resistance to flow contributes to myocardial ischemia and has consequences for decision-making during percutaneous coronary interventions.
Estrogen Receptor–Mediated, Nitric Oxide–Dependent Modulation of the Immunologic Barrier Function of the Endothelium
Authors: Amant Carole , Holm Pernille , Xu Shu-hua , Tritman Neil , Kearney Marianne , Losordo Douglas W.
Published: September 2007

Background

Premenopausal women have a lower incidence of coronary artery disease than postmenopausal women or same-age men. Although the mechanisms of this apparent relative protection against atherosclerosis remain ill defined, estradiol, which is present in higher concentrations before menopause, is considered to play a central role. Recently, Fas ligand (FasL) expression by the vascular endothelium has been shown to inhibit the migration of inflammatory cells into the vessel wall, an event that is considered crucial for the development of atherosclerosis.

Methods and Results

The regulation of endothelial FasL expression by estradiol was investigated in vivo and in vitro. In an ovariectomized, cholesterol-clamped rabbit model, FasL expression was shown to be downregulated by elevations in serum cholesterol, which also resulted in invasion of the arterial wall by macrophages. Estradiol replacement resulted in restoration of FasL expression, with resultant inhibition of leukocyte traffic across the endothelium. Inhibition of NO production by addition of L-NAME to the drinking water of the estradiol-treated rabbits abrogated these effects. In vitro, estradiol is shown to regulate FasL expression at the transcriptional level via an estrogen receptor–mediated, NO-dependent mechanism.

Conclusions

Estradiol transcriptionally regulates endothelial FasL expression by a mechanism involving at least one of the estrogen receptors. In an animal model of atherosclerosis, estradiol restores FasL expression, which is suppressed by atherogenic levels of serum cholesterol. The maintenance of endothelial FasL expression by estradiol may represent a mechanism of estrogen’s apparent antiatherogenic effect.
Coronary Artery Calcification in Older Adults to Age 99
Authors: Newman Anne B. , Naydeck Barbara L. , Sutton-Tyrrell Kim , Feldman Adam , Edmundowicz Daniel , Kuller Lewis H.
Published: September 2007

Background

Coronary artery calcification has been proposed as a noninvasive method to assess cardiovascular disease (CVD) risk. However, the prevalence and risk factors for coronary artery calcification in populations >65 years have not been well studied.

Methods and Results

Electron beam tomography was performed to assess coronary artery calcium (CAC) in 614 older adults aged, on average, 80 years (range, 67 to 99 years); 367 (60%) were women, and 143 (23%) were black. Calcium scores ranged from 0 to 5459. Median scores were 622 for men and 205 for women. Scores increased by age and were lower in blacks than in whites. Nine percent of subjects (n=57) had no CAC, and 31% (n=190) had a score lower than 100. A history of CVD was associated with calcium score. Age, male sex, white race, CVD, triglyceride level, pack-years of smoking, and asthma, emphysema, or bronchitis (chronic obstructive pulmonary disease) were independently associated with CAC score in the fourth quartile.

Conclusions

A wide range of CAC scores was observed, suggesting adaptation with aging. CAC may have potential to predict CVD in older adults, but this remains to be determined.
Carotid Intimal-Medial Thickness Is Related to Cardiovascular Risk Factors Measured From Childhood Through Middle Age
Authors: Davis Patricia H. , Dawson Jeffrey D. , Riley Ward A. , Lauer Ronald M.
Published: September 2007

Background

Higher carotid intimal-medial thickness (IMT) is associated with cardiovascular risk factors and is predictive of coronary artery disease and stroke in older adults. Carotid IMT was measured in young and middle-aged adults to determine its relationship with risk factors measured (1) in childhood, (2) currently, and (3) as a “load” from childhood to adulthood.

Methods and Results

Carotid ultrasound studies were performed in 346 men and 379 women aged 33 to 42 years who were representative of a cohort followed since childhood and who live in Muscatine, Iowa. The mean of the measurements of maximal carotid IMT at 12 locations was determined for each subject. A medical questionnaire was completed, and measurements of anthropometric characteristics and risk factors were obtained. The mean maximum carotid IMT was 0.79±0.12 mm for men and 0.72±0.10 mm for women. On the basis of multivariable analysis, the significant current predictors of IMT were age and LDL cholesterol in both sexes and diastolic blood pressure in women. Total cholesterol was a significant childhood predictor in both sexes, while childhood body mass index was significant only in women. For men, LDL cholesterol, HDL cholesterol, and diastolic blood pressure were predictive of carotid IMT in a risk factor load model, whereas in women, LDL cholesterol, body mass index, and triglycerides were predictive.

Conclusions

Higher carotid IMT in young and middle-aged adults is associated with childhood and current cardiovascular risk factors, as well as risk factor load.
Effect of an Aggressive Lipid-Lowering Strategy on Progression of Atherosclerosis in the Left Main Coronary Artery From Patients in the Post Coronary Artery Bypass Graft Trial
Authors: White Carl W. , Gobel Fredarick L. , Campeau Lucien , Knatterud Genell L. , Forman Sandra A. , Forrester James S. , Geller Nancy L. , Herd J. Alan , Hickey Ann , Hoogwerf Byron J. , Hunninghake Donald B. , Rosenberg Yves , Terrin Michael L. ,   the Post Coronary Artery Bypass Graft Trial Investigators
Published: September 2007

Background

The Post Coronary Artery Bypass Graft Trial, designed to compare the effects of two lipid-lowering regimens and low-dose anticoagulation versus placebo on progression of atherosclerosis in saphenous vein grafts of patients who had had CABG surgery, demonstrated that aggressive lowering of LDL cholesterol levels to a mean yearly cholesterol level from 93 to 97 mg/dL compared with a moderate reduction to a level of 132 to 136 mg/dL decreased the progression of atherosclerosis in saphenous vein grafts. Low-dose anticoagulation did not affect progression. This secondary analysis tested the hypothesis that a similar decrease in progression of atherosclerosis would also be present in native coronary arteries as measured in the left main coronary artery (LMCA).

Methods and Results

A sample of 402 patients was randomly selected from 1102 patients who had baseline and follow-up views of the LMCA suitable for analysis. Patients treated with the aggressive lipid-lowering strategy had less progression of atherosclerosis in the LMCA as measured by changes in minimum (
P
=0.0003) lumen diameter or the maximum percent stenosis (
P
=0.001), or the presence of substantial progression (
P
=0.008), or vascular occlusion (
P
=0.005) when compared with the moderate strategy.

Conclusions

A strategy of aggressive lipid lowering results in significantly less atherosclerosis progression than a moderate approach in LMCAs.
Out-of-Hospital Cardiac Arrest in Men and Women
Authors: Kim Catherine , Fahrenbruch Carol E. , Cobb Leonard A. , Eisenberg Mickey S.
Published: September 2007

Background

The incidence of sudden cardiac death is roughly 3 times greater in men than in women. However, in patients treated for out-of-hospital cardiac arrest, the relationships between sex and survival after adjustment for age and cardiac rhythm are unclear.

Methods and Results

In this retrospective cohort study, we examined 7069 men and 2582 women who were treated for out-of-hospital cardiac arrest in Seattle and suburban King County between 1990 and 1998. We compared successful prehospital resuscitation (hospital admission) and survival from event to discharge in men and women. Women had markedly reduced rates of ventricular fibrillation (VF), slightly older age, fewer witnessed arrests, and fewer arrests in public locations than men. Although their unadjusted resuscitation rate was lower (29% versus 32%,
P
<0.0001), women had a greater likelihood of resuscitation than men after adjustment for VF (odds ratio [OR] 1.13; 95% confidence interval [CI], 1.03 to 1.25) and after adjustment for VF plus additional factors (OR, 1.27; 95% CI, 1.14 to 1.41). The difference in resuscitation rates between men and women decreased as they aged (test for trend,
P
<0.0001). Unadjusted survival rates were also lower in women than in men (11% versus 15%,
P
<0.0001). Women had similar survival after adjustment for VF (OR, 0.97; 95% CI, 0.85 to 1.11) and after adjustment for VF plus additional factors (OR, 1.09; 95% CI, 0.93 to 1.27).

Conclusions

The lower unadjusted resuscitation and survival rates observed in women were primarily due to women’s lower incidence of VF, a relatively favorable cardiac rhythm. After adjustment for VF and other factors, women had higher resuscitation rates than men, but similar rates of survival from event to discharge.
Sex Steroids Used in Hormonal Treatment Increase Vascular Procoagulant Activity by Inducing Thrombin Receptor (PAR-1) Expression
Authors: Herkert Olaf , Kuhl Herbert , Sandow Jurgen , Busse Rudi , Schini-Kerth Valérie B.
Published: September 2007

Background

The use of sex steroids in oral contraception or hormonal replacement therapy is associated with an increased risk of cardiovascular thromboembolic complications. Although both the estrogen and the progestin components have been involved, the underlying mechanisms responsible are unclear.

Methods and Results

This study examined whether sex steroids promote hemostasis indirectly by increasing the procoagulant activity of blood vessels. Treatment of vascular smooth muscle cells with several progestins (progesterone, 3-keto-desogestel, gestodene, and medroxyprogesterone acetate) upregulated proteolytically activatable thrombin receptor (PAR-1) expression, resulting in a potentiated thrombin-induced tissue factor expression and surface procoagulant activity. In contrast, neither the progestins levonorgestrel, norethisterone, and norgestimate nor the synthetic estrogen 17α-ethinylestradiol had such effects. The effect of the stimulatory progestins, which induce glucocorticoid-like effects in several cell systems, was mimicked by dexamethasone and inhibited by the progesterone and glucocorticoid receptor antagonist RU-38486. In addition, long-term administration of progesterone, 3-keto-desogestrel, or medroxyprogesterone acetate to ovariectomized rats increased PAR-1 protein level in the arterial wall, resulting in an increased responsiveness of isolated aortic rings to thrombin.

Conclusions

These data demonstrate that several progestins markedly potentiate the vascular procoagulant effects of thrombin by increasing the availability of membrane thrombin receptors in the smooth muscle, an effect that is most likely due to their glucocorticoid-like activity.
Endothelial Cell Dysfunction in Mice After Transgenic Knockout of Type 2, but Not Type 1, 11β-Hydroxysteroid Dehydrogenase
Authors: Hadoke Patrick W.F. , Christy Clare , Kotelevtsev Yuri V. , Williams Brent C. , Kenyon Christopher J. , Seckl Jonathan R. , Mullins John J. , Walker Brian R.
Published: September 2007

Background

11β-Hydroxysteroid dehydrogenase (11βHSD) isozymes catalyze the interconversion of active and inactive glucocorticoids, allowing local regulation of corticosteroid receptor activation. Both are present in the vessel wall; here, using mice with selective inactivation of 11βHSD isozymes, we test the hypothesis that 11βHSDs influence vascular function.

Methods and Results

Thoracic aortas were obtained from weight-matched male wild-type (MF1×129 cross
+/+
), 11βHSD1
−/−
, and 11βHSD2
−/−
mice. mRNA for both isozymes was detected in wild-type aortas by RT-PCR. 11βHSD activity in aortic homogenates (48.81±4.65% conversion) was reduced in both 11βHSD1
−/−
(6.36±2.47% conversion;
P
<0.0002) and 11βHSD2
−/−
(24.71±3.69;
P
=0.002) mice. Functional responses were unaffected in aortic rings isolated from 11βHSD1
−/−
mice. In contrast, aortas from 11βHSD2
−/−
mice demonstrated selectively enhanced constriction to norepinephrine (E
max
4.28±0.56 versus 1.72±0.47 mN/mm;
P
=0.004) attributable to impaired endothelium-derived nitric oxide activity. Relaxation responses to endothelium-dependent and -independent vasodilators were also impaired. To control for chronic renal mineralocorticoid excess, MF1 mice were treated with fludrocortisone (16 weeks) but did not reproduce the functional changes observed in 11βHSD2
−/−
mice.

Conclusions

Although both 11βHSD isozymes are present in the vascular wall, reactivation of glucocorticoids by 11βHSD1 does not influence aortic function. Mice with 11βHSD2 knockout, however, have endothelial dysfunction causing enhanced norepinephrine-mediated contraction. This appears to be independent of renal sodium retention and may contribute to hypertension in 11βHSD2 deficiency.
Metabolic Gene Expression in Fetal and Failing Human Heart
Authors: Razeghi Peter , Young Martin E. , Alcorn Joseph L. , Moravec Christine S. , Frazier O.H. , Taegtmeyer Heinrich
Published: September 2007

Background
—

Previous studies suggest that the failing heart reactivates fetal genes and reverts to a fetal pattern of energy substrate metabolism. We tested this hypothesis by examining metabolic gene expression profiles in the fetal, nonfailing, and failing human heart.

Methods and Results
—

Human left ventricular tissue (apex) was obtained from 9 fetal, 10 nonfailing, and 10 failing adult hearts. Using quantitative reverse transcription-polymerase chain reaction, we measured transcript levels of atrial natriuretic factor, myosin heavy chain-α and -β, and 13 key regulators of energy substrate metabolism, of which 3 are considered “adult” isoforms (GLUT4, mGS, mCPT-I) and 3 are considered “fetal” isoforms (GLUT1, lGS, and lCPT-I), primarily through previous studies in rodent models. Compared with the nonfailing adult heart, steady-state mRNA levels of atrial natriuretic factor were increased in both the fetal and the failing heart. The 2 myosin heavy chain isoforms showed the highest expression level in the nonfailing heart. Transcript levels of most of the metabolic genes were higher in the nonfailing heart than the fetal heart. Adult isogenes predominated in all groups and always showed a greater induction than the fetal isogenes in the nonfailing heart compared with the fetal heart. In the failing heart, the expression of metabolic genes decreased to the same levels as in the fetal heart.

Conclusions
—

In the human heart, metabolic genes exist as constitutive and inducible forms. The failing adult heart reverts to a fetal metabolic gene profile by downregulating adult gene transcripts rather than by upregulating fetal genes.
Impact of Hyperthyroidism and Its Correction on Vascular Reactivity in Humans
Authors: Napoli Raffaele , Biondi Bernadette , Guardasole Vincenzo , Matarazzo Margherita , Pardo Francesco , Angelini Valentina , Fazio Serafino , Saccà Luigi
Published: September 2007

Background
—

Although thyroid hormone (TH) exerts relevant effects on the cardiovascular system, it is unknown whether TH also regulates vascular reactivity in humans.

Methods and Results
—

We studied 8 patients with hyperthyroidism, basally (H) and 6 months after euthyroidism was restored by methimazole (EU). Thirteen healthy subjects served as control subjects (C). We measured forearm blood flow (FBF) by strain-gauge plethysmography during intrabrachial graded infusion of acetylcholine, sodium nitroprusside (SNP), norepinephrine, and L-NMMA (inhibitor of NO synthesis). Basal FBF (in mL · dL
−1
· min
−1
) was markedly higher in H than in C (5.8±1.2 and 1.9±0.1, respectively;
P
<0.001) and was close to normal in EU (2.6±0.3,
P
<0.01 versus H). During acetylcholine infusion, FBF increased much more in H (+33±5) than in C (+14±3,
P
<0.01 versus H) and in EU (+20±5,
P
=0.01 versus H and
P
=NS versus C). In contrast, the response to SNP infusion was comparable in the patients and control subjects. During norepinephrine infusion, the fall in FBF was much more pronounced in H (−6±1) than in C (−0.7±0.3,
P
<0.005 versus H) and in EU (−1.5±0.3,
P
<0.01 versus H). Finally, inhibition of NO synthesis by L-NMMA decreased FBF by 2.8±0.6, 0.61±0.7, and 1.4±0.3 in H, C, and EU, respectively (H versus C and EU,
P
<0.05).

Conclusions
—

In hyperthyroidism, (1) the marked basal vasodilation is largely accounted for by excessive endothelial NO production, (2) vascular reactivity is exaggerated because of enhanced sensitivity of the endothelial component, (3) the vasoconstrictory response to norepinephrine is potentiated, and (4) this abnormal vascular profile is corrected when euthyroidism is restored by medical therapy. The data demonstrate that vascular endothelium is a specific target of TH.
Interleukin-12 Receptor/STAT4 Signaling Is Required for the Development of Autoimmune Myocarditis in Mice by an Interferon-γ–Independent Pathway
Authors: Afanasyeva Marina , Wang Yan , Kaya Ziya , Stafford Elizabeth A. , Dohmen K. Malte , Sadighi Akha Amir A. , Rose Noel R.
Published: September 2007

Background
—

Interleukin (IL)-12 exerts a potent proinflammatory effect by stimulating T-helper (Th) 1 responses. This effect is believed to be mediated primarily through the activation of STAT4 and subsequent production of interferon (IFN)-γ.

Methods and Results
—

We examined the role of IL-12 receptor (IL-12R) signaling in the development of murine experimental autoimmune myocarditis (EAM) induced by cardiac myosin immunization. Both IL-12Rβ1–deficient mice and STAT4-deficient mice were resistant to the induction of myocarditis. Treatment with exogenous IL-12 exacerbated disease. We questioned whether IFN-γ is required for the disease-promoting activity of IL-12. On the contrary, we found that IFN-γ suppresses EAM. Lack of IFN-γ due to either depletion with an antibody or a genetic deficiency exacerbated myocarditis. Spleens from IFN-γ–deficient mice immunized with cardiac myosin showed increased cellularity; greater numbers of CD3+, CD4+, CD8+, and IL-2–producing cells; and heightened ability to produce cytokines on stimulation in vitro. Treatment of mice with recombinant IFN-γ suppressed the development of myocarditis.

Conclusions
—

IL-12
/
IL-12R/STAT4 signaling promotes the development of EAM. In contrast, IFN-γ plays a protective role. The disease-limiting effects of IFN-γ might be explained by its ability to control the expansion of activated T lymphocytes.
Disordered Cellular Migration and Angiogenesis in
cd39-
Null Mice
Authors: Goepfert Christian , Sundberg Christian , Sévigny Jean , Enjyoji Keiichi , Hoshi Tomokazu , Csizmadia Eva , Robson Simon
Published: September 2007

Background
—

Nucleoside triphosphate diphosphohydrolase-1 (NTPDase1)/CD39 is the major ectonucleotidase of endothelial cells and monocytes and catalyzes phosphohydrolysis of extracellular nucleoside diphosphates (NDP) and triphosphates (NTP, eg, ATP and UTP). Deletion of
cd39
causes perturbations in the hydrolysis of NTP and NDP in the vasculature. Activation of P2 receptors appears to influence endothelial cell chemotactic and mitogenic responses in vitro. Therefore, aberrant regulation of nucleotide P2 receptors may influence angiogenesis in
cd39
-null mice.

Methods and Results
—

In control mice, implanted Matrigel plugs containing growth factors were rapidly populated by monocyte/macrophages, endothelial cells, and pericytes, with the development of new vessels over days. In
cd39
-null mice, migrating cells were completely confined to the tissue-Matrigel interface in a clearly stratified manner. Absolute failure of new vessel ingrowth was consistently observed in the mutant mice. Linked to these findings, chemotaxis of
cd39
-null monocyte/macrophages to nucleotides was impaired in vitro. This abnormality was associated with desensitization of nucleotide receptor P2Y-mediated signaling pathways.

Conclusions
—

Our findings demonstrate a role for NTPDase1 and phosphohydrolysis of extracellular nucleotides in the regulation of the cellular infiltration and new vessel growth in a model of angiogenesis.
Genetic Variation in Coagulation and Fibrinolytic Proteins and Their Relation With Acute Myocardial Infarction
Authors: Boekholdt S. Matthijs , Bijsterveld Nick R. , Moons Arno H.M. , Levi Marcel , Büller Harry R. , Peters Ron J.G.
Published: September 2007

Background
—

It is pathophysiologically conceivable that genetic variations in coagulation and fibrinolytic proteins are associated with the risk of myocardial infarction.

Methods and Results
—

We performed a literature search to identify published case-control studies correlating the factor V Leiden or prothrombin G20210A mutations or fibrinogen G−455A or plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphisms with the risk of myocardial infarction. Studies were included only if they used solid diagnostic criteria and complied with published methodological criteria. A common OR with corresponding 95% CI was calculated for the risk of myocardial infarction in a fixed-effect model according to Mantel-Haenszel. The factor V Leiden and prothrombin G20201A mutations did not significantly correlate with myocardial infarction (OR 1.26, 95% CI 0.94 to 1.67,
P
=0.12 and OR 0.89, 95% CI 0.59 to 1.35,
P
=0.6, respectively). Inclusion of the studies that investigated young patients (<55 years) made the association significant for factor V Leiden (OR 1.29, 95% CI 1.03 to 1.61,
P
=0.02). Homozygosity for the fibrinogen −455A allele was significantly associated with a decreased risk of myocardial infarction (OR 0.66, 95% CI 0.44 to 0.99,
P
=0.04), whereas the PAI-1 4G4G genotype was significantly associated with increased risk (OR 1.20, 95% CI 1.04 to 1.39,
P
=0.04).

Conclusions
—

Associations between these genetic variations and myocardial infarction were weak or absent. In the absence of clinical implications, our results indicate that screening of patients with myocardial infarction for these genetic variations is not warranted.
Sex-Based Differences in Early Mortality of Patients Undergoing Primary Angioplasty for First Acute Myocardial Infarction
Authors: Vakili Babak A. , Kaplan Robert C. , Brown David L.
Published: September 2007

Background
—

Morbidity and mortality after an acute myocardial infarction (AMI) has been reported to be higher in women than men. However, in some prior reports, women were not treated as aggressively as men, suggesting a treatment bias. We sought to determine whether sex influenced short-term outcomes in a cohort of AMI patients, all of whom underwent primary angioplasty.

Methods and Results
—

We conducted a retrospective cohort study of all patients undergoing primary angioplasty for a first AMI in New York State in 1995. A total of 1044 patients, 317 women and 727 men, were identified. Mean age was 59±12 years in men and 65±12 years in women (
P
<0.05). Women had a higher prevalence of hypertension (59% versus 44%,
P
<0.05), diabetes (19% versus 14%,
P
<0.05), and peripheral vascular or carotid disease (9.5% versus 5.5%,
P
<0.05) than men. Men were more likely to be treated earlier (within 6 hours) from the time of symptom onset than women (74% versus 63%,
P
<0.05). Women had a higher incidence of shock or hemodynamic instability than men (25% versus 17%,
P
<0.05). The unadjusted in-hospital mortality rate was 7.9% in women and 2.3% in men (
P
<0.05). After multivariate logistic regression analysis, women maintained a 2.3-fold higher risk of in-hospital death compared with their male counterparts (95% confidence interval [CI], 1.2 to 4.6,
P
=0.016).

Conclusions
—

After correcting for age and baseline risk differences, women undergoing primary angioplasty for AMI have a significantly higher in-hospital mortality rate than men.
Minimum Bandwidth Requirements for Recording of Pediatric Electrocardiograms
Authors: Rijnbeek Peter R. , Kors Jan A. , Witsenburg Maarten
Published: September 2007

Background
—

Previous studies that determined the frequency content of the pediatric ECG had their limitations: the study population was small or the sampling frequency used by the recording system was low. Therefore, current bandwidth recommendations for recording pediatric ECGs are not well founded. We wanted to establish minimum bandwidth requirements using a large set of pediatric ECGs recorded at a high sampling rate.

Methods and Results
—

For 2169 children aged 1 day to 16 years, a 12-lead ECG was recorded at a sampling rate of 1200 Hz. The averaged beats of each ECG were passed through digital filters with different cut off points (50 to 300 Hz in 25-Hz steps). We measured the absolute errors in maximum QRS amplitude for each simulated bandwidth and determined the percentage of records with an error >25 μV. We found that in any lead, a bandwidth of 250 Hz yields amplitude errors <25 μV in >95% of the children <1 year. For older children, a gradual decrease in ECG frequency content was demonstrated.

Conclusions
—

We recommend a minimum bandwidth of 250 Hz to record pediatric ECGs. This bandwidth is considerably higher than the previous recommendation of 150 Hz from the American Heart Association.
Tumor Necrosis Factor Antagonism With Etanercept Improves Systemic Endothelial Vasoreactivity in Patients With Advanced Heart Failure
Authors: Fichtlscherer Stephan , Rössig Lothar , Breuer Susanne , Vasa Mariuca , Dimmeler Stefanie , Zeiher Andreas M.
Published: September 2007

Background
—

Anti–tumor necrosis factor (TNF)-α therapy with etanercept, a recombinant TNF receptor that binds to and functionally inactivates TNF-α, was shown to improve the functional status of patients with congestive heart failure (CHF). Because administration of TNF-α has been shown experimentally to depress endothelium-dependent relaxation, we hypothesized that TNF-α antagonism with etanercept might improve the depressed systemic endothelial vasodilator function, which importantly contributes to increased peripheral vascular resistance in patients with advanced CHF.

Methods and Results
—

Endothelium-dependent (acetylcholine, ACH; 10 to 50 μg/min) and endothelium-independent (sodium nitroprusside, SNP; 2 to 8 μg/min) forearm blood flow (FBF) responses were measured by venous occlusion plethysmography in 13 patients with documented CHF (New York Heart Association class III) before, 6 hours after, and 7 days after subcutaneous injection of a single dose of 25 mg etanercept. Maximum ACH-induced FBF increased significantly from 6.9±1.0 to 13.0±1.6 mL/min per 100 mL of forearm tissue (
P
<0.05) 6 hours after administration of etanercept and returned to 7.0±1.1 mL/min per 100 mL of forearm tissue after 7 days (
P
=NS), whereas SNP-induced FBF responses were not significantly affected. In contrast, FBF responses were not altered in control CHF patients, who did not receive etanercept (n=5). Etanercept-induced increases in ACH-mediated FBF were closely correlated with baseline TNF-α serum levels (
r
=0.66;
P
<0.02).

Conclusions
—

The administration of etanercept profoundly improves systemic endothelial vasodilator capacity in patients with advanced heart failure, suggesting an important role of inflammatory mediators for impaired endothelial vasoreactivity in CHF. Improvement of systemic endothelial function might importantly contribute to the beneficial effects of etanercept on the functional status of patients with CHF.
Oxidative DNA Damage and Repair in Experimental Atherosclerosis Are Reversed by Dietary Lipid Lowering
Authors: Martinet Wim , Knaapen Michiel W. M. , De Meyer Guido R. Y. , Herman Arnold G. , Kockx Mark M.
Published: September 2007

Abstract
—Increased oxidative stress is a major characteristic of hypercholesterolemia-induced atherosclerosis. The oxidative environment is mainly created by the production of reactive oxygen species, which are assumed to mediate vascular tissue injury. Oxidative DNA damage resulting from free radical attack remains, however, a poorly examined field in atherosclerosis. Male New Zealand White rabbits were fed a cholesterol-rich diet (0.3%) for 24 weeks. The induced atherosclerotic plaques showed elevated levels of the DNA damage marker 7,8-dihydro-8-oxoguanine (8-oxoG) as demonstrated by immunohistochemistry. 8-oxoG immunoreactivity was found predominantly in the superficial layer of the plaque containing numerous macrophage-derived foam cells but not in the media or in arteries of age-matched control animals. Alkaline single-cell gel electrophoresis revealed that the number of DNA strand breaks was significantly higher in the plaque as compared with control samples of normolipemic animals. These changes were associated with the upregulation of DNA repair enzymes (poly[ADP-ribose] polymerase-1, p53, phospho-p53 [phosphorylated at Ser392], and XRCC1 [x-ray repair cross-complementing 1]). DNA strand breaks normalized after 4 weeks of dietary lipid lowering. However, a significant reduction of 8-oxoG immunoreactivity was only observed after a prolonged period of lipid lowering (12 to 24 weeks). Repair pathways started to decline progressively when cholesterol-fed animals were placed on a normal diet. In conclusion, oxidative DNA damage and increased levels of DNA repair, both associated with diet-induced hypercholesterolemia, are strongly reduced during dietary lipid lowering. These findings may provide a better insight into the benefits of lipid-lowering therapy on plaque stabilization.
Adenoviral Delivery of a Leukocyte-Type 12 Lipoxygenase Ribozyme Inhibits Effects of Glucose and Platelet-Derived Growth Factor in Vascular Endothelial and Smooth Muscle Cells
Authors: Patricia Mary Kim , Natarajan Rama , Dooley Alek N. , Hernandez Felicia , Gu Jia-Li , Berliner Judith A. , Rossi John J. , Nadler Jerry L. , Meidell Robert S. , Hedrick Catherine C.
Published: September 2007

Abstract
—The lipoxygenase (LO) pathway has been implicated as an important mediator of chronic glucose and platelet-derived growth factor (PDGF)-induced effects in the vascular system. Endothelial cells treated with 12LO products or cultured in high glucose showed enhanced monocyte adhesion, an important step in atherogenesis. We have previously reported that PDGF increased HETE levels in porcine aortic smooth muscle cells. Although several pharmacological inhibitors to the LO pathway are available, most lack specificity and may harbor undesirable side effects. Therefore, we developed a recombinant adenovirus expressing a hammerhead ribozyme (AdRZ) targeted against the porcine leukocyte-type 12LO mRNA to investigate the involvement of LO in glucose- and PDGF-mediated effects in vascular cells. Infection of porcine aortic endothelial cells with AdRZ reduced the level of glucose-enhanced 12LO mRNA expression as determined by quantitative, real-time reverse transcriptase–polymerase chain reaction. Reverse-phase HPLC and RIA analysis also revealed a corresponding decrease in glucose-stimulated 12HETE production in both the cellular and supernatant fractions. In the ribozyme-treated porcine aortic endothelial cells, there was marked inhibition of high glucose-stimulated monocyte adhesion. Infection with AdRZ also reduced PDGF-induced porcine aortic smooth muscle cell migration by approximately 50%. These studies demonstrate the efficacy of recombinant adenovirus expressing 12LO ribozyme in studying the effects of 12LO in vascular wall cells. They document an important role for the 12LO pathway in regulating inflammatory changes in endothelial cells and smooth muscle cells.
Novel Arrhythmogenic Mechanism Revealed by a Long-QT Syndrome Mutation in the Cardiac Na
+
Channel
Authors: Abriel Hugues , Cabo Candido , Wehrens Xander H. T. , Rivolta Ilaria , Motoike Howard K. , Memmi Mirella , Napolitano Carlo , Priori Silvia G. , Kass Robert S.
Published: September 2007

Abstract
—Variant 3 of the congenital long-QT syndrome (LQTS-3) is caused by mutations in the gene encoding the α subunit of the cardiac Na
+
channel. In the present study, we report a novel LQTS-3 mutation, E1295K (EK), and describe its functional consequences when expressed in HEK293 cells. The clinical phenotype of the proband indicated QT interval prolongation in the absence of T-wave morphological abnormalities and a steep QT/R-R relationship, consistent with an LQTS-3 lesion. However, biophysical analysis of mutant channels indicates that the EK mutation changes channel activity in a manner that is distinct from previously investigated LQTS-3 mutations. The EK mutation causes significant positive shifts in the half-maximal voltage (V
1/2
) of steady-state inactivation and activation (+5.2 and +3.4 mV, respectively). These gating changes shift the window of voltages over which Na
+
channels do not completely inactivate without altering the magnitude of these currents. The change in voltage dependence of window currents suggests that this alteration in the voltage dependence of Na
+
channel gating may cause marked changes in action potential duration because of the unique voltage-dependent rectifying properties of cardiac K
+
channels that underlie the plateau and terminal repolarization phases of the action potential. Na
+
channel window current is likely to have a greater effect on net membrane current at more positive potentials (EK channels) where total K
+
channel conductance is low than at more negative potentials (wild-type channels), where total K
+
channel conductance is high. These findings suggest a fundamentally distinct mechanism of arrhythmogenesis for congenital LQTS-3.