bluuebunny/crossref_metadata_2025 huggingface dataset:
Modulation of Anthracycline-Induced Myofibrillar Disarray in Rat Ventricular Myocytes by Neuregulin-1β and Anti-erbB2
Authors: Sawyer Douglas B. , Zuppinger Christian , Miller Thomas A. , Eppenberger Hans M. , Suter Thomas M.
Published: July 2002

Background

—

There is an increased incidence of heart failure in patients treated concurrently with anthracyclines and the chemotherapeutic anti-erbB2 agent trastuzumab (Herceptin). On the basis of our previous studies with recombinant neuregulin-1β (NRG-1β), a ligand for the erbB2 receptor tyrosine kinase, we hypothesized that activation of erbB2 by anti-erbB2 versus NRG-1 would cause differential effects on myocyte intracellular signaling as well as anthracycline-induced myofibrillar injury and might potentially account for the clinical toxicity of trastuzumab in the setting of concurrent anthracycline therapy.

Methods and Results

—

We tested this hypothesis using adult rat ventricular myocytes (ARVMs) in culture, assessing myofibrillar structure by immunostaining for myomesin and filamentous actin. Activation of erbB2, extracellular signal–regulated kinase 1/2 (Erk1/2), and Akt was assessed by use of antibodies to phosphorylated activated receptor or kinase detected by immunoblot. ARVMs treated with doxorubicin (0.1 to 0.5 μmol/L) showed a concentration-dependent increase in myofilament disarray. NRG-1β (10 ng/mL) activated erbB2, Erk1/2, and Akt in ARVMs and significantly reduced anthracycline-induced disarray. In contrast to NRG-1β, anti-erbB2 (1 μg/mL) caused rapid phosphorylation of erbB2 but not Erk1/2 or Akt, with downregulation of erbB2 by 24 hours. Concomitant treatment of myocytes with anti-erbB2 and doxorubicin caused a significant increase in myofibrillar disarray versus doxorubicin alone.

Conclusions

—

NRG-1β/erbB signaling regulates anthracycline-induced myofilament injury. The increased susceptibility of myofilaments to doxorubicin in the presence of antibody to erbB2 may explain the contractile dysfunction seen in patients receiving concurrent trastuzumab and anthracyclines.
Does Oral Folic Acid Lower Total Homocysteine Levels and Improve Endothelial Function in Children With Chronic Renal Failure?
Authors: Bennett-Richards K. , Kattenhorn M. , Donald A. , Oakley G. , Varghese Z. , Rees L. , Deanfield J.E.
Published: July 2002

Background
—

Accelerated vascular disease is common in chronic renal failure (CRF) and accounts for significant mortality and morbidity. Elevated homocysteine levels may contribute by an effect on endothelial function.

Methods and Results
—

We performed a double-blind placebo-controlled randomized crossover trial of folic acid at 5 mg/m
2
in 25 normotensive children 12±3 (7 to 17) years of age with CRF (glomerular filtration rate 26.8±13.2 mL/min per 1.73 m
2
) of noninflammatory etiology. Each subject underwent two 8-week periods of folic acid and placebo separated by an 8-week washout period. The effect of folic acid on homocysteine levels, LDL oxidation, and both endothelial-dependent and -independent vascular function were measured. After oral folic acid, serum folate levels rose from 11.7±4.25 to 635±519 μg/L (
P
=0.001), red cell folate levels rose from 364±195 to 2891±2623 μg/L (
P
<0.001), and total homocysteine levels fell from 10.28±4.16 to 8.62±2.32 μmol/L (
P
=0.03). In addition, there was a significant improvement in flow-mediated dilatation (FMD) (endothelial-dependent dilatation) from 7.21±2.8% to 8.47±3.01% (
P
=0.036) with no change in response to glyceryl trinitrate (endothelial-independent dilatation). There was no significant change in FMD or glyceryl trinitrate during the placebo phase. There was, however, no significant difference in final FMD after placebo or folic acid. Lag times for LDL oxidation were prolonged during the treatment phase (58.4±18.7 to 68.1±25.9 minutes,
P
=0.01).

Conclusion
—

Folic acid supplementation in children with CRF may improve endothelial function with an increased resistance of LDL to oxidation.
Induction of Atherosclerotic Plaque Rupture in Apolipoprotein E
−/−
Mice After Adenovirus-Mediated Transfer of p53
Authors: von der Thüsen Jan H. , van Vlijmen Bart J.M. , Hoeben Rob C. , Kockx Mark M. , Havekes L.M. , van Berkel Theo J.C. , Biessen Erik A.L.
Published: July 2002

Background

—

The presence of the tumor-suppressor gene p53 in advanced atherosclerotic plaques and the sensitivity to p53-induced cell death of smooth muscle cells isolated from these plaques have fueled speculation about the role of p53 in lesion destabilization and plaque rupture. In this study, we describe a strategy to promote (thrombotic) rupture of preexisting atherosclerotic lesions using p53-induced lesion remodeling.

Methods and Results

—

Carotid atherogenesis was initiated in apolipoprotein E knockout mice by placement of a perivascular silastic collar. The resulting plaques were incubated transluminally with recombinant adenovirus carrying either a p53 or β-galactosidase (
lacZ
) transgene. p53 transfection was restricted to the smooth muscle cell-rich cap of the plaque and led to an increase in cap cell apoptosis 1 day after transfer. p53 overexpression resulted in a marked decrease in the cellular and extracellular content of the cap, reflected by a markedly reduced cap/intima ratio (0.21±0.04 versus 0.46±0.03,
P
<0.001). The latter is a characteristic feature of plaque vulnerability to rupture, and whereas spontaneous rupture of p53-treated lesions was rare, it was found in 40% of cases after treatment with the vasopressor compound phenylephrine (
P
=0.003).

Conclusions

—

We have demonstrated a potential role of p53-induced remodeling in atherosclerotic plaque destabilization. Being the first example of inducible rupture at a predefined location, this model offers a unique opportunity to delineate the processes that precede rupture and to evaluate plaque-stabilizing therapies.
Angiotensin II Induces Tumor Necrosis Factor Biosynthesis in the Adult Mammalian Heart Through a Protein Kinase C–Dependent Pathway
Authors: Kalra Dinesh , Sivasubramanian Natarajan , Mann Douglas L.
Published: July 2002

Background

—

Previous studies suggest that angiotensin II (Ang II) upregulates the expression of tumor necrosis factor (TNF) in nonmyocyte cell types; however, the effect of Ang II on TNF expression in the adult mammalian heart is not known.

Methods and Results

—

To determine whether Ang II was sufficient to provoke TNF biosynthesis in the adult heart, we examined the effects of Ang II in isolated buffer-perfused Langendorff feline hearts. Ang II (10
−7
mol/L) treatment resulted in a time- and dose-dependent increase in myocardial TNF mRNA and protein biosynthesis in the heart as well as in cultured adult cardiac myocytes. The effects of Ang II on myocardial TNF mRNA and protein synthesis were mediated through the angiotensin type 1 receptor (AT
1
R), insofar as an AT
1
R antagonist (AT
1
a) blocked the effects of Ang II, whereas an angiotensin type 2 receptor (AT
2
R) antagonist (AT
2
a) had no effect. Stimulation with Ang II led to the activation of nuclear factor-κB and activator protein-1 (AP-1), two transcription factors that are important for TNF gene expression. Nuclear factor-κB activation was accompanied by phosphorylation of IκBα on serine 32 as well as degradation of IκBα, suggesting that the effects of Ang II were mediated through an IκBα-dependent pathway. The important role of protein kinase C (PKC) was suggested by studies in which a phorbol ester triggered TNF biosynthesis, and a PKC inhibitor abrogated Ang II–induced TNF biosynthesis.

Conclusions

—

These studies suggest that Ang II provokes TNF biosynthesis in the adult mammalian heart through a PKC-dependent pathway.
Phase 1/2 Placebo-Controlled, Double-Blind, Dose-Escalating Trial of Myocardial Vascular Endothelial Growth Factor 2 Gene Transfer by Catheter Delivery in Patients With Chronic Myocardial Ischemia
Authors: Losordo Douglas W. , Vale Peter R. , Hendel Robert C. , Milliken Charles E. , Fortuin F. David , Cummings Nancie , Schatz Richard A. , Asahara Takayuki , Isner Jeffrey M. , Kuntz Richard E.
Published: July 2002

Background

—

This phase 1/2 study investigated the safety of percutaneous catheter-based gene transfer of naked plasmid DNA encoding for vascular endothelial growth factor 2 (phVEGF2) to left ventricular (LV) myocardium in a prospective, randomized, double-blind, placebo-controlled, dose-escalating study of inoperable patients with class III or IV angina.

Methods and Results

—

A steerable deflectable 8F catheter with a 27-gauge needle at its distal tip was advanced percutaneously to the endocardial surface of the LV in 19 patients (age, 61±2 years) with chronic myocardial ischemia who were not candidates for conventional revascularization. Patients were randomized in a double-blind fashion to receive 6 injections (total volume, 6.0 mL) of placebo or phVEGF2 in doses of 200 μg (n=9), 800 μg (n=9), or 2000 μg (n=1) guided by LV electromechanical (NOGA) mapping with a gene-to-placebo ratio of 2:1. A total of 114 LV injections were delivered and caused no hemodynamic alterations, sustained ventricular arrhythmias, ECG evidence of infarction, or ventricular perforation. End-point analysis at 12 weeks disclosed a statistically significant improvement in Canadian Cardiovascular Society (CCS) angina class in phVEGF2-treated versus placebo-treated patients (−1.3 versus −0.1,
P
=0.04). Remaining efficacy end points—including change in exercise duration (91.8 versus 3.9 seconds), functional improvement by ≥2 CCS classes (9 of 12 versus 1 of 6), and Seattle Angina Questionnaire data—all showed strong trends favoring efficacy of phVEGF2 versus placebo treatment.

Conclusions

—

This phase 1/2, double-blind, randomized trial provides preliminary data that support safety of phVEGF2 catheter-mediated myocardial gene transfer. The statistically significant reduction in anginal class and strong positive trends for remaining end points suggest that a larger phase 2/3 trial is warranted.
Outcomes of Patients With Chronic Renal Insufficiency in the Bypass Angioplasty Revascularization Investigation
Authors: Szczech L.A. , Best P.J. , Crowley E. , Brooks M.M. , Berger P.B. , Bittner V. , Gersh B.J. , Jones R. , Califf R.M. , Ting H.H. , Whitlow P.J. , Detre K.M. , Holmes D.
Published: July 2002

Background

—

Although severe chronic kidney disease (CKD) is an independent predictor of mortality among patients with coronary artery disease, the impact of mild CKD on morbidity and mortality has not been fully defined.

Methods and Results

—

Morbidity and mortality for the 3608 patients with multivessel coronary artery disease enrolled in the Bypass Angioplasty Revascularization Investigation randomized trial and registry were compared on the basis of the presence and absence of CKD, defined as a preprocedure serum creatinine level of >1.5 mg/dL. Seventy-six patients had CKD. Patients with renal insufficiency were older and more likely to have a history of diabetes, hypertension, and other comorbidities. Among patients undergoing PTCA, patients with CKD had a greater frequency of in-hospital death and cardiogenic shock (
P
<0.05 and 0.01, respectively). There was a trend toward a larger proportion of patients with CKD experiencing angina at 5 years (
P
=0.079). Patients with CKD had more cardiac admissions (
P
=0.003 and <0.0001 for patients undergoing PTCA and CABG, respectively) and a shorter time to subsequent CABG after initial revascularization than patients without CKD (
P
=0.01). CKD was associated with a higher risk of death at 7 years, both of all causes (relative risk 2.2,
P
<0.001) and of cardiac causes (relative risk 2.8,
P
<0.001).

Conclusions

—

CKD is associated with an increased risk of recurrent hospitalization, subsequent CABG, and mortality. This increased risk of death is independent of and additive to the risk associated with diabetes.
Influenza Vaccine Pilot Study in Acute Coronary Syndromes and Planned Percutaneous Coronary Interventions
Authors: Gurfinkel Enrique P. , de la Fuente Ricardo Leon , Mendiz Oscar , Mautner Branco
Published: July 2002

Background

—

Recent reports have detected an increase in the number of patients with acute coronary syndromes during the flu season. In addition, the World Health Organization recommended vaccination against influenza infection for the Southern hemisphere in the winter of 2001.We evaluated the preventive impact of vaccination on subsequent ischemic events in myocardial infarction patients and in subjects undergoing planned percutaneous coronary angioplasty.

Methods and Results

—

We included 200 myocardial infarction patients admitted in the first 72 hours and 101 planned angioplasty/stent (PCI) patients without unstable coronary artery disease, prior bypass surgery, angioplasty, or tissue necrosis, in a prospective, multicenter log during the winter season. Infarct patients received a standard therapy and were then randomly allocated in a single-blind manner to either a unique intramuscular influenza vaccination or a control group. Similarly, PCI patients were allocated to either vaccination or control groups. Combined end points (death, reinfarction, and rehospitalization for ischemia) were assessed at 6 months’ follow-up. The first primary outcome, cardiovascular death, occurred in 2% of the patients in the vaccine group compared with 8% in the control group (relative risk with vaccine as compared with controls, 0.25; 95% CI 0.07 to 0.86;
P
=0.01). The triple composite end point occurred in 11% of the patients in the vaccine group compared with 23% in controls (
P
=0.009).

Conclusions

—

Influenza vaccination may reduce the risk of death and ischemic events in patients suffering from infarction and those recovering from angioplasty during flu season. This response could be related to a humoral immune response with positive consequences during flu seasons.
B-Type Natriuretic Peptide Predicts Sudden Death in Patients With Chronic Heart Failure
Authors: Berger Rudolf , Huelsman Martin , Strecker Karin , Bojic Anja , Moser Petra , Stanek Brigitte , Pacher Richard
Published: July 2002

Background

—

Given the high incidence of sudden death in patients with chronic heart failure (CHF) and the efficacy of implantable cardioverter-defibrillators, an appropriate tool for the prediction of sudden death is desirable. B-type natriuretic peptide (BNP) has prognostic significance in CHF, and the stimuli for its production cause electrophysiological abnormalities. This study tests BNP levels as a predictor of sudden death.

Methods and Results

—

BNP levels, in addition to other neurohormonal, clinical, and hemodynamic variables, were obtained from 452 patients with a left ventricular ejection fraction (LVEF) ≤35%. For prediction of sudden death, only survivors without heart transplantation (HTx) or a mechanical assist device and patients who died suddenly were analyzed. Up to 3 years, 293 patients survived without HTx or a mechanical assist device, 89 patients died, and 65 patients underwent HTx. Mode of death was sudden in 44 patients (49%), whereas 31 patients (35%) had pump failure and 14 patients (16%) died from other causes. Univariate risk factors of sudden death were log BNP (
P
=0.0006), log N-terminal atrial natriuretic peptide (
P
=0.003), LVEF (
P
=0.005), log N-terminal BNP (
P
=0.006), systolic blood pressure (
P
=0.01), big endothelin (
P
=0.03), and NYHA class (
P
=0.04). In the multivariate model, log BNP level was the only independent predictor of sudden death (
P
=0.0006). Using a cutoff point of log BNP <2.11 (130 pg/mL), Kaplan-Meier sudden death–free survival rates were significantly higher in patients below (99%) compared with patients above (81%) this cutoff point (
P
=0.0001).

Conclusion

—

BNP levels are a strong, independent predictor of sudden death in patients with CHF.
Statin Therapy, Cardiovascular Events, and Total Mortality in the Heart and Estrogen/Progestin Replacement Study (HERS)
Authors: Herrington David M. , Vittinghoff Eric , Lin Feng , Fong Josephine , Harris Fran , Hunninghake Donald , Bittner Vera , Schrott Helmut G. , Blumenthal Roger S. , Levy Robert
Published: July 2002

Background

—

Although effects of statins on cardiovascular outcomes are well established in men, fewer data exist for women. Furthermore, the effects of statins plus hormone replacement therapy (HRT) on cardiovascular outcomes are uncertain.

Methods and Results

—

We examined statin use, cardiovascular events, and total mortality in the Heart and Estrogen/progestin Replacement Study (HERS), a randomized clinical trial of estrogen plus progestin versus placebo in postmenopausal women with heart disease (n=2763). A nonrandomized comparison of statin users and nonusers revealed lower rates of the primary outcome, nonfatal myocardial infarction or coronary heart disease death (relative hazard [RH]=0.79, 95% confidence intervals [CI] 0.63 to 0.99,
P
=0.04), and total mortality (RH=0.67, 95% CI 0.51 to 0.87,
P
=0.003). Rates of venous thromboembolic events were also lower among statin users (RH=0.45, 95% CI 0.23 to 0.88,
P
=0.02). HRT resulted in a significant increase in early risk for primary events in women who did not use statins (RH=1.75, 95% CI 1.02 to 3.03,
P
=0.04) but not in statin users (RH=1.34, 95% CI 0.63 to 2.86,
P
=0.45). Adjustment for postrandomization statin use showed no effect of HRT on risk for the primary outcome (RH=0.96, 95% CI 0.77 to 1.29;
P
=0.72).

Conclusions

—

In HERS, statin use was associated with lower rates of cardiovascular events, venous thromboembolic events, and total mortality. These data provide strong support for statin use in eligible women with coronary disease.
Different Metabolic Predictors of White-Coat and Sustained Hypertension Over a 20-Year Follow-Up Period
Authors: Björklund Kristina , Lind Lars , Vessby Bengt , Andrén Bertil , Lithell Hans
Published: July 2002

Background

—

The clinical significance of white-coat hypertension is still unclear. Moreover, no study has examined metabolic predictors of white-coat versus sustained hypertension.

Methods and Results

—

We investigated men (n=602) in a longitudinal population-based cohort who at age 70 years were identified as normotensive, white-coat hypertensive (office blood pressure [BP] ≥140/90 and daytime ambulatory BP <135/85 mm Hg), and sustained hypertensive (office BP ≥140/90 and daytime ambulatory BP ≥135/85 mm Hg). At baseline, when the subjects were aged 50 years, blood glucose, insulin, lipids, and fatty acid composition of the serum cholesterol esters were analyzed. The investigations at age 70 years included determination of insulin sensitivity and target organ damage. At age 50 years, individuals who 20 years later were identified as white-coat hypertensive or sustained hypertensive showed significantly elevated BP, heart rate, and impaired glucose tolerance compared with normotensive subjects but white coat hypertensive subjects were leaner and had a more favorable serum cholesterol ester fatty acid profile than did sustained hypertensive subjects. At age 70 years, both white-coat and sustained hypertensive subjects showed an impaired insulin sensitivity, elevated blood glucose, and increased serum insulin and heart rate compared with normotensive subjects, but left ventricular mass and urinary albumin excretion were increased only in sustained hypertensive subjects.

Conclusions

—

These findings indicate that although metabolic abnormalities and elevated heart rate were consistent over time in both hypertensive groups, a lower body mass index and more favorable dietary fat composition predicted the development of white-coat as opposed to sustained hypertension over 20 years.
Quantitative Assessment of Intrinsic Regional Myocardial Deformation by Doppler Strain Rate Echocardiography in Humans
Authors: Edvardsen Thor , Gerber Bernhard L. , Garot Jérôme , Bluemke David A. , Lima João A.C. , Smiseth Otto A.
Published: July 2002

Background

—

Tissue Doppler echocardiography–derived strain rate and strain measurements (SDE) are new quantitative indices of intrinsic cardiac deformation. The aim of this study was to validate and compare these new indices of regional cardiac function to measurements of 3-dimensional myocardial strain by tagged MRI.

Methods and Results

—

The study population included 33 healthy volunteers, 17 patients with acute myocardial infarction, and 8 patients with suspected coronary artery disease who were studied during dobutamine stress echocardiography. Peak systolic myocardial velocities were measured by tissue Doppler echocardiography, peak systolic strain rates and strains by SDE, and strains by tagged MRI. In healthy individuals, longitudinal myocardial Doppler velocities decreased progressively from base to apex, whereas myocardial strain rates and strains were uniform in all segments. In patients with acute infarction, abnormal strains clearly identified dysfunctional areas. In infarcted regions, SDE showed 1.5±4.3% longitudinal stretching compared with −15.0±3.9% shortening in remote myocardium (
P
<0.001), and radial measurements showed −6.9±4.1% thinning and 14.3±5.0% thickening (
P
<0.001), respectively. During dobutamine infusion, longitudinal strains by SDE increased significantly from −13.5% to −23.8% (
P
<0.01) and radial strains increased from 13.1±3.1% to 29.3±11.5% (
P
<0.01). Comparisons between myocardial strains by SDE and tagged MRI in healthy individuals (n=11), in infarct patients (n=17), and during stress echo (n=4) showed excellent correlations (
r
=0.89 and
r
=0.96 for longitudinal and radial strains, respectively,
P
< 0.001).

Conclusions

—

The present study demonstrates the ability of Doppler echocardiography to measure myocardial strains in a clinical setting. Myocardial strains by Doppler may represent a new powerful method for quantifying left ventricular function noninvasively in humans.
Noninvasive Measurement of Myocardial Activity Concentrations and Perfusion Defect Sizes in Rats With a New Small-Animal Positron Emission Tomograph
Authors: Kudo Takashi , Fukuchi Kazuki , Annala Alexander J. , Chatziioannou Arion F. , Allada Vivekanand , Dahlbom Magnus , Tai Yuan-Chuan , Inubushi Masayuki , Huang Sung-Cheng , Cherry Simon R. , Phelps Michael E. , Schelbert Heinrich R.
Published: July 2002

Background

—

We explored the feasibility of measuring regional tracer activity concentrations and flow defects in myocardium of rats with a high spatial resolution small-animal PET system (microPET).

Methods and Results

—

Myocardial images were obtained after intravenous
18
F-fluorodeoxyglucose (
18
FDG) in 11 normal rats (group 1) and assembled into polar maps. Regional
18
F activity concentrations were measured in 9 regions of interest and compared with tissue activity concentrations measured by well counting. In another 9 rats (group 2), myocardial perfusion images were acquired with
13
N
-ammonia at baseline and during coronary occlusion. On the polar maps recorded during coronary occlusion, the size of perfusion defects was measured as the myocardium with <50% of maximum activity and expressed as percent total myocardium and was correlated with the area at risk defined by postmortem staining. The diagnostic quality of
18
FDG and
13
N
-ammonia microPET images was good to excellent; the images were easily assembled into polar maps. In group 1, regional
18
F concentrations by microPET and postmortem were correlated linearly (
r
=0.99;
P
<0.01 for average and
r
=0.97;
P
<0.01 for regional concentrations). In group 2, perfusion defect sizes by microPET and postmortem were correlated linearly (
P
<0.01;
r
=0.93).

Conclusions

—

The findings indicate the feasibility of noninvasive studies of the myocardium in rats with a dedicated small-animal PET-imaging device.
Omapatrilat Reduces Pulse Pressure and Proximal Aortic Stiffness in Patients With Systolic Hypertension
Authors: Mitchell Gary F. , Izzo Joseph L. , Lacourcière Yves , Ouellet Jean-Pascal , Neutel Joel , Qian Chunlin , Kerwin Linda J. , Block Alan J. , Pfeffer Marc A.
Published: July 2002

Background

—

Increased pulse pressure, an indicator of conduit vessel stiffness, is a strong independent predictor of cardiovascular events in hypertensive cohorts, which suggests that reduction of conduit vessel stiffness may be desirable in hypertension.

Methods and Results

—

We assessed changes in pulse pressure and conduit vessel stiffness in a 12-week double-blind, randomized clinical trial that compared monotherapy with the ACE inhibitor enalapril 40 mg daily (n=87) versus the vasopeptidase (dual ACE and neutral endopeptidase) inhibitor omapatrilat 80 mg daily (n=80) in patients with systolic hypertension. Patients were withdrawn from antihypertensive medications 1 to 2 weeks before enrollment, and systolic pressure was confirmed to be ≥160 mm Hg. With the use of calibrated tonometry and pulsed Doppler, pulsatile hemodynamics were assessed before randomization and at 12 weeks. Characteristic impedance (Z
c
), a direct measure of the stiffness of the central aorta, was calculated from the ratio of changes in carotid pressure and aortic flow in early systole. Omapatrilat compared with enalapril produced greater reductions in peripheral (−8.2±12.2 versus −4.0±12.2 mm Hg,
P
<0.05) and central (−10.2±16.2 versus −3.2±16.9 mm Hg,
P
<0.01) pulse pressures and Z
c
(237±83 to 208±70 versus 225±87 to 231±94 dyne · s/cm
5
,
P
<0.001); the latter remained significant (
P
<0.05) after adjusting for change in mean pressure.

Conclusions

—

Greater reductions in pulse pressure and Z
c
in hypertensive subjects treated with omapatrilat compared with enalapril suggest that aortic stiffness is maintained by specific, partially reversible mechanisms and underscore a potential role for pharmacological modulation of natriuretic peptides in the treatment of hypertension.
Interleukin-18 Is a Strong Predictor of Cardiovascular Death in Stable and Unstable Angina
Authors: Blankenberg Stefan , Tiret Laurence , Bickel Christoph , Peetz Dirk , Cambien François , Meyer Jürgen , Rupprecht Hans J.
Published: July 2002

Background

—

Interleukin (IL)-18 plays a central role in orchestrating the cytokine cascade and accelerates atherosclerosis and plaque vulnerability in animal models. However, epidemiological data evaluating the role of IL-18 levels in atherosclerosis are lacking.

Methods and Results

—

In a prospective study of 1229 patients with documented coronary artery disease, we measured baseline serum concentrations of IL-18 and other markers of inflammation. During the follow-up period (median, 3.9 years), 95 patients died of cardiovascular causes. Median serum concentrations of IL-18 were significantly higher among patients who had a fatal cardiovascular event than among those who did not (68.4 versus 58.7 pg/mL;
P
<0.0001). The hazard risk ratio of future cardiovascular death increased with increasing quartiles of IL-18 (hazard risk ratio, 1.46; 95% CI 1.21 to 1.76;
P
for trend <0.0001). After adjustment for most potential confounders, including the strong predictor ejection fraction as well as the inflammatory variables IL-6, high-sensitive C-reactive protein, and fibrinogen, this relation remained almost unchanged, such that patients within the highest quartile of IL-18 had a 3.3-fold increase in hazard risk compared with those in the first quartile (95% CI, 1.3 to 8.4,
P
=0.01). This relation was observed in patients with stable angina and patients with unstable angina at baseline.

Conclusions

—

Serum IL-18 level was identified as a strong independent predictor of death from cardiovascular causes in patients with coronary artery disease regardless of the clinical status at admission. This result strongly supports recent experimental evidence of IL-18–mediated inflammation leading to acceleration and vulnerability of atherosclerotic plaques.
Stroke Complicating Percutaneous Coronary Interventions
Authors: Fuchs Shmuel , Stabile Eugenio , Kinnaird Timothy D. , Mintz Gary S. , Gruberg Luis , Canos Daniel A. , Pinnow Ellen E. , Kornowski Ran , Suddath William O. , Satler Lowell F. , Pichard Augusto D. , Kent Kenneth M. , Weissman Neil J.
Published: July 2002

Background

—

Stroke associated with percutaneous coronary intervention (PCI) is an infrequent although devastating complication. We investigated the incidence, predictors, and prognostic impact of periprocedural stroke in unselected patients undergoing PCI.

Methods and Results

—

A total of 9662 patients who underwent 12 407 PCIs between January 1990 and July 1999 were retrospectively studied. Stroke was diagnosed in 43 patients (0.38% of procedures). Patients with stroke were older (72±11 versus 64±11 years,
P
<0.001), had lower left ventricular ejection fraction (42±12 versus 46±13%,
P
=0.04) and more diabetes (39.5% versus 27.2%,
P
=0.07), and experienced a higher rate of intraprocedural complications necessitating emergency use of intra-aortic balloon pump (IABP) (23.3% versus 3.3%,
P
<0.001). In-hospital mortality (37.2% versus 1.1%,
P
<0.001) and 1-year mortality (56.1% versus 6.5%,
P
<0.001) were higher in patients with stroke. Compared with hemorrhagic stroke, patients with ischemic stroke had higher rate of in-hospital major adverse cardiac events (57.1% versus 25%,
P
=0.037). Multivariate logistic regression analysis identified emergency use of IABP as the strongest predictors for stroke (OR=9.6, CI 3.9 to 23.9,
P
<0.001), followed by prophylactic use of IABP (OR=5.1), age >80 years (OR=3.2, compared with age <50 years), and vein graft intervention (OR=2.7).

Conclusions

—

Stroke associated with contemporary PCI is associated with substantial increased mortality. Elderly patients who experience intraprocedural complications necessitating the use of IABP are at particularly high risk.
Predisposition to Atherosclerosis by Infections
Authors: Prasad Abhiram , Zhu Jianhui , Halcox Julian P.J. , Waclawiw Myron A. , Epstein Stephen E. , Quyyumi Arshed A.
Published: July 2002

Background

—

Several microorganisms have been implicated in the pathogenesis of atherosclerosis. We hypothesized that infections may predispose to atherosclerosis by inflicting endothelial injury.

Methods and Results

—

Of 375 patients undergoing coronary angiography, 218 had assessment of endothelial function using intracoronary acetylcholine (ACH) and of endothelium-independent function with sodium nitroprusside and adenosine. Immunoglobulin-G antibody titers to cytomegalovirus,
Chlamydia pneumoniae
,
Helicobacter pylori
, hepatitis A virus, and herpes simplex virus-1 were measured. Pathogen burden was defined as the number of positive antibodies. Although positive serology to individual pathogens tended to be associated with increased incidence of coronary arteriosclerosis (CAD), the pathogen burden correlated with the presence of CAD, even after adjustment for risk factors (OR 1.3; 95% CI, 1.05 to 1.6,
P
=0.018). Moreover, the severity of CAD was independently associated with the pathogen burden (
P
=0.001). Pathogen burden was an independent predictor of endothelial dysfunction, determined as the percent change in coronary vascular resistance in response to ACH (
P
=0.009) but not the responses to sodium nitroprusside or adenosine. Pathogen burden was also an independent determinant of endothelial function in the subgroup with angiographically normal coronary arteries.

Conclusions

—

The immunoglobulin-G antibody response to multiple pathogens (pathogen burden) is an independent risk factor for endothelial dysfunction and the presence and severity of CAD. Endothelial dysfunction provides the crucial link by which pathogens may contribute to atherogenesis.
Heritability of Coronary Artery Calcium Quantity Measured by Electron Beam Computed Tomography in Asymptomatic Adults
Authors: Peyser Patricia A. , Bielak Lawrence F. , Chu Julia S. , Turner Stephen T. , Ellsworth Darrell L. , Boerwinkle Eric , Sheedy Patrick F.
Published: July 2002

Background

—

Electron beam computed tomography is an accurate, noninvasive method to detect and quantify coronary artery calcification (CAC), a marker of subclinical and clinical coronary artery atherosclerosis. CAC quantity predicts future coronary artery disease end points in asymptomatic adults, but measured risk factors explain less than half the variability in CAC quantity. Although several candidate genes for CAC have been identified, the relative importance of genetic influences on CAC quantity has not been assessed in asymptomatic adults in a community.

Methods and Results

—

We quantified the relative contributions of measured risk factors and genetic influences on CAC quantity measured by electron beam computed tomography in 698 asymptomatic white adults from 302 families. Before adjusting for any risk factors, 43.5% of the variation in CAC quantity was attributable to genetic factors (
P
=0.0007). Independent predictors of CAC quantity were identified with stepwise linear regression. After adjusting for these risk factors, including age, sex, fasting glucose level, systolic blood pressure, pack-years of smoking, and LDL cholesterol, 41.8% of the residual variation in CAC quantity was attributable to genetic factors (
P
=0.0003).

Conclusions

—

These results demonstrate the importance of genetic factors in subclinical coronary atherosclerosis variation as measured by CAC quantity. The presence of genetic effects suggests that unknown genes that influence CAC quantity are yet to be identified.
Insulin-Dependent Activation of Endothelial Nitric Oxide Synthase Is Impaired by O-Linked Glycosylation Modification of Signaling Proteins in Human Coronary Endothelial Cells
Authors: Federici Massimo , Menghini Rossella , Mauriello Alessandro , Hribal Marta Letizia , Ferrelli Francesca , Lauro Davide , Sbraccia Paolo , Spagnoli Luigi Giusto , Sesti Giorgio , Lauro Renato
Published: July 2002

Background

—

Hyperglycemia impairs functional properties of cytosolic and nuclear proteins via O-linked glycosylation modification (O-GlcNAcylation). We studied the effects of O-GlcNAcylation on insulin signaling in human coronary artery endothelial cells.

Methods and Results

—

O-GlcNAcylation impaired the metabolic branch of insulin signaling, ie, insulin receptor (IR) activation of the IR substrate (IRS)/phosphatidylinositol 3-kinase (PI3-K)/Akt, whereas it enhanced the mitogenic branch, ie, ERK-1/2 and p38 (mitogen-activated protein kinase). Both in vivo and in vitro phosphorylation of endothelial nitric oxide synthase (eNOS) by Akt were reduced by hyperglycemia and hexosamine activation. Insulin-induced eNOS activity in vivo was reduced by hyperglycemia and hexosamine activation, which was coupled to increased activation and expression of matrix metalloproteinase-2 and -9; these phenomena were reversed by inhibition of the hexosamine pathway. Finally, carotid plaques from type 2 diabetic patients showed increased endothelial O-GlcNAcylation with respect to nondiabetics.

Conclusions

—

Our data show that hyperglycemia, through the hexosamine pathway, impairs activation of the IR/IRS/PI3-K/Akt pathway, resulting in deregulation of eNOS activity.
Epithelial COX-2 Expression Is Not Regulated By Nitric Oxide in Rodent Renal Cortex
Authors: Theilig Franziska , Câmpean Valentina , Paliege Alexander , Breyer Matthew , Briggs Josie P. , Schnermann Jürgen , Bachmann Sebastian
Published: July 2002

In the adult rodent kidney cortex, cyclooxygenase-2 (COX-2), NO synthase (NOS1), and renin synthesis change in parallel on alterations in distal tubular NaCl concentration, and their products in part may mutually determine synthesis and activity of these enzymes. Epithelial NO synthesis has been postulated to exert a stimulatory role on COX-2 expression. Changes in COX-2 and NOS1 may be assessed histochemically by determining changes in the number of positive cells. In rat, macula densa and adjacent cells may co-express COX-2 and NOS1, whereas cell groups of the upstream thick ascending limb (cTAL) express COX-2 alone. We have tested whether the stimulation of COX-2 expression by short- and long-term unilateral renal artery stenosis, low salt, and furosemide treatment depends on co-expression of NOS1. These conditions produced significant respective increases (40% to 351%,
P
<0.05) in the number of COX-2 immunoreactive cells, regardless of whether NOS1 was present or not, suggesting that co-expression of NOS1 is not necessary to produce these changes. Under high-salt conditions, analogous though inverse changes were recorded (−62% to −73%,
P
<0.05). In mice with genetic deletion of NOS1, low- and high-salt diets caused similar changes of COX-2 immunoreactivity (106% and −52%,
P
<0.05) than those seen in wild-type mice (43% and −78%,
P
<0.05). We conclude that alterations of distal tubular NaCl concentration and presumably NaCl transport induce changes in epithelial COX-2 expression that does not depend on presence of co-expressed NOS1. It therefore seems unlikely that NO is part of a signal transduction chain between tubular chloride sensing and the modulating effects of prostaglandins in tubulo-vascular information transfer.
Norepinephrine and Concentric Hypertrophy in Patients With End-Stage Renal Disease
Authors: Zoccali Carmine , Mallamaci Francesca , Tripepi Giovanni , Parlongo Saverio , Cutrupi Sebastiano , Benedetto Francesco Antonio , Cataliotti Alessandro , Malatino Lorenzo Salvatore
Published: July 2002

We have recently observed that in patients with end-stage renal disease (ESRD) raised plasma norepinephrine (NE) is an independent predictor of incident cardiovascular events but that its prognostic power is reduced when this sympathetic marker is tested in statistical models including also left ventricular mass. Because left ventricular hypertrophy (LVH) may be a mechanism whereby NE contributes to the high rate of cardiovascular events in ESRD, we examined the relationship between plasma NE and echocardiographic parameters of left ventricle mass in a large group of ESRD patients. Mean wall thickness (MWT) was higher in patients in the third NE tertile than in the other 2 tertiles (
P
=0.001), and such an increase was paralleled by a rise in relative wall thickness (RWT) (
P
=0.006). Concentric LVH was more prevalent in patients in the third NE tertile (46%) than in the second (38%) and first (25%) NE tertiles. Multivariate regression analysis confirmed that the association of plasma NE with the muscular component of left ventricle (MWT) and with RWT was independent (
P
≤0.001) of other cardiovascular risk factors, and in these models, plasma NE ranked as the second correlate of MWT and RWT. Similarly, multiple logistic regression analysis showed that the association of plasma NE with concentric LVH was strong and again independent of other risk factors (
P
=0.003). Plasma NE is associated to concentric LVH in ESRD patients. These observations constitute a sound basis for testing the effect of anti-adrenergic drugs on left ventricle mass and on cardiovascular outcomes in patients with ESRD.
High-Salt Diet Enhances Insulin Signaling and Induces Insulin Resistance in Dahl Salt-Sensitive Rats
Authors: Ogihara Takehide , Asano Tomoichiro , Ando Katsuyuki , Sakoda Hideyuki , Anai Motonobu , Shojima Nobuhiro , Ono Hiraku , Onishi Yukiko , Fujishiro Midori , Abe Miho , Fukushima Yasushi , Kikuchi Masatoshi , Fujita Toshiro
Published: July 2002

A high-salt diet, which is known to contribute to the pathogenesis of hypertension, is also reportedly associated with insulin resistance. We investigated the effects of a high-salt diet on insulin sensitivity and insulin signaling in salt-sensitive (Dahl-S) and salt resistant (Dahl-R) strains of the Dahl rat. Evaluation of hyperinsulinemic-euglycemic clamp studies and glucose uptake into the isolated soleus muscle revealed that salt loading (8% NaCl) for 4 weeks induced hypertension and significant insulin resistance in Dahl-S rats, whereas no significant effects were observed in Dahl-R rats. Despite the presence of insulin resistance, insulin-induced tyrosine phosphorylation of the insulin receptor and insulin receptor substrates, activation of phosphatidylinositol 3-kinase, and phosphorylation of Akt were all enhanced in Dahl-S rats fed a high-salt diet. The mechanism underlying this form of insulin resistance thus differs from that previously associated with obesity and dexamethasone and is likely due to the impairment of one or more metabolic steps situated downstream of phosphatidylinositol 3-kinase and Akt activation. Interestingly, supplementation of potassium (8% KCl) ameliorated the changes in insulin sensitivity in Dahl-S rats fed a high-salt diet; this was associated with a slight but significant decrease in blood pressure. Evidence presented suggest that there is an interdependent relationship between insulin sensitivity and salt sensitivity of blood pressure in Dahl-S rats, and it is suggested that supplementing the diet with potassium may exert a protective effect against both hypertension and insulin resistance in salt-sensitive individuals.
Isoform-Specific Modulation of Voltage-Gated Na
+
Channels by Calmodulin
Authors: Deschênes Isabelle , Neyroud Nathalie , DiSilvestre Deborah , Marbán Eduardo , Yue David T. , Tomaselli Gordon F.
Published: July 2002

Calmodulin (CaM) is a calcium-sensing protein that binds to Na
+
channels, with unknown functional consequences. Wild-type CaM produced a hyperpolarizing shift in the steady-state availability of expressed skeletal muscle (μ1) but not cardiac (hH1) Na
+
channels. Mutant CaM
1234
did not alter the voltage dependence or the kinetics of gating of either μ1 or hH1. Mutation of the highly conserved IQ motif in the carboxyl terminus of both isoforms (IQ/AA) slowed the kinetics of current decay and abolished the effect of wild-type CaM on μ1, but did not alter hH1 currents. The IQ/AA mutation eliminated CaM binding to the carboxyl terminus of both μ1 and hH1 channels. Inhibition of Ca
2+
/CaM kinase (CaM-K) slowed the current decay, the rate of entry into inactivation, and shifted the voltage dependence of hH1 in the depolarizing direction independent of CaM overexpression with no effect on μ1 Na
+
channels. CaM signaling modulates Na
+
currents in an isoform-specific manner, via direct interaction with skeletal muscle Na
+
channels and through CaM-K in the case of the cardiac isoform. The full text of this article is available at http://www.circresaha.org.
Phosphorylation of Glycogen Synthase Kinase-3β During Preconditioning Through a Phosphatidylinositol-3-Kinase–Dependent Pathway Is Cardioprotective
Authors: Tong Haiyan , Imahashi Kenichi , Steenbergen Charles , Murphy Elizabeth
Published: July 2002

We previously reported that activation of phosphatidylinositol-3-kinase (PI3-kinase) is involved in ischemic preconditioning (PC). Our goal was to determine downstream targets of PI3-kinase. In perfused rat hearts, PC (4 cycles of 5 minutes of ischemia and 5 minutes of reflow) increased phosphorylation of glycogen synthase kinase-3β (GSK-3β), a downstream target of PI3-kinase and protein kinase B (PKB), an effect that was blocked by wortmannin. Because phosphorylation inactivates GSK-3β, we examined whether PC-induced phosphorylation and inhibition of GSK-3β is important in PC by using two inhibitors of GSK-3β, lithium and SB 216763. Pretreatment of perfused rat hearts with lithium or SB 216763, before ischemia, mimicked the protective effects of PC; hearts treated with either lithium or SB 216763 had improved postischemic function and reduced infarct size. These findings indicate that inhibition of GSK-3β is protective and that this PI3-kinase–dependent signaling pathway may play an important role in ischemic preconditioning.
Role of Endogenous Adrenomedullin in the Regulation of Vascular Tone and Ischemic Renal Injury
Authors: Nishimatsu Hiroaki , Hirata Yasunobu , Shindo Takayuki , Kurihara Hiroki , Kakoki Masao , Nagata Daisuke , Hayakawa Hiroshi , Satonaka Hiroshi , Sata Masataka , Tojo Akihiro , Suzuki Etsu , Kangawa Kenji , Matsuo Hisayuki , Kitamura Tadaichi , Nagai Ryozo
Published: July 2002

Adrenomedullin (AM) is a potent depressor peptide whose vascular action is suggested to involve nitric oxide (NO) release. To explore the role of endogenous AM in vascular and renal function, we examined the effects of acetylcholine (ACh), AM, and AM receptor antagonists AM(22-52) and CGRP(8-37) on the renal perfusion pressure (RPP) of kidneys isolated from AM transgenic (TG)/heterozygote knockout (KO) mice and wild-type littermates (WT). Furthermore, we evaluated the renal function and histology 24 hours after bilateral renal artery clamp for 45 minutes in TG, KO, and WT mice. Baseline RPP was significantly lower in TG than in KO and WT mice (KO 93.4±4.6, WT 85.8±4.2, TG 72.4±2.4 mm Hg [mean±SE],
P
<0.01). ACh and AM caused a dose-related reduction in RPP, but the degree of vasodilatation was smaller in TG than that in KO and WT (%ΔRPP 10
−7
mol/L ACh: KO −48.1±3.9%, WT −57.5±5.6%, TG −22.8±4.8%,
P
<0.01), whereas
N
G
-nitro-
l
-arginine methyl ester (L-NAME) caused greater vasoconstriction in TG (%ΔRPP 10
−4
mol/L: KO 33.1±3.3%, WT 55.5±7.2%, TG 152.6±21.2%,
P
<0.01). Both AM antagonists increased RPP in TG to a greater extent compared with KO and WT mice (%ΔRPP 10
−6
mol/L CGRP(8-37): KO 12.8±2.6%, WT 19.4±3.6%, TG 41.8±8.7%,
P
<0.01). In mice with ischemic kidneys, serum levels of urea nitrogen and renal damage scores showed smaller values in TG and greater values in KO mice (urea nitrogen: KO 104±5>WT 98±15>TG 38±7 mg/dL,
P
<0.05 each). Renal NO synthase activity was also greater in TG mice. However, the differences in serum urea nitrogen and renal damage scores among the 3 groups of mice were not observed in mice pretreated with L-NAME. In conclusion, AM antagonists increased renal vascular tone in WT as well as in TG, suggesting that endogenous AM plays a role in the physiological regulation of the vascular tone. AM is likely to protect renal tissues from ischemia/reperfusion injury through its NO releasing activity.
A Dominant-Negative p65 PAK Peptide Inhibits Angiogenesis
Authors: Kiosses William B. , Hood John , Yang Suya , Gerritsen Mary E. , Cheresh David A. , Alderson Nazilla , Schwartz Martin Alexander
Published: July 2002

PAK1 is a protein kinase downstream of the small GTPases Rac and Cdc42 that previous work has implicated in endothelial cell migration via modulation of cell contraction. The first proline-rich region of PAK that binds to an SH3 domain from the adapter protein NCK was responsible for these dominant-negative effects. To test the role of PAK in angiogenesis, we prepared a peptide in which the proline-rich region was fused to the polybasic sequence from the HIV Tat protein to facilitate entry into cells. We show that the short peptide selectively binds NCK, whereas a mutant peptide does not. Treatment of cells with the PAK peptide but not the control peptide disrupts localization of PAK. This peptide specifically inhibited endothelial cell migration and contractility similarly to full-length dominant-negative PAK. In an in vitro tube-forming assay, the PAK peptide specifically blocked formation of multicellular networks. In an in vivo chick chorioallantoic membrane assay, the PAK peptide specifically blocked angiogenesis. These results, therefore, suggest a role for PAK in angiogenesis.