bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasma Homocysteine Concentration, Statin Therapy, and the Risk of First Acute Coronary Events
Authors: Ridker Paul M. , Shih Jessie , Cook Thomas J. , Clearfield Michael , Downs John R. , Pradhan Aruna D. , Weis Stephan E. , Gotto Antonio M.
Published: July 2002

Background—

Elevated homocysteine levels are associated with increased coronary risk, and it has been suggested that homocysteine screening may provide a method to identify high-risk patients for aggressive primary prevention.

Methods and Results—

Homocysteine was measured at baseline and after 1 year among 5569 participants in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), a randomized trial of lovastatin in the primary prevention of acute coronary events. The effects of homocysteine, LDL cholesterol, and lovastatin on risk were assessed over 5.2 years of trial follow-up. Median baseline homocysteine levels were significantly higher among study participants who subsequently had acute coronary events compared with those who did not (12.1 versus 10.9 μmol/L,
P
<0.001). The relative risks of future events from lowest (referent) to highest quartile of homocysteine were 1.0, 1.6, 1.6, and 2.2 (
P
<0.001). These effects were similar among those allocated to lovastatin and those allocated to placebo and were modestly attenuated after adjustment for other traditional risk factors. As predicted, the subgroup of participants with elevated LDL cholesterol and elevated homocysteine levels were at high risk and benefited greatly from statin therapy (relative risk, 0.46; 95% CI, 0.29 to 0.75; number needed to treat=26). However, in contrast to findings in this trial for C-reactive protein, homocysteine evaluation did not help to define low LDL subgroups with different responses to lovastatin therapy.

Conclusions—

Although homocysteine predicted future coronary events in AFCAPS/TexCAPS, we found little evidence that homocysteine evaluation provided an improved method to target statin therapy among those with low-to-normal LDL cholesterol levels.
Allelic Variants in Long-QT Disease Genes in Patients With Drug-Associated Torsades de Pointes
Authors: Yang Ping , Kanki Hideaki , Drolet Benoit , Yang Tao , Wei Jian , Viswanathan Prakash C. , Hohnloser Stefan H. , Shimizu Wataru , Schwartz Peter J. , Stanton Marshall , Murray Katherine T. , Norris Kris , George Alfred L. , Roden Dan M.
Published: July 2002

Background

—

DNA variants appearing to predispose to drug-associated “acquired” long-QT syndrome (aLQTS) have been reported in congenital long-QT disease genes. However, the incidence of these genetic risk factors has not been systematically evaluated in a large set of patients with aLQTS. We have previously identified functionally important DNA variants in genes encoding K
+
channel ancillary subunits in 11% of an aLQTS cohort.

Methods and Results

—

The coding regions of the genes encoding the pore-forming channel proteins KvLQT1, HERG, and SCN5A were screened in (1) the same aLQTS cohort (n=92) and (2) controls, drawn from patients tolerating QT-prolonging drugs (n=67) and cross sections of the Middle Tennessee (n=71) and US populations (n=90). The frequency of three common nonsynonymous coding region polymorphisms was no different between aLQTS and control subjects, as follows: 24% versus 19% for H558R (SCN5A), 3% versus 3% for R34C (SCN5A), and 14% versus 14% for K897T (HERG). Missense mutations (absent in controls) were identified in 5 of 92 patients. KvLQT1 and HERG mutations (one each) reduced K
+
currents in vitro, consistent with the idea that they augment risk for aLQTS. However, three SCN5A variants did not alter
I
Na
, which argues that they played no role in the aLQTS phenotype.

Conclusions

—

DNA variants in the coding regions of congenital long-QT disease genes predisposing to aLQTS can be identified in ≈10% to 15% of affected subjects, predominantly in genes encoding ancillary subunits.
Mental Stress–Induced Ischemia and All-Cause Mortality in Patients With Coronary Artery Disease
Authors: Sheps David S. , McMahon Robert P. , Becker Lewis , Carney Robert M. , Freedland Kenneth E. , Cohen Jerome D. , Sheffield David , Goldberg A. David , Ketterer Mark W. , Pepine Carl J. , Raczynski James M. , Light Kathleen , Krantz David S. , Stone Peter H. , Knatterud Genell L. , Kaufmann Peter G.
Published: July 2002

Background
—

Ischemia during laboratory mental stress tests has been linked to significantly higher rates of adverse cardiac events. Previous studies have not been designed to detect differences in mortality rates.

Methods and Results
—

To determine whether mental stress–induced ischemia predicts death, we evaluated 196 patients from the Psychophysiological Investigations of Myocardial Ischemia (PIMI) study who had documented coronary artery disease and exercise-induced ischemia. Participants underwent bicycle exercise and psychological stress testing with radionuclide imaging. Cardiac function data and psychological test results were collected. Vital status was ascertained by telephone and by querying Social Security records 3.5±0.4 years and 5.2±0.4 years later. Of the 17 participants who had died, new or worsened wall motion abnormalities during the speech test were present in 40% compared with 19% of survivors (
P
=0.04) and significantly predicted death (rate ratio=3.0; 95% CI, 1.04 to 8.36;
P
=0.04). Ejection fraction changes during the speech test were similar in patients who died and in survivors (
P
=0.9) and did not predict death even after adjusting for resting ejection fraction (
P
=0.63), which was similar in both groups (mean, 56.4 versus 59.7;
P
=0.24). Other indicators of ischemia during the speech test (ST-segment depression, chest pain) did not predict death, nor did psychological traits, hemodynamic responses to the speech test, or markers of the presence and severity of ischemia during daily life and exercise.

Conclusions
—

In patients with coronary artery disease and exercise-induced ischemia, the presence of mental stress–induced ischemia predicts subsequent death.
Early Protection Against Sudden Death by n-3 Polyunsaturated Fatty Acids After Myocardial Infarction
Authors: Marchioli Roberto , Barzi Federica , Bomba Elena , Chieffo Carmine , Di Gregorio Domenico , Di Mascio Rocco , Franzosi Maria Grazia , Geraci Enrico , Levantesi Giacomo , Maggioni Aldo Pietro , Mantini Loredana , Marfisi Rosa Maria , Mastrogiuseppe G. , Mininni Nicola , Nicolosi Gian Luigi , Santini Massimo , Schweiger Carlo , Tavazzi Luigi , Tognoni Gianni , Tucci Corrado , Valagussa Franco
Published: July 2002

Background

—

Our purpose was to assess the time course of the benefit of n-3 polyunsaturated fatty acids (PUFAs) on mortality documented by the GISSI-Prevenzione trial in patients surviving a recent (<3 months) myocardial infarction.

Methods and Results

—

In this study, 11 323 patients were randomly assigned to supplements of n-3 PUFAs, vitamin E (300 mg/d), both, or no treatment (control) on top of optimal pharmacological treatment and lifestyle advice. Intention-to-treat analysis adjusted for interaction between treatments was carried out. Early efficacy of n-3 PUFA treatment for total, cardiovascular, cardiac, coronary, and sudden death; nonfatal myocardial infarction; total coronary heart disease; and cerebrovascular events was assessed by right-censoring follow-up data 12 times from the first month after randomization up to 12 months. Survival curves for n-3 PUFA treatment diverged early after randomization, and total mortality was significantly lowered after 3 months of treatment (relative risk [RR] 0.59; 95% CI 0.36 to 0.97;
P
=0.037). The reduction in risk of sudden death was specifically relevant and statistically significant already at 4 months (RR 0.47; 95% CI 0.219 to 0.995;
P
=0.048). A similarly significant, although delayed, pattern after 6 to 8 months of treatment was observed for cardiovascular, cardiac, and coronary deaths.

Conclusions

—

The early effect of low-dose (1 g/d) n-3 PUFAs on total mortality and sudden death supports the hypothesis of an antiarrhythmic effect of this drug. Such a result is consistent with the wealth of evidence coming from laboratory experiments on isolated myocytes, animal models, and epidemiological and clinical studies.
Adenylyl Cyclase Increases Survival in Cardiomyopathy
Authors: Roth David M. , Bayat Hamed , Drumm Jeffrey D. , Gao Mei Hua , Swaney James S. , Ander Aziz , Hammond H. Kirk
Published: July 2002

Background

—

To test the hypothesis that increased cardiac adenylyl cyclase type VI (AC
VI
) content, which results in increased cAMP generation, would increase survival in cardiomyopathy, we crossbred mice with Gq-associated cardiomyopathy and those with cardiac-directed expression of AC
VI
. We also assessed myocardial hypertrophy after prolonged cardiac expression of Gq versus coexpression of Gq and AC
VI
.

Methods and Results

—

Three experimental groups, Gq/AC (double positive), Gq, and control (double negative), were studied. Survival was increased by cardiac-directed expression of AC
VI
(
P
<0.0001), and Gq/AC mice had survival rates indistinguishable from control mice. Myocardial hypertrophy developed in older Gq mice but was abrogated by cardiac expression of AC
VI
, as documented by the ratio of ventricular weight to tibial length (Gq, 11.93±0.99 mg/mm, n=11; Gq/AC, 8.00±0.73 mg/mm, n=9;
P
<0.01) and by left ventricular cardiac myocyte size (Gq, 2800±254 μm
2
, n=4; Gq/AC, 1721±166 μm
2
, n=5;
P
<0.01). Hearts of Gq mice were dilated, and function was impaired. Concurrent expression of AC reduced end-diastolic diameter (Gq, 4.20±0.15 mm, n=12; Gq/AC, 3.68±0.12 mm, n=7;
P
<0.05) and increased fractional shortening (Gq, 32±1%, n=12; Gq/AC, 41±2%, n=7;
P
<0.001). Cardiac myocytes from Gq/AC mice showed increased forskolin-stimulated cAMP production (Gq, 3.8±1.3 fmol/cell, n=5; Gq/AC, 10.7±2.6 fmol/cell, n=6;
P
<0.02), documenting increased AC function.

Conclusions

—

Cardiac-directed expression of AC
VI
restores myocyte AC function, improves heart function, increases cAMP generation, abrogates myocardial hypertrophy, and increases survival in Gq cardiomyopathy.
Familial Aggregation of Blood Lipid Response to Exercise Training in the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family Study
Authors: Rice Treva , Després Jean-Pierre , Pérusse Louis , Hong Yuling , Province Michael A. , Bergeron Jean , Gagnon Jacques , Leon Arthur S. , Skinner James S. , Wilmore Jack H. , Bouchard Claude , Rao D.C.
Published: July 2002

Background

—

Fasting levels of plasma lipids and lipoproteins are reported to improve with regular exercise training. However, little is known on whether the training responses are influenced by heritable factors.

Methods and Results

—

The lipid profile was assessed in 115 black (224 individuals) and 99 white families (469 individuals), who participated in the HERITAGE Family Study, while in a sedentary state (baseline visit) and after exercise training for 20 weeks (post visit). Variables included total cholesterol, triglyceride, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A-I, and HDL-C subfractions 2 (HDL
2
-C) and 3 (HDL
3
-C). Familial correlations for the training responses (Δ=post−baseline) were significant for most variables, and the percent variance accounted for by familial factors (ie, maximal heritabilities) ranged from 25% to 38%. Exceptions were for higher heritabilities near 60% for ΔApoB in blacks and ΔHDL
2
-C in whites and a lower estimate of zero for ΔLDL-C in blacks.

Conclusions

—

Heritable factors in part determine lipid profile responses to regular exercise. Maximal heritabilities were similar across ethnic groups and variables, except for ΔLDL-C, ΔApoB, and ΔHDL
2
-C. Molecular studies to identify the markers and genes associated with these influences are currently underway.
Efficacy and Temporal Stability of Reduced Safety Margins for Ventricular Defibrillation
Authors: Gold Michael R. , Higgins Steven , Klein Richard , Gilliam F. Roosevelt , Kopelman Harry , Hessen Scott , Payne John , Strickberger S. Adam , Breiter David , Hahn Stephen
Published: July 2002

Background

—

Traditionally, a safety margin of at least 10 J between the maximum output of the pulse generator and the energy needed for ventricular defibrillation has been used because lower safety margins were associated with unacceptably high rates of failed defibrillation and sudden cardiac death. The Low Energy Safety Study (LESS) was a prospective, randomized assessment of the safety margin requirements for modern implantable cardioverter-defibrillator (ICD) systems.

Methods and Results

—

A total of 636 patients undergoing initial ICD implantation with a dual-coil lead and active pulse generator were evaluated. The defibrillation threshold (DFT) and enhanced DFT (DFT+ and DFT++) were measured using a modified step-down protocol. Conversion testing of induced ventricular fibrillation before discharge, at 3 months, and at 12 months was performed, as was randomization to chronic programming at either 2 steps above DFT++ or maximal output. The induced ventricular fibrillation data had conversion success rates of 91.4%, 97.9%, 99.1%, 99.6%, and 99.8% for safety margins of 0, 1, 2, 3, and 4 steps above the DFT++, respectively. A margin of 4 to 6 J was adequate to maintain high conversion success over time (98.9% before discharge versus 99.2% at 12 months;
P
=NS). Over a mean follow-up of 24±13 months, conversion of spontaneously occurring ventricular tachyarrhythmias >200 bpm was identical (97.3%), despite a safety margin difference of 5.2±1.1 J for the 2-step group versus 20.8±4.2 J for maximal output.

Conclusions

—

With a rigorous implantation algorithm, a safety margin of about 5 J is adequate for safe implantation of modern ICD systems.
Protection of Myocytes From Hypoxia-Reoxygenation Injury by Nitric Oxide Is Mediated by Modulation of Transforming Growth Factor-β
1
Authors: Mehta J.L. , Chen H.J. , Li D.Y.
Published: July 2002

Background

—

Reoxygenation injury is a result of several complex events, including release of reactive oxygen species, protein kinase C (PKC) activation, and altered expression of transforming growth factor-β
1
(TGF-β
1
). Nitric oxide (NO) generally protects tissues from reperfusion injury.

Methods and Results

—

We examined the modulation of TGF-β
1
expression and activity and PKC activation in cultured rat heart myocytes exposed to a brief period of hypoxia-reoxygenation (H-R) by NO donor 3-morpholino-sydnonimine (SIN-1). H-R resulted in an increased expression of total TGF-β
1
(mRNA and protein) but a decrease in the release of active TGF-β
1
. Myocyte PKC-α protein level was not altered by H-R, but its phosphorylation was augmented. Pretreatment of myocytes with SIN-1 diminished myocyte injury quantified as lactate dehydrogenase release. Simultaneously, release of active TGF-β
1
increased and total TGF-β
1
expression decreased (all
P
<0.05 versus H-R alone). PKC-α phosphorylation increased further in cells treated with SIN-1. The effects of SIN-1 were blocked by the NO scavenger phenyl-tetramethyl-imidazoline-oxyl-oxide as well as by the PKC inhibitor staurosporine. To examine if another NO donor would have a similar effect, cardiomyocytes were treated with nitroglycerin before H-R. With nitroglycerin treatment, similar to SIN-1 treatment, myocyte injury was diminished, TGF-β
1
release increased, and total TGF-β
1
expression decreased.

Conclusions

—

These observations suggest modulation of TGF-β
1
expression as a novel mechanism of salutary effect of NO donors. PKC-α activation may play an important role in the protective effect of NO against H-R injury.
Percutaneous Left Atrial Appendage Occlusion (PLAATO) for Preventing Cardioembolism
Authors: Nakai Toshiko , Lesh Michael D. , Gerstenfeld Edward P. , Virmani Renu , Jones Russell , Lee Randall J.
Published: July 2002

Background

—

Atrial fibrillation is associated with a high risk for cardioembolic stroke. The left atrial appendage (LAA) is the source of the vast majority of these thromboemboli. A novel implanted device for percutaneous LAA transcatheter occlusion (PLAATO) has been designed to seal the LAA. The purpose of this study was to test the feasibility and safety of transcatheter LAA occlusion in dogs.

Methods and Results

—

A PLAATO implant was delivered to the LAA through a 12F transseptal catheter in 25 dogs. The PLAATO device was repositioned until occlusion was seen, or it was recaptured and replaced with a different size. LAA sealing was confirmed by intracardiac echocardiography and contrast fluoroscopy. Follow-up was performed 2 days to 6 months after implantation. After imaging assessment, dogs were euthanized and LAA was examined for device healing, migration, perforation, and any thrombosis, both grossly and histologically. The LAA was occluded in all cases. No mobile thrombi associated with the implantation were seen. Healing on the atrial-facing surface was 90% at 1 month and was complete by 3 months, which was confirmed by gross and histological examination. Light microscopic examination of brain, kidney, and spleen showed no evidence of emboli or infarct.

Conclusions

—

Transcatheter LAA occlusion is simple and feasible. At the follow-up study, the device remained in the LAA, with benign healing and no evidence of new thrombus or damage to surrounding structures. This new strategy may provide an alternative treatment for patients with nonvalvular atrial fibrillation who are less than optimal candidates for warfarin.
No-Reflow Phenomenon and Lesion Morphology in Patients With Acute Myocardial Infarction
Authors: Tanaka Atsushi , Kawarabayashi Takahiko , Nishibori Yoshiharu , Sano Toshihiko , Nishida Yukio , Fukuda Daiju , Shimada Kenei , Yoshikawa Junichi
Published: July 2002

Background

—

The no-reflow phenomenon is associated with poor functional and clinical outcomes for patients with acute myocardial infarction (AMI). In the era of primary intervention, accurately identifying lesions at high risk of no reflow is of crucial importance. At present, no study into the relationship between lesion morphology and no reflow has been performed. The aim of this study was to investigate the relationship between preintervention intravascular ultrasound (IVUS) lesion morphology and the no-reflow phenomenon.

Methods and Results

—

This study comprised 100 consecutive patients with AMI who underwent preintervention IVUS and were successfully recanalized with primary balloon angioplasty or stenting. IVUS was again performed to identify and exclude any mechanical vessel obstruction in cases of thrombolysis in myocardial infarction flow grade 0, 1, or 2 after intervention in the absence of angiographic stenosis. Angiographic no reflow was seen in 13 patients (13%). Univariate analysis indicated that hypercholesterolemia, fissure and dissection, lipid pool–like image, lesion, and reference external elastic membrane cross-sectional area correlate with the no-reflow phenomenon. Multivariate logistic regression analysis showed that lipid pool–like image (
P
<0.05; odds ratio 118; 95% CI, 1.28 to 11 008) and lesion elastic membrane cross-sectional area (
P
<0.05; odds ratio 1.55; 95% CI 1.01 to 2.38) are independent predictive factors of no-reflow phenomenon after reperfusion for AMI.

Conclusions

—

Large vessels with lipid pool–like image are at high risk for no reflow after primary intervention for AMI. Also, plaque content may play a role in damage to the microcirculation after primary intervention for AMI.
Percutaneous Left Atrial Appendage Transcatheter Occlusion to Prevent Stroke in High-Risk Patients With Atrial Fibrillation
Authors: Sievert Horst , Lesh Michael D. , Trepels Thomas , Omran Heyder , Bartorelli Antonio , Della Bella Paola , Nakai Toshiko , Reisman Mark , DiMario Carlo , Block Peter , Kramer Paul , Fleschenberg Dirk , Krumsdorf Ulrike , Scherer Detlef
Published: July 2002

Background

—

Thromboembolism due to atrial fibrillation (AF) is a frequent cause of stroke. More than 90% of thrombi in AF form in the left atrial appendage (LAA). Obliteration of the appendage may prevent embolic complications.

Methods and Results

—

We evaluated the feasibility and safety of implanting a novel device for percutaneous left atrial appendage transcatheter occlusion (PLAATO). LAA occlusion using the PLAATO system was attempted in 15 patients with chronic AF at high risk for stroke, who are poor candidates for long-term warfarin therapy. The implant consists of a self-expanding nitinol cage covered with a polymeric membrane (ePTFE). The LAA was successfully occluded in 15/15 patients (100%). Angiography and transesophageal echocardiography (TEE) during the procedure showed that the device was well-seated in all patients and that there was no evidence of perforation, device embolization, or interference with surrounding structures. In 1 patient, the first procedure was complicated by a hemopericardium, which occurred during LAA access. A second attempt 30 days later was successful with no untoward sequela. No other complications occurred. At 1-month follow-up, chest fluoroscopy and TEE revealed continued stable implant position with smooth atrial-facing surface and no evidence of thrombus.

Conclusions

—

Thus, transcatheter closure of the LAA is feasible in humans. This novel implant technology may be appropriate for patients with AF who are not suitable candidates for anticoagulation therapy. Further trials are needed to show the long-term safety and its efficacy in reducing stroke.
Paradoxical Reduction of Fatty Streak Formation in Mice Lacking Endothelial Nitric Oxide Synthase
Authors: Shi Weibin , Wang Xuping , Shih Diana M. , Laubach Victor E. , Navab Mohamad , Lusis Aldons J.
Published: July 2002

Background

—

The endothelial isoform of nitric oxide synthase (eNOS) has been considered to exert an antiatherosclerotic role through synthesis of NO. However, eNOS has been shown to generate superoxide, which could oxidize LDL and promote atherosclerosis. We sought to determine the role of eNOS in diet-induced fatty streak formation through the use of eNOS-deficient mice.

Methods and Results

—

Mice were fed an atherogenic diet containing 15% fat, 1.25% cholesterol, and 0.5% sodium cholate for 12 weeks, and atherosclerotic lesions at the aortic root were measured after oil-red O staining. Unexpectedly, eNOS-deficient mice developed much smaller aortic lesions than did wild-type control mice (2544±1107 versus 7023±1569 μm
2
/section;
P
=0.03). This reduction in lesion formation could not be explained by changes in plasma levels of lipids and susceptibility of lipoproteins to oxidation. To examine whether eNOS contributed to the oxidation of LDL within the arterial wall, endothelial cells were isolated from the aorta of mice and incubated with native LDL in the absence or presence of N-Ω-nitro-
l
-arginine methyl ester (L-NAME), a specific NOS inhibitor. L-NAME significantly inhibited LDL oxidation by endothelial cells from wild-type animals (
P
<0.05), but it had no effect on LDL oxidation by endothelial cells from eNOS-deficient mice.

Conclusions

—

These data indicate that absence of eNOS-mediated LDL oxidation may contribute to the reduction of fatty-streak formation in eNOS-deficient mice.
Proinsulin Is an Independent Predictor of Coronary Heart Disease
Authors: Zethelius Björn , Byberg Liisa , Hales C. Nicholas , Lithell Hans , Berne Christian
Published: July 2002

Background

—

Some, but not all, studies have reported a relationship between plasma insulin and coronary heart disease (CHD). Conventional nonspecific insulin assays are also measuring various fractions of proinsulin-like molecules due to cross-reactivity. The long-term relationship between proinsulin-like molecules and CHD is largely unknown. For this reason, the longitudinal relationships between intact proinsulin, split proinsulin, specific insulin, immunoreactive insulin, and CHD, were studied in a population-based cohort of 50-year-old men (n=874), with a follow-up of 27 years.

Methods and Results

—

Fasting proinsulin-like molecule and specific-insulin concentrations were measured in plasma (stored frozen since baseline 1970 to 1973) by specific 2-site immunometric assays. Immunoreactive insulin concentrations were determined at baseline. The associations between proinsulin-like molecules, specific insulin, immunoreactive insulin, and CHD mortality (International Classification of Diseases [9th revision] codes 410 to 414) were analyzed using Cox’s proportional hazards regression and presented as hazard ratios (HRs) with their 95% confidence intervals (CIs) for a 1-SD increase in a predictor variable. In the univariate analysis, intact proinsulin (HR, 1.69; 95% CI, 1.41 to 2.01) was the strongest predictor of death from CHD. In the multivariate analysis, smoking (HR, 1.57; 95% CI, 1.03 to 2.38), intact proinsulin (HR, 1.47; 95% CI, 1.18 to 1.82), systolic blood pressure (HR, 1.38; 95% CI, 1.14 to 1.66), and LDL/HDL cholesterol ratio (HR, 1.31; 95% CI, 1.12 to 1.53) were independent predictors of CHD mortality (adjusted for body mass index, triglycerides, and fasting glucose), whereas specific insulin and immunoreactive insulin were not (HR, 1.12; 95% CI, 0.90 to 1.40). The increased risk was restricted to the upper third of the proinsulin distribution.

Conclusion

—

Increased proinsulin concentrations predict death and morbidity caused by CHD over a period of 27 years, independent of other major cardiovascular risk factors.
Efficacy and Safety of a Novel Cholesteryl Ester Transfer Protein Inhibitor, JTT-705, in Humans
Authors: de Grooth Greetje J. , Kuivenhoven Jan Albert , Stalenhoef Anton F.H. , de Graaf Jacqueline , Zwinderman Aeilko H. , Posma Jan L. , van Tol Arie , Kastelein John J.P.
Published: July 2002

Background

—

Cholesteryl ester transfer protein (CETP) mediates the transfer of neutral lipids between lipoproteins. High plasma levels of CETP are correlated with low HDL cholesterol levels, a strong risk factor for coronary artery disease. In earlier studies, JTT-705, a novel CETP inhibitor, was shown to increase plasma HDL cholesterol and to inhibit the progression of atherosclerosis in cholesterol-fed rabbits. This study describes the first results using this CETP inhibitor in humans.

Methods and Results

—

In a randomized, double-blind, and placebo-controlled trial, we evaluated the efficacy and safety of daily treatment with 300, 600, and 900 mg JTT-705 in 198 healthy subjects with mild hyperlipidemia. Treatment with 900 mg JTT-705 for 4 weeks led to a 37% decrease in CETP activity (
P
<0.0001), a 34% increase in HDL cholesterol (
P
<0.0001), and a 7% decrease in LDL cholesterol (
P
=0.017), whereas levels of triglycerides, phospholipid transfer protein, and lecithin-cholesterol acyltransferase were unaffected. In line with the increase of total HDL, a rise of HDL
2,
HDL
3
, and apolipoprotein A-I was also noted. JTT-705 showed no toxicity with regard to physical examination and routine laboratory tests.

Conclusions

—

We show that the use of the CETP inhibitor JTT-705 in humans is an effective means to raise HDL cholesterol levels with minor gastrointestinal side effects (
P
=0.06). Although these results hold promise, further studies are needed to investigate whether the observed increase in HDL cholesterol translates into a concomitant reduction in coronary artery disease risk.
Functional Inhibition of Ras by

S

-

trans

,

trans

-Farnesyl Thiosalicylic Acid Attenuates Atherosclerosis in Apolipoprotein E Knockout Mice
Authors: George Jacob , Afek Arnon , Keren Pnina , Herz Itzhak , Goldberg Iris , Haklai Roni , Kloog Yoel , Keren Gad
Published: July 2002

Background

—

Atherosclerosis is a multifactorial disorder involving inflammatory processes. These responses are associated with robust activation of signaling cascades by diverse cell surface receptors in a variety of cell types. The processes that are involved in atherosclerosis would likely require intact Ras pathways, which play a key role in the control of cell growth, differentiation, and apoptosis.

Methods and Results

—

We examined whether the Ras inhibitor farnesyl thiosalicylic acid (FTS) can suppress atherogenesis in the apolipoprotein E–deficient mouse model. Mice were treated with FTS or a control regimen 3 times weekly for 6 weeks and fed a normal chow diet. Two additional groups included FTS-treated and control-treated mice that were fed a high-fat diet for 10 weeks. FTS reduced both fatty streaks and advanced lesions compared with the control treatment. Ras inhibition in vivo was evidenced by the reduced content of the active form of Ras (Ras-GTP) in aortas of FTS-treated mice. Splenocytes from the FTS-treated versus control mice exhibited reduced proliferation to oxidized LDL (OxLDL) but not to concanavalin A. IgG anti-OxLDL antibody levels were reduced in FTS-treated mice compared with controls. Whereas no effect of FTS was evident on plaque T lymphocyte and macrophage content, lesional vascular cell adhesion molecule-1 and nuclear factor-κB expression were considerably reduced compared with controls.

Conclusions

—

FTS suppressed atherosclerotic plaques in apolipoprotein E–deficient mice, providing a useful tool for research in atherosclerosis.
Lethal Perinatal Thrombosis in Mice Resulting From the Interaction of Tissue Factor Pathway Inhibitor Deficiency and Factor V Leiden
Authors: Eitzman Daniel T. , Westrick Randal J. , Bi Xiaoming , Manning Sara L. , Wilkinson John E. , Broze George J. , Ginsburg David
Published: July 2002

Background

—

Factor V Leiden (FVL) is a common genetic risk factor for thrombosis in humans. The incomplete penetrance of FVL suggests important contributions from other genetic or environmental modifying factors. Variation in the expression of tissue factor pathway inhibitor (
TFPI
) has also been proposed as a risk factor for venous thrombosis and has been shown to enhance the prothrombotic effect of FVL in vitro.

Methods and Results

—

To examine the potential in vivo interaction between
Tfpi
and
FvL
, we analyzed crosses between mice carrying
FvL
and a deficiency of TFPI. The
Fv
Q/Q
,
Tfpi
+/−
genotype was nearly completely fatal in the early perinatal period. Increased fibrin deposition was observed in multiple organs from the
Fv
Q/Q
,
Tfpi
+/−
fetuses, suggesting disseminated thrombosis.

Conclusions

—

These observations demonstrate the prothrombotic effect of modest variations in the level of
TFPI
expression and suggest that
TFPI
could be an important genetic modifier for the thrombosis associated with FVL in humans.
Impact of Clinical Syndrome Acuity on the Differential Response to 2 Glycoprotein IIb/IIIa Inhibitors in Patients Undergoing Coronary Stenting
Authors: Stone Gregg W. , Moliterno David J. , Bertrand Michel , Neumann Franz-Josef , Herrmann Howard C. , Powers Eric R. , Grines Cindy L. , Moses Jeffrey W. , Cohen David J. , Cohen Eric A. , Cohen Marc , Wolski Kathy , DiBattiste Peter M. , Topol Eric J.
Published: July 2002

Background

—

Although glycoprotein IIb/IIIa inhibitors have been shown to reduce periprocedural and late ischemic events in patients undergoing stent implantation, the relative safety and efficacy of different agents in this class is less established. Also unknown is whether the acuity of the presenting clinical syndrome, which may affect the degree of platelet inhibition required or achieved, influences the response to different antiplatelet agents.

Methods and Results

—

A prospective, multicenter, double-blind, randomized trial was performed in which 4809 patients undergoing planned stenting were randomized to receive abciximab or tirofiban. In patients with acute coronary syndromes (ACS; n=3025), abciximab resulted in lower rates of myocardial infarction at 30 days (5.8% versus 8.5%;
P
=0.004) and 6 months (7.2% versus 9.8%;
P
=0.013), although 6-month mortality rates were identical (1.39% in both groups;
P
=0.99). Conversely, in patients without ACS (n=1784), myocardial infarction rates were not significantly lower with tirofiban, survival was similar, and target vessel revascularization was reduced, which translated into a trend toward enhanced 6-month event-free survival with tirofiban (89.7% versus 86.6%;
P
=0.056).

Conclusions

—

In patients with ACS undergoing stent implantation, abciximab use compared with tirofiban results in greater suppression of periprocedural myonecrosis, although a survival benefit has not been demonstrated. Patients with stable coronary syndromes may have equivalent or better outcomes with tirofiban relative to abciximab, with fewer adverse hematologic and hemorrhagic events. These data raise important issues regarding the relative pharmacodynamic inhibition of platelet function required in varying clinical scenarios and have important implications for the cost-effective utilization of glycoprotein IIb/IIIa inhibitors.
Myosin Light Chain Mutation Causes Autosomal Recessive Cardiomyopathy With Mid-Cavitary Hypertrophy and Restrictive Physiology
Authors: Olson Timothy M. , Karst Margaret L. , Whitby Frank G. , Driscoll David J.
Published: July 2002

Background

—

Autosomal dominant hypertrophic cardiomyopathy (HCM) is caused by inherited defects of sarcomeric proteins. We tested the hypothesis that homozygosity for a sarcomeric protein defect can cause recessive HCM.

Methods and Results

—

We studied a family with early-onset cardiomyopathy in 3 siblings, characterized by mid-cavitary hypertrophy and restrictive physiology. Genotyping of DNA markers spanning 8 genes for autosomal dominant HCM revealed inheritance of an identical paternal and maternal haplotype at the
essential light chain of myosin
locus by the affected children. Sequencing showed that these individuals were homozygous for a Glu143Lys substitution of a highly conserved amino acid that was absent in 150 controls. Family members with one Glu143Lys allele had normal echocardiograms and ECGs, even in late adulthood, whereas those with two mutant alleles developed severe cardiomyopathy in childhood. These findings, coupled with previous studies of myosin light chain structure and function in the heart, suggest a loss-of-function disease mechanism.

Conclusions

—

Distinct mutations affecting the same sarcomeric protein can cause either dominant or recessive cardiomyopathy. Electrostatic charge reversal of a highly conserved amino acid may be benign in the heterozygous state as the result of compensatory mechanisms that preserve cardiac structure and function. By contrast, homozygous carriers of a sarcomeric protein defect may have a malignant course. Recognizing recessive inheritance in children with cardiomyopathy is essential for appropriate family counseling.
Assessment of Coronary Function in Children With a History of Kawasaki Disease Using
15
O-Water Positron Emission Tomography
Authors: Furuyama Hideto , Odagawa Yasuhisa , Katoh Chietsugu , Iwado Yasuyoshi , Yoshinaga Keiichiro , Ito Yoshinori , Noriyasu Kazuyuki , Mabuchi Megumi , Kuge Yuji , Kobayashi Kunihiko , Tamaki Nagara
Published: July 2002

Background
—

Coronary abnormalities after Kawasaki disease (KD) may be associated with endothelial dysfunction due to intimal hypertrophy. The purpose of this study was to evaluate myocardial flow reserve (MFR) and endothelial function in regressed aneurysmal regions after KD.

Methods and Results
—

Subjects were 12 patients aged 16.0±2.6 years who suffered from KD at 1.7±1.5 years and 12 normal subjects aged 26.5±3.4 years. MFR and endothelial function were estimated, respectively, by changes in myocardial blood flow (MBF) during ATP infusion and by that during cold pressor test using
15
O-water positron emission tomography. Data from 24 regressed aneurysmal regions were compared with those from the corresponding regions (n=36) in the control group. Although the MBF at rest in the regressed aneurysmal regions was similar to that in controls, the MBF at a hyperemic state induced by ATP infusion in the regressed aneurysmal regions was significantly lower than that in the control regions. Therefore, the MFR in regressed aneurysmal regions was significantly lower than that in controls (3.53±0.95 versus 4.60±1.14;
P
<0.05). MBF at rest and during the cold pressor test did not change in the control regions, but it was significantly reduced in regressed aneurysmal regions. The ratio of MBF during the cold pressor test to MBF at rest was significantly lower in regressed aneurysmal regions than in control regions (0.67±0.15 versus 1.00±0.15;
P
<0.05).

Conclusions
—

MFR and endothelial function are often impaired in regressed aneurysmal regions after KD, and tomography enables the noninvasive evaluation of coronary function.
S
-Nitroso Human Serum Albumin Treatment Reduces Ischemia/Reperfusion Injury in Skeletal Muscle via Nitric Oxide Release
Authors: Hallström Seth , Gasser Harald , Neumayer Christoph , Fügl Alexander , Nanobashvili Joseph , Jakubowski Andrzej , Huk Ihor , Schlag Günther , Malinski Tadeusz
Published: July 2002

Background

—

Peroxynitrite generated from nitric oxide (NO) and superoxide (O
2
−
) contributes to ischemia/reperfusion (I/R) injury. Feedback inhibition of endothelial NO synthase by NO may inhibit O
2
−
production generated also by endothelial NO synthase at diminished local
l
-arginine concentrations accompanying I/R.

Methods and Results

—

During hindlimb I/R (2.5 hours/2 hours), in vivo NO was monitored continuously (porphyrinic sensor), and high-energy phosphates, reduced and oxidized glutathione (chromatography), and I/R injury were measured intermittently. Rabbits receiving human serum albumin (HSA) (controls) were compared with those receiving
S
-nitroso human serum albumin (S-NO-HSA) beginning 30 minutes before reperfusion for 1 hour or 30 minutes before ischemia for 3.5 hours (0.1 μmol · kg
−1
· h
− 1
). The onset of ischemia led to a rapid increase of NO from its basal level (50±12 nmol/L) to 120±20 and 220±15 nmol/L in the control and S-NO-HSA–treated groups, respectively. In control animals, NO dropped below basal levels at the end of ischemia and to undetectable levels (<1 nmol/L) during reperfusion. In S-NO-HSA–treated animals, maximal NO levels never decreased below basal concentration and on reperfusion were 100±15 nmol/L (S-NO-HSA preischemia group, 175±15 nmol/L). NO supplementation by S-NO-HSA led to partial and in the preischemia group to total preservation of high-energy phosphates and glutathione status in reperfused muscle (eg, preischemia groups: ATP, 30.23±5.02 μmol/g versus control, 15.75±4.33 μmol/g,
P
<0.0005; % oxidized glutathione, 4.49± 1.87% versus control, 22.84±6.39%,
P
<0.0001). S-NO-HSA treatment in all groups led to protection from vasoconstriction and reduced edema formation after reperfusion (eg, preischemia groups: interfiber area, 12.94±1.36% versus control, 27.83±1.95%,
P
< 0.00001).

Conclusions

—

Long-lasting release of NO by S-NO-HSA provides significant protection of skeletal muscle from I/R injury.
Morphological Predictors of Restenosis After Coronary Stenting in Humans
Authors: Farb Andrew , Weber Deena K. , Kolodgie Frank D. , Burke Allen P. , Virmani Renu
Published: July 2002

Background

—

Experimental studies suggest that arterial injury and inflammation lead to increased neointimal growth after stenting. Despite the increased use of coronary stents in humans, there are only limited pathological data on the morphological features of in-stent restenosis.

Methods and Results

—

Detailed histology was performed on 116 stents, implanted ≥90 days in 87 coronary arteries, from 56 patients (mean age, 59±13 years). The mean duration of stent implant was 10 months. In-stent restenosis was defined as a stent area stenosis of >75%. Lumen area increased as stent area increased (
r
2
=0.27,
P
=0.0001), but there was a much stronger correlation between stent area and neointimal area (
r
2
=0.70,
P
<0.0001). Arterial medial fracture was associated with a 29% increase (
P
<0.01) in neointimal thickness compared with arteries with an intact media. Neointimal thickness (
P
=0.0001), inflammatory cell density (
P
<0.0001), and neointimal vascular channel density (
P
<0.0001) were greater when struts were in contact with a ruptured arterial media compared with fibrous plaque or an intact fibrous cap. Stent strut penetration into a lipid core was associated with increased neointimal thickness (
P
=0.04) and inflammatory cell density (
P
=0.03). Neointimal inflammatory cell content was 2.4-fold greater in stents with restenosis versus no restenosis, and inflammation was associated with increased neoangiogenesis.

Conclusions

—

Coronary stenting that is accompanied by medial damage or penetration of the stent into a lipid core induces increased arterial inflammation, which is associated with increased neointimal growth. These data suggest the use of stenting strategies that reduce inflammation and neoangiogenesis to reduce the incidence of restenosis.
Role of Cyclic Guanosine Monophosphate in Late Preconditioning in Conscious Rabbits
Authors: Kodani Eitaro , Xuan Yu-Ting , Takano Hitoshi , Shinmura Ken , Tang Xian-Liang , Bolli Roberto
Published: July 2002

Background

—

Although NO has been shown to serve both as the trigger and the mediator of the late phase of ischemic preconditioning (PC), it is unknown whether NO acts via activation of soluble guanylate cyclase (sGC). The objective of this study was to investigate the role of sGC in late PC in conscious rabbits using the selective sGC inhibitor 1
H
-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ).

Methods and Results

—

A total of 172 conscious rabbits were used. When nonpreconditioned rabbits were subjected to a sequence of 4-minute coronary occlusion/4-minute reperfusion cycles, myocardial cyclic guanosine monophosphate (cGMP) levels increased significantly at the end of the third and sixth occlusions. In rabbits preconditioned 24 hours earlier (on day 1) with six occlusion/reperfusion cycles, myocardial cGMP levels on day 2 were significantly higher than in nonpreconditioned rabbits even before ischemia but did not increase further during a second sequence of 4-minute occlusion/reperfusion cycles. Administration of ODQ before the six occlusion/reperfusion cycles on day 1 did not prevent the development of late PC against either stunning or infarction on day 2. In contrast, administration of ODQ on day 2 completely ablated the late PC effect against both stunning and infarction.

Conclusions

—

These results indicate that enhanced synthesis of cGMP by sGC is not necessary for ischemia to trigger a late PC effect but is required for the protection to become manifest 24 hours later. This implies that NO participates in late PC via two distinct mechanisms; ie, it triggers late PC on day 1 via a cGMP-independent mechanism and it mediates late PC on day 2 via a cGMP-dependent mechanism.
Long-Term Clinical and Angiographic Follow-Up After Coronary Stent Placement in Native Coronary Arteries
Authors: Kimura Takeshi , Abe Kenichi , Shizuta Satoshi , Odashiro Keita , Yoshida Yoshinori , Sakai Koyu , Kaitani Kazuaki , Inoue Katsumi , Nakagawa Yoshihisa , Yokoi Hiroyoshi , Iwabuchi Masashi , Hamasaki Naoya , Nosaka Hideyuki , Nobuyoshi Masakiyo
Published: July 2002

Background

—

Although coronary stents have been proved effective in reducing clinical cardiac events for up to 3 to 5 years, longer term clinical and angiographic outcomes have not yet been fully clarified.

Methods and Results

—

To evaluate longer term (7 to 11 years) outcome, clinical and angiographic follow-up information was analyzed in 405 patients with successful stenting in native coronary arteries. Primary or secondary stabilization, which was defined as freedom from death, coronary artery bypass grafting, and target lesion-percutaneous coronary intervention (TL-PCI) during the 14 months after the initial procedure or after the last TL-PCI, was achieved in 373 patients (92%) overall. Only 7 patients (1.7%) underwent TL-PCI more than twice. After the initial 14-month period, freedom from TL-PCI reached a plateau at 84.9% to 80.7% over 1 to 8 years. However, quantitative angiographic analysis in 179 lesions revealed a triphasic luminal response characterized by an early restenosis phase until 6 months, an intermediate-term regression phase from 6 months to 3 years, and a late renarrowing phase beyond 4 years. Minimal luminal diameter in 131 patients with complete serial data were 2.62±0.4 mm immediately after stenting, 2.0±0.49 mm at 6 months, 2.19±0.49 mm at 3 years, and 1.85±0.56 mm beyond 4 years (
P
<0.0001).

Conclusions

—

The efficacy and safety of coronary stenting seemed to be clinically sustained at 7 to 11 years of follow-up. However, late luminal renarrowing beyond 4 years was common, which demonstrates the need for further follow-up.
Stromal Cell–Derived Factor-1α in Unstable Angina
Authors: Damås Jan K. , Wæhre Torgun , Yndestad Arne , Ueland Thor , Müller Fredrik , Eiken Hans Geir , Holm Are M. , Halvorsen Bente , Frøland Stig S. , Gullestad Lars , Aukrust Pål
Published: July 2002

Background

—

Chemokines play a pathogenic role in atherogenesis and plaque destabilization by activating and directing leukocytes into the atherosclerotic plaque. However, stromal cell–derived factor (SDF)-1 was recently found to have antiinflammatory effects, and we hypothesized that this chemokine could play a beneficial role in coronary artery disease.

Methods and Results

—

Plasma levels of SDF-1α were significantly decreased in patients with stable (n=30) and unstable angina (n=30) compared with healthy control subjects (n=20), particularly in those with unstable disease. By flow cytometry and RNase protection assay, we found decreased surface expression but increased gene expression of the SDF-1α receptor CXCR-4 in peripheral blood mononuclear cells (PBMC) from patients with stable angina and patients with unstable angina. In vitro, SDF-1α (500 ng/mL) reduced both unstimulated and endotoxin/mitogen-stimulated mRNA and protein levels of monocyte chemoattractant protein-1, interleukin-8, matrix metalloproteinase-9, and tissue factor while increasing tissue inhibitor of metalloproteinases-1 in PBMC from patients with unstable angina. The SDF-1α–mediated suppression of monocyte chemoattractant protein-1 and interleukin-8 appears to involve cAMP/protein kinase A type I–dependent pathways. Finally, although SDF-1α suppressed the spontaneous release of these inflammatory mediators in unstable angina, enhancing effects were seen in unstimulated PBMC from healthy control subjects, possibly reflecting that PBMC in unstable angina are preactivated in vivo.

Conclusions

—

In contrast to several other chemokines, our findings suggest that SDF-1α, at least in high concentrations, may mediate antiinflammatory and matrix-stabilizing effects in unstable angina. These effects may promote plaque stabilization, and therapeutic intervention that enhances SDF-1α activity could potentially be beneficial in acute coronary syndromes.