bluuebunny/crossref_metadata_2025 huggingface dataset:
Fosinopril Versus Amlodipine Comparative Treatments Study
Authors: Pahor Marco , Franse Lonneke V. , Deitcher Steven R. , Cushman William C. , Johnson Karen C. , Shorr Ronald I. , Kottke-Marchant Kandice , Tracy Russell P. , Somes Grant W. , Applegate William B.
Published: July 2002

Background
—

ACE inhibitors and calcium antagonists may modulate fibrinolysis. We conducted a randomized controlled trial to assess the effects of these drugs on plasminogen activator inhibitor-1 (PAI-1) antigen, an inhibitor of fibrinolysis.

Methods and Results
—

Participants with hypertension and type 2 diabetes mellitus (n=96, 51% black) were randomized after an initial 4 weeks of placebo to double-blind 20 or 40 mg fosinopril or 5 or 10 mg amlodipine daily for 4 weeks in a fixed-dose regimen. After 4 weeks of placebo washout, the patients received 4 weeks of crossover treatments. After treatment with placebo, systolic and diastolic blood pressure were 143±2 and 86±1 mm Hg and plasma PAI-1 was 43.4±2.3 ng/mL. Amlodipine achieved a greater systolic and diastolic blood pressure reduction than fosinopril (10 mm Hg versus 8 mm Hg,
P
=0.029, and 5 mm Hg versus 3 mm Hg,
P
=0.040, respectively) but tended to increase PAI-1, whereas fosinopril tended to decrease PAI-1 (5.4±3.6 versus −3.8±2.5 ng/mL,
P
=0.045). The PAI-1 changes depended on drug dose (6.5±6.1 and 3.4±3.9 ng/mL with amlodipine 10 and 5 mg, respectively, and −0.4±3.1 and −7.4±4.0 ng/mL with fosinopril 20 and 40 mg, respectively,
P
for trend 0.024). No significant differences between fosinopril and amlodipine were found for short-term changes in tissue plasminogen activator antigen, fibrinogen, C-reactive protein, and interleukin-6. The findings were similar in black and white participants.

Conclusions
—

Short-term treatment with fosinopril significantly reduced PAI-1 compared with amlodipine in a dose-dependent fashion. This effect, which was independent of blood pressure reduction, may account for the improved clinical outcomes achieved with ACE inhibitors compared with calcium antagonists.
Utility of B-Natriuretic Peptide in Detecting Diastolic Dysfunction
Authors: Lubien Emily , DeMaria Anthony , Krishnaswamy Padma , Clopton Paul , Koon Jen , Kazanegra Radmila , Gardetto Nancy , Wanner Erin , Maisel Alan S.
Published: July 2002

Background

—

Although Doppler echocardiography has been used to identify abnormal left ventricular (LV) diastolic filling dynamics, inherent limitations suggest the need for additional measures of diastolic dysfunction. Because data suggest that B-natriuretic peptide (BNP) partially reflects ventricular pressure, we hypothesized that BNP levels could predict diastolic abnormalities in patients with normal systolic function.

Methods and Results

—

We studied 294 patients referred for echocardiography to evaluate ventricular function. Patients with abnormal systolic function were excluded. Cardiologists making the assessment of LV function were blinded to BNP levels. Patients were classified as normal, impaired relaxation, pseudonormal, and restrictivelike filling patterns. Patients diagnosed with evidence of abnormal LV diastolic function (n=119) had a mean BNP concentration of 286±31 pg/mL; those in the normal LV group (n=175) had a mean BNP concentration of 33±3 pg/mL. Patients with restrictivelike filling patterns on echocardiography had the highest BNP levels (408±66 pg/mL), and patients with symptoms had higher BNP levels in all diastolic filling patterns. The area under the receiver-operating characteristic curve for BNP to detect any diastolic dysfunction was 0.92 (95% CI, 0.87 to 0.95;
P
<0.001). A BNP value of 62 pg/mL had a sensitivity of 85%, a specificity of 83%, and an accuracy of 84% for detecting diastolic dysfunction.

Conclusions

—

A rapid assay for BNP can reliably detect the presence of diastolic abnormalities on echocardiography. In patients with normal systolic function, elevated BNP levels and diastolic filling abnormalities might help to reinforce the diagnosis diastolic dysfunction.
Quality of Life in the Antiarrhythmics Versus Implantable Defibrillators Trial
Authors: Schron Eleanor B. , Exner Derek V. , Yao Qing , Jenkins Louise S. , Steinberg Jonathan S. , Cook James R. , Kutalek Steven P. , Friedman Peter L. , Bubien Rosemary S. , Page Richard L. , Powell Judy ,   the AVID Investigators
Published: July 2002

Background

—

Implantable cardioverter defibrillator (ICD) use reduces mortality in patients with serious ventricular arrhythmias compared with antiarrhythmic drug (AAD) use. However, the relative impact of these therapies on self-perceived quality of life (QoL) is unknown.

Methods and Results

—

Three self-administered instruments were used to measure generic and disease-specific QoL in Antiarrhythmics Versus Implantable Defibrillators trial participants. Generalized linear models were used to assess the relationships between self-perceived QoL and treatment (AAD versus ICD) and adverse symptoms and ICD shocks. To minimize the impact of missing data, only patients surviving 1 year were included in the primary analyses. Baseline characteristics among QoL participants (n=905) and nonparticipants (n=111) were similar, but participants who survived 1 year (n=800) were healthier at baseline than nonsurvivors (n=105). Of the 800 patients in the primary analysis, characteristics of those randomized to AAD (n=384) versus ICD (n=416) were similar. Overall, ICD and AAD use were associated with similar alterations in QoL. The development of sporadic shocks and adverse symptoms were each associated with reduced physical functioning and mental well-being and increased concerns among ICD recipients, whereas development of adverse symptoms was associated with reduced physical functioning and increased concerns among AAD recipients.

Conclusions

—

ICD and AAD therapy are associated with similar alterations in self-perceived QoL over 1-year follow-up. Adverse symptoms were associated with reduced self-perceived QoL in both groups, and sporadic shocks were associated with reduced QoL in ICD recipients.
Minor Myocardial Damage and Prognosis
Authors: Akkerhuis K. Martijn , Alexander John H. , Tardiff Barbara E. , Boersma Eric , Harrington Robert A. , Lincoff A. Michael , Simoons Maarten L.
Published: July 2002

Background

—

The relevance of the adverse prognostic implications of CK-MB elevation after percutaneous coronary intervention (PCI) remains controversial. Therefore, we compared the relationship between the level of postprocedural CK-MB elevation and 6-month mortality in patients undergoing PCI with the relationship between the level of spontaneous, non–PCI-related CK-MB elevation and 6-month mortality in patients with acute coronary syndromes (ACS) treated medically.

Methods and Results

—

In the PURSUIT trial, 5583 of 9461 patients who presented with a non–ST-elevation ACS did not undergo PCI or CABG and had at least 1 CK-MB sample collected during index-hospitalization. There was a gradual increase in 6-month mortality with higher CK-MB levels: 4.1%, 8.6%, 9.0%, 14.3%, 15.5% for CK-MB ratios 0 to 1, >1 to 3, >3 to 5, >5 to 10, and >10 times the upper limit of normal. A combined analysis in 8838 patients undergoing PCI in 5 large, clinical trials revealed a proportional relationship between postprocedural CK-MB levels (≤48 hours after PCI) and 6-month mortality. In patients with CK-MB ratios 0 to 1, >1 to 3, >3 to 5, >5 to 10, and >10, the risk of death was 1.3%, 2.0%, 2.3%, 4.3%, and 7.4%, respectively. The absolute mortality rates were lower after procedure-related infarcts compared with spontaneous infarcts. Yet, the relative increase in 6-month mortality with each increase in peak CK-MB level was similar for PCI-related myocardial necrosis and spontaneous myocardial necrosis, as all tests for heterogeneity of the odds ratios were nonsignificant.

Conclusions

—

The present analysis indicates that the adverse prognostic implications of periprocedural myocardial necrosis should be considered similar to the adverse consequences of spontaneous myocardial necrosis.
Steps Toward Percutaneous Aortic Valve Replacement
Authors: Boudjemline Younes , Bonhoeffer Philipp
Published: July 2002

Background

—

To date, the surgical approach is the only option to replace the aortic valve. Percutaneous pulmonary valve replacement has recently opened new perspectives on transcatheter replacement of cardiac valves. We report our experience of aortic valve replacement through a percutaneous technique in lambs.

Methods and Results

—

A bovine jugular vein containing a valve was dissected and sutured into a stent. Twelve lambs were divided into 3 groups. In the first, a valved stent was implanted in the descending aorta after creation of an aortic insufficiency. In the second, the valve was implanted in the native position. In the third, we inserted a valved stent in the native position using an orientation mechanism. All valves were successfully delivered and functioned perfectly in short-term evaluation. All experiments in group 2 failed: 1 valve obstructed the coronary artery orifices, 1 stent was responsible for a major mitral valve insufficiency, and the third implant migrated prematurely. A paraprosthetic leak occurred in the last animal in this group. Animals in group 3 had successful implantation of the valved stent. The orientation mechanism allowed perfect alignment of the device without any damage to the coronary circulation or to mitral valve function.

Conclusions

—

Nonsurgical implantation of an aortic valve is possible in lambs in the descending aorta and in the native position. An orientation mechanism is obviously needed to avoid obstruction of the coronary orifices. With further improvements, this technique should be feasible in humans.
Inflammatory Response After Open Heart Surgery
Authors: Dybdahl Brit , Wahba Alexander , Lien Egil , Flo Trude H. , Waage Anders , Qureshi Nilofer , Sellevold Olav F.M. , Espevik Terje , Sundan Anders
Published: July 2002

Background

—

Coronary artery bypass grafting with the use of cardiopulmonary bypass is known to mediate an inflammatory response. The stress-inducible heat-shock protein (HSP) 70 has been detected in myocardial cells after CABG, and toll-like receptors (TLRs) are suggested as putative signaling receptors for the HSPs, mediating synthesis of inflammatory cytokines. The main aims of our study were to explore the release of HSP70 and the regulation of monocyte TLR-2 and TLR-4 expression after CABG.

Methods and Results

—

Twenty patients referred for elective CABG were included in this study. Using immunoassays, we detected HSP70 in plasma after CABG, with peak concentration immediately after surgery. Interleukin-6 in plasma reached peak concentration 5 hours after surgery. Monocyte CD14, TLR-2, and TLR-4 expression, as analyzed by flow cytometry, was initially downregulated. On day 1, CD14 expression normalized, whereas TLR-2 and TLR-4 expression was upregulated. TLR-4 was significantly upregulated even on postoperative day 2. Additional experiments revealed that peritoneal macrophages from control (C3H/HeN) mice responded to HSP70 with release of tumor necrosis factor, whereas macrophages from mutated TLR-4 (C3H/HeJ) mice were unresponsive. In vitro, human adherent monocytes responded to recombinant HSP70 with interleukin-6 and tumor necrosis factor release. CD14 and TLR-4 monoclonal antibodies inhibited the cytokine response.

Conclusions

—

In this study, we observed an immediate release of HSP70 into the circulation and a modulation of monocyte TLR-2 and TLR-4 expression after CABG. TLR-4 and CD14 appear to be involved in an HSP70-mediated activation of innate immunity.
In Vitro Susceptibility to Thrombin-Induced Platelet Microbicidal Protein Is Associated With Reduced Disease Progression and Complication Rates in Experimental

Staphylococcus aureus

Endocarditis
Authors: Kupferwasser Leon Iri , Yeaman Michael R. , Shapiro Shelley M. , Nast Cynthia C. , Bayer Arnold S.
Published: July 2002

Background

—

Mammalian platelets contain small, cationic, staphylocidal peptides, termed thrombin-induced platelet-microbicidal proteins (tPMPs). Evidence suggests that tPMPs play a key role in host defense against endovascular infections, such as infective endocarditis (IE). In the present study, we evaluated the influence of differences in staphylococcal tPMP-susceptibility profiles in vitro on disease severity in experimental IE.

Methods and Results

—

Experimental IE was induced in rabbits with either a tPMP-susceptible or an isogenic tPMP-resistant
Staphylococcus aureus
strain. Vegetation size, left ventricular fractional shortening, and onset of aortic valvular regurgitation were serially assessed by echocardiography over an 11-day postinfection period. In addition, blood cultures were performed daily. Parameters delineated at autopsy included vegetation weights; bacterial densities in vegetations, myocardium, and kidneys; extent of valvular and perivalvular tissue damage; and renal embolization. The following significant differences were observed in animals infected with the tPMP-susceptible versus the tPMP-resistant
S aureus
strain: substantially lower bacteremia rates (
P
=0.02); reduced vegetation growth (
P
<0.001) and weight (
P
<0.001); a later onset of aortic valvular regurgitation (
P
=0.0039); increased preservation of left ventricular function (
P
<0.001); reduced valvular tissue damage (
P
=0.01) and perivalvular inflammation (
P
=0.015); and reduced bacterial densities in vegetations (
P
<0.001) and kidneys (
P
<0.01).

Conclusions

—

The in vitro tPMP-susceptibility profile in
S aureus
substantially affects a number of well-defined cardiac and microbiological parameters related to disease severity and prognosis in IE. These findings underscore the likelihood that platelets mitigate the pathogenesis of endovascular infections via local secretion of antimicrobial peptides.
Fluvastatin, a 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor, Attenuates Left Ventricular Remodeling and Failure After Experimental Myocardial Infarction
Authors: Hayashidani Shunji , Tsutsui Hiroyuki , Shiomi Tetsuya , Suematsu Nobuhiro , Kinugawa Shintaro , Ide Tomomi , Wen Jing , Takeshita Akira
Published: July 2002

Background
—

Short-term administration of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, statins, has been shown to attenuate ischemia-reperfusion injury. However, the effects of long-term administration of statins on left ventricular (LV) remodeling and failure after myocardial infarction remain unknown.

Methods and Results
—

Mice were subjected to coronary artery ligation and were treated for 4 weeks with vehicle or fluvastatin (10 mg/kg per day PO). Fluvastatin increased survival (61% versus 86%;
P
<0.05) without affecting the infarct size (52±2% versus 49±3%;
P
=NS). Fluvastatin not only attenuated LV dilatation but also decreased LV end-diastolic pressure and lung weight. Furthermore, it reduced cardiac myocyte hypertrophy and interstitial fibrosis of the noninfarcted LV and also improved LV ejection performance. LV matrix metalloproteinase (MMP)-2 and MMP-13 were increased in myocardial infarction, which was attenuated in fluvastatin-treated mice.

Conclusions
—

Fluvastatin increased survival in a murine model of postinfarct heart failure, which was associated with the amelioration of LV structural remodeling and contractile failure. Moreover, these effects were associated with the attenuation of increased MMP activity. Thus, long-term treatment with fluvastatin might be beneficial also in patients with heart failure and might improve their long-term survival.
Porphyromonas gingivalis

Infection Accelerates the Progression of Atherosclerosis in a Heterozygous Apolipoprotein E–Deficient Murine Model
Authors: Li Li , Messas Emmanuel , Batista Eraldo L. , Levine Robert A. , Amar Salomon
Published: July 2002

Background
—

Current epidemiological data suggest that dental infections affecting tooth-supporting tissues (periodontitis) can disseminate into the systemic circulation and thereby contribute to atherosclerosis progression. To test this hypothesis, we investigated the effect of repeated systemic inoculations with
Porphyromonas gingivalis
(
Pg
), a putative periodontal pathogen, on the progression of atherosclerosis in heterozygous apolipoprotein E–deficient (ApoE
+/−
) mice.

Methods and Results
—

Ten-week-old, male ApoE
+/−
mice fed either a high-fat diet or regular chow were inoculated intravenously with live
Pg
(10
7
CFU) or vehicle once per week for 10, 14, or 24 consecutive weeks. Histomorphometry of plaque cross-sectional area in the proximal aortas, en face measurement of plaque area over the aortic trees,
Pg
16S ribosomal DNA amplification with polymerase chain reaction, ELISA for systemic proinflammatory mediators, and immunolocalization of macrophages in the proximal aorta were performed. Atherosclerotic lesions of the proximal aortas and aortic trees were more advanced in
Pg
-challenged animals than in vehicle control animals and occurred earlier (at 10 weeks) when no lesions were apparent in control animals. At 24 weeks after inoculation, proximal aortic lesion size quantified by histomorphometry was 9-fold greater in chow-fed mice inoculated with
Pg
than in noninoculated mice (
P
<0.001) and was 2-fold greater in
Pg
-inoculated versus noninoculated high-fat diet–fed mice (
P
<0.001); all atherosclerotic lesions were macrophage-rich.
Pg
ribosomal DNA was found in the aortas, livers, and hearts 24 weeks after inoculation.

Conclusions
—

These results provide evidence that long-term systemic challenge with
Porphyromonas gingivalis
, an oral pathogen, can accelerate atherogenic plaque progression.
Subgroup Interactions in the Heart and Estrogen/Progestin Replacement Study
Authors: Furberg Curt D. , Vittinghoff Eric , Davidson Michael , Herrington David M. , Simon Joel A. , Wenger Nanette K. , Hulley Stephen
Published: July 2002

Background

—

The Heart and Estrogen/Progestin Replacement Study (HERS) showed no overall benefit of postmenopausal hormone treatment in women with coronary heart disease (CHD). We analyzed the HERS data to determine whether there were specific subgroups of women who responded differently to treatment, either during the first year or in the overall study.

Methods and Results

—

In the search for significant treatment interactions, we analyzed a total of 86 subgroups defined by baseline characteristics. These included demographics and lifestyle factors, laboratory and physical examination variables, medical history and symptoms by self-report, medication use, and prior CHD history by chart review. We examined within-subgroup treatment effects for baseline variables that significantly interacted with treatment assignment. Under the null hypothesis, 4 (5%) of the 86 interactions would be expected to be nominally significant (
P
<0.05) by chance alone at each time point. Six of the interaction values were
P
<0.05 at 1 year, and 3 were
P
<0.05 at trial completion. The findings are discussed in the context of known mechanisms of action and prior scientific knowledge. Use of digitalis and history of myocardial infarction emerged as 2 possible modifiers of the effect of hormone therapy during the first year, and lipoprotein(a) emerged as a possible modifier during the overall study.

Conclusions

—

Extensive post hoc analyses did not identify any subgroup of HERS participants in which postmenopausal hormone treatment was clearly beneficial or harmful, but several possibilities emerged for testing in future trials.
Detection of Lipid Pool, Thin Fibrous Cap, and Inflammatory Cells in Human Aortic Atherosclerotic Plaques by Near-Infrared Spectroscopy
Authors: Moreno Pedro R. , Lodder Robert A. , Purushothaman K. Raman , Charash William E. , O’Connor William N. , Muller James E.
Published: July 2002

Background

—

A method is needed to identify nonstenotic, lipid-rich coronary plaques that are likely to cause acute coronary events. Near-infrared (NIR) spectroscopy can provide information on the chemical composition of tissue. We tested the hypothesis that NIR spectroscopy can identify plaque composition and features associated with plaque vulnerability in human aortic atherosclerotic plaques obtained at the time of autopsy.

Methods and Results

—

A total of 199 samples from 5 human aortic specimens were analyzed by NIR spectroscopy. Features of plaque vulnerability were defined by histology as presence of lipid pool, thin fibrous cap (<65 μm by ocular micrometry), and inflammatory cell infiltration. An InfraAlyzer 500 spectrophotometer was used. Spectral absorbance values were obtained as log (1/R) data from 1100 to 2200 nm at 10-nm intervals. Principal component regression was used for analysis. An algorithm was constructed with 50% of the samples used as a reference set; blinded predictions of plaque composition were then performed on the remaining samples. NIR spectroscopy sensitivity and specificity for histological features of plaque vulnerability were 90% and 93% for lipid pool, 77% and 93% for thin cap, and 84% and 89% for inflammatory cells, respectively.

Conclusions

—

NIR spectroscopy can identify plaque composition and features associated with plaque vulnerability in postmortem human aortic specimens. These results support efforts to develop an NIR spectroscopy catheter system to detect vulnerable coronary plaques in living patients.
Perfusion Versus Function: The Ischemic Cascade in Demand Ischemia
Authors: Leong-Poi Howard , Rim Se-Joong , Le D. Elizabeth , Fisher Nick G. , Wei Kevin , Kaul Sanjiv
Published: July 2002

Background

—

We hypothesized that during demand ischemia, abnormal perfusion will precede abnormal function, the spatial extent of perfusion abnormality will be greater than that of functional abnormality, and the spatiotemporal disparity between abnormal perfusion and abnormal function will be more marked in the presence of single-vessel stenosis (SVS) versus multivessel stenosis (MVS).

Methods and Results

—

Nine dogs each underwent either SVS or MVS placement. These noncritical stenoses were classified as mild, moderate, or severe on the basis of the transstenotic pressure gradient (10 to 14, 15 to 20, or >20 mm Hg). Dobutamine was infused starting at 10 and reaching 40 μg/kg
−1
· min
−1
. Wall thickening (WT) and myocardial perfusion (myocardial contrast echocardiography) were assessed at each stage. Resting perfusion and function were normal in all dogs. In SVS, abnormal perfusion (delayed rate of microbubble replenishment) was seen at the lowest dose of dobutamine irrespective of the stenosis severity, whereas WT abnormality was seen only at high doses of dobutamine and was influenced by the stenosis severity. The spatial extent of abnormal perfusion exceeded that of WT abnormality at all but the highest dobutamine dose. This spatiotemporal discordance between abnormal perfusion and function was significantly less in MVS, where it was possible to identify separate regions with abnormal function at lower doses of dobutamine.

Conclusions

—

These data support the occurrence of the ischemic cascade during demand ischemia. They also explain the higher sensitivity of abnormal perfusion compared with abnormal function for the detection of coronary stenosis as well as the higher sensitivity of dobutamine echocardiography for MVS compared with SVS.
Different Effects of Carvedilol, Metoprolol, and Propranolol on Left Ventricular Remodeling After Coronary Stenosis or After Permanent Coronary Occlusion in Rats
Authors: Yaoita Hiroyuki , Sakabe Atsushi , Maehara Kazuhira , Maruyama Yukio
Published: July 2002

Background

—

Although carvedilol attenuates left ventricular (LV) remodeling in coronary occlusion-reperfusion, it is not known whether it attenuates ischemic LV remodeling because of coronary stenosis (CS) or permanent coronary occlusion (CO).

Methods and Results

—

We administered a vehicle, carvedilol, propranolol (2, 10, and 30 mg/kg per day, each), metoprolol (6, 30, and 90 mg/kg per day), or bunazosin (0.2 and 1 mg/kg per day), orally for 12 weeks to a total of 608 rats with CS or CO. In these groups and the sham (n=40), we assessed LV function by echocardiography, CS severity, myocardial blood flow and coronary flow reserve, serum ascorbyl free radical, and vitamin C. Both CS and CO increased LV end-diastolic and end-systolic diameters and decreased ejection fraction. The 4 agents failed to attenuate LV remodeling caused by CO. In contrast, the 3 β-blockers attenuated (
P
<0.01) or tended to attenuate the increase in LV end-diastolic diameters caused by CS. With similar blood pressure and heart rate lowering by 3 β-blockers, carvedilol additionally attenuated the increase in end-systolic diameters and improved ejection fraction. The CS reduced myocardial blood flow and coronary flow reserve, which was reversed by carvedilol without modifying the CS severity. Among the 4 agents, only carvedilol decreased ascorbyl free radical and increased vitamin C.

Conclusions

—

The effects of β blockade on ischemic cardiac dysfunction seem to depend on the different properties of the β-blockers and the doses used. Among the β-blockers tested, carvedilol provided potent cardioprotection for compromised ischemic but viable myocardium rather than for infarcted myocardium.
Inflammation and Atherosclerosis
Authors: Libby Peter , Ridker Paul M. , Maseri Attilio
Published: July 2002

Atherosclerosis, formerly considered a bland lipid storage disease, actually involves an ongoing inflammatory response. Recent advances in basic science have established a fundamental role for inflammation in mediating all stages of this disease from initiation through progression and, ultimately, the thrombotic complications of atherosclerosis. These new findings provide important links between risk factors and the mechanisms of atherogenesis. Clinical studies have shown that this emerging biology of inflammation in atherosclerosis applies directly to human patients. Elevation in markers of inflammation predicts outcomes of patients with acute coronary syndromes, independently of myocardial damage. In addition, low-grade chronic inflammation, as indicated by levels of the inflammatory marker C-reactive protein, prospectively defines risk of atherosclerotic complications, thus adding to prognostic information provided by traditional risk factors. Moreover, certain treatments that reduce coronary risk also limit inflammation. In the case of lipid lowering with statins, this anti-inflammatory effect does not appear to correlate with reduction in low-density lipoprotein levels. These new insights into inflammation in atherosclerosis not only increase our understanding of this disease, but also have practical clinical applications in risk stratification and targeting of therapy for this scourge of growing worldwide importance.
Sex Differences in Hospital Mortality After Coronary Artery Bypass Surgery
Authors: Vaccarino Viola , Abramson Jerome L. , Veledar Emir , Weintraub William S.
Published: July 2002

Background

—

Data are conflicting over whether women have higher mortality than men after coronary artery bypass graft (CABG) surgery. Younger but not older women hospitalized for acute myocardial infarction have higher in-hospital mortality rates than men. We hypothesized that younger women also have higher in-hospital mortality rates after CABG.

Methods and Results

—

We studied 51 187 patients (30% women) included in the National Cardiovascular Network database who received CABG at 23 clinical centers between October 1993 and December 1999. Compared with men, fewer women were white and more women had risk factors and comorbidities. These differences were more apparent in younger patients. In all age groups, however, women had higher left ventricular ejection fraction and fewer diseased vessels. Women had higher in-hospital mortality rates than men, but sex differences in mortality were more marked among younger patients. Women <50 years of age were 3 times more likely to die than men (3.4% versus 1.1%), and women 50 to 59 years of age were 2.4 times more likely to die than men (2.6% versus 1.1%). In the older age categories, the sex difference in in-hospital mortality was less marked (
P
<0.001 for the interaction between sex and age). Adjustment for preoperative risk factors only slightly decreased the strength of this interaction.

Conclusions

—

Younger women undergoing CABG surgery are at a higher risk of in-hospital death than men, but this difference in risk decreases with advancing age. Additional investigation is needed to determine why in-hospital mortality is higher in women after CABG, with particular focus on younger women.
Progression of Systolic Abnormalities in Patients With “Isolated” Diastolic Heart Failure and Diastolic Dysfunction
Authors: Yu Cheuk-Man , Lin Hong , Yang Hua , Kong Shun-Ling , Zhang Qing , Lee Steven Wai-Luen
Published: July 2002

Background

—

The definition of diastolic heart failure (DHF) relies on the use of sensitive tools to exclude the presence of systolic dysfunction. The use of ejection fraction (EF) of 50% as the cutoff point may not be adequate to address such a task. We believe that systolic dysfunction is common in DHF.

Methods and Results

—

Echocardiography with tissue Doppler imaging was performed in 339 subjects, of whom 92 had systolic heart failure (SHF) (EF<50%), 73 had DHF (EF≥50% with diastolic abnormalities on Doppler echocardiography), and 68 had isolated diastolic dysfunction (DD); 106 were normal control subjects. Regional myocardial velocity curves were constructed off-line with the use of a 6-basal, 6-midsegmental model. The peak regional myocardial sustained systolic (S
M
) and early diastolic (E
M
) velocities were significantly lower in patients with SHF, DHF, and DD than in control subjects in almost all the myocardial segments. Likewise, the mean S
M
(SHF<DHF<DD<control subjects; 3.3±1.0<4.6±1.3<5.4±1.0<6.3±1.0 cm/s; all
P
≤0.001) and mean E
M
(SHF=DHF<DD<control subjects; 3.6±1.2 =3.9±1.3<5.3±1.6<7.2±1.7 cm/s; all
P
<0.001) from the six basal segments were decreased in all the disease groups. A mean S
M
of 4.4cm/s (−2 SD of control subjects) predicted the presence of systolic dysfunction in 92% of patients with SHF, 52% with DHF, and 14% with DD.

Conclusions

—

Through the use of tissue Doppler imaging, systolic abnormalities were evident in patients previously labeled as DHF and to a much lesser extent, isolated DD. This indicates the common coexistence of systolic and diastolic dysfunction in a spectrum of different severity in the pathophysiological process of heart failure.
Local Delivery of Plasmid DNA Into Rat Carotid Artery Using Ultrasound
Authors: Taniyama Yoshiaki , Tachibana Katsuro , Hiraoka Kazuya , Namba Tsunetatsu , Yamasaki Keita , Hashiya Naotaka , Aoki Motokuni , Ogihara Toshio , Yasufumi Kaneda , Morishita Ryuichi
Published: July 2002

Background

—

Although viral vector systems are efficient to transfect foreign genes into blood vessels, safety issues remain in relation to human gene therapy. In this study, we examined the feasibility of a novel nonviral vector system by using high-frequency, low-intensity ultrasound irradiation for transfection into blood vessels.

Methods and Results

—

Luciferase plasmid mixed with or without echo contrast microbubble (Optison) was transfected into cultured human vascular smooth muscle cells (VSMC) and endothelial cells (EC) with the use of ultrasound. Interestingly, luciferase activity was markedly increased in both cell types treated with Optison. We then transfected luciferase plasmid mixed with Optison by means of therapeutic ultrasound into rat artery. Two days after transfection, luciferase activity was significantly higher in carotid artery transfected with luciferase gene with Optison and ultrasound than with plasmid alone. In addition, we transfected an anti-oncogene (p53) plasmid into carotid artery after balloon injury as a model of gene therapy for restenosis. Two weeks after transfection, the intimal-to-medial area ratio in rats transfected with wild-type p53 plasmid complexed with Optison by means of ultrasound was significantly decreased as compared with control, accompanied by a significant increase in p53 protein. No apparent toxicity such as inflammation could be detected in blood vessels transfected with plasmid DNA with ultrasound and Optison.

Conclusions

—

Overall, we demonstrated that an ultrasound transfection method with Optison enhanced transfection efficiency of naked plasmid DNA into blood vessels without any apparent toxicity. Transfection of p53 plasmid with the use of this method should be useful for safe clinical gene therapy without a viral vector system.
Unique Topographical Distribution of M Cells Underlies Reentrant Mechanism of Torsade de Pointes in the Long-QT Syndrome
Authors: Akar Fadi G. , Yan Gan-Xin , Antzelevitch Charles , Rosenbaum David S.
Published: July 2002

Background

—

Specific ion channel mutations underlie the congenital long-QT syndrome (LQTS). However, the mechanisms by which dysfunction at the molecular level translates into functional electrical instability leading to torsade de pointes (TdP) in LQTS are poorly understood.

Methods and Results

—

The cellular basis of TdP was investigated using a novel approach of transmural optical imaging in the canine wedge preparation (n=14). The spatial organization of repolarization and arrhythmogenesis were determined in a surrogate model of LQT2. Action potentials were recorded simultaneously from 128 sites spanning the transmural wall of the left ventricle. In LQT2, QT interval prolongation was paralleled by an abrupt rise in transmural dispersion of repolarization (DOR) from 2.7±0.9 ms/mm (controls) to 12.2±2.1 ms/mm (LQT2). Islands of midmyocardial (M) cells formed zones of increased refractoriness in LQT2, producing steep spatial gradients of repolarization that were directly responsible for conduction block and self-sustained intramural reentrant circuits underlying TdP.

Conclusions

—

These data provide direct evidence supporting the functional expression of M cells in intact myocardium and a central role for M cells in the development of reentrant TdP arrhythmias in LQTS.
Long-Term Survival of Dialysis Patients in the United States With Prosthetic Heart Valves
Authors: Herzog Charles A. , Ma Jennie Z. , Collins Allan J.
Published: July 2002

Background

—

Minimal data exist on the long-term survival of dialysis patients after cardiac valve surgery. Current practice guidelines of the American College of Cardiology/American Heart Association Task Force on the management of patients with valvular heart disease proscribe the use of bioprosthetic (tissue) valves in hemodialysis patients.

Methods and Results

—

Dialysis patients hospitalized for heart valve replacement surgery from 1978 to 1998 were retrospectively identified from the US Renal Data System database. Long-term survival was estimated by the life-table method. The impact of demographic differences and comorbidity on outcome were examined in a Cox proportional hazards model. The in-hospital mortality of 5858 dialysis patients undergoing valve surgery was 20.7%. Aortic valve replacement was performed in 3415 patients (58%), mitral valve replacement in 1848 patients (32%), and combined aortic and mitral valve replacement in 562 patients (10%). Tissue valves were used in 881 patients. There was no significant difference in survival related to type of prosthetic valve. The 2-year survival rate was 39.7±3.5% with tissue valves versus 39.7±1.4% for nontissue valves. Compared with nontissue prosthetic valves, the use of tissue valves was not predictive of death (RR 0.98; 95% CI 0.90 to 1.07).

Conclusions

—

There is no significant difference in survival of dialysis patients after cardiac valve replacement with tissue versus nontissue prosthetic valves. Current practice guidelines proscribing the use of bioprosthetic heart valves in hemodialysis patients should be rescinded.
Sex Differences in the Association Between Proinsulin and Intact Insulin With Coronary Heart Disease in Nondiabetic Older Adults
Authors: Oh Jee-Young , Barrett-Connor Elizabeth , Wedick Nicole M.
Published: July 2002

Background

—

Insulin or insulin resistance is considered a coronary heart disease (CHD) risk factor, but proinsulin may have a stronger association with CHD than insulin. The role of sex differences in this association is unclear. We examined the cross-sectional association of proinsulin and insulin with CHD in older men and women without diabetes.

Methods and Results

—

A cross-sectional study of community-dwelling men (n=554) and women (n=902), 50 to 97 years of age, without diabetes by history or oral glucose tolerance test, was done between 1992 and 1996; plasma levels of intact insulin, proinsulin, and C-peptide were measured by radioimmunoassay. Based on questionnaire, medical history, or ECG abnormalities, 25% of men (n=136) and 24% of women (n=214) had prevalent CHD. All insulin variables were positively correlated with CHD risk factors. Compared with those without CHD, men and women with CHD had significantly higher levels of proinsulin. Women but not men with CHD also had higher levels of C-peptide and fasting and postchallenge insulin. Only proinsulin was significantly and independently associated with prevalent CHD in both men (OR=2.41, 1.42 to 4.11) and women (OR=1.80, 1.22 to 2.64) (adjusted for age, body mass index, systolic blood pressure, and HDL cholesterol). Similar analyses for fasting and postchallenge intact insulin and for C-peptide showed that among these three variables, only postchallenge insulin was significantly associated with CHD, and only in women.

Conclusions

—

In older nondiabetic men and women, proinsulin was more strongly and consistently associated with CHD than was intact insulin.
Barium Reduces Resting Blood Flow and Inhibits Potassium-Induced Vasodilation in the Human Forearm
Authors: Dawes Matthew , Sieniawska Christine , Delves Trevor , Dwivedi Rahul , Chowienczyk Philip J. , Ritter James M.
Published: July 2002

Background

—

Increasing extracellular K
+
concentration within and just above the physiological range hyperpolarizes and relaxes vascular smooth muscle in vitro. These actions involve inwardly rectifying potassium channels (K
IR
) and Na
+
/K
+
ATPase, which are inhibited, respectively, by Ba
2+
and ouabain. The role (if any) of K
IR
in controlling human resistance vessel tone is unknown, and we investigated this in the forearm.

Methods and Results

—

Blood flow was measured by plethysmography in healthy men. Drugs and electrolytes were infused through the brachial artery. BaCl
2
(4 μmol/min, also used in subsequent experiments) increased Ba
2+
plasma concentration in the infused forearm to 50±0.8 μmol/L (mean±SEM) and reduced blood flow by 24±4% (n=8,
P
<0.001) without causing systemic effects. Ouabain (2.7 nmol/min), alone and with BaCl
2
, reduced flow by 10±2% and 28±3%, respectively (n=10). Incremental infusions of KCl (0.05, 0.1, and 0.2 mmol/min) increased flow from baseline by 1.0±0.2, 2.0±0.4, and 4.2±0.5 mL/min per deciliter forearm, respectively. Responses to KCl (0.2 mmol/min) were inhibited by BaCl
2
, alone and plus ouabain, by 60±9% and 88±6%, respectively (both
P
≤0.01). In control experiments, norepinephrine (240 pmol/min) reduced blood flow by 24±2% but had no significant effect on K
+
-induced vasodilation. BaCl
2
, alone or with ouabain, did not significantly influence responses to verapamil or nitroprusside.

Conclusions

—

Ba
2+
increases forearm vascular resistance. K
+
-induced vasodilation is selectively inhibited by Ba
2+
and almost abolished by Ba
2+
plus ouabain, suggesting a role for K
IR
and Na
+
/K
+
ATPase in controlling basal tone and in K
+
-induced vasorelaxation in human forearm resistance vessels.
Effect of Medroxyprogesterone Acetate on Vascular Inflammatory Markers in Postmenopausal Women Receiving Estrogen
Authors: Wakatsuki Akihiko , Okatani Yuji , Ikenoue Nobuo , Fukaya Takao
Published: July 2002

Background

—

Estrogen increases C-reactive protein (CRP) in postmenopausal women. Estrogen also decreases cell adhesion molecules, whereas elevated CRP stimulates the expression of cell adhesion molecules. Because androgens have antiinflammatory effects, androgenic progestins such as medroxyprogesterone acetate (MPA) may inhibit proinflammatory effects of estrogen. We investigated the effects of MPA on estrogen-induced changes in acute inflammatory proteins and cell adhesion molecules in postmenopausal women.

Methods and Results

—

Postmenopausal women were treated daily with conjugated equine estrogen (CEE, 0.625 mg), CEE plus MPA 2.5 mg, or CEE plus MPA 5.0 mg for 3 months. CEE significantly increased CRP concentrations by 320.1±210.2% (
P
<0.05). The addition of MPA to CEE, however, inhibited the increase in CRP in a concentration-dependent manner (MPA 2.5 mg, 169.8±66.9%,
P
<0.05; MPA 5 mg, 55.0±30.4%, not significant). Similarly, CEE increased amyloid A protein concentrations, whereas MPA reversed this effect. Interleukin-6 concentration did not change significantly in any treatment group. CEE alone significantly decreased the concentration of E-selectin, but the concentrations of intercellular adhesion molecule and vascular cellular adhesion molecule did not change significantly. The addition of MPA tended to decrease the levels of cell adhesion molecules, and use of 5.0 mg MPA showed significant decreases in all cell-adhesion molecule concentrations.

Conclusions

—

Concurrent MPA administration may attenuate estrogen’s proinflammatory effect. Because MPA in combination with CEE decreased cell adhesion molecule concentrations, the anti-inflammatory effect of MPA may actually be responsible for the favorable effect of estrogen-progestogen combinations on cell adhesion molecules in postmenopausal women.
Inhibition of Protein Kinase Cβ Prevents Impaired Endothelium-Dependent Vasodilation Caused by Hyperglycemia in Humans
Authors: Beckman Joshua A. , Goldfine Allison B. , Gordon Mary Beth , Garrett Leslie A. , Creager Mark A.
Published: July 2002

The bioavailability of nitric oxide is decreased in animal models and humans with diabetes mellitus. Hyperglycemia, in particular, attenuates endothelium-dependent vasodilation in healthy subjects. In vitro and in vivo animal studies implicate activation of protein kinase Cβ as an important mechanism whereby hyperglycemia decreases endothelium-derived nitric oxide. Accordingly, this study tested the hypothesis that inhibition of protein kinase Cβ would prevent impairment of endothelium-dependent vasodilation in healthy humans exposed to hyperglycemia. This study was a randomized, double-blind, placebo-controlled, crossover trial. Healthy subjects were treated with an orally active, selective, protein kinase Cβ inhibitor, LY333531, or matching placebo once a day for 7 days before vascular function testing. Forearm blood flow was measured using venous-occlusion, strain-gauge plethysmography. Endothelium-dependent vasodilation was measured via incremental brachial artery administration of methacholine chloride (0.3 to 10 μg/min) during euglycemia and after 6 hours of hyperglycemic clamp. The forearm blood flow dose-response curve to methacholine was significantly attenuated by hyperglycemia after placebo treatment (
P
=0.009 by ANOVA, euglycemia versus hyperglycemia) but not after treatment with LY333531. Inhibition of protein kinase Cβ prevents the reduction in endothelium-dependent vasodilation induced by acute hyperglycemia in healthy humans in vivo. These findings suggest that hyperglycemia impairs endothelial function, in part, via protein kinase Cβ activation.
Destabilization of AT
1
Receptor mRNA by Calreticulin
Authors: Nickenig Georg , Michaelsen Frank , Müller Cornelius , Berger Anja , Vogel Thomas , Sachinidis Agapios , Vetter Hans , Böhm Michael
Published: July 2002

AT
1
receptor activation leads to vasoconstriction, blood pressure increase, free radical release, and cell growth. AT
1
receptor regulation contributes to the adaptation of the renin-angiotensin system to long-term stimulation and serves as explanation for the involvement of the AT
1
receptor in the pathogenesis of cardiovascular disease. The molecular mechanisms involved in AT
1
receptor regulation are poorly understood. Here, we report that angiotensin II accelerates AT
1
receptor mRNA decay in vascular smooth muscle cells. A cognate mRNA region within the 3′ untranslated region at bases 2175 to 2195 governs the inducible decay of the AT
1
receptor mRNA. Sequential protein purifications led to the discovery of a novel mRNA binding protein, calreticulin, which mediates destabilization of the AT
1
receptor mRNA. Angiotensin II–caused phosphorylation of calreticulin enables binding of calreticulin to the AT
1
receptor mRNA at bases 2175 to 2195 and propagates calreticulin-induced acceleration of AT
1
receptor mRNA decay. Thus, a novel mRNA binding protein, calreticulin, is discovered, which causes AT
1
receptor mRNA degradation via binding to a distinct mRNA region in the 3′ untranslated region. These findings display a novel mechanism of posttranscriptional mRNA processing.
Cardiotrophin-1 Stimulation of Cardiac Fibroblast Growth
Authors: Tsuruda Toshihiro , Jougasaki Michihisa , Boerrigter Guido , Huntley Brenda K. , Chen Horng H. , D’Assoro Antonino B. , Lee Shang C. , Larsen Amy M. , Cataliotti Alessandro , Burnett John C.
Published: July 2002

Cardiotrophin-1 (CT-1), a member of the interleukin-6 superfamily, and endothelin-1 (ET-1) are potent hypertrophic factors in cardiomyocytes. Although CT-1 and ET-1 gene expression in the heart is upregulated in experimental heart failure, their role in the activation of the cardiac fibroblast is unknown. This study was designed to identify the presence and action of CT-1 and its receptor complex, glycoprotein130 (gp130) and leukemia inhibitory factor (LIF) receptor, on cardiac fibroblast growth in cultured adult canine cardiac fibroblasts. In addition, we investigated the interaction between CT-1/gp130/LIF receptor and ET-1/endothelin type A (ET
A
) receptor axis. Immunohistochemistry was performed using the indirect immunoperoxidase method, while we assessed the cell cycle of cardiac fibroblasts by flow cytometry, DNA synthesis by [
3
H]thymidine incorporation, and collagen synthesis by [
3
H]proline incorporation, respectively. CT-1 and gp130/LIF receptor were widely present in the cytoplasm of the cardiac fibroblasts. Exogenous CT-1 markedly stimulated [
3
H]thymidine and [
3
H]proline incorporations (
P
<0.01), with accumulation of cells in the S phase. Blockade of gp130 or LIF receptor inhibited basal growth as well as CT-1– or ET-1–stimulated cardiac fibroblast growth. The specific ET
A
receptor antagonist, BQ123, significantly inhibited CT-1–stimulated DNA synthesis. This study demonstrates that CT-1 and its receptors are present in cardiac fibroblasts. In addition, growth of these cells stimulated by endogenous and exogenous CT-1 requires gp130/LIF receptor as well as ET
A
receptor activation. We conclude that gp130/LIF receptor and ET
A
receptor activation are essential for cardiac fibroblast growth by CT-1 and that there is synergism with ET-1/ET
A
receptor axis.