bluuebunny/crossref_metadata_2025 huggingface dataset:
Endogenous Vitronectin and Plasminogen Activator Inhibitor-1 Promote Neointima Formation in Murine Carotid Arteries
Authors: Peng Lin , Bhatia Nitin , Parker Andrew C. , Zhu Yanhong , Fay William P.
Published: July 2002

We examined the roles of vitronectin and plasminogen activator inhibitor-1 (PAI-1) in neointima development. Neointima formation after carotid artery ligation or chemical injury was significantly greater in wild-type mice than in vitronectin-deficient (
Vn
−/−
) mice. Vascular smooth muscle cell (VSMC) proliferation did not differ between groups, suggesting that vitronectin promoted neointima development by enhancing VSMC migration. Neointima formation was significantly attenuated in PAI-1–deficient (
PAI-1
−/−
) mice compared with control mice. Because intravascular fibrin may function as a provisional matrix for invading VSMCs, we examined potential mechanisms by which vitronectin and PAI-1 regulate fibrin stability and fibrin-VSMC interactions. Inhibition of activated protein C by PAI-1 was markedly attenuated in vitronectin-deficient plasma. The capacity of PAI-1 to inhibit clot lysis was significantly attenuated in vitronectin-deficient plasma, and this effect was not explained simply by the PAI-1–stabilizing properties of vitronectin. The adhesion and spreading of VSMCs were significantly greater on wild-type plasma clots and PAI-1–deficient plasma clots than on vitronectin-deficient plasma clots. We conclude that endogenous levels of vitronectin and PAI-1 enhance neointima formation in response to vascular occlusion or injury. Their effects may be mediated to a significant extent by their capacity to promote intravascular fibrin deposition and by the capacity of vitronectin to enhance VSMC-fibrin interactions.
Simvastatin Reduces Expression of Cytokines Interleukin-6, Interleukin-8, and Monocyte Chemoattractant Protein-1 in Circulating Monocytes From Hypercholesterolemic Patients
Authors: Rezaie-Majd Abdolreza , Maca Thomas , Bucek Robert A. , Valent Peter , Müller Michael R. , Husslein Peter , Kashanipour Ahmad , Minar Erich , Baghestanian Mehrdad
Published: July 2002

Objective—A number of studies have shown that statins decrease morbidity and mortality in patients with cardiovascular diseases. The anti-inflammatory effects of statins have recently been implicated in the clinical benefit that can be obtained in the treatment of atherosclerosis. Little is known about the mechanisms by which statins counteract inflammation.

Methods and Results—In this study, we asked whether simvastatin can influence in vitro and in vivo production of the proinflammatory cytokines interleukin (IL)-6, IL-8, and monocyte chemoattractant protein-1. A total of 107 hypercholesterolemic patients were treated with simvastatin. As measured by ELISA, serum levels of cytokines significantly decreased after 6 weeks of treatment (P<0.05). Furthermore, simvastatin decreased the expression of IL-6, IL-8, and monocyte chemoattractant protein-1 mRNA in peripheral blood mononuclear cells. Similar results were obtained in vitro by using cultured human umbilical vein endothelial cells and peripheral blood mononuclear cells from healthy normolipemic donors. Exposure to simvastatin, atorvastatin, or cerivastatin caused downregulation of the expression of cytokine mRNA in a time- and dose-dependent manner. Furthermore, all statins tested were able to reduce the concentrations of cytokines in cellular and extracellular fractions of human umbilical vein endothelial cells (P<0.05).

Conclusions—Our data show that simvastatin is anti-inflammatory through the downregulation of cytokines in the endothelium and leukocytes. These effects may explain some of the clinical benefits of these drugs in the treatment of atherosclerosis.
Transvascular Low-Density Lipoprotein Transport in Patients With Diabetes Mellitus (Type 2)
Authors: Kornerup Karen , Nordestgaard Børge Grønne , Feldt-Rasmussen Bo , Borch-Johnsen Knut , Jensen Kurt Svarre , Jensen Jan Skov
Published: July 2002

Objective

—

The increased risk of atherosclerosis associated with diabetes cannot be explained by conventional cardiovascular risk factors alone. We hypothesized that transvascular lipoprotein transport may be increased in patients with diabetes, possibly explaining increased intimal lipoprotein accumulation and, thus, atherosclerosis.

Methods and Results

—

We developed an in vivo method for measurement of transvascular transport of low density lipoprotein (LDL) and applied it in 16 patients with maturity-onset diabetes (type 2) and 29 healthy control subjects. Autologous
131
I-labeled LDL was reinjected intravenously in addition to
125
I-labeled albumin, and the 1-hour fractional escape rates were taken as indices of transvascular transport. Both parameters were normally distributed, and they were tightly correlated (
R
2
=0.69,
P
<0.0001). Transvascular LDL transport was 5.4±2.9%/h and 4.1±1.5%/h in patients with diabetes and control subjects, respectively (
P
<0.05); equivalent values for albumin were 6.5±2.5%/h and 5.3±1.6%/h (
P
<0.05). This difference most likely was not caused by altered hepatic LDL receptor expression, glycosylation of LDL, small LDL size, nephropathy, statin use, or different plasma insulin levels in diabetic patients.

Conclusions

—

Transvascular LDL transport may be increased in patients with type 2 diabetes. This suggests that lipoprotein flux into the arterial wall is increased in people with diabetes, possibly explaining the accelerated development of atherosclerosis.
A New Paradigm for Plaque Stabilization
Authors: Ambrose John A. , Martinez Eulogio E.
Published: July 2002

Abstract:

The concept of plaque stabilization was developed to explain how lipid lowering could decrease adverse coronary events without a substantial reduction in the regression of atherosclerosis. Plaques were stabilized by reducing serum cholesterol leading to several favorable pathobiological changes in the vessel wall of lipid-rich plaques responsible for a majority of acute coronary events. However, this concept is limited for several reasons including that it does not incorporate strategies directed against either plaques that have already destabilized or non-lipid-rich plaques, which are the substrate for at least one third of major coronary thrombi and may or may not be stabilized by lipid lowering. For the destabilized plaque with overlying thrombus, either percutaneous intervention, long-term antithrombotic and/or anticoagulant therapy, or possibly aggressive lipid lowering stabilizes lesions by reducing subsequent thrombosis at the lesion site and, at least with lipid lowering, by improving endothelial function and possibly reducing inflammation. Short-term, in-hospital antithrombotic approaches alone with agents like the GP platelet IIb/IIIa inhibitors have not been effective in this situation. For other plaques not presently destabilized, the main goal of therapy is reducing future acute coronary events. Several classes of drugs, including ACE inhibitors, β-blockers, and antithrombotic agents in addition to lipid-lowering agents, reduce events, and this may be attributable, at least in part, to plaque-stabilizing effects.
Risk Stratification for Postoperative Cardiovascular Events via Noninvasive Assessment of Endothelial Function
Authors: Gokce Noyan , Keaney John F. , Hunter Liza M. , Watkins Michael T. , Menzoian James O. , Vita Joseph A.
Published: July 2002

Background

—

Brachial artery endothelial function is impaired in individuals with atherosclerosis and coronary risk factors and improves with risk reduction therapy. However, the predictive value of brachial artery endothelial dysfunction for future cardiovascular events is unknown.

Methods and Results

—

We preoperatively examined brachial artery vasodilation using ultrasound in 187 patients undergoing vascular surgery. Patients were prospectively followed for 30 days after surgery. Forty-five patients had a postoperative event, including cardiac death (3), myocardial infarction (12), unstable angina/ischemic ventricular fibrillation (2), stroke (3), or elevated troponin I, reflecting myocardial necrosis (25). Preoperative endothelium-dependent flow-mediated dilation was significantly lower in patients with an event (4.9±3.1%) than in those without an event (7.3±5%;
P
<0.001), whereas endothelium-independent vasodilation to nitroglycerin was similar in both groups. In a Cox proportional-hazards model, the independent predictors of events were age (
P
=0.001), renal insufficiency (
P
=0.03), noncarotid surgery (
P
=0.05), and lower brachial artery flow-mediated dilation (
P
=0.007). If troponin I elevation was not considered an event, low flow-mediated dilation remained an independent predictor of risk (odds ratio 9.0, 95% CI 1.2 to 68;
P
=0.03). When a flow-mediated dilation cutpoint of 8.1% was used, endothelial function had a sensitivity of 95%, specificity of 37%, and negative predictive value of 98% for events.

Conclusions

—

Impaired brachial artery endothelial function independently predicts postoperative cardiac events, which supports a role for endothelial dysfunction in the pathogenesis of cardiovascular disease. The strong negative predictive value of preserved endothelial function raises the possibility that assessment of brachial artery flow-mediated dilation will be useful in the management of patients undergoing vascular surgery.
Prevalence of Anderson-Fabry Disease in Male Patients With Late Onset Hypertrophic Cardiomyopathy
Authors: Sachdev B. , Takenaka T. , Teraguchi H. , Tei C. , Lee P. , McKenna W.J. , Elliott P.M.
Published: July 2002

Background

—

Although studies have suggested that “late-onset” hypertrophic cardiomyopathy (HCM) may be caused by sarcomeric protein gene mutations, the cause of HCM in the majority of patients is unknown. This study determined the prevalence of a potentially treatable cause of hypertrophy, Anderson-Fabry disease, in a HCM referral population.

Methods and Results

—

Plasma α-galactosidase A (α-Gal) was measured in 79 men with HCM who were diagnosed at ≥40 years of age (52.9±7.7 years; range, 40–71 years) and in 74 men who were diagnosed at <40 years (25.9±9.2 years; range, 8–39 years). Five patients (6.3%) with late-onset disease and 1 patient (1.4%) diagnosed at <40 years had low α-Gal activity. Of these 6 patients, 3 had angina, 4 were in New York Heart Association class 2, 5 had palpitations, and 2 had a history of syncope. Hypertrophy was concentric in 5 patients and asymmetric in 1 patient. One patient had left ventricular outflow tract obstruction. All patients with low α-Gal activity had α-Gal gene mutations.

Conclusion

—

Anderson-Fabry disease should be considered in all cases of unexplained hypertrophy. Its recognition is important given the advent of specific replacement enzyme therapy.
Primary Pulmonary Hypertension Is Associated With Reduced Pulmonary Vascular Expression of Type II Bone Morphogenetic Protein Receptor
Authors: Atkinson Carl , Stewart Susan , Upton Paul D. , Machado Rajiv , Thomson Jennifer R. , Trembath Richard C. , Morrell Nicholas W.
Published: July 2002

Background

—

Mutations in the type II receptor for bone morphogenetic protein (BMPR-II), a receptor member of the transforming growth factor-β (TGF-β) superfamily, underlie many familial and sporadic cases of primary pulmonary hypertension (PPH).

Methods and Results

—

Because the sites of expression of BMPR-II in the normal and hypertensive lung are unknown, we studied the cellular localization of BMPR-II and the related type I and II receptors for TGF-β by immunohistochemistry in lung sections from patients undergoing heart-lung transplantation for PPH (n=11, including 3 familial cases) or secondary pulmonary hypertension (n=6) and from unused donor lungs (n=4). In situ hybridization was performed for BMPR-II mRNA. Patients were screened for the presence of mutations in
BMPR2
. In normal lungs, BMPR-II expression was prominent on vascular endothelium, with minimal expression in airway and arterial smooth muscle. In pulmonary hypertension cases, the intensity of BMPR-II immunostaining varied between lesions but involved endothelial and myofibroblast components. Image analysis confirmed that expression of BMPR-II was markedly reduced in the peripheral lung of PPH patients, especially in those harboring heterozygous
BMPR2
mutations. A less marked reduction was also observed in patients with secondary pulmonary hypertension. In contrast, there was no difference in level of staining for TGF-βRII or the endothelial marker CD31.

Conclusions

—

The cellular localization of BMPR-II is consistent with a role in the formation of pulmonary vascular lesions in PPH, and reduced BMPR-II expression may contribute to the process of vascular obliteration in severe pulmonary hypertension.
Superoxide Production and Expression of Nox Family Proteins in Human Atherosclerosis
Authors: Sorescu Dan , Weiss Daiana , Lassègue Bernard , Clempus Roza E. , Szöcs Katalin , Sorescu George P. , Valppu Liisa , Quinn Mark T. , Lambeth J. David , Vega J. David , Taylor W. Robert , Griendling Kathy K.
Published: July 2002

Background

—

NAD(P)H oxidases are important sources of superoxide in the vasculature, the activity of which is associated with risk factors for human atherosclerosis. This study was designed to investigate the localization of superoxide production and the expression of the Nox family of NAD(P)H oxidase proteins (gp91phox, Nox1, and Nox4) in nonatherosclerotic and atherosclerotic human coronary arteries.

Methods and Results

—

In coronary artery segments from explanted human hearts, we examined intracellular superoxide production with dihydroethidium. In nonatherosclerotic coronary arteries, superoxide was present homogenously throughout the intima, media, and adventitia. In atherosclerotic arteries, there was an additional intense area of superoxide in the plaque shoulder, which is rich in macrophages and α-actin–positive cells. p22phox colocalized with gp91phox mainly in macrophages, whereas Nox4 was found only in nonphagocytic vascular cells. Expression of gp91phox and p22phox mRNA was associated with the severity of atherosclerosis. gp91phox correlated with the plaque macrophage content, whereas Nox4 correlated with the content of α-actin–positive cells. Nox1 expression was low both in human coronary arteries and isolated vascular cells.

Conclusions

—

Several Nox proteins, including gp91phox and Nox4, may contribute to increased intracellular oxidative stress in human coronary atherosclerosis in a cell-specific manner and thus may be involved in the genesis and progression of human coronary atherosclerotic disease.
Suppression of Murine Cardiac Allograft Arteriopathy by Long-Term Blockade of CD40-CD154 Interactions
Authors: Wang Catherine Y. , Mazer Sean P. , Minamoto Kanji , Takuma Shin , Homma Shunichi , Yellin Michael , Chess Leonard , Fard Ali , Kalled Susan L. , Oz Mehmet C. , Pinsky David J.
Published: July 2002

Background

—

The interaction between CD40 on antigen-presenting cells and CD40L on T cells is critical in allograft rejection. CD154 blockade suppresses allograft rejection, but the role of this pathway in allograft vasculopathy remains obscure.

Methods and Results

—

A vascularized murine heterotopic cardiac transplant model was used to test whether perioperative CD154 blockade suppresses allograft vasculopathy or whether long-term CD154 blockade is required to suppress allograft vasculopathy. Perioperative CD154 blockade consisted of MR1 given on days −1, 1, and 3; long-term blockade consisted of MR1 given on days −1, 1, and 3 and continued twice weekly for 8 weeks. Allografts treated with perioperative or long-term CD154 blockade survived indefinitely. Perioperative and long-term treatment with control antibody (Ha4/8) resulted in uniform early rejection. Perioperative CD154 blockade transiently reduced early T-cell and macrophage infiltration in parallel with a transient reduction in endothelial adhesion receptor expression. Although perioperative CD154 blockade prevented allograft failure, it did not reduce allograft vasculopathy; mean neointimal cross-sectional area in perioperative MR1-treated and Ha4/8-treated recipients was 43±7% and 50±12%, respectively (
P
=NS). In contrast, mean neointimal cross-sectional area in long-term, MR1-treated recipients was 19±3% (
P
<0.001 versus perioperative MR1). Long-term CD154 blockade also suppressed endothelial E-selectin, P-selectin, and intracellular adhesion molecule-1 expression and improved graft function 3.5-fold versus control (
P
<0.05).

Conclusions

—

These data show that perioperative CD154 blockade mitigates acute rejection but long-term CD154 blockade may result in decreased allograft endothelial activation and is required to suppress allograft arteriopathy.
Validation of Myocardial Acceleration During Isovolumic Contraction as a Novel Noninvasive Index of Right Ventricular Contractility
Authors: Vogel Michael , Schmidt Michael R. , Kristiansen Steen B. , Cheung Michael , White Paul A. , Sorensen Keld , Redington Andrew N.
Published: July 2002

Background—

We have demonstrated that myocardial acceleration during isovolumic contraction (IVA) is a sensitive index of left ventricular contractile function. In this study, we assessed the utility of IVA to measure right ventricular (RV) contractile function.

Methods and Results—

We examined 8 pigs by using tissue Doppler imaging of the RV free wall and simultaneous measurements of intraventricular pressure, volume, maximal elastance (e
max
), preload recruitable stroke work, and dP/dt
max
by conductance catheterization. Animals were paced in the right atrium at a rate of 130 beats per minute (bpm). IVA was compared with elastance during contractility modulation by esmolol and dobutamine and during preload reduction and afterload increase by transient balloon occlusion of the inferior vena cava and pulmonary artery, respectively. Data were also obtained during incremental atrial pacing from 110 to 210 bpm. Esmolol led to a decrease in IVA and dP/dt
max
. During dobutamine infusion, IVA, dP/dt
max
, preload recruitable stroke work, and e
max
all increased significantly. During preload reduction and afterload increase, IVA remained constant up to a reduction of RV volume by 54% and an RV systolic pressure increase of 58%. Pacing up to a rate of 190 bpm led to a stepwise increase in IVA and dP/dt
max
, with a subsequent fall at a pacing rate of 210 bpm.

Conclusions—

IVA is a measurement of RV contractile function that is unaffected by preload and afterload changes in a physiological range and is able to measure the force-frequency relation. This novel index may be ideally suited to the assessment of acute changes of RV function in clinical studies.
Statin Attenuates Increase in C-Reactive Protein During Estrogen Replacement Therapy in Postmenopausal Women
Authors: Koh Kwang Kon , Schenke William H. , Waclawiw Myron A. , Csako Gyorgy , Cannon Richard O.
Published: July 2002

Background

—

HMG-CoA reductase inhibitor (statin) therapy reduces cardiovascular risk, mechanisms of which may include diminished arterial inflammation, as suggested by reduction in levels of C-reactive protein (CRP). Because oral estrogens increase CRP in postmenopausal women, with potential inflammatory and thrombotic consequences that could compromise any benefit to cardiovascular risk, we determined whether the coadministration of a statin might modify the estrogenic effect on CRP.

Methods and Results

—

In a double-blind, 3-period crossover study, 28 postmenopausal women (average LDL cholesterol 163±36 mg/dL) were randomly assigned to daily conjugated equine estrogens (CEEs) 0.625 mg, simvastatin 10 mg, or their combination for 6 weeks, with each treatment period separated by 6 weeks. CEEs increased median CRP levels from 0.27 to 0.46 mg/dL, simvastatin decreased CRP from 0.29 to 0.28 mg/dL, and the therapies combined increased CRP from 0.28 to 0.36 mg/dL (all
P
≤0.02 versus respective baseline values). Post hoc testing showed that the 29% increase in CRP on the combination of CEEs with simvastatin was significantly less than the 70% increase in CRP on CEEs alone (
P
<0.05). The effect of combination therapy on CRP levels did not correlate with baseline CRP or with baseline or treatment-induced changes in levels of interleukin-6, lipoproteins, or flow-mediated dilation of the brachial artery as a measure of nitric oxide bioactivity.

Conclusions

—

The combination of statin with estrogen may attenuate the potential harmful effects of estrogen therapy in postmenopausal women and maximize any benefit to cardiovascular risk.
Genetic Modifier Loci Affecting Survival and Cardiac Function in Murine Dilated Cardiomyopathy
Authors: Suzuki Miwako , Carlson Kerri M. , Marchuk Douglas A. , Rockman Howard A.
Published: July 2002

Background
—

Understanding the role for genetic factors in human heart failure is difficult because environmental factors cannot be standardized and genetic variation is great. One approach to identify genes that modify disease outcome is to use mouse models that show strong genetic variation of the disease phenotype.

Methods and Results
—

In this study, we used transgenic mice that develop severe dilated cardiomyopathy due to the cardiac-specific overexpression of calsequestrin. Transgenic mice showed marked strain-specific variation of cardiac function and survival, independent of transgene expression. A reciprocal backcross strategy was employed using two inbred strains showing distinct differences in survival and cardiac function. To map the genes that modified the heart failure phenotype, progeny from the 2 reciprocal backcrosses were used in a genome-wide scan for linkage. We identified two loci significantly linked to survival with a maximum likelihood ratio statistic of 36.2 (LOD score ≈7.8) on chromosome 2 and of 26.5 (LOD score ≈5.7) on chromosome 3. The chromosome 3 locus was also significantly linked to cardiac function with a maximum likelihood ratio statistic of 42.9 (LOD score ≈9.3). Because only a single strong modifier locus was found in each backcross, we applied a haplotype analysis to map crossovers and successfully narrowed the critical intervals for each locus.

Conclusion
—

Using a sensitized mouse model, we identified major modifier loci that affect the genetically complex disease of heart failure. This approach should allow the rapid identification of candidate genes involved in disease susceptibility in human populations and new insights into the pathogenesis of heart failure.
Myocardial Ischemic Injury After Heart Transplantation Is Associated With Upregulation of Vitronectin Receptor (α
v
β
3
), Activation of the Matrix Metalloproteinase Induction System, and Subsequent Development of Coronary Vasculopathy
Authors: Yamani Mohamad H. , Tuzcu E. Murat , Starling Randall C. , Ratliff Norman B. , Yu Yang , Vince D. Geoffrey , Powell Kimerly , Cook Daniel , McCarthy Patrick , Young James B.
Published: July 2002

Background

—

Myocardial ischemic injury after heart transplantation is associated with subsequent development of graft vasculopathy. Both vitronectin receptor (integrin α
v
β
3
) and tissue factor play key roles in vascular endothelial cell injury. Matrix metalloproteinases (MMPs) are activated in ischemic injury models.

Methods and Results

—

Thirteen patients developed myocardial ischemic injury within 2 weeks of cardiac transplantation (ischemia group). These were compared with 10 transplantation patients who had no evidence of ischemia (control group). Endomyocardial biopsies were evaluated within 2 weeks of transplantation for α
v
β
3
, tissue factor, and extracellular MMP inducer (EMMPRIN). At 1 year, MMPs were evaluated, and interstitial myocardial fibrosis was quantified. All patients underwent intravascular ultrasound at 1 month and 1 year after transplantation. Compared with control, the ischemia group demonstrated evidence of significant increased expression of α
v
β
3
(3.2-fold,
P
<0.001), tissue factor (2.5-fold,
P
<0.001), and EMMPRIN (1.9-fold,
P
=0.01). At 1 year, the ischemia group had a significant increase in myocardial fibrosis (24±1.8% versus 14±1.1%,
P
<0.001) and zymographic activity of MMP-2 (1.4-fold,
P
<0.001), MMP-3 (1.2-fold,
P
<0.001), and MMP-9 (1.3-fold,
P
=0.01). Coronary vasculopathy progression was also more advanced in the ischemia group (change in coronary maximal intimal thickness over 1 year 0.54±0.1 versus 0.26±0.06 mm;
P
=0.031).

Conclusions

—

Myocardial ischemic injury after cardiac transplantation is associated with upregulation of α
v
β
3
, tissue factor, and activation of the MMP induction system, which may contribute to the subsequent development of allograft remodeling and vasculopathy.
Endovascular Aneurysm Repair
Authors: Pitton Michael Bernhard , Schmenger Ralf Patrick , Neufang Achim , Konerding Moritz Anton , Düber Christoph , Thelen Manfred
Published: July 2002

Background—The purpose of the present study was to systematically analyze the histopathologic organization processes in excluded aneurysms after endovascular stenting and to develop a noninvasive monitoring method for these processes using MRI.

Methods and Results—In 36 mongrel dogs, autologous aortic aneurysms were created. Endovascular treatment was performed using covered stents. Follow-up was after 1 week, 6 weeks, and 6 months. MRI was performed with T2-weighted turbo-spin-echo sequences and T1-weighted spin-echo sequences and was repeated after contrast bolus with gadolinium. Histopathologic findings were correlated to signal intensities (SIs) of MRI images. SIs of distinct areas were analyzed and related to the SI of the reference tissue (SI ratio). The histological organization process was gradated in the following 4 classes: class 0, detritus without organization; classes I and II, connective tissue proliferation with increasing fiber synthesis; and class III, dense fibrous connective tissue. The SI ratios of T2-weighted images were significantly reduced from 4.76 in detritus (0) to 1.70 in dense fibrous connective tissue (III) as a function of histopathologic classes. SI ratios of T1-weighted images were reduced from 1.84 (0) to 1.12 (III). Contrast bolus with gadolinium-DTPA showed no change of SI ratio in detritus (0.99) but an increase from 1.12 (I) to 1.70 (III) as organization increased.

Conclusions—The histological organization of excluded aneurysms can be monitored by MRI. Progressive organization is indicated by decreasing SIs in T2- and an increasing signal increase in T1-weighted images after gadolinium bolus.
Identification of Atherosclerotic Plaque Components With Intravascular Ultrasound Elastography In Vivo
Authors: de Korte Chris L. , Sierevogel Marion J. , Mastik Frits , Strijder Chaylendra , Schaar Johannes A. , Velema Evelyn , Pasterkamp Gerard , Serruys P.W. , van der Steen Anton F.W.
Published: July 2002

Background

—

Intravascular ultrasound elastography assesses the local strain of the atherosclerotic vessel wall. In the present study, the potential to identify different plaque components in vivo was investigated.

Methods and Results

—

Atherosclerotic external iliac and femoral arteries (n=24) of 6 Yucatan pigs were investigated. Before termination, elastographic data were acquired with a 20-MHz Visions catheter. Two frames acquired at end-diastole with a pressure differential of ≈4 mm Hg were acquired to obtain the elastograms. Before dissection, x-ray was used to identify the arterial segments that had been investigated by ultrasound. Specimens were stained for collagen, fat, and macrophages. Plaques were classified as absent, early fibrous lesion, early fatty lesion, or advanced fibrous plaque. The average strains in the plaque-free arterial wall (0.21%) and the early (0.24%) and advanced fibrous plaques (0.22%) were similar. Higher average strain values were observed in fatty lesions (0.46%) compared with fibrous plaques (
P
=0.007). After correction for confounding by lipid content, no additional differences in average strain were found between plaques with and without macrophages (
P
=0.966). Receiver operating characteristic analysis revealed a sensitivity and a specificity of 100% and 80%, respectively, to identify fatty plaques. The presence of a high-strain spot (strain >1%) has 92% sensitivity and 92% specificity to identify macrophages.

Conclusions

—

To the best of our knowledge, this is the first time that intravascular ultrasound elastography has been validated in vivo. Fatty plaques have an increased mean strain value. High-strain spots are associated with the presence of macrophages.
Human Leukocyte Antigen-G Expression After Heart Transplantation Is Associated With a Reduced Incidence of Rejection
Authors: Lila Nermine , Amrein Catherine , Guillemain Romain , Chevalier Patrick , Latremouille Christian , Fabiani Jean-Noël , Dausset Jean , Carosella Edgardo D. , Carpentier Alain
Published: July 2002

Background

—

Human leukocyte antigen (HLA)-G, a nonclassic major histocompatibility complex class I molecule expressed in the extravillous cytotrophoblast at the feto-maternal interface, is known to protect the fetus from maternal cellular immunity. In a preliminary study, we showed that HLA-G is expressed in the hearts of some patients after heart transplantation.

Methods and Results

—

In the present study, a larger number of patients was investigated to confirm this finding and to look for possible correlations between HLA-G expression and the number and types of rejection. Expression of HLA-G in endomyocardial biopsy specimens was investigated by immunohistochemical analysis, and detection of the soluble HLA-G in the serum was performed by immunoprecipitation followed by Western blot analysis. HLA-G was detected in the biopsy specimens and serum of 9 of 51 patients (18%). The number of episodes of acute rejection was significantly lower in HLA-G-positive patients (1.2±1.1) as compared with HLA-G-negative patients (4.5±2.8) (
P
<0.001). No chronic rejection was observed in HLA-G-positive patients, whereas 15 HLA-G-negative patients had chronic rejection (
P
<0.032). A longitudinal study of these patients reveals that the status of HLA-G expression was maintained after 6 months both in serum and in biopsy specimens. During this period, HLA-G-positive patients did not have chronic rejection.

Conclusions

—

There is a significant correlation between rejection and HLA-G expression in the heart after transplantation. HLA-G expression and its effect in reducing the incidence and severity of rejection seem to be stable throughout the evolution.
Incidence, Morphology, Angiographic Findings, and Outcomes of Intramural Hematomas After Percutaneous Coronary Interventions
Authors: Maehara Akiko , Mintz Gary S. , Bui Anh B. , Castagna Marco T. , Walter Olga R. , Pappas Chrysoula , Pinnow Ellen E. , Pichard Augusto D. , Satler Lowell F. , Waksman Ron , Suddath William O. , Laird John R. , Kent Kenneth M. , Weissman Neil J.
Published: July 2002

Background

—

Intramural hematomas during percutaneous coronary intervention (PCI) have not been well studied.

Methods and Results

—

We used intravascular ultrasound to determine the incidence, morphology, and clinical features of post-PCI intramural hematomas. In 905 patients with 1025 consecutive native coronary artery, non–in-stent restenosis lesions undergoing PCI, 72 hematomas were detected in 69 arteries in 68 patients. The incidence of intramural hematomas per artery was 6.7% (69 of 1025); 36% (26 of 72) involved the proximal reference artery, 18% (13 of 72) were confined to the lesion, and 46% (33 of 72) involved the distal reference artery. The entry site from the lumen into the hematoma was identified in 86% of hematomas (62 of 72) and had the appearance of a dissection into the media. Conversely, a re-entry site was identifiable in only 8% (6 of 72). The axial extension of the hematoma was distal in 63% and proximal in 37%. In 60% of the hematomas (42 of 72) the angiogram had the appearance of a dissection; in 11% (8 of 72), it appeared to be a new stenosis; and in 29% (22 of 72), no significant abnormality was detected. Non–Q-wave myocardial infarctions occurred in 26% of patients (17 of 65). In 3 patients, the creatine kinase-MB was not measured during the hospital stay. Repeat revascularization occurred in 2 patients in-hospital, 2 additional patients at 1 month, and 8 additional patients at 1 year. There were 3 sudden deaths at 1 year.

Conclusions

—

Intravascular ultrasound identified intramural hematomas after 6.7% of PCIs. The mechanism appeared to be a dissection into the media where blood accumulated because of a lack of re-entry. A third of ultrasound-identified hematomas showed no angiographic abnormalities. There was a high rate of non–Q-wave myocardial infarction, need for repeat revascularization, and sudden death in patients with hematomas.
Ultrasonographic and Biochemical Markers of Human Fetal Cardiac Dysfunction in Placental Insufficiency
Authors: Mäkikallio Kaarin , Vuolteenaho Olli , Jouppila Pentti , Räsänen Juha
Published: July 2002

Background

—

Placental insufficiency may lead to fetal cardiovascular compromise. We sought to determine whether ultrasonographic parameters of fetal cardiovascular function correlate with umbilical arterial levels of biochemical markers of myocardial dysfunction and damage in placental insufficiency.

Methods and Results

—

In 48 fetuses with placental insufficiency, umbilical artery blood was obtained at delivery for assessment of
N
-terminal peptide of proatrial natriuretic peptide (NT-proANP) and cardiac troponin-T (cTnT). Group 1 fetuses (n=12) had normal NT-proANP and cTnT serum concentrations. Group 2 fetuses (n=25) showed increased NT-proANP (>1145 pmol/L) and normal cTnT values. Group 3 fetuses (n=11) had increased NT-proANP and cTnT (>0.10 ng/mL) levels. The ultrasonographic parameters of fetal cardiovascular function were compared between the groups. Pulsatility indices for veins of the ductus venosus, left hepatic vein, and inferior vena cava correlated significantly with NT-proANP levels. In group 3, ductus venosus, left hepatic vein, and inferior vena cava pulsatility indices for veins were higher (
P
<0.01) than in groups 1 and 2. The proportion of left ventricular cardiac output of combined cardiac output was greater (
P
<0.05) and that of right ventricle was smaller (
P
<0.05) in group 3 than in group 2. In group 3, tricuspid regurgitation was noted most often (
P
<0.05), and right ventricular fractional shortening was less (
P
<0.01) than in group 2.

Conclusions

—

Pulsatility in human fetal systemic veins correlated significantly with the cardiac secretion of ANP. Fetuses with myocardial damage demonstrate increased systemic venous pressure, a change in the distribution of cardiac output toward the left ventricle, and a rise in right ventricular afterload.
Load-Dependent and -Independent Regulation of Proinflammatory Cytokine and Cytokine Receptor Gene Expression in the Adult Mammalian Heart
Authors: Baumgarten Georg , Knuefermann Pascal , Kalra Dinesh , Gao Feng , Taffet George E. , Michael Lloyd , Blackshear Perry J. , Carballo Ester , Sivasubramanian Natarajan , Mann Douglas L.
Published: July 2002

Background

—

Although previous studies have examined the effects of acute hemodynamic pressure overload on proinflammatory cytokine gene expression, the effects of sustained hemodynamic overloading have not been examined.

Methods and Results

—

Sustained hemodynamic pressure overloading was produced in mice by transverse constriction of the aorta. Proinflammatory cytokine and cytokine receptor gene expression were determined by ribonuclease protection assays (RPA) at 6 hours and at 3, 7, 14 and 35 days after banding. M-mode echocardiography was used to assess left ventricular structure and function at identical time points. RPA showed that tumor necrosis factor (TNF), interleukin (IL)-1β, and IL-6 mRNA levels were maximal at 6 hours and returned to baseline levels within 72 hours. There was a significant increase in IL-1RII and IL-6Rα receptor mRNA levels after overloading but no significant increase in TNFR1, TNFR2, IL-1RI, or gp130 mRNA levels. The transient increase in expression of proinflammatory cytokine gene expression was not explained by changes in left ventricular loading conditions, left ventricular wall stress, desensitization of proinflammatory genes, or decreased nuclear factor-κB activation. It is interesting that transverse constriction of the aorta provoked an increase in the expression of tristetraprolin, a homeostatic zinc finger protein that is known to destabilize TNF mRNA.

Conclusion

—

Sustained hemodynamic overloading provokes a transient increase in proinflammatory cytokine and cytokine receptor gene expression; however, the decrease in proinflammatory cytokine gene expression occurred in the absence of changes in loading conditions, suggesting that the expression of proinflammatory cytokines in the heart is regulated, at least in part, by load-dependent and load-independent mechanisms.
Adverse Neonatal and Cardiac Outcomes Are More Common in Pregnant Women With Cardiac Disease
Authors: Siu Samuel C. , Colman Jack M. , Sorensen Sheryll , Smallhorn Jeffrey F. , Farine Dan , Amankwah Kofi S. , Spears John C. , Sermer Mathew
Published: July 2002

Background

—

Pregnant women with heart disease (HD) are at increased risk for cardiac (CV) complications. However, the frequency of neonatal (NE) complications in pregnant women with HD relative to pregnant women without HD has not been examined.

Methods and Results

—

Pregnant women with HD were prospectively monitored during 302 pregnancies. The frequency of NE and CV complications was compared with those in a control group without HD during 572 pregnancies. The frequency of NE complications was higher in the HD group (18% versus 7%; HD versus controls). The NE complication rate was lowest in pregnancies of women age 20 to 35 years who did not smoke during pregnancy, did not receive anticoagulants, and had no obstetric risk factors: 4% in control patients, 5% in HD patients with no cardiac risk factors for NE complications (left heart obstruction, poor functional class, or cyanosis), and 7% in HD patients with ≥1 such risk factor. In contrast, the event rate in pregnancies of controls age <20 or >35 years who had obstetric risk factors or multiple gestation or who smoked was 11%. In the HD group, women age <20 or >35 years who had obstetric risk factors or multiple gestation, who smoked, or who received anticoagulants experienced an even higher NE complication rate (27% with no cardiac risks for NE events and 33% in the presence of ≥1 cardiac risk factors). The frequency of CV complications was higher in the HD group (17% versus 0%; HD versus controls).

Conclusion

—

Pregnant women with HD are at increased risk for both NE and CV complications. The risk for NE adverse events in pregnant women with HD is highest in those with both obstetric and cardiac risk factors for NE complications.
Biological Gradient Between Long-Term Arsenic Exposure and Carotid Atherosclerosis
Authors: Wang Chih-Hao , Jeng Jiann-Shing , Yip Ping-Keung , Chen Chi-Ling , Hsu Lin-I , Hsueh Yu-Mei , Chiou Hung-Yi , Wu Meei-Mann , Chen Chien-Jen
Published: July 2002

Background
—

Long-term exposure to ingested arsenic has been documented to induce peripheral vascular disease, ischemic heart disease, and cerebral infarction in a dose-response relationship. This study further examined the biological gradient between ingested inorganic arsenic and carotid atherosclerosis.

Methods and Results
—

We studied 199 male and 264 female adult residents from the southwestern area of endemic arseniasis in Taiwan. The extent of carotid atherosclerosis was assessed by duplex ultrasonography. Diabetes mellitus was determined by oral glucose tolerance test, hypertension by mercury sphygmomanometers, and serum lipid profiles by autoanalyzers. Information regarding the consumption of high-arsenic artesian well water, cigarette smoking, and alcohol consumption was obtained through standardized questionnaire interviews. Logistic regression analysis was used to estimate the odds ratio and its 95% CI of carotid atherosclerosis for various risk factors. Three indices of long-term exposure to ingested arsenic, including the duration of consuming artesian well water, the average arsenic concentration in consumed artesian well water, and cumulative arsenic exposure, were all significantly associated with prevalence of carotid atherosclerosis in a dose-response relationship. The biological gradient remained significant after adjustment for age, sex, hypertension, diabetes mellitus, cigarette smoking, alcohol consumption, waist-to-hip ratio, and serum levels of total cholesterol and LDL cholesterol. The multivariate-adjusted odds ratio was 3.1 (95% CI 1.3 to 7.4) for those who had a cumulative arsenic exposure of ≥20 mg/L-years compared with those without exposure to arsenic from drinking artesian well water.

Conclusions
—

Carotid atherosclerosis is associated with ingested inorganic arsenic, showing a significant biological gradient.
Increased Expression of Macrophage Colony–Stimulating Factor After Coronary Artery Balloon Injury Is Inhibited by Intracoronary Brachytherapy
Authors: Finkelstein Ariel , Makkar Raj , Doherty Terence M. , Vegesna Vijaya R. , Tripathi Pinky , Liu Ming , Bergman Jonathan , Fishbein Michael , Hausleiter Joerg , Takizawa Kaname , Rukshin Vladimir , Shah Prediman K. , Rajavashisth Tripathi B.
Published: July 2002

Background

—

The mechanisms underlying the reduced neointimal proliferation (NP) by intracoronary brachytherapy (ICBT) are unknown. We hypothesized that ICBT inhibits NP by reducing expression of macrophage colony–stimulating factor (M-CSF).

Methods and Results

—

Thirty coronary arteries from 10 pigs were divided into 3 groups of 10 each: control (C), balloon injury (BI), and BI followed by ICBT (16 Gy at 0.5-mm tissue depth with a
32
P balloon system). Pigs were killed at 24 hours (n=3) and at 7 (n=4) and 14 (n=3) days. Expression of M-CSF was assessed by Western blot, ELISA, and quantitative immunostaining. Persistently increased levels of M-CSF after BI (to 1.4±0.2 nmol/L [ELISA] and 29.4±4.9% of cross-sectional area stained [immunocytochemistry];
P
< 0.001 versus control for both) were observed in the injured arteries. Treatment of BI arteries with ICBT reduced M-CSF expression compared with BI alone (to 0.7±0.1 nmol/L [ELISA] and 13.5±2.9% of cross-sectional area stained [immunocytochemistry];
P
<0.001 versus BI and
P
=NS versus control for both) and remained similar to control M-CSF expression for the 14-day study period. Neointimal thickness increased after BI (to 4.8±2.9 mm
2
;
P
<0.001 versus control), but this was reduced by ICBT (1.4±0.4 mm
2
;
P
<0.001 versus BI).

Conclusions

—

In porcine coronary arteries, BI is associated with increased expression of M-CSF and NP, but neither occurs after ICBT. The beneficial effects of ICBT on NP involve inhibition of M-CSF expression.
Cellular Cardiomyoplasty Improves Survival After Myocardial Injury
Authors: Roell Wilhelm , Lu Zhong J. , Bloch Wilhelm , Siedner Sharon , Tiemann Klaus , Xia Ying , Stoecker Eva , Fleischmann Michaela , Bohlen Heribert , Stehle Robert , Kolossov Eugen , Brem Gottfried , Addicks Klaus , Pfitzer Gabriele , Welz Armin , Hescheler Juergen , Fleischmann Bernd K.
Published: July 2002

Background

—

Cellular cardiomyoplasty is discussed as an alternative therapeutic approach to heart failure. To date, however, the functional characteristics of the transplanted cells, their contribution to heart function, and most importantly, the potential therapeutic benefit of this treatment remain unclear.

Methods and Results

—

Murine ventricular cardiomyocytes (E12.5–E15.5) labeled with enhanced green fluorescent protein (EGFP) were transplanted into the cryoinjured left ventricular walls of 2-month-old male mice. Ultrastructural analysis of the cryoinfarction showed a complete loss of cardiomyocytes within 2 days and fibrotic healing within 7 days after injury. Two weeks after operation, EGFP-positive cardiomyocytes were engrafted throughout the wall of the lesioned myocardium. Morphological studies showed differentiation and formation of intercellular contacts. Furthermore, electrophysiological experiments on isolated EGFP-positive cardiomyocytes showed time-dependent differentiation with postnatal ventricular action potentials and intact β-adrenergic modulation. These findings were corroborated by Western blotting, in which accelerated differentiation of the transplanted cells was detected on the basis of a switch in troponin I isoforms. When contractility was tested in muscle strips and heart function was assessed by use of echocardiography, a significant improvement of force generation and heart function was seen. These findings were supported by a clear improvement of survival of mice in the cardiomyoplasty group when a large group of animals was analyzed (n=153).

Conclusions

—

Transplanted embryonic cardiomyocytes engraft and display accelerated differentiation and intact cellular excitability. The present study demonstrates, as a proof of principle, that cellular cardiomyoplasty improves heart function and increases survival on myocardial injury.
Common Estrogen Receptor Polymorphism Augments Effects of Hormone Replacement Therapy on E-Selectin but Not C-Reactive Protein
Authors: Herrington David M. , Howard Timothy D. , Brosnihan K. Bridget , McDonnell Donald P. , Li Xiaolin , Hawkins Gregory A. , Reboussin David M. , Xu Jianfeng , Zheng Siqun L. , Meyers Deborah A. , Bleecker Eugene R.
Published: July 2002

Background

—

The estrogen receptor-α (ER-α) IVS1-401 polymorphism identifies a group of women (≈20%) who have augmented effects of hormone replacement therapy (HRT) on levels of HDL cholesterol. This study sought to determine if this augmentation extends to HRT regulation of E-selectin and C-reactive protein (CRP) and to explore possible mechanisms by which this polymorphism might influence estrogen action.

Methods and Results

—

Serum levels of soluble E-selectin and CRP were measured at baseline and 1 year in 264 postmenopausal women randomized to treatment with oral conjugated equine estrogen (0.625 mg/d), estrogen plus progestin (medroxyprogesterone acetate 2.5 mg/d), or placebo. Women with the ER-α IVS1-401 C/C genotype receiving HRT had nearly a 2-fold greater reduction in E-selectin compared with C/T or T/T women (
P
for interaction=0.02). In contrast, there was no augmentation of the HRT-associated increase in CRP among the C/C women compared with C/T or T/T women (
P
for interaction=0.54). Of luciferase reporter constructs containing sequences spanning the IVS1-401 T/C polymorphism, expression of the construct containing the C allele was enhanced >10-fold, with cotransfection of a constitutively expressed B-myb vector. In contrast, B-myb resulted in only a 2.5-fold increase in expression of the T allele construct.

Conclusions

—

Women with the ER-α IVS1-401 C/C genotype have greater reductions in E-selectin but no further increases in CRP with HRT. The C allele produces a functional binding site for the transcription factor B-myb. The impact of this polymorphism on ER-α transcription and other estrogen-sensitive intermediate and clinical end points has not yet been established.