bluuebunny/crossref_metadata_2025 huggingface dataset:
Fibrillin-1 Genotype Is Associated With Aortic Stiffness and Disease Severity in Patients With Coronary Artery Disease
Authors: Medley Tanya L. , Cole Timothy J. , Gatzka Christoph D. , Wang William Y.S. , Dart Anthony M. , Kingwell Bronwyn A.
Published: July 2002

Background
—

Elevated pulse pressure is associated strongly with adverse cardiovascular outcome; however, the genetic basis of this condition is unknown. This study examined whether genotypic variation in the extracellular matrix protein fibrillin-1, the Marfan gene, was associated with aortic stiffening and therefore could contribute to cardiovascular risk associated with pulse pressure elevation in coronary disease.

Methods and Results
—

Patients (n=145; 113 men), 62±9 years of age (mean±SD), with angiographically confirmed coronary disease, were studied. Carotid applanation tonometry was used to assess central blood pressures, and in conjunction with Doppler velocimetry, to assess aortic input and characteristic impedance. Fibrillin-1 genotype was characterized by a variable nucleotide tandem repeat and 2 single-nucleotide polymorphisms. The variable nucleotide tandem repeat was a good predictor of underlying haplotypes with 3 genotypes (2-2, 2-4, and 2-3) accounting for 86% of the population. The 2-3 genotype had higher input impedance (
P
=0.002), characteristic impedance (
P
=0.005), and carotid pulse pressure (
P
=0.002) compared with the 2-2 and 2-4 genotypes. Disease severity assessed by previous angioplasties and the number of patients with a stenosis >90% was also greater in the 2-3 genotype. Furthermore, in a multivariate analysis, fibrillin-1 genotype and central pulse pressure were independent of conventional risk factors in determining coronary disease severity. There was no difference in age, sex ratio, body mass index, smoking status, cholesterol level, or medication among the 3 genotypes.

Conclusions
—

Although a causative link has not been shown, these data are consistent with an important role for fibrillin-1 genotype in cardiovascular risk associated with large-artery stiffening and pulse pressure elevation in individuals with coronary disease.
Change in Diastolic Left Ventricular Filling After One Year of Antihypertensive Treatment
Authors: Wachtell Kristian , Bella Jonathan N. , Rokkedal Jens , Palmieri Vittorio , Papademetriou Vasilios , Dahlöf Björn , Aalto Tapio , Gerdts Eva , Devereux Richard B.
Published: July 2002

Background
—

It is well established that hypertensive patients with left ventricular (LV) hypertrophy have impaired diastolic filling. However, the impact of antihypertensive treatment and LV mass reduction on LV diastolic filling remains unclear.

Methods and Results
—

Echocardiograms were recorded in 728 hypertensive patients with ECG-verified LV hypertrophy (Cornell voltage-duration or Sokolow-Lyon) at baseline and after 1 year of blinded treatment with either losartan or atenolol-based regimen. Systolic and diastolic blood pressures (BP) were reduced on average 23/11 mm Hg; isovolumic relaxation time and E/A ratio became more normal, and LV inflow deceleration time prolonged (all
P
<0.001). Directionally opposite changes in isovolumic relaxation time (IVRT) and deceleration time indicate improvement in active LV relaxation and passive chamber stiffness during early diastole. Prevalences of normal LV filling increased, abnormal relaxation and pseudonormalization decreased, and restrictive filling pattern remained unchanged (
P
<0.05). Patients with reduction in LV mass had smaller left atrial diameter, shortened IVRT, increased E/A ratio, and prolonged LV inflow deceleration time (all
P
<0.001). Patients without LV mass reduction had no change in diastolic filling parameters (
P
=NS). IVRT shortening was independently associated with reduction in LV mass. Increase in E/A ratio was independently associated with reduction in diastolic BP, and increase in the deceleration time was independently associated with reduced end-systolic relative wall thickness.

Conclusions
—

Antihypertensive therapy resulting in LV mass or relative wall thickness regression is associated with significant improvement of diastolic filling parameters related to active relaxation and passive chamber stiffness compared with patients without regression, independent of BP reduction; however, abnormalities of diastolic LV filling remain common.
Electrophysiological Mechanism of Enhanced Susceptibility of Hypertrophied Heart to Acquired Torsade de Pointes Arrhythmias
Authors: Kozhevnikov Dmitry O. , Yamamoto Keiji , Robotis Dionyssios , Restivo Mark , El-Sherif Nabil
Published: July 2002

Background
—

Cardiac hypertrophy is associated with increased incidence of sudden death and susceptibility to proarrhythmic effects of antiarrhythmic agents. However, the in vivo electrophysiologic mechanism of the arrhythmias has not been investigated in detail.

Methods and Results
—

Dose-dependent susceptibility to Torsade de Pointes (TdP) by class III drug dofetilide, 3, 10, and 30 μg/kg, was compared in 6 control dogs (C) and in 5 dogs 6 to 8 weeks after induction of complete atrioventricular block (AVB) that resulted in ventricular hypertrophy (H). Tridimensional ventricular activation and repolarization (R) patterns were simultaneously analyzed from unipolar extracellular electrograms, and local R was measured from activation recovery intervals. Both R and transmural dispersion of R (TDR) were significantly greater in dogs with H compared with C. Dofetilide resulted in cycle length–dependent and dose-dependent prolongation of R, which was more marked in left ventricular endocardium/midmyocardium compared with epicardium, resulting in significant increase of TDR. These changes were more accentuated in dogs with H compared with C. All 5 dogs with H developed TdP at a dose of 3 to 10 μg/kg, whereas only 1 of 6 C dogs developed TdP at 30 μg/kg. TdP was initiated by subendocardial focal activity that infringed on TDR, resulting in functional conduction block and reentrant excitation.

Conclusions
—

Enhanced susceptibility of hypertrophied heart to class III drugs is attributable to baseline increased TDR and greater dose-related accentuation of TDR compared with nonhypertrophied heart. This provides the electrophysiologic substrate for drug-induced TdP.
Effects of Long-Term Biventricular Stimulation for Resynchronization on Echocardiographic Measures of Remodeling
Authors: Saxon Leslie A. , De Marco Teresa , Schafer Jill , Chatterjee Kanu , Kumar Uday N. , Foster Elyse
Published: July 2002

Background

—

Long-term ventricular resynchronization therapy improves symptom status. Changes in left ventricular remodeling have not been adequately evaluated.

Methods and Results

—

Fifty-three patients with systolic heart failure and bundle-branch block underwent implantation of biventricular stimulation (BVS) devices as part of a randomized trial. Echocardiograms were acquired at randomization and at 6-week intervals until completion of 12 weeks of continuous BVS. There were no changes in heart rate or QRS duration after 12 weeks of BVS. Serum norepinephrine values did not change with BVS. After 12 weeks of BVS, left atrial volume decreased. Left ventricular end-systolic and end-diastolic dimensions and left ventricular end-systolic volume also decreased after 12 weeks of BVS. Sphericity index did not change. Measures of systolic function, including left ventricular outflow tract and aortic velocity time integral and myocardial performance index, improved.

Conclusions

—

Long-term resynchronization therapy results in atrial and ventricular reverse remodeling and improved hemodynamics.
Long-Term Effects of Carotid Sinus Denervation on Arterial Blood Pressure in Humans
Authors: Smit Arthur A.J. , Timmers Henri J.L.M. , Wieling Wouter , Wagenaar Mariette , Marres Henri A.M. , Lenders Jacques W.M. , van Montfrans Gert A. , Karemaker John M.
Published: July 2002

Background

—

After experimental carotid sinus denervation in animals, blood pressure (BP) level and variability increase markedly but normalize to preoperative levels within 10 to 14 days. We investigated the course of arterial BP level and variability after bilateral denervation of the carotid sinus baroreceptors in humans.

Methods and Results

—

We studied 4 women (age 41 to 63 years) who were referred for evaluation of arterial baroreflex function because of clinical suspicion of carotid sinus denervation attributable to bilateral carotid body tumor resection. The course of BP level and variability was assessed from repeated office and 24-hour ambulatory measurements (Spacelabs/Portapres) during 1 to 10 years of (retrospective) follow-up. Rapid cardiovascular reflex adjustments to active standing and Valsalva’s maneuver were assessed. Office BP level increased from 132/86 mm Hg (range, 118 to 148/80 to 92 mm Hg) before bilateral surgery to 160/105 mm Hg (range, 143 to 194/90 to 116 mm Hg) 1 to 10 years after surgery. During continuous 24-hour noninvasive BP recording (Portapres), a marked BP variability was apparent in all 4 patients. Initial symptomatic hypotension on change to the upright posture and abnormal responses to Valsalva’s maneuver were observed.

Conclusions

—

Acute carotid sinus denervation, as a result of bilateral carotid body tumor resection, has a long-term effect on the level, variability, and rapid reflex control of arterial BP. Therefore, in contrast to earlier experimental observations, the compensatory ability of the baroreceptor areas outside the carotid sinus seems to be of limited importance in the regulation of BP in humans.
Influence of

Helicobacter pylori

Infection During Atherogenesis In Vivo in Mice
Authors: Mach François , Sukhova Galina K. , Michetti Murielle , Libby Peter , Michetti Pierre
Published: July 2002

Inflammatory diseases may have a role in the pathogenesis of atherosclerosis. Several epidemiological and clinical studies have explored the possible association between
Helicobacter pylori
seropositivity, cardiovascular risk factors, and ischemic heart disease. The contradictory results of these studies have fueled a debate regarding the link between
H pylori
infection and atherogenesis. This study tested the hypothesis that
H pylori
infection might influence atherosclerosis in vivo in mice. Male wild-type C57/Bl6 mice and LDL-receptor deficient congenic mice were randomly assigned for infection with
H pylori
. All animals were fed a high-cholesterol diet (1.25%) for 6 or 12 weeks. At autopsy, we compared aortic atherosclerotic lesion formation and lipid deposition.
H pylori
infection influenced neither the progression of atherosclerotic lesions nor lipid deposition. Moreover, the cellularity of atherosclerotic lesions (macrophages and T cells) did not differ between mice infected or not infected with
H pylori
. This in vivo study performed in a mouse model of atherosclerosis revealed no indication that
H pylori
infection might contribute to the development of atherosclerotic lesion formation. The full text of this article is available at http://www.circresaha.org.
Poly(ADP-Ribose) Polymerase Inhibition Reduces Reperfusion Injury After Heart Transplantation
Authors: Szabó Gábor , Bährle Susanne , Stumpf Nicole , Sonnenberg Karin , Szabó Éva , Pacher Pál , Csont Tamás , Schulz Richard , Dengler Thomas J. , Liaudet Lucas , Jagtap Prakash G. , Southan Garry J. , Vahl Christian F. , Hagl Siegfried , Szabó Csaba
Published: July 2002

The aim of the present study was to investigate the effects of the novel poly(ADP-ribose) polymerase (PARP) inhibitor PJ34 (
N
-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-
N
,
N
-dimethylacetamide) on myocardial and endothelial function after hypothermic ischemia and reperfusion in a heterotopic rat heart transplantation model. After a 1-hour ischemic preservation, reperfusion was started either after application of placebo or PJ34 (3 mg/kg). The assessment of left ventricular pressure–volume relations, total coronary blood flow, endothelial function, myocardial high energy phosphates, and histological analysis were performed at 1 and 24 hours of reperfusion. After 1 hour, myocardial contractility and relaxation, coronary blood flow, and endothelial function were significantly improved and myocardial high energy phosphate content was preserved in the PJ34-treated animals. Improved transplant function was also seen with treatment with another, structurally different PARP inhibitor, 5-aminoisoquinoline. The PARP inhibitors did not affect baseline cardiac function. Immunohistological staining confirmed that PJ34 prevented the activation of PARP in the transplanted hearts. The activation of P-selectin and ICAM-1 was significantly elevated in the vehicle-treated heart transplantation group. Thus, pharmacological PARP inhibition reduces reperfusion injury after heart transplantation due to prevention of energy depletion and downregulation of adhesion molecules and exerts a beneficial effect against reperfusion-induced graft coronary endothelial dysfunction.
cGMP-Dependent Protein Kinase I Mediates the Negative Inotropic Effect of cGMP in the Murine Myocardium
Authors: Wegener Jörg W. , Nawrath Hermann , Wolfsgruber Wiebke , Kühbandner Susanne , Werner Claudia , Hofmann Franz , Feil Robert
Published: July 2002

To study the role of cGMP-dependent protein kinase I (cGKI) for cardiac contractility, force of contraction (F
c
) was studied in electrically driven heart muscle from wild-type (WT) mice and from conventional and conditional cGKI knockout mice. Both 8-Br-cGMP and 8-pCPT-cGMP reduced Fc in cardiac muscle from juvenile WT but not from juvenile cGKI-null mutants. Similarly, the cGMP analogues reduced F
c
in forskolin-stimulated ventricular muscle from WT mice but not from cGKI-null mutants. In contrast, carbachol reduced F
c
in both groups of animals. 8-Br-cGMP reduced F
c
also in heart muscle from adult WT mice but not from adult cardiomyocyte-specific cGKI-knockout mice. These results demonstrate that cGKI mediates the negative inotropic effect of cGMP in the myocardium of juvenile and adult mice.
Cyclic Nucleotide Phosphodiesterase 1C Promotes Human Arterial Smooth Muscle Cell Proliferation
Authors: Rybalkin Sergei D. , Rybalkina Irina , Beavo Joseph A. , Bornfeldt Karin E.
Published: July 2002

Proliferation of arterial smooth muscle cells (SMCs) is a key event in the formation of advanced atherosclerotic lesions and restenosis after angioplasty. Cyclic nucleotides (cAMP and cGMP) inhibit arterial SMC proliferation, and elevation of cyclic nucleotides reduces neointimal formation after angioplasty in animal models. Degradation of cAMP and cGMP is catalyzed by cyclic nucleotide phosphodiesterases (PDEs). One of these, PDE1C, hydrolyzes cAMP and cGMP and is expressed in proliferating human SMCs but is absent in quiescent human aorta. Thus, PDE1C expression is low in cultured human SMCs made quiescent by attaching to fibrillar collagen type I. After release from the fibrillar collagen, PDE1C expression is induced and associated with traverse through S-phase of the cell cycle. Further, PDE1C is expressed in vivo in human fetal aorta containing proliferating SMCs, but not in newborn aorta in which SMC proliferation has ceased. Inhibition of PDE1C in SMCs isolated from normal aorta or from lesions of atherosclerosis using antisense oligonucleotides or a PDE1 inhibitor results in suppression of SMC proliferation. In conclusion, PDE1C expression is a marker of human SMC proliferation ex vivo and in vivo. Inhibition of PDE1C leads to inhibition of human SMC proliferation. Because PDE1C is absent in quiescent SMCs, PDE1C inhibitors may target proliferating SMCs in lesions of atherosclerosis or restenosis.
Carbon Monoxide-Releasing Molecules
Authors: Motterlini Roberto , Clark James E. , Foresti Roberta , Sarathchandra Padmini , Mann Brian E. , Green Colin J.
Published: July 2002

Carbon monoxide (CO) is generated in living organisms during the degradation of heme by the enzyme heme oxygenase, which exists in constitutive (HO-2 and HO-3) and inducible (HO-1) isoforms. Carbon monoxide gas is known to dilate blood vessels in a manner similar to nitric oxide and has been recently shown to possess antiinflammatory and antiapoptotic properties. We report that a series of transition metal carbonyls, termed here carbon monoxide-releasing molecules (CO-RMs), liberate CO to elicit direct biological activities. Specifically, spectrophotometric and NMR analysis revealed that dimanganese decacarbonyl and tricarbonyldichlororuthenium (II) dimer release CO in a concentration-dependent manner. Moreover, CO-RMs caused sustained vasodilation in precontracted rat aortic rings, attenuated coronary vasoconstriction in hearts ex vivo, and significantly reduced acute hypertension in vivo. These vascular effects were mimicked by induction of HO-1 after treatment of animals with hemin, which increases endogenously generated CO. Thus, we have identified a novel class of compounds that are useful as prototypes for studying the bioactivity of CO. In the long term, transition metal carbonyls could be utilized for the therapeutic delivery of CO to alleviate vascular- and immuno-related dysfunctions. The full text of this article is available at http://www.circresaha.org.
Interleukin-18 Enhances Atherosclerosis in Apolipoprotein E
−/−
Mice Through Release of Interferon-γ
Authors: Whitman Stewart C. , Ravisankar Punnaivanam , Daugherty Alan
Published: July 2002

We have previously shown that interferon-γ (IFN-γ) is a potent enhancer of atherogenesis. Interleukin-18 (IL-18) promotes inflammatory responses through release of IFN-γ, although it can also exert direct actions on other inflammatory mediators. In this present study, we determined the effects of IL-18 on atherogenesis and the role of IFN-γ in this response. Male apolipoprotein E
−/−
mice (
apo
e
−/−
; aged 16 weeks, n=10/group) were fed a normal diet and injected intraperitoneally for 30 days with either recombinant IL-18 (30 ng/g/day) or saline. Atherosclerotic lesion size was quantified in 2 vascular beds: the ascending aorta and the aortic arch. IL-18 administration did not affect serum cholesterol concentrations or lipoprotein-cholesterol distribution; however, exogenous IL-18 administration increased lesion size 2-fold in both the ascending aorta (50 642±12 515 versus 112 399±13 227 μm
2
,
P
=0.004; saline versus IL-18 groups, respectively) and the aortic arch (3.1±0.3% versus 6.2±0.9% area,
P
=0.006). Exogenous IL-18 promoted a 4-fold increase in the number of lesion-associated T lymphocytes (11±3 versus 50±5 cells;
P
<0.0001) and cells expressing major histocompatability complex class II (9±3 versus 40±6 cells;
P
=0.0002). To determine the role of IFN-γ production in this response, exogenous IL-18 was administered to
apo
e
−/−
mice that were IFN-γ deficient. These studies demonstrated that lack of endogenous IFN-γ ablated the effects of IL-18 on atherosclerosis. Therefore, these data strongly implicates IL-18 in the atherogenic process and suggests that IL-18 increases lesion development through enhancement of an inflammatory response involving an IFN-γ–dependent mechanism. The full text of this article is available at http://www.circresaha.org.
Role of the Carboxyl Terminal of Connexin43 in Transjunctional Fast Voltage Gating
Authors: Moreno Alonso P. , Chanson Marc , Anumonwo Justus , Scerri Isabelle , Gu Hong , Taffet Steven M. , Delmar Mario
Published: July 2002

Previous studies show that chemical regulation of connexin43 (Cx43) gap junction channels depends on the integrity of the carboxyl terminal (CT) domain. Experiments using
Xenopus
oocytes show that truncation of the CT domain alters the time course for current inactivation; however, correlation with the behavior of single Cx43 channels has been lacking. Furthermore, whereas chemical gating is associated with a “ball-and-chain” mechanism, there is no evidence whether transjunctional voltage regulation for Cx43 follows a similar model. We provide data on the properties of transjunctional currents from voltage-clamped pairs of mammalian tumor cells expressing either wild-type Cx43 or a mutant of Cx43 lacking the carboxyl terminal domain (Cx43M257). Cx43 transjunctional currents showed bi-exponential decay and a residual steady-state conductance of approximately 35% maximum. Transjunctional currents recorded from Cx43M257 channels displayed a single, slower exponential decay. Long transjunctional voltage pulses caused virtual disappearance of the residual current at steady state. Single channel data revealed disappearance of the residual state, increase in the mean open time, and slowing of the transition times between open and closed states. Coexpression of CxM257 with Cx43CT in a separate fragment restored the lower conductance state. We propose that Cx43CT is an effector of fast voltage gating. Truncation of Cx43CT limits channel transitions to those occurring across the higher energy barrier that separates open and closed states. We further propose that a ball-and-chain interaction provides the fast component of voltage-dependent gating between CT domain and a receptor affiliated with the pore.
α
4
β
1
Integrin Activation of L-Type Calcium Channels in Vascular Smooth Muscle Causes Arteriole Vasoconstriction
Authors: Waitkus-Edwards Kelli R. , Martinez-Lemus Luis A. , Wu Xin , Trzeciakowski Jerome P. , Davis Michael J. , Davis George E. , Meininger Gerald A.
Published: July 2002

A pathway for the regulation of vascular tone appears to involve coupling between integrins and extracellular matrix proteins or their fragments and the subsequent modulation of ion movement across the smooth muscle cell membrane. Here, we report that the activation of L-type voltage-activated Ca
2+
channels occurs through a novel interaction of α
4
β
1
integrin with peptides containing the Leu-Asp-Val (LDV) integrin–binding sequence, which is found in the CS-1 region of an alternately spliced fibronectin variant. Experiments were conducted on arterioles isolated from rat skeletal muscle. Arterioles exhibited sustained concentration-dependent vasoconstriction to LDV peptides but not to Leu-Glu-Val (LEV) control peptides. The constriction was associated with increased smooth muscle cell [Ca
2+
]
i
, as measured by using fura 2. The response could be inhibited with a function-blocking anti–α
4
integrin antibody. Removal of the endothelium did not alter the vasoconstrictor response. Further experiments demonstrated that the vasoconstriction was abolished by the L-type Ca
2+
channel inhibitor nifedipine and the Src family kinase inhibitor PP2. In studies of isolated smooth muscle cells using whole-cell patch-clamp methods, the L-type current was enhanced by the LDV but not LEV peptide and was blocked by PP2 or antibodies to α
4
integrin. Collectively, these data indicate that activation of α
4
β
1
integrin leads to enhanced influx of Ca
2+
through L-type channels by activating a tyrosine kinase pathway, leading to vasoconstriction. Involvement of integrins in the modulation of vascular tone may be particularly important in vascular responses to mechanical signals, such as pressure and flow, and to tissue injury after damage to the extracellular matrix.
The Influence of Platelet Collagen Receptor Polymorphisms in Hemostasis and Thrombotic Disease
Authors: Kunicki Thomas J.
Published: July 2002

Extracellular collagens modulate the rate of platelet activation and thereby markedly influence hemostasis and thrombosis. Platelet receptors for collagens, such as the integrin α
2
β
1
, platelet glycoprotein (GP) VI or, indirectly, the GPIb complex, are unexploited targets of pharmacological control, and polymorphisms of these receptors have recently become factored into the genetic risk for thrombosis. Seemingly contradictory findings already exist with regard to the contribution of GPIbα and integrin α
2
polymorphisms, but these discrepancies will be resolved once there is better standardization of clinical studies. There is already substantial evidence that GPIbα VNTR A or B alleles, the GPIbα-5C allele, and integrin α
2
allele 1 (T
807
) each contribute to increased risk for morbidity in thrombotic disease. However, larger, prospective genetic and epidemiological studies are needed to clarify the role of each of these polymorphisms, the contribution of other platelet receptor polymorphisms, and the synergistic effects of combinations of these factors. In addition, in vitro studies that establish the functional relevance of these polymorphisms will provide sound biological explanations for the results of clinical correlation studies.
Lipoprotein Lipase in the Arterial Wall
Authors: Pentikäinen Markku O. , Oksjoki Riina , Öörni Katariina , Kovanen Petri T.
Published: July 2002

For low density lipoprotein (LDL) particles to be atherogenic, increasing evidence indicates that their residence time in the arterial intima must be sufficient to allow their modification into forms capable of triggering extracellular and intracellular lipid accumulation. Recent reports have confirmed the longstanding hypothesis that the major determinant(s) of initial LDL retention in the preatherosclerotic arterial intima is the proteoglycans. However, once the initial atherosclerotic lesions have formed, a shift to retention facilitated by macrophage-derived lipoprotein lipase (LPL) appears, leading to the progression of the lesions. Here, we review recent findings on the mechanisms enabling LPL to promote LDL retention and extracellular lipid accumulation in the arterial intima, and we describe the structures in the extracellular matrix that are held to be important in this process. Finally, the potentially harmful consequences of LDL linking by LPL and of other LPL actions in the arterial intima are briefly reviewed.
Diagnosis of Familial Combined Hyperlipidemia Based on Lipid Phenotype Expression in 32 Families
Authors: Veerkamp Mario J. , de Graaf Jacqueline , Bredie Sebastian J.H. , Hendriks Jan C.M. , Demacker Pierre N.M. , Stalenhoef Anton F.H.
Published: July 2002

Familial combined hyperlipidemia (FCH) is characterized by a variable expression of hypercholesterolemia and/or hypertriglyceridemia. We evaluated the variability in lipid phenotype expression over a 5-year period and studied factors affecting the lipid phenotype expression. A total of 32 families (299 subjects) were studied in 1994 and in 1999. Subjects were classified as having FCH when total cholesterol and/or triglyceride levels exceeded the 90th percentile adjusted for age and sex. In 1994, 93 (31%) of the 299 subjects were affected, whereas 206 (69%) of the subjects were unaffected relatives. In 1999, a diagnosis of FCH was consistent in 69 (74%) of the 93 subjects. So, 26% of the FCH subjects in 1994 showed a sporadic normolipidemic pattern (ie, total cholesterol and/or triglycerides <90th percentile) in 1999. Among the 206 unaffected relatives in 1994, 178 (86%) remained unaffected in 1999, and 28 (14%) developed an FCH lipid phenotype. Multiple regression analysis showed that sex (odds ratio 2.03, 95% CI 1.09 to 3.87;
P
=0.03) and body mass index (odds ratio 1.14, 95% CI 1.05 to 1.24;
P
<0.01) significantly contributed to the variability in lipid phenotype expression. Thus, a diagnosis of FCH, based on plasma total cholesterol and/or triglyceride levels, is consistent in only 74% of the subjects over a 5-year period. Two other major characteristics of our FCH group, compared with the unaffected relatives, included elevated apolipoprotein B (apoB) levels and the presence of small dense low density lipoprotein (LDL), as reflected by a low value of the parameter
K
(apoB 1461±305 versus 997±249 mg/L, respectively [
P
<0.001];
K
value −0.22±0.19 versus −0.02±0.19, respectively [
P
<0.001]). We now report that the apoB concentration and the
K
value show less variability in time and are more consistently associated with FCH, inasmuch as affected FCH subjects, compared with the unaffected relatives, persistently show a higher apoB level and a lower value of parameter
K
, reflecting small dense LDL, even when they present a sporadic normolipidemic pattern. In conclusion, our results emphasize the need for reevaluation of the diagnostic criteria for FCH. We demonstrate that apoB and small dense LDL are attractive new candidates for defining FCH. Further studies are indicated to evaluate the role of apoB and small dense LDL as diagnostic criteria for FCH.
Phospholipid-Binding Domain of Factor VIII Is Involved in Endothelial Cell–Mediated Activation of Factor X by Factor IXa
Authors: Brinkman Herm-Jan M. , Mertens Koen , van Mourik Jan A.
Published: July 2002

Apparently quiescent, nonapoptotic endothelial cells mediate the activation of factor X by activated factor IX in the presence of its cofactor, activated factor VIII. In a previous study, we reported that during the activation of factor X, the interaction of the cofactor with the endothelial cell membrane clearly differs from the interaction of the cofactor with artificial lipid membranes. In the present study, we identified the peptide domain of factor VIII involved in the assembly of the enzyme-cofactor complex on the endothelial cell surface. With the use of monoclonal antibodies against different peptide sequences on the factor VIII light chain, it was observed that the lipid-binding region of the C2 domain on the factor VIII light chain mediates the assembly of the factor X–activating complex on the endothelial cell surface. In addition, a synthetic peptide that constitutes region Ala2318-Tyr2332 of the C2 domain and that is known for its ability to inhibit the binding of factor VIII to artificial lipid membranes also showed inhibition of the cofactor activity of factor VIII on endothelial cells. Thus, the carboxy-terminal part of the factor VIII light chain not only contains sites involved in lipid binding but also contains sites involved in complex assembly on the endothelial cell membrane.
Elevated Soluble Cellular Adhesion Molecules in Subjects With Low HDL-Cholesterol
Authors: Calabresi Laura , Gomaraschi Monica , Villa Barbara , Omoboni Laura , Dmitrieff Camille , Franceschini Guido
Published: July 2002

The purpose of this study was to investigate whether the expression of cellular adhesion molecules (CAMs) is enhanced in individuals with low HDL cholesterol (HDL-C). Plasma levels of soluble vascular cell adhesion molecule-1 (sVCAM-1), intercellular adhesion molecule-1 (sICAM-1), and E-selectin (sE-selectin) were measured in subjects with low (below the 10th percentile for the Italian population), average, or high (above the 90th percentile) HDL-C. Average sICAM-1 and sE-selectin levels were significantly higher in two groups of 65 individuals with low HDL levels, either hyperlipidemic (320.5±16.0 and 61.4±3.5 ng/mL) or normolipidemic (309.6±13.0 and 60.0±2.7 ng/mL), than in subjects with average HDL levels, either hyperlipidemic (267.0±10.1 and 50.4±2.8 ng/mL) or normolipidemic (257.9±5.4 and 51.1±2.4 ng/mL), or with high HDL levels (254.8±10.2 and 52.5±3.2 ng/mL). No significant difference was found in the plasma sVCAM-1 concentration. HDL-C was inversely correlated with sICAM-1 and sE-selectin in the low-HDL subjects (
r
2
=0.087 and 0.035,
P
=0.0007 and 0.033, respectively), but not in individuals with normal or elevated HDL-C (
r
2
=0.012 and 0.006). A fenofibrate-induced increase of HDL-C in 20 low-HDL subjects was associated with a significant reduction of plasma sICAM-1 and sE-selectin concentrations. An increased CAMs expression may be a mechanism by which a low plasma HDL level promotes atherogenesis and causes acute atherothrombotic events.
Oxidative Stress in Rats With Heatstroke-Induced Cerebral Ischemia
Authors: Yang Chih-Ya , Lin Mao-Tsun
Published: July 2002

Background and Purpose

—

Heatstroke is associated with cerebral ischemia as well as increased levels of interleukin-1β, dopamine, and glutamate in the brain. These factors are known to increase free radical production. This study attempted to ascertain whether an excessive accumulation of cytotoxic free radicals in the brain and oxidative stress can occur during heatstroke.

Methods

—

Urethane-anesthetized rats underwent instrumentation for the measurement of mean arterial pressure, cerebral blood flow, neuronal damage score, and colonic temperature. Rats were exposed to heat stress (ambient temperature, 42°C) until mean arterial pressure and cerebral blood flow began to decrease from their peak levels, which was arbitrarily defined as the onset of heatstroke. Controlled rats were exposed to 24°C. Concentrations of dihydroxybenzoic acid, lipid peroxidation, rate of O
2
·
−
generation, superoxide dismutase, and catalase activity of the brain or other vital organs were assessed during heatstroke.

Results

—

The values of mean arterial pressure and cerebral blood flow after heatstroke onset were all significantly lower than those in control rats. However, the values of colonic temperature, dihydroxybenzoic acid levels in the striatum, and neuronal damage score were greater. The extent of lipid peroxidation in the brain and the rate of O
2
·
−
generation in the brain, liver, and heart were all greater in rats after heatstroke onset. In contrast, the values of total superoxide dismutase in the brain, liver, and heart and the catalase activity in the brain were lower.

Conclusions

—

Taken together, these results indicate that hydroxyl radicals mediate cerebral ischemic injury associated with heatstroke.
Effects of Hypertonic (10%) Saline in Patients With Raised Intracranial Pressure After Stroke
Authors: Schwarz Stefan , Georgiadis Dimitrios , Aschoff Alfred , Schwab Stefan
Published: July 2002

Background and Purpose

—

The aim of this study was to evaluate the effects of hypertonic saline in stroke patients with increased intracranial pressure (ICP) after conventional therapy with mannitol had failed.

Methods

—

Twenty-two episodes of ICP crisis occurred in 8 patients in whom the standard treatment of 200 mL of 20% mannitol was not effective. ICP crisis was defined as an increase in ICP of 20 mm Hg (n=18), pupillary abnormality (n=3), or a combination of both (n=1). The patients were treated with 75 mL of 10% saline over the course of 15 minutes. ICP, mean arterial blood pressure, and cerebral perfusion pressure were monitored for 4 hours. Blood gases, hematocrit, hemoglobin, pH, osmolarity, and electrolytes levels were measured before and 15 and 60 minutes after the start of infusion. Treatment was regarded as effective if ICP decreased >10% or the pupillary reaction had normalized.

Results

—

Treatment was effective in all 22 episodes. The maximum ICP decrease was 9.9 mm Hg 35 minutes after the start of infusion. Thereafter, ICP began to rise again. There was no constant effect on mean arterial blood pressure, whereas cerebral perfusion pressure was consistently increased. Blood osmolarity rose by 9 mmol/L and serum sodium by 5.6 mmol/L. Potassium levels, hemoglobin, hematocrit, and pH were slightly decreased. No unexpected side effects were noted.

Conclusions

—

Infusion of 75 mL hypertonic (10%) saline decreases elevated ICP and increases cerebral perfusion pressure in stroke patients in whom mannitol had failed. The effect on the ICP and cerebral perfusion pressure reaches its maximum after the end of infusion and is seen for 4 hours.
Severe ADC Decreases Do Not Predict Irreversible Tissue Damage In Humans
Authors: Fiehler Jens , Foth Mascha , Kucinski Thomas , Knab Renée , von Bezold Michael , Weiller Cornelius , Zeumer Hermann , Röther Joachim
Published: July 2002

Background and Purpose

—

A mismatch between diffusion- and perfusion-weighted MRI is thought to define tissue at risk of infarction. This concept is based on the assumption that diffusion slowing of and decreases in the apparent diffusion coefficient (ADC) serve as indicator of tissue proceeding to infarction. We tested this hypothesis.

Methods

—

MRI (diffusion weighted, perfusion weighted, MRA, T2 weighted) was performed in 15 patients with acute stroke within 2.9±0.8 hours (mean±SD) of onset and on days 1 and 7. After intraindividual realignment of the ADC maps, the development of ADC range volumes and ADC values was determined.

Results

—

An increase (354%, group A1) in the total ADC-based lesion volume below a threshold of <80% occurred in 4 patients on day 1, persisting on day 7 with a pronounced increase of ADC range volumes with low ADC values. An increase in total ADC-based lesion volume (201%, group A2) followed by a secondary drop to day 7 was found in 7 patients. A significant reduction in total ADC-based lesion volume (14%, group B) was found in 4 patients. ADC-based lesion volume increase was associated with persistent vessel occlusion in group A, whereas recanalization in group B resulted in ADC volume decrease. ADC normalization was observed independently from the degree of the initial ADC decrease on days 1 and 7 in group B.

Conclusions

—

In line with results from animal experiments, ADC decreases do not reliably indicate tissue infarction Even severely decreased ADC values may normalize in human stroke, and it seems likely that ADC normalization depends on the duration and severity of ischemia rather than the absolute value.
Inhibition of Glutamate Release via Recovery of ATP Levels Accounts for a Neuroprotective Effect of Aspirin in Rat Cortical Neurons Exposed to Oxygen-Glucose Deprivation
Authors: De Cristóbal Javier , Cárdenas Antonio , Lizasoain Ignacio , Leza Juan Carlos , Fernández-Tomé Paz , Lorenzo Pedro , Moro María Ángeles
Published: July 2002

Background and Purpose

—

Aspirin is preventive against stroke not only because of its antithrombotic properties but also by other direct effects. The aim of this study was to elucidate its direct neuroprotective effects.

Methods

—

Viability parameters, glutamate release and uptake, and ATP levels were measured in cultured cortical neurons exposed to oxygen-glucose deprivation (OGD). In addition, ATP levels and oxygen consumption were studied in isolated brain mitochondria or submitochondrial particles.

Results

—

Aspirin inhibited OGD-induced neuronal damage at concentrations lower (0.3 mmol/L) than those reported to act via inhibition of the transcription factor nuclear factor-κB (which are >1 mmol/L), an effect that correlated with the inhibition caused by aspirin on glutamate release. This effect was shared by sodium salicylate but not by indomethacin, thus excluding the involvement of cyclooxygenase. A pharmacological dissection of the components involved indicated that aspirin selectively inhibits the increase in extracellular glutamate concentration that results from reversal of the glutamate transporter, a component of release that is due to ATP depletion. Moreover, aspirin-afforded neuroprotection occurred in parallel with a lesser decrease in ATP levels after OGD. Aspirin elevated ATP levels not only in intact cortical neurons but also in isolated brain mitochondria, an effect concomitant with an increase in NADH-dependent respiration by brain submitochondrial particles.

Conclusions

—

Taken together, our present findings show a novel mechanism for the neuroprotective effects of aspirin, which takes place at concentrations in the antithrombotic-analgesic range, useful in the management of patients with high risk of ischemic events.
Selective Vulnerability of the Lumbosacral Spinal Cord After Cardiac Arrest and Hypotension
Authors: Duggal N. , Lach B.
Published: July 2002

Background and Purpose

—

It is generally accepted that the gray matter in the watershed area of the midthoracic level of the spinal cord is the ischemic watershed zone of the spinal cord. We performed a retrospective study to reevaluate the frequency and distribution of spinal cord injury after a global ischemic event.

Methods

—

Clinical files and neuropathology specimens of all adult patients with either a well-documented cardiac arrest or a severe hypotensive episode, as well as pathologically confirmed ischemic encephalopathy and/or myelopathy, were reviewed by an independent reviewer.

Results

—

Among 145 cases satisfying selection criteria, ischemic myelopathy was found in 46% of patients dying after either a cardiac arrest or a severe hypotensive episode. Among the patients with myelopathy, predominant involvement of the lumbosacral level with relative sparing of thoracic levels was observed in >95% of cardiac arrest and hypotensive patients. None of the examined patients developed neuronal necrosis limited to the thoracic level only.

Conclusions

—

Our findings indicate a greater vulnerability of neurons in the lumbar or lumbosacral spinal cord to ischemia than other levels of the spinal cord.
Effect of Controlled Release/Extended Release Metoprolol on Carotid Intima-Media Thickness in Patients With Hypercholesterolemia
Authors: Wiklund Olov , Hulthe Johannes , Wikstrand John , Schmidt Caroline , Olofsson Sven-Olof , Bondjers Göran
Published: July 2002

Background and Purpose

—

β-Adrenergic blockade has in several studies been shown to improve survival after myocardial infarction. In animal experiments β-blockers have also shown an antiatherosclerotic effect. The aim of this study was to test the hypothesis that the β-blocker metoprolol succinate controlled release/extended release (CR/XL), when given to patients with hypercholesterolemia on concomitant lipid-lowering therapy, provides an additional antiatherosclerotic effect to that provided by the statins, measured as carotid intima-media thickness (IMT).

Methods

—

We conducted a randomized, double-blind, placebo-controlled, single center trial to compare the effect of metoprolol CR/XL (100 mg once daily) and placebo on the progression of carotid IMT during 36 months of treatment in patients with hypercholesterolemia and signs of early atherosclerosis in the carotid artery. Most patients were prescribed lipid-lowering treatment with statins.

Results

—

A highly significant difference in the progression rate of the composite variable of carotid bulb IMT+common carotid IMT was observed between the metoprolol CR/XL and placebo groups after 1 year of treatment (−0.08 versus −0.01 mm;
P
=0.004), an effect that was sustained after 3 years of follow-up (−0.06 versus +0.03 mm;
P
=0.011). The patients had high levels of total cholesterol at randomization: 9.4 mmol/L in the metoprolol CR/XL group and 8.6 mmol/L in the placebo group. During the study the 2 randomization groups were treated with lipid-lowering drugs, mainly statins, to a similar extent, and total cholesterol was reduced to 6.4 mmol/L at end of follow-up in both groups.

Conclusions

—

The results from the present study in patients with hypercholesterolemia under concomitant lipid-lowering therapy are the first clinical data to show an antiatherosclerotic effect of β-blockade as additional therapy to statins. The data indicate that statin treatment and treatment with β-blockers affect different mechanisms in the atherosclerotic process and have additive beneficial effects.
Quality of Life, Anxiety, and Depression in Patients With an Untreated Intracranial Aneurysm or Arteriovenous Malformation
Authors: van der Schaaf Irene C. , Brilstra Eva H. , Rinkel Gabriel J.E. , Bossuyt Patrick M. , van Gijn J.
Published: July 2002

Background and Purpose

—

The objective of this study was to assess the health-related quality of life and symptoms of anxiety and depression in patients who are aware of the presence of a patent aneurysm or arteriovenous malformation.

Methods

—

Participants were retrospectively identified and invited to participate in the study; consenting participants were interviewed in a face-to-face setting by means of 2 questionnaires assessing health-related quality of life (Sickness Impact Profile [SIP] and the MOS Short Form-36 [SF-36]) and psychological state (Hospital Anxiety and Depression Scale [HADS]). We used Student’s
t
test statistics to compare the scores of the study population with the scores of reference populations.

Results

—

We identified 21 patients, of whom 9 had an aneurysm and 12 had an arteriovenous malformation. Compared with the reference population, these patients had a reduced quality of life for sleep and rest (difference of SIP means, 6.8; 95% CI, 3.1 to 10.5), emotional behavior (10.1; 95% CI, 5.7 to 14.6), mobility (5.4; 95% CI, 2.1 to 8.7), social interactions (5.3; 95% CI, 1.6 to 8.9), and alertness behavior (11.9; 95% CI, 6.2 to 17.5). The SIP psychosocial subscore (7.1; 95% CI, 3.9 to 10.2) and total SIP score (4.7; 95% CI, 2.2 to 7.2) were also significantly impaired. For the SF-36 domains, social functioning was significantly decreased compared with the reference population (8.9; 95% CI, 0.1 to 17.7). HADS scores for depression were similar for patients and the reference population.

Conclusions

—

Our study shows that knowledge of harboring an unoccluded untreated intracranial aneurysm or arteriovenous malformation reduces quality of life, most prominently on the psychosocial domains, without leading to substantially raised levels of anxiety and depression.
Inhibition of Factor IX(a) Is Protective in a Rat Model of Thromboembolic Stroke
Authors: Toomey John R. , Valocik Richard E. , Koster Paul F. , Gabriel Melanie A. , McVey Matt , Hart Timothy K. , Ohlstein Eliot H. , Parsons Andrew A. , Barone Frank C.
Published: July 2002

Background and Purpose

—

Although used clinically to prevent stroke, there are few examples of anticoagulant investigations in the treatment of acute thromboembolic stroke in animal models. The treatment of thromboembolic stroke in experimental models has been investigated almost exclusively around the use of tissue plasminogen activator (tPA). In this study, using a rat thromboembolic stroke model, we investigated the use of an inhibitory anti–factor IX(a) monoclonal antibody (SB 249417) for the treatment of thromboembolic stroke and compared its efficacy to that of tPA.

Methods

—

Stroke was initiated by delivering 6 clots into the internal carotid artery. After 2, 4, or 6 hours, rats received either intravenous vehicle, 10.0 mg/kg tPA, or 1.0, 2.0, or 3.0 mg/kg SB 249417. At 24 hours after stroke, infarct volumes and neurological deficits were assessed.

Results

—

Treatment with tPA 2, 4, or 6 hours after stroke reduced infarct volumes by 35% (
P
=NS), 45%, and 39%, respectively. tPA treatment did not improve neurological deficits at any time point. Treatment with SB 249417 (3.0 mg/kg) 2, 4, or 6 hours after stroke reduced infarct volumes by 44%, 50%, and 13% (
P
=NS), respectively. Neurological deficits were reduced by 49%, 42%, and 13% (
P
=NS), respectively. Neither mortality nor hemorrhage was affected by either treatment.

Conclusions

—

The data indicate that the inhibition of factor IX(a) within 4 hours of thromboembolic stroke produced a more favorable outcome than tPA. When treatment was initiated 6 hours after stroke, the benefits of factor IX(a) inhibition were lost, whereas tPA continued to suppress lesion development, albeit without a corresponding improvement in functional deficits. This study suggests that cerebral ischemia and the resultant perfusion deficit are exacerbated by the activation of blood coagulation and that anticoagulants like SB 249417 may find utility in the treatment of ischemic stroke.