bluuebunny/crossref_metadata_2025 huggingface dataset:
Group 1 β-lactamases ofAeromonas caviaeand their resistance to β-lactam antibiotics
Authors: Lupiola-Gómez P A , González-Lama Z , Tejedor-Junco M T , González-Martín M , Martín-Barrasa J L
Published: June 2003

The contribution of β-lactamase production to β-lactam antibiotic resistance was examined in an Aeromonas caviae mutant strain, selected in vitro by cefotaxime and derived from a wild-type strain isolated in our laboratory from crude sewage. Both strains produced β-lactamase. The mutant strain (AC7m) produced β-lactamase constitutively, in contrast to the parental strain (AC7), which was inducible by cefoxitin. AC7m was regarded as a mutant from AC7, which over-expressed β-lactamase. The mutant strain showed a remarkable reduction in sensitivity to most of the β-lactam antibiotics tested, such as (i) aminopenicillins and their combinations with clavulanic acid and sulbactam, (ii) carboxypenicillins, (iii) ureidopenicillins, and (iv) cephalosporins. This strain remained susceptible to ceftazidime, imipenem, and aztreonam. Isoelectric focusing of sonic extracts revealed that both strains AC7 and AC7m shared a common major β-lactamase band at pI 6.5. The plasmid DNA assays showed that the β-lactamases expressed by each A. caviae strain were chromosomally encoded. Based on substrate and inhibitor profiles determined in sonic extracts for AC7 and AC7m, the enzymes displayed on isoelectric focusing at pI 6.5 were assigned to chromosomal Group 1 β-lactamases. Imipenem would therefore be the appropriate choice for therapy of infections caused by A. caviae β-lactamase over-expressing mutants.Key words: Aeromonas caviae, β-lactamases, antibiotic resistance.
Renoprotective Effects of Omapatrilat Are Mediated Partially by Bradykinin
Authors: Zhou Xiaoyan , Ono Hidehiko , Ono Yuko , Frohlich Edward D.
Published: June 2003

Aim: To investigate the effects of omapatrilat on systemic and renal hemodynamics, glomerular dynamics, renal function, and histopathological changes as well as the participation of the bradykinin B2 receptor in WKY, SHR, and L-NAME/SHR rats. Methods: Eight groups of 17-week-old rats were examined using renal micropuncture techniques and histopathological analyses after 3 weeks of treatment: group 1, WKY control; group 2, WKY+omapatrilat (40 mg/kg/day); group 3, SHR control; group 4, SHR+omapatrilat; group 5, SHR+L-NAME (50 mg/l); group 6, SHR+L-NAME+omapatrilat; group 7, SHR+L-NAME for 3 weeks followed by omapatrilat for a subsequent 3 weeks, and group 8, SHR+L-NAME+omapatrilat+bradykinin antagonist icatibant (500 µg/kg/day). Results: In WKY and SHR, omapatrilat significantly reduced the mean arterial pressure, increased effective renal blood flow and single nephron plasma flow associated with reduced glomerular arteriolar resistances. Furthermore, omapatrilat prevented and reversed L-NAME induced urinary protein excretion, glomerular and arteriolar injuries, glomerular morphometric alterations, and glomerular apoptosis (at least, p < 0.05). Icatibant partially inhibited these beneficial effects of omapatrilat. Conclusion: Omapatrilat provided potent antihypertensive and renoprotective actions, which were mediated, in part, by bradykinin.
Genetic Background Selectively Influences Innominate Artery Atherosclerosis
Authors: Reardon Catherine A. , Blachowicz Lydia , Lukens John , Nissenbaum Michael , Getz Godfrey S.
Published: June 2003

Objective—We sought to examine whether there is a site-specific effect on atherosclerosis of the absence of mature T and B cells caused by a recombination activating-gene deficiency in LDL receptor-deficient mice and whether this effect is influence by the extent of backcrossing to C57BL/6 mice.

Methods and Results—Male mice were fed atherogenic diets for 3 months. In strain 1 mice, in which ≈93% of the genes were from C57BL/6 mice, the absence of mature T and B cells led to a significant reduction in atherosclerosis in both the aortic sinus and the innominate artery. In strain 2 mice, in which ≈99+% of the genes were from C57BL/6 mice, immune system deficiency led to a site-specific effect on atherosclerosis, with a reduction in atherosclerosis in the aortic sinus but not in the innominate artery, similar to previous results obtained with apolipoprotein E−/− mice. All of the immune system-incompetent mice had lower plasma total and VLDL cholesterol levels regardless of strain or diet, indicating that differences in lipid levels were unlikely to be responsible for these site-specific effects of immune system deficiency.

Conclusions—These results suggest that immune system deficiency has a site-specific effect on atherosclerosis that is sensitive to the genetic background of the mice.
Increased Mitogenic and Decreased Contractile P2 Receptors in Smooth Muscle Cells by Shear Stress in Human Vessels With Intact Endothelium
Authors: Wang Lingwei , Andersson Maria , Karlsson Lena , Watson Marie-Ange , Cousens Diane J. , Jern Sverker , Erlinge David
Published: June 2003

Objective—

We investigated the role of shear stress in regulating P2 receptors in human umbilical vein.

Methods and Results—

Using a novel, computerized, biomechanical perfusion model, parallel vessel segments were randomized to simultaneous perfusion under high (25 dyn/cm
2
) or low (<4 dyn/cm
2
) shear stress at identical mean perfusion pressure (20 mm Hg) for 6 hours. In the endothelium, no significant P2 receptor mRNA differences were found. In smooth muscle cells (SMCs), high shear stress decreased P2X
1
receptors, whereas P2Y
2
and P2Y
6
receptors were upregulated. These findings were consistent at the mRNA level (real-time reverse transcription–polymerase chain reaction), protein level (Western blot), and morphologically (immunohistochemistry). The changes were more pronounced in the subintimal layer of the media.

Conclusions—

Our findings suggest that shear stress might regulate gene expression in SMCs more than in the endothelium in intact vessels. Decreased expression of the contractile P2X
1
receptor could lead to reduced vascular tonus and increased blood flow. Because P2Y
2
and P2Y
6
receptors stimulate growth and migration of SMCs, increased expression of these receptors could promote vascular remodeling induced by shear stress. The pattern of upregulation of mitogenic P2Y receptors and downregulation of contractile P2X
1
receptor is similar to changes seen in the phenotypic shift from contractile to synthetic SMCs.
Association of High Coronary Heart Disease Risk Status With Circulating Oxidized LDL in the Well-Functioning Elderly
Authors: Holvoet Paul , Harris Tamara B. , Tracy Russell P. , Verhamme Peter , Newman Anne B. , Rubin Susan M. , Simonsick Eleanor M. , Colbert Lisa H. , Kritchevsky Stephen B.
Published: June 2003

Objective—

Although circulating oxidized LDL (oxLDL) is elevated in persons with coronary heart disease (CHD), whether oxLDL is elevated in persons with high CHD risk before any events is unknown. Therefore, we studied the association between high, predicted CHD risk and oxLDL in the Health ABC cohort.

Methods and Results—

This cohort included 385 persons with CHD and 1183 persons at high risk; the latter were all persons with CHD risk equivalents: noncoronary forms of clinical atherosclerotic disease, diabetes, and a 10-year risk for CHD >20% by Framingham scoring. The remaining 1535 participants were at low risk. Levels of oxLDL were 1.18±0.61 mg/dL for low-risk persons, 1.50±0.81 mg/dL for high-risk persons without diagnosed CHD, and 1.32±0.83 mg/dL for persons with CHD (
P
<0.001). The odds ratio for high CHD risk in the highest quintile of oxLDL, compared with the lowest quintile and after adjusting for age, sex, race, LDL cholesterol, smoking status, and C-reactive protein, was 2.79 (
P
<0.001).

Conclusion—

The odds ratio for elevated oxLDL among persons with high CHD risk before any CHD events was higher than that among persons with established CHD. A likely explanation is that once CHD is diagnosed, individuals are frequently treated with a statin, which is associated with lowering of LDL cholesterol and oxLDL levels.
Cholesteryl Ester Transfer Protein Expression Prevents Diet-Induced Atherosclerotic Lesions in Male db/db Mice
Authors: MacLean Paul S. , Bower Joseph F. , Vadlamudi Satyaprasad , Osborne Jody N. , Bradfield John F. , Burden Hubert W. , Bensch William H. , Kauffman Raymond F. , Barakat Hisham A.
Published: June 2003

Objective—

Accompanying more atherogenic lipoprotein profiles and an increased incidence of atherosclerosis, plasma cholesteryl ester transfer protein (CETP) is depressed in diabetic obese patients compared with nondiabetic obese counterparts. The depressed levels of CETP in the plasma of diabetic obese individuals may contribute to the development of an atherogenic lipoprotein profile and atherogenesis. We have examined the effect of CETP expression on vascular health in the db/db model of diabetic obesity.

Methods and Results—

Transgenic mice expressing the human CETP minigene were crossed with db/db strain, and 3 groups of offspring (CETP, db, and db/CETP) were placed on an atherogenic diet for 16 weeks. The proximal aorta was then excised and examined for the presence of atherosclerotic plaques. In db mice, 9 of 11 had intimal lesions with a mean area of 26 098±7486 μm
2
. No lesions greater than 1000 μm
2
were observed in db/CETP or CETP mice. CETP-expressing mice had lower circulating cholesterol concentrations than db mice. Fractionating plasma lipids by FPLC indicated that the difference in total cholesterol was primarily attributable to differences in VLDL and LDL.

Conclusions—

The expression of human CETP in db/db mice prevented the formation of diet-induced lesions, suggesting an antiatherogenic effect of CETP in the context of diabetic obesity.
Anterior Mitral Leaflet Mobility Is Limited by the Basal Stay Chords
Authors: Goetz Wolfgang A. , Lim Hou-Sen , Pekar Filip , Saber Hashim A. , Weber Patricia A. , Lansac Emmanuel , Birnbaum Dietrich E. , Duran Carlos M.G.
Published: June 2003

Background—

We hypothesize that 2 tendon-like anterior basal stay chords, which remain taut during the entire cardiac cycle, limit the motion of the anterior mitral leaflet.

Methods and Results—

Sonomicrometric crystals were implanted in 6 sheep at the insertion of stay chords at anterior mitral leaflet (S1 and S2), papillary muscle tips, fibrous trigones, mitral annulus, and the tip of the anterior leaflet (AL). Distances between crystals were recorded before and after section of stay chords. During the cardiac cycle, the angle α between mitral annulus and AL changed by +54.2±12.4 degrees; the angles between mitral annulus and S1 (β
1)
changed by +25.7±14.6 degrees, and between mitral annulus and S2 (β
2
) by +20.4±7.8 degrees. During diastole, AL twice crossed the virtual plane formed by the stay chords: during E-wave by a maximum of 6.5 mm (mean, 2.5±2.2 mm) and during A-wave by a maximum of 3.2 mm (mean, 1.7±0.9 mm). After section of both stay chords, total anterior mitral leaflet motion increased as follows: AL, +6.9±3.4 degrees; S1, +13.1±4.4 degrees; and S2, +30.9±11.7 degrees (
P
<0.05).

Conclusions—

Although the lateral movement of anterior mitral leaflet is limited by stay chords, the midportion moves unimpaired toward the septum, like a sail, between the 2 stay chords during diastole. A diastolic left ventricular-inflow and systolic left ventricular-outflow funnel mechanism is created. Stay chord section increased lateral anterior mitral leaflet movement.
Stimulation of Protein Kinase C Inhibits Bursting in Disease-Linked Mutant Human Cardiac Sodium Channels
Authors: Tateyama M. , Kurokawa J. , Terrenoire C. , Rivolta I. , Kass R.S.
Published: June 2003

Background—

Mutations in
SCN5A
, the gene coding for the human cardiac Na
+
channel α-subunit, are associated with variant 3 of the long-QT syndrome (LQT-3). Several LQT-3 mutations promote a mode of Na
+
channel gating in which a fraction of channels fail to inactivate, contributing sustained Na
+
channel current (
I
sus
), which can delay repolarization and prolong the QT interval. Here, we investigate the possibility that stimulation of protein kinase C (PKC) may modulate
I
sus
, which is prominent in disease-related Na
+
channel mutations.

Methods and Results—

We measured the effects of PKC stimulation on Na
+
currents in human embryonic kidney (HEK 293) cells expressing 3 previously reported disease-associated Na
+
channel mutations (Y1795C, Y1795H, and ΔKPQ). We find that the PKC activator 1-oleoyl-2-acetyl-
sn
-glycerol (OAG) significantly reduced
I
sus
in the mutant but not wild-type channels. The effect of OAG on
I
sus
was reduced by the PKC inhibitor staurosporine (2.5 μmol/L), ablated by the mutation S1503A, and mimicked by the mutation S1503D.
I
sus
recorded in myocytes isolated from mice expressing ΔKPQ channels was similarly inhibited by OAG exposure or stimulation of α
1
-adrenergic receptors by phenylephrine. The actions of phenylephrine on
I
sus
were blocked by the PKC inhibitor chelerythrine.

Conclusions—

We conclude that stimulation of PKC inhibits channel bursting in disease-linked mutations via phosphorylation-induced alteration of the charge at residue 1503 of the Na
+
channel α-subunit. Sympathetic nerve activity may contribute directly to suppression of mutant channel bursting via α-adrenergic receptor–mediated stimulation of PKC.
Prognostic Impact of Hemodynamic Response to Adenosine in Patients Older Than Age 55 Years Undergoing Vasodilator Stress Myocardial Perfusion Study
Authors: Abidov Aiden , Hachamovitch Rory , Hayes Sean W. , Ng Chee Keong , Cohen Ishac , Friedman John D. , Germano Guido , Berman Daniel S.
Published: June 2003

Background—

The prognostic importance of various hemodynamic responses to adenosine infusion in patients undergoing adenosine stress myocardial perfusion stress (MPS) has not been defined.

Methods and Results—

We identified 3444 unique patients (53.5% women, mean age 74.0±8.4 years) who underwent adenosine (with no additional exercise) stress myocardial perfusion single photon emission computed tomography (MPS) and were followed up for 2.0±0.8 years. Multivariable Cox proportional hazards analysis was used to assess the prognostic value of hemodynamic variables in predicting cardiac death (CD). Two hundred twenty-four CDs (6.5%) occurred during follow-up. By multivariable analysis, higher rest heart rate (HR) and to a lesser extent lower peak HR were markers of CD. When added to the multivariable model in place of peak and rest HR, the peak/rest HR ratio was an independent predictor of CD. Peak/rest HR ratio additionally risk-stratified patients within each MPS category. A significant interaction was found between gender and peak systolic blood pressure (SBP), in which there was an increased risk associated with a low peak SBP (<90 mm Hg at end of adenosine infusion) in men but not in women.

Conclusions—

Patients undergoing adenosine stress MPS with high rest HR and low peak/rest HR ratio have increased risk of CD, as do male patients with a low peak SBP. Assessment of the hemodynamic response to adenosine adds incremental prognostic value to MPS results and enhances identification of patients at risk for CD.
Selective Impairment in Sympathetic Vasomotor Control With Norepinephrine Transporter Inhibition
Authors: Tank Jens , Schroeder Christoph , Diedrich Andre , Szczech Elke , Haertter Sebastian , Sharma Arya M. , Luft Friedrich C. , Jordan Jens
Published: June 2003

Background—

Norepinephrine transporter (NET) inhibition increases the responsiveness to vasoactive medications and attenuates the response to sympathetic stimuli. The phenomenon may be a result of impaired regulation of sympathetic vasomotor tone.

Methods and Results—

We studied the effects of the selective NET blocker reboxetine and placebo on baroreflex control of heart rate (HR) and sympathetic traffic in a randomized, double-blind, crossover manner in healthy subjects. Subjects ingested 8 mg reboxetine or placebo 12 hours and 1 hour before testing. ECGs were measured for HR, brachial and finger blood pressure (BP), and muscle sympathetic nerve activity (MSNA). Sympathetic and parasympathetic baroreflex slopes were determined by use of incremental phenylephrine and nitroprusside infusions. The dose to reach BP changes of 12.5 mm Hg was significantly lower during NET inhibition (0.25 versus 0.64 μg · kg
−1
· min
−1
phenylephrine and 0.40 versus 1.10 μg · kg
−1
· min
−1
nitroprusside,
P
<0.01). Baroreflex control of HR was similar (16 ms/mm Hg with placebo versus 14 ms/mm Hg with reboxetine) but reset to higher BP values. MSNA and sympathetically mediated low-frequency BP oscillations were profoundly reduced at baseline and failed to increase sufficiently during nitroprusside infusion. Reboxetine attenuated BP and MSNA responses to cold pressor testing.

Conclusions—

NET inhibition profoundly and selectively reduces baroreflex control of sympathetic vasomotor tone and attenuates the responsiveness to sympathetic stimuli. The reduction in baroreflex buffering increases the sensitivity to vasoactive medications. Therefore, our findings represent a novel mechanism for drug interactions.
Nitric Oxide-Induced Decrease in Calcium Sensitivity of Resistance Arteries Is Attributable to Activation of the Myosin Light Chain Phosphatase and Antagonized by the RhoA/Rho Kinase Pathway
Authors: Bolz Steffen-Sebastian , Vogel Lukas , Sollinger Daniel , Derwand Roland , de Wit Cor , Loirand Gervaise , Pohl Ulrich
Published: June 2003

Background—

NO-induced dilations in resistance arteries (RAs) are not associated with decreases in vascular smooth muscle cell Ca
2+
. We tested whether a cGMP-dependent activation of the smooth muscle myosin light chain phosphatase (MLCP) resulting in a Ca
2+
desensitization of the contractile apparatus was the underlying mechanism and whether it could be antagonized by the RhoA pathway.

Methods and Results—

The Ca
2+
sensitivity of RA was assessed as the relation between changes in diameter and [Ca
2+
]
i
in depolarized RA (120 mol/L K
+
) exposed to stepwise increases in Ca
2+
ex
(0 to 3 mmol/L). Effects of 10 μmol/L sodium nitroprusside (SNP) on Ca
2+
sensitivity were determined before and after application of the soluble guanylate cyclase inhibitor ODQ (1 μmol/L) and the MLCP inhibitor calyculin A (120 nmol/L) and in presence of the RhoA-activating phospholipid sphingosine-1-phosphate (S1P, 12 nmol/L). SNP-induced dilations were also studied in controls and in RAs pretreated with the Rho kinase inhibitor Y27632 or transfected with a dominant-negative RhoA mutant (N19RhoA). Constrictions elicited by increasing Ca
2+
ex
were significantly attenuated by SNP, which, however, left associated increases in [Ca
2+
]
i
unaffected. This NO-induced attenuation was blocked by ODQ, calyculin A, and S1P. The S1P-induced translocation of RhoA indicating activation of the GTPase was not reversed by SNP. Inhibition of RhoA/Rho kinase by N19RhoA or Y27632 significantly augmented SNP-induced dilations.

Conclusions—

NO dilates RA by activating the MLCP in a cGMP-dependent manner, thereby reducing the apparent Ca
2+
sensitivity of the contractile apparatus. MLCP inactivation via the RhoA/Rho kinase pathway antagonizes this Ca
2+
-desensitizing effect that, in turn, can be restored using RhoA/Rho kinase inhibitors.
Intracoronary β-Irradiation With a Rhenium-188–Filled Balloon Catheter
Authors: Höher Martin , Wöhrle Jochen , Wohlfrom Markus , Kamenz Joachim , Nusser Thorsten , Grebe Olaf C. , Hanke Hartmut , Kochs Matthias , Reske Sven N. , Hombach Vinzenz , Kotzerke Jörg
Published: June 2003

Background—

Restenosis requiring reintervention is the main limitation of coronary angioplasty. Intracoronary irradiation reduces neointimal proliferation. We studied the efficacy of a self-centering liquid rhenium-188–filled balloon catheter for coronary β-brachytherapy.

Methods and Results—

After successful coronary angioplasty with or without stenting, 225 patients (71% de novo lesions) were randomly assigned to receive 22.5 Gy intravascular β-irradiation in 0.5-mm tissue depth (n=113) or to receive no additional intervention (n=112). Clinical and procedural data did not differ between the groups except a higher rate of stenting in the control group (63%) compared with the rhenium-188 group (45%,
P
<0.02). After 6 months of follow-up, late loss was significantly lower in the irradiated group compared with the control group, both of the target lesion (0.11±0.54 versus 0.69±0.81 mm,
P
<0.0001) and of the total segment (0.22±0.67 versus 0.70±0.82 mm,
P
<0.0001). This was also evident in the subgroup of patients with de novo lesions and independent from stenting. Binary restenosis rates were significantly lower at the target lesion (6.3% versus 27.5%,
P
<0.0001) and of the total segment (12.6% versus 28.6%,
P
<0.007) after rhenium-188 brachytherapy compared with the control group. Target vessel revascularization rate was significantly lower in the rhenium-188 (6.3%) compared with the control group (19.8%,
P
=0.006).

Conclusions—

Intracoronary β-brachytherapy with a rhenium-188 liquid-filled balloon is safe and efficiently reduces restenosis and revascularization rates after coronary angioplasty.
Functional Changes in Coronary Microcirculation After Valve Replacement in Patients With Aortic Stenosis
Authors: Rajappan Kim , Rimoldi Ornella E. , Camici Paolo G. , Bellenger Nicholas G. , Pennell Dudley J. , Sheridan Desmond J.
Published: June 2003

Background—

Increased extravascular compression and reduced diastolic perfusion time (DPT), rather than vascular remodeling, influence coronary microcirculatory dysfunction in aortic stenosis (AS). However, alterations after aortic valve replacement (AVR) remain unclear. The aim of the present study was to quantify changes in transmural perfusion and coronary vasodilator reserve (CVR), a measure of microcirculatory function, after AVR and determine the relative contribution of left ventricular mass (LVM) regression, change in aortic valve area (AVA), and DPT.

Methods and Results—

Twenty-two patients with AS were studied before and 1 year after AVR using echocardiography to measure AVA, cardiovascular magnetic resonance to assess LVM, and positron emission tomography to quantify resting and hyperemic myocardial blood flow (MBF) and CVR. Regression of LVM occurred in all patients (from 129±30 to 94±24 g/m
2
;
P
<0.0001), and there was a significant reduction in resting MBF and increase in CVR corrected for rate-pressure product after AVR, although these changes displayed marked heterogeneity. Regression of LVM was linearly related to change in resting total LV blood flow but not CVR. Increase in hyperemic MBF and CVR transmurally was directly related to the increase in AVA after AVR. A significant relationship existed between the change in hyperemic DPT (1.0±4.7 s/min [range, 6.8 to 9.6]) and change in transmural CVR (y=0.08x+0.18;
r
=0.44;
P
=0.04).

Conclusions—

Changes in coronary microcirculatory function in patients with AS after AVR are not directly dependent on regression of LVM. Reduced extravascular compression and increased DPT are proposed as the main mechanisms for improvement in MBF and CVR after AVR.
Phosphodiesterase Type 5 as a Target for the Treatment of Hypoxia-Induced Pulmonary Hypertension
Authors: Sebkhi A. , Strange Julian W. , Phillips Steven C. , Wharton John , Wilkins Martin R.
Published: June 2003

Background—

Phosphodiesterase type 5 (PDE5) is a novel therapeutic target for the treatment of pulmonary hypertension. This study examined the distribution of PDE5 in normal and hypoxic lung and the effect of chronic PDE5 inhibition with sildenafil, initiated before and during exposure to hypoxia, on pulmonary artery pressure (PAP) and structure.

Methods and Results—

Sprague-Dawley rats were exposed to hypoxia (10% O
2
) for up to 42 days. PAP, measured continuously by telemetry, increased gradually by 20 to 40 mm Hg, reaching a plateau between 10 and 14 days, and declined to normal levels on return to normoxia. PDE5 immunoreactivity was localized to smooth muscle cells in the medial layer of pulmonary arteries and veins in the normal lung and in distal muscularized arteries (<25 μm diameter) after hypoxia-induced pulmonary hypertension. Sildenafil (25 or 75 mg · kg
−1
· d
−1
) given before hypoxia produced marked dose-dependent inhibition in the rise of PAP (60% to 90% reduction;
P
<0.0001) and vascular muscularization (28.4±5.0% reduction;
P
<0.001). When begun after 14 days of hypoxia, sildenafil significantly reduced PAP (30% reduction;
P
<0.0001) and partially reversed pulmonary artery muscularization (39.9±4.9% reduction;
P
<0.001).

Conclusions—

PDE5 is found throughout the muscularized pulmonary vascular tree, including in newly muscularized distal pulmonary arteries exposed to hypoxia. PDE5 inhibition attenuates the rise in PAP and vascular remodeling when given before chronic exposure to hypoxia and when administered as a treatment during ongoing hypoxia-induced pulmonary hypertension.
Detection of TIMI-3 Flow Before Mechanical Reperfusion With Ultrasonic Tissue Characterization in Patients With Anterior Wall Acute Myocardial Infarction
Authors: Iwakura Katsuomi , Ito Hiroshi , Kawano Shigeo , Okamura Atsushi , Asano Katsuaki , Kuroda Tadashi , Tanaka Koji , Masuyama Tohru , Hori Masatsugu , Fujii Kenshi
Published: June 2003

Background—

Spontaneous coronary reperfusion with TIMI-3 flow is associated with favorable clinical outcomes in patients with acute myocardial infarction (AMI). We investigated the ability of analyzing cardiac cycle-dependent variation of myocardial integrated backscatter (IBS) for predicting spontaneous reperfusion in anterior AMI.

Methods and Results—

We recorded IBS images on admission in 104 patients with first anterior wall AMI and subsequently performed coronary angiography and coronary intervention. We measured the cyclic variation of IBS within the infarct zone and expressed its magnitude as phase-corrected magnitude (PCM) by giving positive and negative values when it showed synchronous and asynchronous contraction, respectively. Twenty-three patients showing TIMI-3 flow at the initial coronary angiography had smaller peak creatine kinase value than 57 patients with initial TIMI-0/1 flow (864±961 versus 2358±1757 IU/L;
P
=0.0002) and better percent wall thickening within risk area (36.1±15.1%) than those with TIMI-2 (16.7±12.8%,
P
<0.0001) or TIMI-0/1 (5.1±11.6,
P
<0.0001). The patients with initial TIMI-3 had higher PCM (2.7±1.3 dB) than those with TIMI-2 (−0.3±2.2 dB,
P
<0.0001) or those with TIMI-0/1 (−1.1±2.4 dB,
P
<0.0001). Using PCM=1.0 dB as the cutoff point, PCM detected TIMI-3 flow with 95.7% sensitivity and 90.1% specificity. Multivariable logistic regression analysis revealed that only PCM is an independent predictor for spontaneous reperfusion among the hemodynamic, echocardiographic, and electrocardiographic variables.

Conclusions—

Analysis of myocardial IBS could detect spontaneous reperfusion noninvasively in the emergent stage of anterior AMI.
Relationship of Activated Partial Thromboplastin Time to Coronary Events and Bleeding in Patients With Acute Coronary Syndromes Who Receive Heparin
Authors: Anand Sonia S. , Yusuf Salim , Pogue Janice , Ginsberg Jeffrey S. , Hirsh Jack
Published: June 2003

Background—

Antithrombotic therapy with intravenous heparin in conjunction with aspirin reduces negative cardiovascular (CV) outcomes in patients with acute coronary syndromes. The need for a therapeutic range with the activated partial thromboplastin time (APTT) has not been validated in patients with arterial thrombosis who receive heparin. Therefore, it is unclear whether there is an association between recurrent CV events and low APTT values and between bleeding and high APTT values.

Methods and Results—

We examined the relationship between the APTT and recurrent cardiovascular events and bleeding among 5058 patients with an acute coronary syndrome without ST elevation who received intravenous heparin in the OASIS-2 trial. The increase in relative risk of recurrent CV events was 1.54 (95% CI 1.10 to 2.15;
P
=0.01) among patients with APTT values <60 seconds compared with patients with APTT values ≥60 seconds. When patients had persistently subtherapeutic APTT values for more than 48 hours, the increase in relative risk of a recurrent CV event was 1.84 (95% CI 1.25 to 2.70). Higher APTT values were associated with bleeding; for every 10-second increase in the APTT, the probability of major bleeding was increased by 7% (95% CI 3% to 11%;
P
=0.0004).

Conclusions—

In patients with acute coronary syndromes without ST elevation who are treated with intravenous heparin, our findings justify regular APTT monitoring to minimize recurrent ischemic events and bleeding.
Prognostic Value of Plasma von Willebrand Factor and Soluble P-Selectin as Indices of Endothelial Damage and Platelet Activation in 994 Patients With Nonvalvular Atrial Fibrillation
Authors: Conway Dwayne S.G. , Pearce Lesly A. , Chin Bernard S.P. , Hart Robert G. , Lip Gregory Y.H.
Published: June 2003

Background—

Abnormal plasma markers of a prothrombotic state have been described in atrial fibrillation (AF), but no such marker has yet been shown to reliably predict future stroke or cardiovascular outcome in AF. We hypothesized that raised plasma levels of von Willebrand factor (vWf, an index of endothelial damage/dysfunction) and/or soluble P-selectin (sP-sel, an index of platelet activation) might predict vascular events in AF.

Methods and Results—

We measured vWf and sP-sel levels by ELISA in 994 participants receiving aspirin in the Stroke Prevention in Atrial Fibrillation III trial, at study entry or after 3 months, and related these indices to the subsequent incidence of stroke and vascular events. Plasma vWf levels were a significant predictor of both stroke (
P
=0.03) and vascular events (
P
<0.001), with the greatest risk for those with the highest levels of vWf. After adjustment for other clinical predictors, the relationship between vWf and stroke became nonsignificant, but vWf remained an independent predictor of vascular events (relative risk, 1.2 [95% CI, 1.0–1.4] per 20 IU/dL increase in vWf;
P
=0.02). No significant relationships were found between sP-sel levels and outcome.

Conclusion—

Among patients with AF who received aspirin, raised levels of vWf (endothelial damage/dysfunction) were predictive of stroke and vascular events, but raised sP-sel levels (platelet activation) were not associated with increased cardiovascular risk. Endothelial damage/dysfunction (or vWf itself) may play an important role in the mechanisms behind stroke and cardiovascular outcome among aspirin-treated AF patients and might represent a target for novel therapies or an adjunctive aid to risk stratification in AF.
Randomized, Double-Blind, Placebo-Controlled, Pilot Trial of Infliximab, a Chimeric Monoclonal Antibody to Tumor Necrosis Factor-α, in Patients With Moderate-to-Severe Heart Failure
Authors: Chung Eugene S. , Packer Milton , Lo Kim Hung , Fasanmade Adedigbo A. , Willerson James T.
Published: June 2003

Background–

Preclinical and preliminary clinical data have suggested that tumor necrosis factor-α (TNFα) may play a role in the evolution and progression of heart failure and that inhibition of TNFα may favorably modify the course of the disease. We evaluated the efficacy and safety of infliximab, a chimeric monoclonal antibody to TNFα, in patients with moderate-to-severe heart failure.

Methods and Results–

One hundred fifty patients with stable New York Heart Association class III or IV heart failure and left ventricular ejection fraction ≤35% were randomly assigned to receive placebo (n=49), infliximab 5 mg/kg (n=50), or infliximab 10 mg/kg (n=51) at 0, 2, and 6 weeks after randomization and were followed-up prospectively for 28 weeks. Neither dose of infliximab improved clinical status at 14 weeks, the primary endpoint of the study, despite suppression of inflammatory markers (C-reactive protein and interleukin-6) and a modest increase in ejection fraction in the patients receiving 5 mg/kg (
P
=0.013). Furthermore, after 28 weeks, 13, 10, and 20 patients were hospitalized for any reason in the placebo, 5 mg/kg infliximab, and 10 mg/kg infliximab groups, respectively. The combined risk of death from any cause or hospitalization for heart failure through 28 weeks was increased in the patients randomized to 10 mg/kg infliximab (hazard ratio 2.84, 95% confidence interval 1.01 to 7.97; nominal
P
=0.043).

Conclusions–

Short-term TNFα antagonism with infliximab did not improve and high doses (10 mg/kg) adversely affected the clinical condition of patients with moderate-to-severe chronic heart failure.
Antibody Response to Chlamydial Heat Shock Protein 60 Is Strongly Associated With Acute Coronary Syndromes
Authors: Biasucci Luigi M. , Liuzzo Giovanna , Ciervo Alessandra , Petrucca Andrea , Piro Maddalena , Angiolillo Dominick J. , Crea Filippo , Cassone Antonio , Maseri Attilio
Published: June 2003

Background—

Heat shock proteins (HSPs) are a family of proteins with immunogenic and proinflammatory properties. Human and
Chlamydia pneumoniae
(Cp) HSP60 were found in patients with stable coronary disease.

Methods and Results—

We measured the levels of anti–Cp-HSP60 and anti-Cp immunoglobulin G (IgG) in 179 patients with unstable angina, 40 with acute myocardial infarction, and 40 with stable angina (SA), as well as 100 control subjects. Forty-one patients with acute coronary syndromes (ACS) were also studied at follow-up. We also measured plasma levels of high-sensitivity C-reactive protein (hs-CRP) and troponin T (TnT). Seropositivity to Cp-HSP60 was found in 99% of ACS patients but in only 20% of SA patients and none of the control subjects. Seropositivity to Cp was detected in 67% of ACS patients, 60% of SA patients, and 30% of the control subjects. No differences in Cp-HSP60 IgG and in Cp IgG were observed between patients with myocardial infarction and patients with unstable angina. No correlation was found between Cp-HSP60 IgG, TnT, and hs-CRP or between IgG against Cp and hs-CRP. In ACS patients at follow-up, Cp-HSP60 IgG decreased from 0.88±0.25 to 0.45±0.14 arbitrary units (
P
<0.0001), becoming negative in 12 patients
.

Conclusions—

Seropositivity for Cp-HSP60 appears to be a very sensitive and specific marker of ACS, unrelated to Cp IgG antibody titers or hs-CRP and TnT levels. Its causal involvement in instability and its diagnostic role in ACS deserve further study.
Blockade of the Renin-Angiotensin System Increases Adiponectin Concentrations in Patients With Essential Hypertension
Authors: Furuhashi Masato , Ura Nobuyuki , Higashiura Katsuhiro , Murakami Hideyuki , Tanaka Marenao , Moniwa Norihito , Yoshida Daisuke , Shimamoto Kazuaki
Published: June 2003

Adiponectin, an adipocyte-derived protein, has been suggested to play an important role in insulin sensitivity. We examined the association between insulin sensitivity (M value) evaluated by the euglycemic-hyperinsulinemic glucose clamp and adiponectin concentrations in 30 essential hypertensives (EHT) and 20 normotensives (NT) and investigated the effect of blockade of the renin-angiotensin system (RAS) on adiponectin concentrations. EHT were divided into 12 insulin-resistant EHT (EHT-R) and 18 non–insulin-resistant EHT (EHT-N) using mean−1 SD of the M value in NT. There were no intergroup differences in age, gender, and body mass index (BMI). EHT-R had significantly higher levels of insulin and triglyceride and lower levels of adiponectin than did NT and EHT-N. EHT-R had higher levels of free fatty acid and lower levels of high-density lipoprotein (HDL) cholesterol than did EHT-N. Adiponectin concentrations were positively correlated with M value and HDL cholesterol and negatively correlated with BMI, insulin, free fatty acid, and triglyceride but not with blood pressure. M value, BMI, and HDL cholesterol were independent determinants of adiponectin concentrations in multiple and stepwise regression analyses. Sixteen EHT were treated with an angiotensin-converting enzyme inhibitor (temocapril, 4 mg/d; n=9) or an angiotensin II receptor blocker (candesartan, 8 mg/d; n=7) for 2 weeks. Treatment with temocapril or candesartan significantly decreased blood pressure and increased M value and adiponectin concentrations but did not affect BMI and HDL cholesterol. These results suggest that hypoadiponectinemia is related to insulin resistance in essential hypertension and that RAS blockade increases adiponectin concentrations with improvement in insulin sensitivity.
Middle Age Cardiovascular Risk Factors and Abdominal Aortic Aneurysm in Older Age
Authors: Rodin Miriam B. , Daviglus Martha L. , Wong Gordon C. , Liu Kiang , Garside Daniel B. , Greenland Philip , Stamler Jeremiah
Published: June 2003

Few prospective studies have examined associations between major cardiovascular risk factors and occurrence of abdominal aortic aneurysm; findings from cross-sectional studies are inconsistent. This long-term population-based study assessed relationships of major risk factors in middle-age to clinical nonfatal plus fatal abdominal aortic aneurysm in older-age in the Chicago Heart Association Detection Project in Industry cohort—10 574 men and 8700 women baseline ages 40 to 64 years screened for risk factors in 1967–1973 at workplaces. With average follow-up of 30 years and clinical cases identified from Medicare records and death certificates, risk factor relationships to abdominal aortic aneurysm occurrence were assessed by Cox regression. There were among men 309 cases and among women, 109—most from Medicare records. Most findings were qualitatively similar for men and women. In multivariate analyses (5 models), hazard ratios for abdominal aortic aneurysm were significantly greater for men than women (≥1.97), with older age (≥1.63/5 years), higher serum cholesterol (≥1.30/40.0 mg/dL), cigarettes/d (≥2.43/20 cigarettes), past smoking (≥1.41), height (≥1.17/7 cm), evidence of adverse blood pressure (hazard ratio 1.10/20 mm Hg higher systolic pressure, 1.12 to 1.14/12 mm Hg higher diastolic pressure, 1.87 with history of treated hypertension). It is concluded that major cardiovascular risk factors—serum cholesterol, smoking, and blood pressure—in middle age relate significantly to risk of abdominal aortic aneurysm in persons surviving into older age.
Primary Aldosteronism and Hypertensive Disease
Authors: Mosso Lorena , Carvajal Cristian , González Alexis , Barraza Adolfo , Avila Fernando , Montero Joaquín , Huete Alvaro , Gederlini Alessandra , Fardella Carlos E.
Published: June 2003

Recent studies in hypertensive populations that have used the serum aldosterone (SA) to plasma renin activity (PRA) ratio as a screening test have demonstrated a high prevalence of primary aldosteronism (PA). This frequency is higher than that previously described when hypokalemia was used as a screening tool. However, other factors, such as the characteristics of hypertensive disease, could also influence the prevalence of PA. We studied 609 essential hypertensive patients, classified according to the Joint National Committee VI (JNC VI), in 3 different stages depending on the severity of their hypertensive disease. We measured SA and PRA and calculated the SA-PRA ratio for all patients. An SA-PRA ratio >25 was detected in 63 of 609 patients, and the fludrocortisone test confirmed the PA diagnoses in 37 of 609 (6.1%) cases. PA prevalence according to hypertension stage was as follows: stage 1, 6 of 301 cases (1.99%); stage 2, 15 of 187 cases (8.02%); and stage 3, 16 of 121 cases (13.2%). PA patients were slightly younger than the other hypertensive patients (48.4±10.5 vs 53.6±10.2 years;
P
<0.05). Serum potassium levels were normal in 36 of 37 PA patients; only 1 patient had minor hypokalemia. Computed tomography scans showed bilateral adrenal enlargement in 7 and an adrenal nodule in 2 cases. In summary, we found a high frequency of PA in essential hypertensives classified in stages 2 and 3 according to the JNC VI. The low frequency of computed tomography scan abnormalities and hypokalemia suggests that the diagnosis for most PA patients corresponds to attenuated forms of the disease.
T-Tubule Function in Mammalian Cardiac Myocytes
Authors: Brette Fabien , Orchard Clive
Published: June 2003

The transverse tubules (t-tubules) of mammalian cardiac ventricular myocytes are invaginations of the surface membrane. Recent studies have suggested that the structure and function of the t-tubules are more complex than previously believed; in particular, many of the proteins involved in cellular Ca
2+
cycling appear to be concentrated at the t-tubule. Thus, the t-tubules are an important determinant of cardiac cell function, especially as the main site of excitation-contraction coupling, ensuring spatially and temporally synchronous Ca
2+
release throughout the cell. Changes in t-tubule structure and protein expression occur during development and in heart failure, so that changes in the t-tubules may contribute to the functional changes observed in these conditions. The purpose of this review is to provide an overview of recent studies of t-tubule structure and function in cardiac myocytes.
Inducible cAMP Early Repressor (ICER) Is a Negative-Feedback Regulator of Cardiac Hypertrophy and an Important Mediator of Cardiac Myocyte Apoptosis in Response to β-Adrenergic Receptor Stimulation
Authors: Tomita Hideharu , Nazmy Michael , Kajimoto Katsuya , Yehia Ghassan , Molina Carlos A. , Sadoshima Junichi
Published: June 2003

Although stimulation of the β-adrenergic receptor increases levels of cAMP and activation of the cAMP response element (CRE) in cardiac myocytes, the role of the signaling mechanism regulated by cAMP in hypertrophy and apoptosis is not well understood. In this study we show that protein expression of inducible cAMP early repressor (ICER), an endogenous inhibitor of CRE-mediated transcription, is induced by stimulation of isoproterenol (ISO), a β-adrenergic agonist with a peak at ≈12 hours and persisting for more than 24 hours in neonatal rat cardiac myocytes. ICER is also upregulated by phenylephrine but not by endothelin-1. Continuous infusion of ISO also increased ICER in the rat heart in vivo. Overexpression of ICER significantly attenuated ISO- and phenylephrine-induced cardiac hypertrophy but did not inhibit endothelin-1–induced cardiac hypertrophy. Overexpression of ICER also stimulated cardiac myocyte apoptosis. Antisense inhibition of ICER significantly enhanced β-adrenergic hypertrophy, whereas it significantly inhibited β-adrenergic cardiac myocyte apoptosis, suggesting that endogenous ICER works as an important regulator of cardiac hypertrophy and apoptosis. Inhibition of CRE-mediated transcription by dominant-negative CRE binding protein inhibited cardiac hypertrophy, whereas it stimulated cardiac myocyte apoptosis, thereby mimicking the effect of ICER. Both ISO and ICER reduced expression of Bcl-2, an antiapoptotic molecule, whereas antisense ICER prevented ISO-induced downregulation of Bcl-2. These results suggest that ICER is upregulated by cardiac hypertrophic stimuli increasing CRE-mediated transcription in cardiac myocytes and acts as a negative regulator of hypertrophy and a positive mediator of apoptosis, in part through both inhibition of CRE-mediated transcription and downregulation of Bcl-2.
Rho/Rho-Kinase Pathway in Brain Stem Contributes to Blood Pressure Regulation via Sympathetic Nervous System
Authors: Ito Koji , Hirooka Yoshitaka , Sakai Koji , Kishi Takuya , Kaibuchi Kozo , Shimokawa Hiroaki , Takeshita Akira
Published: June 2003

Recent studies have demonstrated that the Rho/Rho-kinase pathway plays an important role in various cellular functions, including actin cytoskeleton organization and vascular smooth muscle contraction. This pathway is also present in the central nervous system and is involved in the maintenance of dendritic spines and axon outgrowth and in the regulation of neurotransmitter release. However, its role in central blood pressure regulation is unknown. In the present study, blockade of the Rho/Rho-kinase pathway in the nucleus tractus solitarii (NTS) of the brain stem by microinjection of a specific Rho-kinase inhibitor decreased blood pressure, heart rate, and renal sympathetic nerve activity in both Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). However, the magnitude of decreases in these variables was greater in SHR than in WKY rats. In addition, an adenovirus vector encoding dominant-negative Rho-kinase decreased blood pressure, heart rate, and urinary norepinephrine excretion in both WKY rats and SHR in an awake and free-moving state. The magnitude of decreases in these variables was also greater in SHR than in WKY rats. Furthermore, membrane RhoA expression and Rho-kinase activity in the NTS were enhanced in SHR compared with WKY rats. These observations indicate that the Rho/Rho-kinase pathway in the NTS contributes to blood pressure regulation via the sympathetic nervous system in vivo and suggest that activation of this pathway is involved in the central mechanisms of hypertension.
Human Embryonic Stem Cells Develop Into Multiple Types of Cardiac Myocytes
Authors: He Jia-Qiang , Ma Yue , Lee Youngsook , Thomson James A. , Kamp Timothy J.
Published: June 2003

Human embryonic stem (hES) cells can differentiate in vitro, forming embryoid bodies (EBs) composed of derivatives of all three embryonic germ layers. Spontaneously contracting outgrowths from these EBs contain cardiomyocytes (CMs); however, the types of human CMs and their functional properties are unknown. This study characterizes the contractions and action potentials (APs) from beating EB outgrowths cultured for 40 to 95 days. Spontaneous and electrical field-stimulated contractions were measured with video edge-detection microscopy. β-Adrenergic stimulation with 1.0 μmol/L isoproterenol resulted in a significant increase in contraction magnitude. Intracellular electrical recordings using sharp KCl microelectrodes in beating EB outgrowths revealed three distinct classes of APs: nodal-like, embryonic atrial-like, and embryonic ventricular-like. The APs were described as embryonic based on the relatively depolarized resting membrane potential and slow AP upstroke. Repeated impalements of an individual beating outgrowth revealed a reproducible AP morphology recorded from different cells, suggesting that each outgrowth is composed of a predominant cell type. Complex functional properties typical of cardiac muscle were observed in the hES cell-derived CMs including rate adaptation of AP duration and provoked early and delayed afterdepolarizations. Repolarization of the AP showed a significant role for
I
Kr
based on E-4031 induced prolongation of AP duration as anticipated for human CMs. In conclusion, hES cells can differentiate into multiple types of CMs displaying functional properties characteristic of embryonic human cardiac muscle. Thus, hES provide a renewable source of distinct types of human cardiac myocytes for basic research, pharmacological testing, and potentially therapeutic applications.