bluuebunny/crossref_metadata_2025 huggingface dataset:
Partial Agonist Activity of Bucindolol Is Dependent on the Activation State of the Human β
1
-Adrenergic Receptor
Authors: Maack Christoph , Böhm Michael , Vlaskin Lydia , Dabew Ewtim , Lorenz Kristina , Schäfers Hans-Joachim , Lohse Martin J. , Engelhardt Stefan
Published: July 2003

Background—

In contrast to other β-blockers, bucindolol has failed to reduce mortality in patients with chronic heart failure. It is currently debated whether this is due to partial agonist activity of this agent. We investigated whether conflicting results previously reported concerning the intrinsic activity of bucindolol can be explained by species differences or by different activation states of β-adrenergic receptors (β-ARs) in the respective tissues.

Methods and Results—

On isolated right atria from transgenic mice with cardiac overexpression of human β
1
-ARs, bucindolol led to a greater increase in beating frequency (
P
<0.05) compared with wild-type mice. The increase amounted to 47% of the effect of xamoterol and was blocked by propranolol. On isolated, electrically stimulated, left ventricular muscle-strip preparations from failing human myocardium, bucindolol did not change the force of contraction under control conditions. In myocardial preparations pretreated with metoprolol (30 μmol/L, 90 minutes, subsequent washout), bucindolol significantly increased the force of contraction (
P
<0.001 vs control). In nonfailing atrial myocardium, isoproterenol pretreatment (1 μmol/L, 60 minutes) abolished the positive inotropic effect of xamoterol that was present under control conditions (
P
<0.05 vs control). The inotropic effects of bucindolol or xamoterol were inversely correlated to the inotropic response to forskolin in the respective specimens (
r
=−0.75 and −0.74, respectively;
P
<0.005).

Conclusions—

We conclude that bucindolol is a partial agonist at the human β
1
-AR. In human failing myocardium, its partial agonist activity is masked by increased activation states of β-ARs and is unmasked after in vitro pretreatment with metoprolol. Thus, the partial agonist activity of bucindolol is dependent on the activation state of the human β
1
-AR.
Efficacy and Safety of Tenecteplase in Combination With the Low-Molecular-Weight Heparin Enoxaparin or Unfractionated Heparin in the Prehospital Setting
Authors: Wallentin L. , Goldstein P. , Armstrong P.W. , Granger C.B. , Adgey A.A.J. , Arntz H.R. , Bogaerts K. , Danays T. , Lindahl B. , Mäkijärvi M. , Verheugt F. , Van de Werf F.
Published: July 2003

Background—

The combination of a single-bolus fibrinolytic and a low-molecular-weight heparin may facilitate prehospital reperfusion and further improve clinical outcome in patients with ST-elevation myocardial infarction.

Methods and Results—

In the prehospital setting, 1639 patients with ST-elevation myocardial infarction were randomly assigned to treatment with tenecteplase and either (1) intravenous bolus of 30 mg enoxaparin (ENOX) followed by 1 mg/kg subcutaneously BID for a maximum of 7 days or (2) weight-adjusted unfractionated heparin (UFH) for 48 hours. The median treatment delay was 115 minutes after symptom onset (53% within 2 hours). ENOX tended to reduce the composite of 30-day mortality or in-hospital reinfarction, or in-hospital refractory ischemia to 14.2% versus 17.4% for UFH (
P
=0.080), although there was no difference for this composite end point plus in-hospital intracranial hemorrhage or major bleeding (18.3% versus 20.3%,
P
=0.30). Correspondingly, there were reductions in in-hospital reinfarction (3.5% versus 5.8%,
P
=0.028) and refractory ischemia (4.4% versus 6.5%,
P
=0.067) but increases in total stroke (2.9% versus 1.3%,
P
=0.026) and intracranial hemorrhage (2.20% versus 0.97%,
P
=0.047). The increase in intracranial hemorrhage was seen in patients >75 years of age.

Conclusions—

Prehospital fibrinolysis allows 53% of patients to receive reperfusion treatment within 2 hours after symptom onset. The combination of tenecteplase with ENOX reduces early ischemic events, but lower doses of ENOX need to be tested in elderly patients. At present, therefore, tenecteplase and UFH are recommended as the routine pharmacological reperfusion treatment in the prehospital setting.
Relation Between Cardiac Sympathetic Activity and Hypertensive Left Ventricular Hypertrophy
Authors: Schlaich Markus P. , Kaye David M. , Lambert Elisabeth , Sommerville Marcus , Socratous Flora , Esler Murray D.
Published: July 2003

Background—

Left ventricular (LV) hypertrophy is an independent risk factor for cardiovascular morbidity and mortality in hypertensive subjects. Sympathetic activation has been suggested to contribute to LV hypertrophy, but this has not yet been conclusively validated in humans.

Methods and Results—

We comprehensively assessed total systemic and regional sympathetic activity by radiotracer dilution methods and microneurography in 15 untreated hypertensive subjects with echocardiographic evidence of LV hypertrophy (EH+), 11 hypertensive subjects with similar blood pressure but without LV hypertrophy (EH−), and 10 age-matched normotensive control subjects (NT). LV mass index was 87±15 g/m
2
in NT, 106±11g/m
2
in EH−, and 138±17g/m
2
in EH+ (
P
<0.001). Total body and renal norepinephrine spillover were higher in both hypertensive groups compared with NT (total norepinephrine spillover, NT 223±145 versus EH− 418±135 versus EH+ 497±303 ng/min; renal norepinephrine spillover, NT 38.8±25.3 versus EH− 88.6±58.0 versus EH+ 103.4±56.2 ng/min; both
P
<0.05). However, muscle sympathetic nerve activity (NT 25±6 versus EH− 38±20 versus EH+ 57±19 bursts per 100 heartbeats;
P
<0.01) and cardiac norepinephrine spillover (NT 11.7±6.2 versus EH− 13.1±7.2 versus EH+ 28.6±17.4 ng/min;
P
<0.01) were only increased in EH+. Cardiac norepinephrine spillover correlated positively with LV mass index in all subjects (
r
=0.52;
P
<0.001).

Conclusions—

Our findings demonstrate that hypertensive LV hypertrophy is associated with increased sympathetic activity largely confined to the heart, suggesting that increased cardiac norepinephrine release is related to the development of LV hypertrophy.
Coronary Artery Disease Risk in Familial Combined Hyperlipidemia and Familial Hypertriglyceridemia
Authors: Hopkins Paul N. , Heiss Gerardo , Ellison R. Curtis , Province Michael A. , Pankow James S. , Eckfeldt John H. , Hunt Steven C.
Published: July 2003

Background—

Conventional wisdom suggests that a diagnosis of familial combined hyperlipidemia (FCHL) carries a substantially greater risk of premature coronary artery disease (CAD) than a diagnosis of familial hypertriglyceridemia (FHTG). However, no population-based studies have critically addressed this issue.

Methods and Results—

FCHL and FHTG were diagnosed in 10.2% and 12.3% of 334 random control families and in 16.7% and 20.5% of 293 families with at least one case of premature CAD. The diagnosis of either FCHL or FHTG in an individual was associated with an odds ratio for CAD of 2.0 (
P
=0.003 and 0.002, respectively). However, odds ratios for premature CAD associated with both lipid disorders decreased substantially and identically with further adjustment for hypertension, diabetes, and especially HDL cholesterol, triglycerides, or apolipoprotein B. Similar results were found for differences in carotid intima-medial thickness and ankle-brachial index. Metabolic syndrome was identified in 65% of FCHL and 71% of FHTG patients compared with 19% in controls without FCHL or FHTG and was associated with an odds ratio of 3.3 (
P
<0.0001). The increased prevalence of the metabolic syndrome alone could account for the elevated CAD risk associated with both FCHL and FHTG.

Conclusions—

FCHL and FHTG appear more alike than dissimilar. Further, the risk of CAD in FCHL and FHTG was strongly related to features of the metabolic syndrome. These findings suggest that the hypertriglyceridemia in FHTG is not benign and may warrant a change in epidemiological, genetic, and clinical approaches to these lipid disorders.
Different Cell Cycle Regulation of Vascular Smooth Muscle in Genetic Hypertension
Authors: Tanner Felix C. , Greutert Helen , Barandier Christine , Frischknecht Karin , Lüscher Thomas F.
Published: July 2003

Vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) proliferate faster than those from Wistar-Kyoto rats (WKY). Therefore regulation of cell cycle progression was examined in VSMC from both strains. Analysis of G1 progression was performed in VSMC synchronized by serum starvation. Double staining for propidium iodide and bromodeoxyuridine revealed that G1 progression was faster in SHR as compared with WKY. Indeed, 59±6% of VSMC from SHR but only 14±10% of those from WKY had left G1 phase after 24 hours of mitogenic stimulation. Moreover, 15±2% of SHR cells had already completed the cycle at this time point. Western blot analysis demonstrated that the level of cyclin D, cyclin E, and cyclin A was higher in SHR cells progressing through G1 phase, whereas expression of cyclin-dependent kinase 2 as well as the cyclin-dependent kinase inhibitors p21 and p27 were similar in the two groups. Consistent with a higher level of cyclins, the activity of cyclin-dependent kinase 2 was more pronounced in SHR cells. Analysis of G2 progression was performed in VSMC synchronized by treatment with aphidicolin and revealed an additional difference in cell cycle regulation between SHR and WKY. Indeed, the level of cell division cycle kinase 2 was higher in cells from SHR, whereas that of its catalytic partner cyclin B was similar. Consistent with this pattern of expression, the activity of cell division cycle kinase 2 was more pronounced in VSMC from SHR as compared with WKY. Thus, these data demonstrate that the different proliferation of VSMC from SHR and WKY is related to a different progression in G1 phase as the result of the expression of cyclin D, cyclin A, and cyclin E as well as a different progression in G2 phase caused by expression of cell division cycle kinase 2.
AT
1
Blockade Prevents Glucose-Induced Cardiac Dysfunction in Ventricular Myocytes
Authors: Privratsky Jamie R. , Wold Loren E. , Sowers James R. , Quinn Mark T. , Ren Jun
Published: July 2003

Enhanced tissue angiotensin (Ang) II levels have been reported in diabetes and might lead to cardiac dysfunction through oxidative stress. This study examined the effect of blocking the Ang II type 1 (AT
1
) receptor on high glucose–induced cardiac contractile dysfunction. Rat ventricular myocytes were maintained in normal- (NG, 5.5 mmol/L) or high- (HG, 25.5 mmol/L) glucose medium for 24 hours. Mechanical and intracellular Ca
2+
properties were assessed as peak shortening (PS), time to PS (TPS), time to 90% relengthening (TR
90
), maximal velocity of shortening/relengthening (±
dL
/
dt
), and intracellular Ca
2+
decay (τ). HG myocytes exhibited normal PS; decreased ±
dL
/
dt
; and prolonged TPS, TR
90
, and τ. Interestingly, the HG-induced abnormalities were prevented with the AT
1
blocker L-158,809 (10 to 1000 nmol/L) but not the Janus kinase-2 (JAK2) inhibitor AG-490 (10 to 100 μmol/L). The only effect of AT
1
blockade on NG myocytes was enhanced PS at 1000 nmol/L. AT
1
antagonist-elicited cardiac protection against HG was nullified by the NADPH oxidase activator sodium dodecyl sulfate (80 μmol/L) and mimicked by the NADPH oxidase inhibitors diphenyleneiodonium (10 μmol/L) or apocynin (100 μmol/L). Western blot analysis confirmed that the protein abundance of NADPH oxidase subunit p47
phox
and the AT
1
but not the AT
2
receptor was enhanced in HG myocytes. In addition, the HG-induced increase of p47
phox
was prevented by L-158,809. Enhanced reactive oxygen species production observed in HG myocytes was prevented by AT
1
blockade or NADPH oxidase inhibition. Collectively, our data suggest that local Ang II, acting via AT
1
receptor–mediated NADPH oxidase activation, is involved in hyperglycemia-induced cardiomyocyte dysfunction, which might play a role in diabetic cardiomyopathy.
Adenovirus-Mediated Overexpression of Caveolin-3 Inhibits Rat Cardiomyocyte Hypertrophy
Authors: Koga Akimasa , Oka Naoki , Kikuchi Toshio , Miyazaki Hiroshi , Kato Seiya , Imaizumi Tsutomu
Published: July 2003

Caveolae are omega-shaped organelles of the cell surface. The protein caveolin-3, a structural component of cardiac caveolae, is associated with cellular signaling. To investigate the effect of adenovirus-mediated overexpression of caveolin-3 on hypertrophic responses in cardiomyocytes, we constructed an adenovirus that encoded human wild-type caveolin-3 (Ad.Cav-3), mutant caveolin-3 (Ad.Cav-3Δ), or bacterial β-galactosidase (Ad.LacZ). This mutant has been reported to cause human limb-girdle muscular dystrophy. It lacks 9 nucleotides in the caveolin scaffolding domain and behaves in a dominant-negative fashion. Rat neonatal cardiomyocytes were infected with the virus and then harvested 36 hours after infection. In noninfected cells, phenylephrine (PE) and endothelin-1 (ET) increased cell size and [
3
H]leucine incorporation, along with the induction of sarcomeric reorganization and the reexpression of β-myosin heavy chain, indicating myocyte hypertrophy. Infection with Ad.LacZ had no effect on those parameters. Ad.Cav-3 prevented the PE- and ET-induced increases in cell size, leucine incorporation, sarcomeric reorganization, and reexpression of β-myosin heavy chain. Ad.Cav-3 also blocked the PE- and ET-induced phosphorylations of extracellular signal-regulated kinases (ERKs) but did not affect
c
-Jun amino-terminal kinase and p38 mitogen-activated protein kinase activities. In contrast, Ad.Cav-3Δ significantly augmented hypertrophic responses to ET, which were associated with increased ET-induced phosphorylation of ERK1/2. These results suggest that caveolin-3 behaves as a negative regulator of hypertrophic responses, probably through suppression of ERK1/2 activity.
Disparate Roles of AT
2
Receptors in the Renal Cortical and Medullary Circulations of Anesthetized Rabbits
Authors: Duke Lisa M. , Eppel Gabriela A. , Widdop Robert E. , Evans Roger G.
Published: July 2003

The contributions of angiotensin II type 1 (AT
1
) and type 2 (AT
2
) receptors to the control of regional kidney blood flow were determined in pentobarbital-anesthetized rabbits. Intravenous candesartan (AT
1
antagonist; 10 μg/kg plus 10 μg · kg
−1
· h
−1
) reduced mean arterial pressure (12%) and increased total renal blood flow (29%) and cortical laser-Doppler flux (18%) but not medullary laser-Doppler flux. Neither intravenous PD123319 (AT
2
antagonist; 1 mg/kg plus 1 mg · kg
−1
· h
−1
) nor saline vehicle significantly affected these variables, and the responses to candesartan plus PD123319 were indistinguishable from those of candesartan alone. In vehicle-treated rabbits, renal-arterial infusions of angiotensin II (1 to 25 ng · kg
−1
· min
−1
) and angiotensin III (5 to 125 ng · kg
−1
· min
−1
) dose-dependently reduced renal blood flow (up to 51%) and cortical laser-Doppler flux (up to 50%) but did not significantly affect medullary laser-Doppler flux or arterial pressure. Angiotensin(1–7) (20 to 500 ng · kg
−1
· min
−1
) had similar effects but of lesser magnitude. CGP42112A (20 to 500 ng · kg
−1
· min
−1
) did not significantly affect these variables. After PD123319 administration, angiotensin II and angiotensin III dose-dependently increased medullary laser-Doppler flux (up to 84%), and reductions in renal blood flow in response to angiotensin II were enhanced. Candesartan abolished renal hemodynamic responses to the angiotensin peptides, even when given in combination with PD123319. We conclude that AT
2
receptor activation counteracts AT
1
-mediated vasoconstriction in the renal cortex but also counteracts AT
1
-mediated vasodilatation in vascular elements controlling medullary perfusion. These mechanisms might have an important effect on the control of medullary perfusion under conditions of activation of the renin-angiotensin system.
Cardioprotective Actions by a Water-Soluble Carbon Monoxide–Releasing Molecule
Authors: Clark James E. , Naughton Patrick , Shurey Sandra , Green Colin J. , Johnson Tony R. , Mann Brian E. , Foresti Roberta , Motterlini Roberto
Published: July 2003

Carbon monoxide, which is generated in mammals during the degradation of heme by the enzyme heme oxygenase, is an important signaling mediator. Transition metal carbonyls have been recently shown to function as carbon monoxide–releasing molecules (CO-RMs) and to elicit distinct pharmacological activities in biological systems. In the present study, we report that a water-soluble form of CO-RM promotes cardioprotection in vitro and in vivo. Specifically, we found that tricarbonylchloro(glycinato)ruthenium(II) (CORM-3) is stable in water at acidic pH but in physiological buffers rapidly liberates CO in solution. Cardiac cells pretreated with CORM-3 (10 to 50 μmol/L) become more resistant to the damage caused by hypoxia-reoxygenation and oxidative stress. In addition, isolated hearts reperfused in the presence of CORM-3 (10 μmol/L) after an ischemic event displayed a significant recovery in myocardial performance and a marked and significant reduction in cardiac muscle damage and infarct size. The cardioprotective effects mediated by CORM-3 in cardiac cells and isolated hearts were totally abolished by 5-hydroxydecanoic acid, an inhibitor of mitochondrial ATP-dependent potassium channels. Predictably, cardioprotection is lost when CORM-3 is replaced by an inactive form (iCORM-3) that is incapable of liberating CO. Using a model of cardiac allograft rejection in mice, we also found that treatment of recipients with CORM-3 but not iCORM-3 considerably prolonged the survival rate of transplanted hearts. These data corroborate the notion that transition metal carbonyls could be used as carriers to deliver CO and highlight the bioactivity and potential therapeutic features of CO-RMs in the mitigation of cardiac dysfunction. The full text of this article is available online at http://www.circresaha.org.
Direct Actions of Urotensin II on the Heart
Authors: Tzanidis Alex , Hannan Ross D. , Thomas Walter G. , Onan Döne , Autelitano Dominic J. , See Fiona , Kelly Darren J. , Gilbert Richard E. , Krum Henry
Published: July 2003

Urotensin II (UII) is a somatostatin-like peptide recently identified as a potent vasoconstrictor. In this study, we examined whether UII promotes cardiac remodeling through nonhemodynamic effects on the myocardium. In a rat model of heart failure after myocardial infarction (MI), increased UII peptide and UII receptor protein expression was observed in both infarct and noninfarct regions of the left ventricle compared with sham. Moreover, post-MI remodeling was associated with a significant 75% increase in UII receptor gene expression in the heart (
P
<0.05 versus sham controls), with this increase noted in both regions of the left ventricle. In vitro, UII (10
−7
mol/L) stimulation of neonatal cardiac fibroblasts increased the level of mRNA transcripts for procollagens α
1
(I), α
1
(III), and fibronectin by 139±15% (
P
<0.01), 59±5% (
P
<0.05), and 141±14% (
P
<0.01), respectively, with a concomitant 23±2% increase in collagen peptide synthesis as determined by
3
H-proline incorporation (
P
<0.01). UII had no effect on cellular hypertrophy, as determined by changes in total protein content in isolated neonatal cardiomyocytes. However, expression of recombinant rat UII receptor in neonatal cardiomyocytes resulted in significant UII-dependent activation of hypertrophic signaling as demonstrated by increased total protein content (unstimulated, 122.4±4.0 μg/well; rat UII, 147.6±7.0 μg/well;
P
<0.01) and activation of the hypertrophic phenotype through Gαq- and Ras-dependent pathways. These results indicate that, in addition to potent hemodynamic effects, UII may be implicated in myocardial fibrogenesis through increased collagen synthesis by cardiac fibroblasts and may also be an important determinant of pathological cardiac hypertrophy in conditions characterized by UII receptor upregulation.
Canine Ventricular KCNE2 Expression Resides Predominantly in Purkinje Fibers
Authors: Pourrier Marc , Zicha Stephen , Ehrlich Joachim , Han Wei , Nattel Stanley
Published: July 2003

Mutations in minK-related peptide 1 (MiRP1), the product of the
KCNE2
gene, have been associated with malignant ventricular arrhythmia syndromes related to impaired repolarization. MiRP1 interacts with a variety of ion-channel α-subunits, dysfunction of which could account for arrhythmia syndromes; however, the observation of very low-level expression of MiRP1 in ventricular tissue has led to doubts about its relevance. The specialized His-Purkinje system plays a key role in cardiac electrophysiology and is an important contributor to ventricular arrhythmias related to abnormal repolarization. We examined the relative abundance of MiRP1 in canine Purkinje versus ventricular tissue and found much greater expression at both mRNA and protein levels in Purkinje tissue. Thus, the cardiac Purkinje system is a strong candidate to play a role in arrhythmic syndromes due to MiRP1 abnormalities.
High Incidence of Cardiac Malformations in Connexin40-Deficient Mice
Authors: Gu Hong , Smith Frank C. , Taffet Steven M. , Delmar Mario
Published: July 2003

Gap junctions are intercellular channels formed by oligomerization of a protein called connexin (Cx). The heart expresses at least three connexin isotypes: Cx40, Cx43, and Cx45. A possible role for Cx40 in cardiac morphogenesis remains to be determined. We have characterized the anatomy and histology of fetal and newborn hearts obtained from crossing Cx40-deficient mice of mixed genetic background (C57BL/6×129Sv). Hearts were serial-sectioned (5 μm) along the coronal plane, stained with hematoxylin-eosin, and visualized by conventional light microscopy. Cardiac malformations in mice lacking Cx40 in one allele (Cx40
+/−
) included bifid atrial appendage, ventricular septal defect, tetralogy of Fallot (TOF), and an aortic arch abnormality. In Cx40
−/−
mice resulting from crossing of Cx40
+/−
mice, the most common cardiac malformations were double-outlet right ventricle (DORV), TOF, and endocardial cushion defects. Overall incidence of cardiac malformations was 6/33 (18%) in Cx40
+/−
mice and 4/12 (33%) in Cx40
−/−
mice. No cardiac malformations were observed in 15 wild-type mice studied. In addition, we examined 39 hearts from offspring of Cx40
−/−
matings. Frequency of cardiac malformations was even higher in this group (44%). Over one third of the hearts (14 of 39) showed conotruncal malformations corresponding to either DORV or TOF. Endocardial cushion defects were found in 3 out of 39 hearts. Our results suggest that Cx40 participates in cardiac morphogenesis, likely in association with other (unknown) products whose expression may vary with the genetic background of the mice.
Molecular and Functional Identification of Cyclic AMP-Sensitive BK
Ca
Potassium Channels (ZERO Variant) and L-Type Voltage-Dependent Calcium Channels in Single Rat Juxtaglomerular Cells
Authors: Friis Ulla G. , Jørgensen Finn , Andreasen Ditte , Jensen Boye L. , Skøtt Ole
Published: July 2003

This study aimed at identifying the type and functional significance of potassium channels and voltage-dependent calcium channels (Ca
v
) in single rat JG cells using whole-cell patch clamp. Single JG cells displayed outward rectification at positive membrane potentials and limited net currents between −60 and −10 mV. Blockade of K
+
channels with TEA inhibited 83% of the current at +105 mV. Inhibition of K
V
channels with 4-AP inhibited 21% of the current. Blockade of calcium-sensitive voltage-gated K
+
channels (BK
Ca
) with charybdotoxin or iberiotoxin inhibited 89% and 82% of the current, respectively. Double immunofluorescence confirmed the presence of BK
Ca
and renin in the same cell. cAMP increased the outward current by 1.6-fold, and this was inhibited by 74% with iberiotoxin. Expression of the cAMP-sensitive splice variant (ZERO) of BK
Ca
was confirmed in single-sampled JG cells by RT-PCR. The resting membrane potential of JG cells was −32 mV and activation of BK
Ca
with cAMP hyperpolarized cells on average 16 mV, and inhibition with TEA depolarized cells by 17 mV. The cells displayed typical high-voltage activated calcium currents sensitive to the L-type Ca
v
blocker calciseptine. RT-PCR analysis and double-immunofluorescence labeling showed coexpression of renin and L-type Ca
v
1.2. The cAMP-mediated increase in exocytosis (measured as membrane capacitance) was inhibited by depolarization to +10 mV, and this inhibitory effect was blocked with calciseptine, whereas K
+
-blockers had no effect. We conclude that JG cells express functional cAMP-sensitive BK
Ca
channels (the ZERO splice variant) and voltage-dependent L-type Ca
2+
channels.
Mechanical Load-Dependent Regulation of Gene Expression in Monocrotaline-Induced Right Ventricular Hypertrophy in the Rat
Authors: Kögler Harald , Hartmann Oliver , Leineweber Kirsten , Nguyen van Phuc , Schott Peter , Brodde Otto-Erich , Hasenfuss Gerd
Published: July 2003

Rats treated with monocrotaline (MCT) develop pulmonary hypertension. Their right ventricles (RVs) exhibit severe pressure overload-induced hypertrophy, whereas the left ventricles (LVs) are normally loaded. In contrast, enhanced neuroendocrine stimulation during the transition to heart failure affects both ventricles. We assessed gene expression levels of Ca
2+
-regulating proteins in RVs and LVs of control and MCT rats in transition to heart failure to identify biomechanical load-regulated genes. In MCT RVs, both mRNA and protein levels of the Ca
2+
-ATPase of the sarcoplasmic/endoplasmic reticulum (SERCA2a) were reduced by 36% (
P
=0.001) and 17% (
P
=0.016), respectively, compared with control RVs. Phospholamban and ryanodine receptor mRNA levels likewise were reduced (by 27% [
P
=0.05] and 21% [
P
=0.011], respectively) in MCT RVs, whereas sarcolemmal Na
+
-Ca
2+
exchanger expression was not altered. MCT LVs exhibited no significant expression changes compared with control LVs. Isometrically contracting MCT intact RV trabeculae showed enhanced baseline force development. Although control RV preparations exhibited a positive force-frequency relationship, MCT RVs showed a negative force-frequency relationship and blunted postrest potentiation. Contractile function of MCT LV trabeculae was normal. Maximum Ca
2+
-activated tension was enhanced by 64% in permeabilized RV MCT preparations (
P
=0.013). β-Myosin heavy chain protein was upregulated in MCT RVs (
P
<0.001) but unaltered in MCT LVs. Degradation of troponin T was prominent in MCT RVs, a phenomenon not observed in the LV. Enhanced biomechanical load is necessary to induce the gene expression changes associated with the hypertrophic phenotype of the pressure-overloaded RV. Neuroendocrine factors, which equally affect both chambers, are not sufficient to alter the expression of Ca
2+
-cycling proteins.
Astrocytic Gap Junctions Composed of Connexin 43 Reduce Apoptotic Neuronal Damage in Cerebral Ischemia
Authors: Nakase Taizen , Fushiki Shinji , Naus Christian C.G.
Published: July 2003

Background and Purpose—

Astrocytes may play a vital role in neuroprotection by providing energy substrates to neurons and regulating the concentration of K
+
and neurotransmitters through gap junctions. Connexin 43 (Cx43) is one of the major gap junction proteins in astrocytes. We have shown that, after focal stroke, heterozygote Cx43 null (Cx43+/−) mice exhibited larger infarction volumes than wild-type (Cx43+/+) mice. We explored the underlying mechanism by which gap junctional intercellular communication influences astrocytic activation and neuroprotection in ischemia.

Methods—

Both Cx43+/− and Cx43+/+ mice underwent right side permanent middle cerebral artery occlusion (MCAO). Mice were prepared by transcardial perfusion, and at 24 hours and 4 days after surgery, brains were prepared for immunohistochemistry or Western blot analysis.

Results—

Four days after MCAO, Cx43+/− mice showed severe apoptosis in the penumbral lesion compared with Cx43+/+ mice. The level of caspase-3 was significantly higher in the stroke lesion of Cx43+/− mice than in Cx43+/+ mice. Four days after MCAO, Cx43+/− mice showed a significantly larger infarct volume but a smaller area of astrogliosis than did Cx43+/+ mice. The penumbra of Cx43+/− mice showed an increased level of Cx30 compared with Cx43+/+ mice.

Conclusions—

Gap junctions may play an important role in astrocytic activation. Reactive astrocytes may reduce neuronal apoptosis under ischemia by regulating extracellular conditions through their gap junction.
Multiple Levels of Regulation of the Interleukin-6 System in Stroke
Authors: Acalovschi Daniela , Wiest Tina , Hartmann Marius , Farahmi Maryam , Mansmann Ulrich , Auffarth Gerd U. , Grau Armin J. , Green Fiona R. , Grond-Ginsbach Caspar , Schwaninger Markus
Published: July 2003

Background and Purpose—

Serum levels of the cytokine interleukin-6 (IL-6) rise markedly in stroke. IL-6 is a key regulator of inflammatory mechanisms that play an important part in stroke pathophysiology. The action of IL-6 is modified by its soluble receptor subunits sgp130 and sIL-6R. The purpose of this study was to investigate whether serum levels of the receptor subunits are changed after ischemic stroke and to define the role of genetic influences on IL-6 expression in acute stroke.

Methods—

In 48 patients with acute stroke and 48 age- and sex-matched control subjects, serum concentrations of IL-6, sgp130, and sIL-6R were measured by enzyme-linked immunosorbent assay. Furthermore, IL-6 promoter haplotypes comprising 4 different polymorphisms (−597G→A, −572G→C, −373A(n)T(n), −174G→C) were determined by DNA sequencing and allele-specific oligonucleotide polymerase chain reaction. The effect of the common haplotypes on IL-6 gene transcription was tested by transfecting reporter fusion genes in the astrocytelike cell line U373.

Results—

Whereas serum concentrations of IL-6 significantly rose (
P
<0.001), sgp130 levels were transiently reduced after stroke (
P
<0.05), and sIL-6R levels remained unchanged. IL-6 levels depended on the infarct size and the haplotype of the promoter region. The common haplotype A-G-8/12-C was associated with low IL-6 levels after stroke and a reduced induction of IL-6 transcription on stimulation with an adenosine analog in vitro.

Conclusions—

The data demonstrate genetic variation in the expression of IL-6 in stroke. Induction of the inflammatory response by IL-6 might be enhanced by a transient downregulation of the potential IL-6 antagonist sgp130.
Risk Factors for Continued Cigarette Use After Subarachnoid Hemorrhage
Authors: Ballard Jennifer , Kreiter Kurt T. , Claassen Jan , Kowalski Robert G. , Connolly E. Sander , Mayer Stephan A.
Published: July 2003

Background and Purpose—

Cigarette smoking is a risk factor for the formation and rupture of intracranial aneurysms. Few studies have examined predictors of resumption of cigarette smoking after a first episode of subarachnoid hemorrhage (SAH).

Methods—

Of 620 SAH patients treated between July 1996 and November 2002, we prospectively evaluated continued cigarette use in 152 smokers alive at 3 months. Univariate and multivariate logistic regression analyses were used to identify potential demographic, social, and clinical predictors of continued cigarette use, defined as smoking ≥1 cigarette per week in the month before follow-up.

Results—

Thirty-seven percent (56 of 152) resumed smoking after their SAH. Patients who continued smoking were younger, were more often black, had begun smoking at an earlier age, and had a higher frequency of prior alcohol or cocaine use and self-reported depression or anxiety than those who quit (all
P
<0.05). Smoking at ≤16 years of age (odds ratio [OR], 5.88; 95% confidence interval [CI], 2.33 to 14.29), self-reported depression (OR, 5.29; 95% CI, 2.10 to 13.35), and prior alcohol use (OR, 4.51; 95% CI, 1.45 to 14.05) independently predicted continued cigarette use. Smokers had a functional outcome similar to that of nonsmokers at 3 months but were more likely to resume alcohol consumption (OR, 3.88; 95% CI, 1.91 to 7.88).

Conclusions—

More than one third of prior smokers continue to use nicotine after SAH. Young age at smoking onset and a history of depression or alcohol use are risk factors for continued cigarette use. Targeted smoking cessation programs are needed to reduce the high rate of smoking resumption after SAH.
Risk Factors for Intracerebral Hemorrhage in the General Population
Authors: Ariesen M.J. , Claus S.P. , Rinkel G.J.E. , Algra A.
Published: July 2003

Background and Purpose—

Although data on some risk factors for intracerebral hemorrhage (ICH) already are beyond doubt, for other factors, the evidence is less clear. We performed a systematic overview of case-control and cohort studies on risk factors for ICH.

Methods—

We searched MEDLINE, LILACS, EXTRAMED, and Pascal from 1966 to 2001 to identify studies. Studies were included if they met predefined methodological criteria. When possible, 2×2 tables were extracted and combined with the Mantel-Haenszel method. Summary odds ratios (ORs) were calculated for case-control studies, and summary relative risks (RRs) were found for cohort studies and for case-control and cohort studies combined.

Results—

Fourteen case-control and 11 cohort studies were identified. We could not always combine the results of case-control and cohort studies. In cohort studies, the crude RR for age (every 10-year increase) was 1.97 (95% confidence interval [CI], 1.79 to 2.16). In case-control studies, the crude OR for high alcohol intake was 3.36 (95% CI, 2.21 to 5.12) and for hypertension was 3.68 (95% CI, 2.52 to 5.38). Two cohort studies showed an increasing risk of ICH with increasing degree of hypertension. In cohort and case-control studies combined, the crude RR for sex (male versus female) was 3.73 (95% CI, 3.28 to 4.25); for current smoking, 1.31 (95% CI, 1.09 to 1.58); and for diabetes, 1.30 (95% CI, 1.02 to 1.67).

Conclusions—

Risk factors for ICH appeared to be age, male sex, hypertension, and high alcohol intake. High cholesterol tends to be associated with a lower risk of ICH. We could not assess whether these risk factors are independent.
Dynamic Autoregulation Testing in Patients With Middle Cerebral Artery Stenosis
Authors: Haubrich C. , Kruska W. , Diehl R.R. , Möller-Hartmann W. , Klötzsch C.
Published: July 2003

Background and Purpose—

Cross-spectral analysis (CSA) of spontaneous oscillations in cerebral blood flow velocity (CBFV) and arterial blood pressure is considered a sensitive and convenient method for dynamic autoregulation testing. So far, it has been unclear whether CSA can be used to assess stenoses of the intracranial arteries.

Methods—

This study for the first time applies CSA to 26 patients with low-, moderate-, and high-degree M1 stenoses and 14 normal control subjects. Using CSA, we studied spontaneous oscillations (M waves, 3 to 9 cpm; B waves, 0.5 to 3 cpm) in continuous recordings of transcranial Doppler of the middle cerebral artery and simultaneously recorded beat-to-beat blood pressure.

Results—

A gradual decrease in pulsatility indexes confirmed the increasing hemodynamic relevance of the stenoses. Compared with control subjects, M-wave phase shifts between CBFV and blood pressure were gradually reduced with increasing degree of M1 stenosis (control subjects, 44.6±21.1°; high-degree stenosis, 16.7±19.5°). The phase relation between B waves in blood pressure and CBFV was shifted to positive values (low-degree stenosis, −9.7±108.4°; high-degree stenosis, 50.9±43.8°).

Conclusions—

Because B- and M-wave phase shifts seem to characterize the degree of autonomy of CBFV modulation, this study suggests that with increasing degree of M1 stenosis, the arteriolar function is impaired. It shows that CSA is of indicative use for the assessment of intracranial artery stenosis.
Differences in Clot Preparation Determine Outcome of Recombinant Tissue Plasminogen Activator Treatment in Experimental Thromboembolic Stroke
Authors: Niessen Frank , Hilger Thomas , Hoehn Mathias , Hossmann Konstantin-A.
Published: July 2003

Background and Purpose—

Thrombin-induced clots used in experimental thromboembolic stroke differ from clots forming spontaneously under clinical conditions. We investigated whether this difference influences the efficacy and outcome of thrombolytic treatment.

Methods—

In rats, the middle cerebral artery was occluded by intracarotid injection of fibrin-rich clots, prepared either according to established methods by adding thrombin to freshly drawn arterial blood or by spontaneous coagulation. The mechanical properties of clots were determined in vitro by elasticity and plasticity tests. One hour after embolism, thrombolysis was started by intra-arterial application of recombinant tissue plasminogen activator (rtPA) (10 mg/kg). Treatment efficacy was monitored by MR measurements of blood perfusion, apparent diffusion coefficient (ADC), T2 relaxation time and blood-brain barrier permeability, and by pictorial measurements of ATP and pH.

Results—

Thrombin-induced clots were classified as elastic, and spontaneously forming clots were classified as plastic. Middle cerebral artery embolism with thrombin-induced or spontaneously forming clots led to similar reduction of perfusion and ADC, but rtPA treatment efficacy differed greatly. In the spontaneously forming clot group, blood perfusion returned to or above control within 2 hours, ADC and ATP normalized, tissue pH exhibited alkalosis, and T2 and blood-brain barrier permeability did not change. In the thrombin-induced clot group, in contrast, blood reperfusion was delayed, ADC and ATP remained reduced, tissue pH was acidic, and edema developed, as reflected by increased T2 and blood-brain barrier permeability.

Conclusions—

rtPA-induced thrombolysis promotes rapid reperfusion and tissue recovery in animals embolized with spontaneously forming clots but not in those embolized with thrombin-induced clots. This difference is explained by the different mechanical and possibly molecular consequences of clot preparation and must be considered for the interpretation of thrombolysis experiments.
Assessment of Cerebral Blood Flow by Means of Blood-Flow-Volume Measurement in the Internal Carotid Artery
Authors: Soustiel J.F. , Glenn T.C. , Vespa P. , Rinsky B. , Hanuscin C. , Martin N.A.
Published: July 2003

Background and Purpose—

We sought to evaluate a new, angle-independent ultrasonic device for assessment of blood flow volume (BFV) in the internal carotid artery (ICA).

Methods—

Nineteen patients and 4 healthy volunteers were enrolled in a comparative study conducted in the Care Unit of the Division of Neurosurgery at UCLA Medical Center. All patients had been admitted because of severe brain injury: 15 patients with severe head trauma (Glasgow Coma Scale score≤8) and 4 patients with subarachnoid hemorrhage due to aneurysm rupture. In all patients and subjects, cerebral blood flow (CBF) values obtained with the
133
xenon-clearance technique were compared with BFV measurements in the ipsilateral ICA.

Results—

Hemispheric CBF values showed a close and linear correlation with BFV measurements (
r
=0.76,
P
<0.0001). Global CBF values showed a higher correlation with the total BFV value obtained from both ICAs (
r
=0.84,
P
<0.0001). With 37 mL · min
−1
· 100 g
−1
as a cutoff value for the ischemic range, a BFV value of 220 mL/min would yield a positive predictive value of 91.7% and a negative predictive value of 82.6% (sensitivity 73.3%, specificity 95%). Conversely, BFV sensitivity and specificity were 60% and 96%, respectively, for the hyperemic range defined by a CBF value >55 mL · min
−1
· 100 g
−1
(positive predictive value of 85.7% and negative prediction value of 85.7%).

Conclusions—

BFV measurements with this new technology proved to accurately correlate with CBF values evaluated by the
133
xenon-clearance technique. These results support the implementation of this technique for bedside assessment of cerebral hemodynamics in critically ill neurosurgical patients.
Feasibility of Neuroprotective Agent Administration by Prehospital Personnel in an Urban Setting
Authors: Crocco Todd , Gullett Travis , Davis Stephen M. , Flores Nicole , Sauerbeck Laura , Jauch Edward , Threlkeld Billie , Pio Brian , Ottaway Michael , Pancioli Arthur , Chenier Thomas
Published: July 2003

Background and Purpose—

Studies have demonstrated the importance of early stroke treatment. If a neuroprotective agent (NA) clinical trial is successful, the greatest benefit might be attained with early prehospital administration. This study determined the potential reduction in time to treatment of stroke patients when NAs were administered in the prehospital setting.

Methods—

Twenty-three urban emergency medical services (EMS) agencies participated in this study. Prehospital personnel completed a stroke assessment checklist on any potential stroke victim. The checklist collected clinical inclusion/exclusion criteria for NA administration and event/decision times. Patients meeting the hypothetical clinical inclusion criteria were enrolled into this study. Time data included scene arrival/departure, emergency department (ED) arrival, and estimated time of theoretical NA administration. The reduction in time to stroke treatment was calculated as the difference between the time of ED arrival and the reported time of NA administration. The
t
test and simple linear regression were used to probe for differences in treatment time reduction between selected subgroups. EMS personnel’s ability to obtain informed consent for theoretical NA administration was calculated.

Results—

Two hundred twenty-two patients were enrolled in this study; of these, 75 were deemed eligible for hypothetical NA administration and had complete time data. On average, EMS personnel documented the theoretical time of NA administration at 12.04±2.07 minutes before arrival at the ED (17.06±1.74 minutes when the NA was given on scene [n=43]; 6.65±1.14 minutes when the NA was given en route [n=32]).

Conclusions—

Prehospital NA administration can potentially significantly reduce the time to first intervention in stroke patients.
Protected Carotid Stenting
Authors: Cremonesi Alberto , Manetti Raffaella , Setacci Francesco , Setacci Carlo , Castriota Fausto
Published: July 2003

Background and Purpose—

Periprocedural embolization of debris during carotid stenting interventions may result in neurological deficit. This study was designed to evaluate in-hospital and 30-day adverse events in patients percutaneously treated for carotid artery disease with embolic protection devices.

Methods—

From 1999 to June 2002, a total of 442 consecutive patients underwent percutaneous angioplasty and/or stenting of the extracranial carotid artery. The endovascular procedure was conducted under embolic protection devices.

Results—

The percutaneous procedure was successful in 440 of 442 patients (99.5%). No periprocedural death occurred with any embolic protection device. All in-hospital stroke/death and 30-day ipsilateral stroke/death rate was 1.1%. The overall complication rate was 3.4%. Major adverse events included 1 major stroke (0.2%), 4 intracranial hemorrhages (0.9%), 1 carotid artery wall fissuration (0.2%), and 1 diffuse cardioembolism (0.2%). Minor adverse events included 4 minor strokes (0.9%) and 4 transient ischemic attacks (0.9%). The cerebral protection device–related complications were 4 (0.9%): 1 case of abrupt closure of the internal carotid artery because of spiral dissection (0.2%), 1 case of trapped guide wire (0.2%), and 2 cases of intimal dissection (0.5%). Transient loss of consciousness, tremors, and fasciculations were present in 6 of 40 patients (15%) in whom occlusive protection devices were used.

Conclusions—

Our data suggest that percutaneous stenting of the carotid artery when a cerebral protection device is used is feasible and effective but not without potential complications. However, a long learning curve may exist for the proper use of some embolic protection devices.
Serum Urate as an Independent Predictor of Poor Outcome and Future Vascular Events After Acute Stroke
Authors: Weir Christopher J. , Muir Scott W. , Walters Matthew R. , Lees Kennedy R.
Published: July 2003

Background and Purpose—

Serum urate concentration is associated with cardiovascular disease, and hyperuricemia predicts first-ever stroke. We explored the association of admission urate level with mortality, placement, and risk of further vascular events after acute stroke.

Methods—

In patients with ischemic stroke or primary intracranial hemorrhage, we determined the association of urate level with 90-day placement (alive at home, good outcome; dead or living in care, poor outcome) and with the subsequent occurrence of ischemic stroke, myocardial infarction, or vascular death. In multivariate analysis (logistic regression for 90-day placement, proportional-hazards regression for time to further vascular event), we adjusted for stroke severity (modified National Institutes of Health stroke scale) and other clinical, biochemical, and radiological variables known to influence stroke outcome.

Results—

We studied 3731 patients and measured serum urate in 2498. Elevated urate level predicted a lower chance of good 90-day outcome (odds ratio, 0.78 per additional 0.1 mmol/L; 95% confidence interval [CI], 0.67 to 0.91) independently of stroke severity and other prognostic factors. Vascular event risk increased with urate level (relative hazard, 1.27 per additional 0.1 mmol/L; 95% CI, 1.18 to 1.36). Higher urate levels have a greater effect on vascular event rates in the presence of diabetes (additional relative hazard, 1.22 per additional 0.1 mmol/L; 95% CI, 1.06 to 1.41).

Conclusions—

Independently of other prognostic factors, higher serum urate levels predicted poor outcome (dead or in care) and higher vascular event rates. The role of urate in stroke pathophysiology remains uncertain, but intervention to lower urate may be worth considering.
Primary Care, Income Inequality, and Stroke Mortality in the United States
Authors: Shi Leiyu , Macinko James , Starfield Barbara , Xu Jiahong , Politzer Robert
Published: July 2003

Background and Purpose—

The goal of this study was to test whether primary care reduces the impact of income inequality on stroke mortality.

Methods—

This study used pooled time-series cross-sectional analysis of 11 years of state-level data (n=549). Analyses controlled for education levels, unemployment, racial/ethnic composition, and percent urban. Contemporaneous and time-lagged covariates were modeled.

Results—

Primary care was negatively associated with stroke mortality in models including all covariates (
P
<0.0001). The impact of income inequality on stroke mortality was reduced in the presence of primary care (
P
<0.0001) but disappeared with the addition of covariates (
P
>0.05).

Conclusions—

In the absence of social policy that addresses sociodemographic determinants of health, primary care promotion may serve as a palliative strategy for combating stroke mortality and reducing the adverse impact of income inequality on health.