bluuebunny/crossref_metadata_2025 huggingface dataset:
Chest Compressions Cause Recurrence of Ventricular Fibrillation After the First Successful Conversion by Defibrillation in Out-of-Hospital Cardiac Arrest
Authors: Berdowski Jocelyn , Tijssen Jan G.P. , Koster Rudolph W.
Published: December 2009

Background—

Unlike Resuscitation Guidelines (GL) 2000, GL2005 advise resuming cardiopulmonary resuscitation (CPR) immediately after defibrillation. We hypothesized that immediate CPR resumption promotes earlier recurrence of ventricular fibrillation (VF).

Methods and Results—

This study used data of a prospective per-patient randomized controlled trial. Automated external defibrillators used by first responders were randomized to either (1) perform postshock analysis and prompt rescuers to a pulse check (GL2000), or (2) resume CPR immediately after defibrillation (GL2005). Continuous recordings of ECG and impedance signals were collected from all patients with an out-of-hospital cardiac arrest to whom a randomized automated external defibrillator was applied. We included patients with VF as their initial rhythm in whom CPR onset could be determined from the ECG and impedance signals. Time intervals are presented as median (Q1-to-Q3). Of 361 patients, 136 met the inclusion criteria: 68 were randomly assigned to GL2000 and 68 to GL2005. Rescuers resumed CPR 30 (21-to-39) and 8 (7-to-9) seconds, respectively, after the first shock that successfully terminated VF (
P
<0.001); VF recurred after 40 (21-to-76) and 21 (10-to-80) seconds, respectively (
P
=0.001). The time interval between start of CPR and VF recurrence was 6 (0-to-67) and 8 (3-to-61) seconds, respectively (
P
=0.88). The hazard ratio for VF recurrence in the first 2 seconds of CPR was 15.5 (95% confidence interval, 5.63 to 57.7) compared with before CPR resumption. After more than 8 seconds of CPR, the hazard of VF recurrence was similar to before CPR resumption.

Conclusions—

Early CPR resumption after defibrillation causes early VF recurrence.

Clinical Trial Registration—

clinicaltrials.gov Identifier: ISRCTN72257677.
Quantitative Trait Locus Mapping and Identification of Zhx2 as a Novel Regulator of Plasma Lipid Metabolism
Authors: Gargalovic Peter S. , Erbilgin Ayça , Kohannim Omid , Pagnon Joanne , Wang Xuping , Castellani Lawrence , LeBoeuf Renee , Peterson Martha L. , Spear Brett T. , Lusis Aldons J.
Published: December 2009

Background—

We previously mapped a quantitative trait locus on chromosome 15 in mice contributing to high-density lipoprotein cholesterol and triglyceride levels and now report the identification of the underlying gene.

Methods and Results—

We first fine-mapped the locus by studying a series of congenic strains derived from the parental strains BALB/cJ and MRL/MpJ. Analysis of gene expression and sequencing followed by transgenic complementation led to the identification of zinc fingers and homeoboxes 2 (Zhx2), a transcription factor previously implicated in the developmental regulation of α-fetoprotein. Reduced expression of the protein in BALB/cJ mice resulted in altered hepatic transcript levels for several genes involved in lipoprotein metabolism. Most notably, the Zhx2 mutation resulted in a failure to suppress expression of lipoprotein lipase, a gene normally silenced in the adult liver, and this was normalized in BALB/cJ mice carrying the Zhx2 transgene.

Conclusions—

We identified the gene underlying the chromosome 15 quantitative trait locus, and our results show that Zhx2 functions as a novel developmental regulator of key genes influencing lipoprotein metabolism.
Comprehensive Analysis of Genomic Variation in the
LPA
Locus and Its Relationship to Plasma Lipoprotein(a) in South Asians, Chinese, and European Caucasians
Authors: Lanktree Matthew B. , Anand Sonia S. , Yusuf Salim , Hegele Robert A.
Published: December 2009

Background—

Functional copy number variation in the apolipoprotein(a) gene (
LPA
) underlies a variable number of protein kringle domains repeated in tandem in the lipoprotein(a) [Lp(a)] particle. Genomic analysis of
LPA
, including both single-nucleotide polymorphisms (SNPs) and kringle IV type 2 (KIV-2) copy number, has yet to be performed.

Methods and Results—

First, we genotyped 49 SNPs within 100 kb of
LPA
in a multiethnic sample comprising South Asians (n=330), Chinese (n=304), and European Caucasians (n=272). Second, using quantitative polymerase chain reaction, we estimated the KIV-2 copy number in each sample. European Caucasians had the lowest KIV-2 copy number but displayed the strongest correlation between KIV-2 copy number and plasma Lp(a) concentration (
r
s
=−0.31,
P
=4.2�10
−7
). SNP rs10455872, only prevalent in European Caucasians, was strongly associated with both plasma Lp(a) concentration (
P
=4.2�10
−29
) and KIV-2 copy number (
P
=7.2�10
−5
).
LPA
SNP rs6415084, within the same haplotype block as the KIV-2 variation, was significantly associated with both Lp(a) concentration and KIV-2 copy number in the same direction in all 3 ethnicities [Lp(a),
P
=5.3�10
−7
; KIV-2,
P
=2.6�10
−4
]. SNPs and KIV-2 copy number together explain a larger proportion of variation in plasma Lp(a) concentrations in European Caucasians (36%) than in Chinese (27%) or South Asians (21%).

Conclusions—

LPA
SNPs are in linkage disequilibrium with KIV-2 copy number, but KIV-2 copy number explains an increment in plasma Lp(a) variation over SNPs alone. Thus, both SNPs and KIV-2 copy number should be included in future genetic epidemiology studies of Lp(a).
Vasoreactive Response to Maternal Hyperoxygenation in the Fetus With Hypoplastic Left Heart Syndrome
Authors: Szwast Anita , Tian Zhiyun , McCann Margaret , Donaghue Denise , Rychik Jack
Published: January 2010

Background—

Cardiopulmonary interactions play an important role in the pathophysiology of hypoplastic left heart syndrome (HLHS). Pulmonary vasculopathy has been identified, especially in those with restrictive/intact atrial septum. Responsiveness of the pulmonary vasculature to maternal hyperoxygenation (MH) may provide a tool to assess the degree of pulmonary vasculopathy present before birth.

Methods and Results—

Doppler echocardiography was performed in 27 normal and 43 HLHS fetuses. In HLHS, sampling was repeated after 10 minutes of MH with 60% FiO
2
and after 5 minutes of recovery. Sampling was performed in the proximal, midportion, and distal branch pulmonary artery (PA). Pulsatility index (PI) was used as a measure of vascular impedance. Of the HLHS fetuses, 34 had an open interatrial septum and 9 had a restrictive/intact atrial septum. At birth, 5 fetuses underwent immediate intervention on the interatrial septum. Middle cerebral artery PI was lower in HLHS versus normal fetuses (
P
<0.001). There was no difference in UA, DA, or branch PA PI between normal fetuses and those with HLHS. MH led to a significant decrease in PI at each of the PA sites sampled in fetuses with an open atrial septum (
P
<0.001); however, there no was significant change in the PI in fetuses that required immediate intervention on the atrial septum at birth. Using a cutoff value of <10% vasoreactivity, the sensitivity of MH testing for determining need for immediate intervention at birth is 100% (0.46 to 1.0); specificity, 94% (0.78 to 0.99); positive predictive value, 71% (0.30 to 0.95); and negative predictive value, 100% (0.86 to 1.0). No untoward effects were seen with MH.

Conclusions—

PA vasoreactivity to MH occurs in the fetus with HLHS. MH testing accurately identifies fetuses requiring urgent postnatal intervention at birth and may be used to select candidates for fetal atrial septoplasty.
Iodinated Contrast Opacification Gradients in Normal Coronary Arteries Imaged With Prospectively ECG-Gated Single Heart Beat 320-Detector Row Computed Tomography
Authors: Steigner Michael L. , Mitsouras Dimitrios , Whitmore Amanda G. , Otero Hansel J. , Wang Chunliang , Buckley Orla , Levit Noah A. , Hussain Alia Z. , Cai Tianxi , Mather Richard T. , Smedby Örjan , DiCarli Marcelo F. , Rybicki Frank J.
Published: January 2010

Background—

To define and evaluate coronary contrast opacification gradients using prospectively ECG-gated single heart beat 320-detector row coronary angiography (CTA).

Methods and Results—

Thirty-six patients with normal coronary arteries determined by 320�0.5-mm detector row coronary CTA were retrospectively evaluated with customized image postprocessing software to measure Hounsfield Units at 1-mm intervals orthogonal to the artery center line. Linear regression determined correlation between mean Hounsfield Units and distance from the coronary ostium (regression slope defined as the distance gradient G
d
), lumen cross-sectional area (G
a
), and lumen short-axis diameter (G
s
). For each gradient, differences between the 3 coronary arteries were analyzed with ANOVA. Linear regression determined correlations between measured gradients, heart rate, body mass index, and cardiac phase. To determine feasibility in lesions, all 3 gradients were evaluated in 22 consecutive patients with left anterior descending artery lesions ≥50% stenosis. For all 3 coronary arteries in all patients, the gradients G
a
and G
s
were significantly different from zero (
P
<0.0001), highly linear (Pearson
r
values, 0.77 to 0.84), and had no significant difference between the left anterior descending, left circumflex, and right coronary arteries (
P
>0.503). The distance gradient G
d
demonstrated nonlinearities in a small number of vessels and was significantly smaller in the right coronary artery when compared with the left coronary system (
P
<0.001). Gradient variations between cardiac phases, heart rates, body mass index, and readers were low. Gradients in patients with lesions were significantly different (
P
<0.021) than in patients considered normal by CTA.

Conclusions—

Measurement of contrast opacification gradients from temporally uniform coronary CTA demonstrates feasibility and reproducibility in patients with normal coronary arteries. For all patients, the gradients defined with respect to the coronary lumen cross-sectional area and short-axis diameters are highly linear, not significantly influenced by the coronary artery (left anterior descending artery versus left circumflex versus right coronary artery), and have only small variation with respect to patient parameters. Preliminary evaluation of gradients across coronary artery lesions is promising but requires additional study.
Noninvasive Assessment of Murine Pulmonary Arterial Pressure
Authors: Thibault Hélène B. , Kurtz Baptiste , Raher Michael J. , Shaik Rahamthulla S. , Waxman Aaron , Derumeaux Geneviève , Halpern Elkan F. , Bloch Kenneth D. , Scherrer-Crosbie Marielle
Published: January 2010

Background—

Genetically modified mice offer the unique opportunity to gain insight into the pathophysiology of pulmonary arterial hypertension. In mice, right heart catheterization is the only available technique to measure right ventricular systolic pressure (RVSP). However, it is a terminal procedure and does not allow for serial measurements. Our objective was to validate a noninvasive technique to assess RVSP in mice.

Methods and Results—

Right ventricle catheterization and echocardiography (30-MHz transducer) were simultaneously performed in mice with pulmonary hypertension induced acutely by infusion of a thromboxane analogue, U-46619, or chronically by lung-specific overexpression of interleukin-6. Pulmonary acceleration time (PAT) and ejection time (ET) were measured in the parasternal short-axis view by pulsed-wave Doppler of pulmonary artery flow. Infusion of U-46619 acutely increased RVSP, shortened PAT, and decreased PAT/ET. The pulmonary flow pattern changed from symmetrical at baseline to asymmetrical at higher RVSPs. In wild-type and interleukin-6–overexpressing mice, the PAT correlated linearly with RVSP (
r
2
=−0.67,
P
<0.0001), as did PAT/ET (
r
2
=−0.76,
P
<0.0001). Sensitivity and specificity for detecting high RVSP (>32 mm Hg) were 100% (7/7) and 86% (6/7), respectively, for both indices (cutoff values: PAT, <21 ms; PAT/ET, <39%). Intraobserver and interobserver variability of PAT and PAT/ET were <6%.

Conclusions—

Right ventricular systolic pressure can be estimated noninvasively in mice. Echocardiography is able to detect acute and chronic increases in RVSP with high sensitivity and specificity as well as to assess the effects of treatment on RVSP. This noninvasive technique may permit the characterization of the evolution of pulmonary arterial hypertension in genetically modified mice.
A Common
MLP
(Muscle LIM Protein) Variant Is Associated With Cardiomyopathy
Authors: Knöll Ralph , Kostin Sawa , Klede Stefanie , Savvatis Kostas , Klinge Lars , Stehle Ina , Gunkel Sylvia , Kötter Sebastian , Babicz Kamila , Sohns Melanie , Miocic Snjezana , Didié Michael , Knöll Gudrun , Zimmermann Wolfram Hubertus , Thelen Paul , Bickeböller Heike , Maier Lars S. , Schaper Wolfgang , Schaper Jutta , Kraft Theresia , Tschöpe Carsten , Linke Wolfgang A. , Chien Kenneth R.
Published: January 2010

Rationale
:

We previously discovered the human 10T→C (Trp4Arg) missense mutation in exon 2 of the muscle LIM protein (MLP, CSRP3) gene.

Objective
:

We sought to study the effects of this single-nucleotide polymorphism in the in vivo situation.

Methods and Results
:

We now report the generation and detailed analysis of the corresponding Mlp
W4R/+
and Mlp
W4R/W4R
knock-in animals, which develop an age- and gene dosage–dependent hypertrophic cardiomyopathy and heart failure phenotype, characterized by almost complete loss of contractile reserve under catecholamine induced stress. In addition, evidence for skeletal muscle pathology, which might have implications for human mutation carriers, was observed. Importantly, we found significantly reduced MLP mRNA and MLP protein expression levels in hearts of heterozygous and homozygous W4R-MLP knock-in animals. We also detected a weaker in vitro interaction of telethonin with W4R-MLP than with wild-type MLP. These alterations may contribute to an increased nuclear localization of W4R-MLP, which was observed by immunohistochemistry.

Conclusions
:

Given the well-known high frequency of this mutation in Caucasians of up to 1%, our data suggest that
W4R-MLP
might contribute significantly to human cardiovascular disease.
Intracellular Ca2+Silences L-Type Ca2+Channels in Mesenteric Veins
Authors: Thakali Keshari M. , Kharade Sujay V. , Sonkusare Swapnil K. , Rhee Sung W. , Stimers Joseph R. , Rusch Nancy J.
Published: January 2010

Rationale:Calcium channel blockers (CCBs) exert their antihypertensive effect by reducing cardiac afterload but not preload, suggesting that Ca2+influx through L-type Ca2+channels (LTCC) mediates arterial but not venous tone.

Objective:The object of this study was to resolve the mechanism of venous resistance to CCBs.

Methods and Results:We compared the sensitivity of depolarization (KCl)-induced constriction of rat small mesenteric arteries (MAs) and veins (MVs) to the dilator effect of CCBs. Initial findings confirmed that nifedipine progressively dilated depolarization-induced constrictions in MAs but not MVs. However, Western blots showed a similar expression of the α1Cpore-forming subunit of the LTCC in both vessels. Patch-clamp studies revealed a similar density of whole-cell Ca2+channel current between single smooth muscle cells (SMCs) of MAs and MVs. Based on these findings, we hypothesized that LTCCs are expressed but “silenced” by intracellular Ca2+in venous SMCs. After depletion of intracellular Ca2+stores by the SERCA pump inhibitor thapsigargin, depolarization-induced constrictions in MVs were blocked 80% by nifedipine suggesting restoration of Ca2+influx through LTCCs. Similarly, KCl-induced constrictions were sensitive to block by nifedipine after depletion of intracellular Ca2+stores by caffeine, ryanodine, or 2-aminoethoxydiphenyl borate. Cell-attached patch recordings of unitary LTCC currents confirmed rare channel openings during depolarization of venous compared to arterial SMCs, but chelating intracellular Ca2+significantly increased the open-state probability of venous LTCCs.

Conclusions:We report that intracellular Ca2+inactivates LTCCs in venous SMCs to confer venous resistance to CCB-induced dilation, a fundamental drug property that was previously unexplained.
Operative and Middle-Term Results of Cardiac Surgery in Nonagenarians
Authors: Speziale Giuseppe , Nasso Giuseppe , Barattoni Maria Cristina , Bonifazi Raffaele , Esposito Giampiero , Coppola Roberto , Popoff Georges , Lamarra Mauro , Scorcin Marcio , Greco Ernesto , Argano Vincenzo , Zussa Claudio , Cristell Donald , Bartolomucci Francesco , Tavazzi Luigi
Published: January 2010

Background—

Age >90 years represents in many centers an absolute contraindication to cardiac surgery. Nonagenarians are a rapidly growing subset of the population posing an expanding clinical problem. To provide helpful information in regard to this complex decision, we analyzed the operative and 5-year results of coronary and valvular surgical procedures in these patients.

Methods and Results—

We retrospectively reviewed 127 patients aged ≥90 years who underwent cardiac surgery within our hospital group in the period 1998 to 2008. Kaplan–Meier and multiple logistic regression analyses were performed. A longer follow-up than most published studies and the largest series published thus far are presented. Mean age was 92 years (range, 90 to 103 years). Mean logistic EuroSCORE was 21.3±6.1. Sixty patients had valvular surgery (including 11 valve repairs), 49 patients had coronary artery bypass grafting, and 18 had valvular plus coronary artery bypass grafting surgery (55 left mammary artery grafts implanted). Forty-five patients (35.4%) were operated on nonelectively. Operative mortality was 13.4% (17 cases). Fifty-four patients (42.5%) had a complicated postoperative course. There were no statistically significant differences in the rate and type of complications between patient strata on the basis of type of surgery performed. Nonelective priority predicted a complicated postoperative course. Predictors of operative mortality were nonelective priority and previous myocardial infarction. Kaplan–Meier survival estimates at 5 years were comparable between patient groups on the basis of procedure performed.

Conclusions—

Although the rate of postoperative complications remains high, cardiac surgery in nonagenarians can achieve functional improvement at the price of considerable operative and follow-up mortality rates. Cardiac operations in these very elderly subjects are supported if appropriate selection is made and if the operation is performed earlier and electively. Our results should contribute to the development of guidelines for cardiac operations in nonagenarians.
Options to Restrict Hematoma Expansion After Spontaneous Intracerebral Hemorrhage
Authors: Steiner Thorsten , Bösel Julian
Published: January 2010

Background and Purpose—

Secondary expansion of hematoma after spontaneous intracerebral hemorrhage occurs frequently and early with the potential sequelae of functional deterioration or death. The aim of this topical review is to give a summary of current evidence- and experience-based options to avoid or attenuate hematoma expansion.

Method—

We reviewed the literature of the past 10 years on efforts to restrict spontaneous intracerebral hemorrhage expansion by searching Medline and adding related articles known to us. Based on evidence, current guidelines, and our own clinical practice, we have collected consistent and inconsistent pieces of data. These were differentiated according to surgical versus medical approaches, weighed and discussed with regard to expectable benefit, potential risk, and practicability. Finally, we have outlined promising future approaches.

Results—

Although consistent evidence on the topic is generally limited, some important studies have provided data on risk factors predicting spontaneous intracerebral hemorrhage expansion implying ways of directing therapy toward these risk factors. Large trials have shed light on 4 major efforts to avoid hematoma expansion: surgical hematoma treatment, reduction of hypertension, reversal of coagulopathies or anticoagulants, and hemostatic therapy. The results were largely disappointing but provide insights for new trials. Future strategies include the combination of surgical and medical treatment and the use of neuroprotectants.

Conclusions—

Early restriction of intracerebral hemorrhage is of paramount importance because secondary volume expansion leads to outcome deterioration and death. Although there appear to be few indications for neurosurgical measures, nonsurgical measures such as reduction of hypertension and normalization of altered coagulation seem to be beneficial. However, the routine use of coagulation factors outside of warfarin-associated spontaneous intracerebral hemorrhage cannot generally be recommended at present. The same applies for future approaches such as combined medical–surgical approaches and neuroprotective therapies at this point.
Four-Fold Increase in Direct Costs of Stroke Survivors With Spasticity Compared With Stroke Survivors Without Spasticity
Authors: Lundström Erik , Smits Anja , Borg Jörgen , Terént Andreas
Published: January 2010

Background and Purpose—

The prevalence of spasticity after first-ever stroke is approximately 20%, but there are no health economic studies on costs associated with spasticity after stroke. The objective of our study was to estimate direct costs of stroke with spasticity for patients surviving up to 1 year after the stroke event in comparison to costs of stroke without spasticity.

Methods—

A representative sample of patients with first-ever stroke hospitalized at Uppsala University Hospital was eligible for our cross-sectional survey. All direct costs during 1 year were identified for each patient, including costs for hospitalization (acute and rehabilitation), primary health care, medication, and costs for municipality services. Swedish currency was converted to Purchasing Power Parities US dollar (PPP$).

Results—

Median age (interquartile range) was 73 years (18), and the proportion of women was 48%. The majority of the direct costs (78%) was associated with hospitalization, whereas 20% was associated with municipality services during 1 year after a first-ever stroke. Only 1% of all direct costs were related to primary health care and 1% to medication. The level of costs for patients with stroke was correlated with the presence of spasticity as measured with the modified Ashworth scale (
r
s
=0.524) and with the degree of disability as measured with modified Rankin Scale (
r
s
=0.624). The mean (median, interquartile range) direct cost for stroke patients with spasticity was PPP$ 84 195 (72 116, 53 707) compared with PPP$ 21 842 (12 385, 17 484) for patients with stroke without spasticity (
P
<0.001).

Conclusions—

Direct costs for 12-month stroke survivors are 4 times higher than direct costs for patients with stroke without spasticity during the first year after the event.
Effects of Early Intensive Blood Pressure-Lowering Treatment on the Growth of Hematoma and Perihematomal Edema in Acute Intracerebral Hemorrhage
Authors: Anderson Craig S. , Huang Yining , Arima Hisatomi , Heeley Emma , Skulina Christian , Parsons Mark W. , Peng Bin , Li Qiang , Su Steve , Tao Qing Ling , Li Yue Chun , Jiang Jian Dong , Tai Li Wen , Zhang Jin Li , Xu En , Cheng Yan , Morgenstern Lewis B. , Chalmers John , Wang Ji Guang
Published: January 2010

Background and Purpose—

The Intensive Blood Pressure Reduction In Acute Cerebral Haemorrhage Trial (INTERACT) study suggests that early intensive blood pressure (BP) lowering can attenuate hematoma growth at 24 hours after intracerebral hemorrhage. The present analyses aimed to determine the effects of treatment on hematoma and perihematomal edema over 72 hours.

Methods—

INTERACT included 404 patients with CT-confirmed intracerebral hemorrhage, elevated systolic BP (150 to 220 mm Hg), and capacity to start BP-lowering treatment within 6 hours of intracerebral hemorrhage. Patients were randomly assigned to an intensive (target systolic BP 140 mmHg) or standard guideline-based management of BP (target systolic BP 180 mm Hg) using routine intravenous agents. Baseline and repeat CTs (24 and 72 hours) were performed using standardized techniques with digital images analyzed centrally. Outcomes were increases in hematoma and perihematomal edema volumes over 72 hours.

Results—

Overall, 296 patients had all 3 CT scans available for the hematoma and 270 for the edema analyses. Mean systolic BP was 11.7 mm Hg lower in the intensive group than in the guideline group during 1 to 24 hours. Adjusted mean absolute increases in hematoma volumes (mL) at 24 and 72 hours were 2.40 and 0.15 in the guideline group compared with −0.74 and −2.31 in the intensive group, respectively, an overall difference of 2.80 (95% CI, 1.04 to 4.56;
P
=0.002). Adjusted mean absolute increases in edema volumes (mL) at 24 and 72 hours were 6.27 and 10.02 in the guideline group compared with 4.19 and 7.34 in the intensive group, respectively, for an overall difference of 2.38 (95% CI, −0.45 to 5.22;
P
=0.10).

Conclusion—

Early intensive BP-lowering treatment attenuated hematoma growth over 72 hours in intracerebral hemorrhage. There were no appreciable effects on perihematomal edema.
Gene Expression Profiles in Human Ruptured and Unruptured Intracranial Aneurysms
Authors: Pera Joanna , Korostynski Michal , Krzyszkowski Tadeusz , Czopek Jacek , Slowik Agnieszka , Dziedzic Tomasz , Piechota Marcin , Stachura Krzysztof , Moskala Marek , Przewlocki Ryszard , Szczudlik Andrzej
Published: January 2010

Background and Purpose—

Mechanisms underlying development and rupture of intracranial aneurysms (IA) are poorly recognized. The majority of studies on human tissue have focused on predefined pathways. We sought to analyze global gene expression patterns of ruptured IA, unruptured IA, and control vessels.

Methods—

Transcription profiles were studied in human ruptured (n=8) and unruptured (n=6) IA, as well as in control intracranial arteries (n=5), using oligonucleotide microarrays. Real-time reverse-transcription polymerase chain reaction was used for confirmation. Functional analysis for determination of over-represented ontological groups among gene expression profiles was also performed.

Results—

The expression of 159 genes differed among the studied groups. Compared to the controls, 131 genes showed common directions of change in both IA groups. The most impacted biological processes for IA are: (1) the muscle system; (2) cell adhesion (downregulation); and (3) the immune system and inflammatory response (upregulation). Ruptured and unruptured IA differed in genes involved in immune/inflammatory processes; expression was reduced in ruptured IA.

Conclusions—

Decreased expression of genes related to muscle system and cell adhesion is important for the development of IA. The role of immune/inflammatory processes is unclear. Inflammation may participate in the healing process within IA while playing a protective role against IA rupture.
Caffeinol at the Receptor Level
Authors: Zhao Xiurong , Strong Roger , Piriyawat Paisith , Palusinski Robert , Grotta James C. , Aronowski Jaroslaw
Published: January 2010

Background and Purpose—Although caffeinol (a combination of a low dose of caffeine and ethanol) was shown to robustly reduce stroke damage in experimental models and is now in clinical evaluation for treatment of ischemic stroke, little is known about the potential mechanism of its action.

Methods—We used an in vivo excitotoxicity model based on intracortical infusion ofN-methyl-d-aspartate (NMDA) and a model of reversible focal ischemia to demonstrate NMDA receptor inhibition as a potential mechanism of caffeinol anti-ischemic activity.

Results—Caffeinol reduced the size of excitotoxic lesion, and substitution of ethanol in caffeinol with the NMDA antagonists CNS-1102 and MK-801 but not with MgSO4produced treatment with strong synergistic effect that was at least as robust in reducing ischemic damage as caffeinol. This NMDA receptor antagonist and caffeine combination demonstrated a long window of opportunity, activity in spontaneously hypertensive rats, and, unlike caffeinol, was fully effective in animals chronically pretreated with ethanol.

Conclusions—Our study suggests that antiexcitotoxic properties may underlie some of the anti-ischemic effect of caffeinol. This study provides strong evidence that the anti-ischemic effect of NMDA receptor blockers in general can be dramatically augmented by caffeine, thus opening a possibility for new use of NMDA-based pharmacology in the treatment of stroke.
Safety and Efficacy of Ultrasound-Enhanced Thrombolysis
Authors: Tsivgoulis Georgios , Eggers Jürgen , Ribo Marc , Perren Fabienne , Saqqur Maher , Rubiera Marta , Sergentanis Theodoros N. , Vadikolias Konstantinos , Larrue Vincent , Molina Carlos A. , Alexandrov Andrei V.
Published: January 2010

Background and Purpose—

Ultrasound-enhanced thrombolysis is a promising new approach to facilitate reperfusion therapies for acute ischemic stroke. So far, 3 different ultrasound technologies were used to increase the thrombolytic activity of tissue plasminogen activator (tPA), including transcranial Doppler (TCD), transcranial color-coded duplex (TCCD), and low-frequency ultrasound. We performed a meta-analysis to evaluate the safety and efficacy of ultrasound-enhanced thrombolysis compared to the current standard of care (intravenous tPA).

Subjects and Methods—

Through Medline, Embase, and Cochrane database search, we identified and abstracted all studies of ultrasound-enhanced thrombolysis in acute cerebral ischemia. Principal investigators were contacted if data not available through peer-reviewed publication were needed. Symptomatic intracerebral hemorrhage (sICH) and recanalization rates were compared between tPA, tPA+TCD±microspheres (μS), tPA+TCCD±μS, and tPA+low-frequency ultrasound.

Results—

A total of 6 randomized (n=224) and 3 nonrandomized (n=192) studies were identified. The rates of symptomatic intracerebral hemorrhage in randomized studies were as follows: tPA+TCD, 3.8% (95% CI, 0%–11.2%); tPA+TCCD, 11.1% (95% CI, 0%–28.9%); tPA+low-frequency ultrasound, 35.7% (95% CI, 16.2%– 61.4%); and tPA alone, 2.9% (95% CI, 0%–8.4%). Complete recanalization rates were higher in patients receiving combination of TCD with tPA 37.2% (95% CI, 26.5%– 47.9%) compared with patients treated with tPA alone 17.2% (95% CI, 9.5%–24.9%). In 8 trials of high-frequency (TCD/TCCD) ultrasound-enhanced thrombolysis, tPA+TCD/TCCD±μS was associated with a higher likelihood of complete recanalization (pooled OR, 2.99; 95% CI, 1.70–5.25;
P
=0.0001) when compared to tPA alone. High-frequency ultrasound-enhanced thrombolysis was not associated with an increased risk of symptomatic intracerebral hemorrhage (pooled OR, 1.26; 95% CI, 0.44–3.60;
P
=0.67).

Conclusions—

The present safety and signal-of-efficacy data of high-frequency ultrasound-enhanced thrombolysis should be taken into account in the design of future randomized controlled trials.
Effects of Perindopril-Based Lowering of Blood Pressure on Intracerebral Hemorrhage Related to Amyloid Angiopathy
Authors: Arima Hisatomi , Tzourio Christophe , Anderson Craig , Woodward Mark , Bousser Marie-Germaine , MacMahon Stephen , Neal Bruce , Chalmers John
Published: January 2010

Background and Purpose—

Patients with cerebral amyloid angiopathy (CAA) are at high risk for intracerebral hemorrhage (ICH), but no effective prevention strategies have been established. The objective is to determine whether lowering of blood pressure (BP) provides protection for this high-risk patient group.

Methods—

This study is a subsidiary analysis of the PROGRESS trial—a randomized, placebo-controlled trial that established the beneficial effects of BP lowering in patients with cerebrovascular disease; 6105 patients were randomly assigned to either active treatment (perindopril for all participants plus indapamide for those with neither an indication for nor a contraindication to a diuretic) or matching placebo. Outcomes were probable CAA-related ICH as defined by the Boston criteria, probable hypertension-related ICH, and unclassified ICH.

Results—

Over a mean follow-up of 3.9 years, 16 probable CAA-related ICH, 51 probable hypertension-related ICH, and 44 unclassified ICH occurred. Active treatment reduced the risk of CAA-related ICH by 77% (95% CI, 19%–93%), that of hypertension-related ICH by 46% (95% CI, 4%–69%), and that of unclassified ICH by 43% (95% CI, −5%–69%). There was no evidence of differences in the magnitude of the effects of treatment among different types of ICH (
P
homogeneity=0.4).

Conclusions—

BP-lowering treatment is likely to provide protection against all types of ICH.
Counting Cavitating Lacunes Underestimates the Burden of Lacunar Infarction
Authors: Potter Gillian M. , Doubal Fergus N. , Jackson Caroline A. , Chappell Francesca M. , Sudlow Cathie L. , Dennis Martin S. , Wardlaw Joanna M.
Published: January 2010

Background and Purpose—

On brain imaging, lacunes, or cerebrospinal fluid–containing cavities, are common and are often counted in epidemiological studies as old lacunar infarcts. The proportion of symptomatic lacunar infarcts that progress to lacunes is unknown. Noncavitating lacunar infarcts may continue to resemble white matter lesions.

Methods—

We identified patients with acute lacunar stroke, with or without an acute lacunar infarct on computed tomography or MRI, who had follow-up imaging. A neuroradiologist classified lacunar infarcts progressing to definite or possible cavities on follow-up imaging. We tested associations between cavitation and patient-related, stroke-related, and imaging-related features, including other features of small vessel disease.

Results—

Among 90 patients (mean age 67 years), any cavitation was present on follow-up imaging in 25 (28%), and definite cavitation in 18 (20%). Definite cavitation was associated with increasing time to follow-up imaging (median 228 days, range 54 to 1722, versus no cavitation 72 days, range 6 to 1440;
P
=0.0003) and deep cerebral atrophy (
P
=0.03) but not with age, stroke severity, larger initial infarct size, or other features of small vessel disease. Hypertension and diabetes were negatively associated with cavitation (
P
=0.01 and 0.02, respectively).

Conclusions—

Definite cavitation occurs in one fifth of symptomatic lacunar ischemic strokes, implying that most continue to resemble white matter lesions. Epidemiology and pathophysiology studies of lacunar stroke, which have only counted lacunes as lacunar infarcts, may have substantially underestimated by as much as 5 times the true burden of lacunar stroke disease.
Prevalence of Embolic Signals in Acute Coronary Syndromes
Authors: Meseguer Elena , Labreuche Julien , Durdilly Cloe , Echeverría Amaya , Lavallee Philippa C. , Ducrocq Gregory , Touboul Pierre-Jean , Steg Philippe Gabriel , Amarenco Pierre
Published: January 2010

Background and Purpose—

The purpose of this study was to assess the prevalence of embolic signals (ES) in acute coronary syndromes (ACS) and their association with stroke.

Methods—

From December 2004 to October 2006, 209 consecutive patients with ACS (without prosthetic heart valves or previous stroke) were studied within 72 hours of symptom onset. Patients underwent ES monitoring in both middle cerebral arteries by transcranial Doppler for 30 minutes. Median follow-up was 14 months after discharge.

Results—

Patients were treated according to current European Society Cardiology guidelines. Specifically, 92% of patients received heparin(s), 100% aspirin, 92% clopidogrel, 67% intravenous glycoprotein IIb/IIIa inhibitors, 9% fibrinolysis, and 67% underwent angioplasty. ES were detected in 7 patients (prevalence 3.4%; 95% CI, 1.4 to 6.8). Except for a higher prevalence of ES in patients with unstable angina versus other ACS categories (8.5% versus 1.9%,
P
=0.047), none of the factors among baseline characteristics, clinical features, ACS treatment, and cardiac findings were associated with the presence of ES. During hospitalization, 3 patients without ES had cerebrovascular events (one stroke and 2 transient ischemic attacks), whereas no cerebrovascular events occurred in patients with ES.

Conclusions—

The prevalence of ES among hospitalized patients with ACS is currently low, possibly because of improvement in ACS treatment. In this ACS sample, ES did not appear associated with short-term risk of cerebrovascular events.
Intima-Media Thickness and Regional Cerebral Blood Flow in Older Adults
Authors: Sojkova Jitka , Najjar Samer S. , Beason-Held Lori L. , Metter E. Jeffrey , Davatzikos Christos , Kraut Michael A. , Zonderman Alan B. , Resnick Susan M.
Published: January 2010

Background and Purpose—

The relationship between the thickness of the carotid intima (IMT) and brain function remains unclear in those without clinical manifestations of cerebrovascular disease. Understanding the neural correlates of this vascular measure is important in view of emerging evidence linking poorer cognitive performance with increased IMT in individuals without clinical cerebrovascular disease.

Methods—

Seventy-three participants in the Baltimore Longitudinal Study of Aging (70.9 years; SD, 7.3) were evaluated with carotid artery ultrasound and resting [
15
O]H
2
O positron emission tomography.

Results—

After adjusting for age, gender, and gray and white matter volumes in the regions where IMT is related to regional cerebral blood flow (rCBF), we found that higher IMT was associated with lower rCBF in lingual, inferior occipital, and superior temporal regions. Higher IMT was also associated with higher rCBF in medial frontal gyrus, putamen, and hippocampal-uncal regions (
P
=0.001). Whereas women had lower IMT (
P
=0.01) and mean arterial pressure (
P
=0.05) than men, they showed more robust associations between IMT and rCBF. The relationship between IMT and rCBF was only minimally affected by additional adjustment for mean arterial pressure.

Conclusions—

IMT is related to patterns of resting rCBF in older adults without clinical manifestations of cerebrovascular disease, suggesting that there are regional differences in CBF that are associated with subclinical vascular disease.
γ-Glutamyltranspeptidase and Incident Stroke Among Japanese Men and Women
Authors: Shimizu Yuji , Imano Hironori , Ohira Tetsuya , Kitamura Akihiko , Kiyama Masahiko , Okada Takeo , Sato Shinichi , Shimamoto Takashi , Yamagishi Kazumasa , Tanigawa Takeshi , Iso Hiroyasu
Published: January 2010

Background and Purpose—

Although serum γ-glutamyltranspeptidase (GGT) levels have been associated with cardiovascular disease incidence, few studies have taken into account the effect of alcohol intake on GGT levels. In this study, we examined the relationship between GGT and stroke incidence according to drinking status.

Methods—

We conducted a prospective cohort study of Japanese women (N=6281) and men (N=3471) aged 40 to 69 years living in communities under systematic surveillance for stroke incidence.

Results—

During the 18-year follow-up, 202 (3.2%) women and 230 (6.6%) men had strokes. Serum GGT levels were positively associated with risk of total stroke for women but not men. The multivariable hazard ratios of total stroke for the highest quartile of GGT compared with the lowest quartile were 1.56 (95% CI, 1.01 to 2.39) for women and 1.37 (95% CI, 0.89 to 2.11) for men. Moreover, GGT was associated with total and ischemic stroke risks for never-drinking women.

Conclusions—

Serum GGT is associated with risk of total and ischemic strokes for Japanese women, especially never-drinkers.
Genome-Wide Association Studies of MRI-Defined Brain Infarcts
Authors: Debette Stéphanie , Bis Joshua C. , Fornage Myriam , Schmidt Helena , Ikram M. Arfan , Sigurdsson Sigurdur , Heiss Gerardo , Struchalin Maksim , Smith Albert V. , van der Lugt Aad , DeCarli Charles , Lumley Thomas , Knopman David S. , Enzinger Christian , Eiriksdottir Gudny , Koudstaal Peter J. , DeStefano Anita L. , Psaty Bruce M. , Dufouil Carole , Catellier Diane J. , Fazekas Franz , Aspelund Thor , Aulchenko Yurii S. , Beiser Alexa , Rotter Jerome I. , Tzourio Christophe , Shibata Dean K. , Tscherner Maria , Harris Tamara B. , Rivadeneira Fernando , Atwood Larry D. , Rice Kenneth , Gottesman Rebecca F. , van Buchem Mark A. , Uitterlinden Andre G. , Kelly-Hayes Margaret , Cushman Mary , Zhu Yicheng , Boerwinkle Eric , Gudnason Vilmundur , Hofman Albert , Romero Jose R. , Lopez Oscar , van Duijn Cornelia M. , Au Rhoda , Heckbert Susan R. , Wolf Philip A. , Mosley Thomas H. , Seshadri Sudha , Breteler Monique M.B. , Schmidt Reinhold , Launer Lenore J. , Longstreth W.T.
Published: January 2010

Background and Purpose—

Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI infarct in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.

Methods—

Using 2.2 million genotyped and imputed single nucleotide polymorphisms, each study performed cross-sectional genome-wide association analysis of MRI infarct using age- and sex-adjusted logistic regression models. Study-specific findings were combined in an inverse-variance-weighted meta-analysis, including 9401 participants with mean age 69.7 (19.4% of whom had ≥1 MRI infarct).

Results—

The most significant association was found with rs2208454 (minor allele frequency, 20%), located in intron 3 of
MACRO domain containing 2
gene and in the downstream region of
fibronectin leucine-rich transmembrane protein 3
gene. Each copy of the minor allele was associated with lower risk of MRI infarcts (odds ratio, 0.76; 95% confidence interval, 0.68–0.84;
P
=4.64×10
−7
). Highly suggestive associations (
P
<1.0×10
−5
) were also found for 22 other single nucleotide polymorphisms in linkage disequilibrium (
r
2
>0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 black participants, although 4 single nucleotide polymorphisms within 200 kb from rs2208454 were associated with MRI infarcts in the black population sample.

Conclusions—

This first community-based, genome-wide association study on covert MRI infarcts uncovered novel associations. Although replication of the association with top single nucleotide polymorphisms failed, possibly because of insufficient power, results in the black population sample are encouraging, and further efforts at replication are needed.
Deferoxamine Treatment for Intracerebral Hemorrhage in Aged Rats
Authors: Okauchi Masanobu , Hua Ya , Keep Richard F. , Morgenstern Lewis B. , Schallert Timothy , Xi Guohua
Published: January 2010

Background and Purpose—

Deferoxamine (DFX) reduces brain edema, neurological deficits, and brain atrophy after intracerebral hemorrhage (ICH) in aged and young rats. Our previous study found that 50 mg/kg is an effective dose in aged rats. In the present study, we explored potential therapeutic time windows and optimal therapeutic durations.

Methods—

Aged male Fischer 344 rats (18 months old) sustained an intracaudate injection of 100 μL autologous whole blood, followed by intramuscular DFX or vehicle beginning at different time points, or continuing for different durations. Subgroups of rats were euthanized at day 3 for brain edema measurement and day 56 for brain atrophy determination. Behavioral tests were performed on days 1, 28, and 56 after ICH.

Results—

Systemic administration of DFX, when begun within 12 hours after ICH, reduced brain edema. DFX treatment started 2 hours after ICH and administered for ≥7 days attenuated ICH-induced ventricle enlargement, caudate atrophy, and neurological deficits. DFX attenuated ICH-induced brain atrophy and neurological deficits without detectable side effects when begun within 24 hours and administered for 7 days.

Conclusions—

To the extent that these results can be translated to humans, the therapeutic time window and the optimal duration for DFX in this aged rat model of ICH may provide useful information for an ongoing DFX-ICH clinical trial.
Ischemia in Broca Area Is Associated With Broca Aphasia More Reliably in Acute Than in Chronic Stroke
Authors: Ochfeld Elisa , Newhart Melissa , Molitoris John , Leigh Richard , Cloutman Lauren , Davis Cameron , Crinion Jennifer , Hillis Argye E.
Published: January 2010

Background and Purpose—

We aimed to determine if ischemia involving Broca area predicts Broca aphasia more reliably in acute or chronic stroke.

Methods—

We included consecutive right-hand-dominant patients with left hemisphere ischemic stroke (<48 hours from onset for acute stroke or >6 months after stroke for chronic stroke). MRI scans were analyzed for ischemic lesions or hypoperfusion in Broca area (Brodmann areas 44 and 45). Patients were scored on the Western Aphasia Battery to classify aphasia syndromes; χ
2
tests were used to identify significant associations.

Results—

The presence of infarct involving any part of Broca area and the presence of Broca or global aphasia was much stronger in acute (χ
2
=38.1;
df
1;
P
<0.0001) than in chronic stroke (χ
2
=0.54;
df
1;
P
=0.46; not significant). The association between infarct or hypoperfusion covering all of Broca area and the presence of Broca or global aphasia was much stronger in acute (χ
2
=35.8;
df
1;
P
<0.0001) than in chronic stroke (χ
2
=1.2;
df
1;
p=
0.27; not significant). In a subset of 20 patients studied longitudinally, the associations were significant only acutely, not chronically (χ
2
=20;
df
1;
P
<0.0001 vs. χ
2
=0;
df
1;
p=
1; not significant for ischemia involving part of Broca area, and χ
2
=16.4;
df
1;
P
<0.0001 vs χ
2
=3.2;
df
1;
p=
0.08; not significant for ischemia covering all of Broca area).

Conclusions—

Broca aphasia is more reliably associated with infarct/ hypoperfusion of Broca area in acute stroke. Many chronic stroke patients with damage to part or all of Broca area had neither Broca nor global aphasia. Broca or global aphasia was sometimes present initially in these patients but resolved by 6 months. Our results indicate that the acute aphasia syndrome may allow the clinician to predict the compromised vascular territory, even when structural imaging shows only a small (or no) infarct.
Downregulation of Potassium Chloride Cotransporter KCC2 After Transient Focal Cerebral Ischemia
Authors: Jaenisch Nadine , Witte Otto W. , Frahm Christiane
Published: January 2010

Background and Purpose—

The potassium chloride cotransporter 2 (KCC2) is the main neuronal chloride extruder in the adult nervous system. Therefore, KCC2 is responsible for an inwardly directed electrochemical gradient of chloride that leads to hyperpolarizing GABA-mediated responses. Under some pathophysiological conditions, GABA has been reported to be depolarizing because of a downregulation of KCC2. This is the first study to our knowledge analyzing the expression of KCC2 after a focal cerebral ischemia.

Methods—

Mild and severe ischemia were induced in rats by a transient occlusion of the middle cerebral artery for 30 and 120 minutes, respectively. KCC2 mRNA and protein expression were studied in the ischemic hemisphere after different reperfusion times (2 hour, 1 day, 7 days, 30 days, 168 days) by using quantitative polymerase chain reaction, Western blotting, and immunohistological staining.

Results—

We found a substantial decrease of KCC2 mRNA and protein levels in the ischemic hemisphere, with a stronger downregulation of KCC2 after severe vs mild ischemia. Long-term surviving cells expressing KCC2 could be detected in the infarct core. These cells were identified as GABAergic interneurons mainly expressing parvalbumin.

Conclusions—

Our study revealed a substantial neuron-specific downregulation of KCC2 after focal cerebral ischemia.