bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic Significance of Cerebral Metabolic Abnormalities in Patients With Congestive Heart Failure
Authors: Lee Cheol Whan , Lee Jung Hee , Lim Tae-Hwan , Yang Hyun Suk , Hong Myeong-Ki , Song Jae-Kwan , Park Seong-Wook , Park Seung-Jung , Kim Jae-Joong
Published: June 2012

Background
—Cerebral metabolic abnormalities were proposed as a potential marker of disease severity in congestive heart failure (CHF), but their prognostic significance remains uncertain.

Methods and Results
—We investigated the prognostic value of cerebral metabolic abnormalities in 130 consecutive patients with advanced CHF (100 men aged 42.6±11.9 years; left ventricular ejection fraction, 22.2±6.2%). Proton magnetic resonance spectroscopy data were obtained from localized regions (≈8 mL) of the occipital gray matter and the parietal white matter. The primary end point was the occurrence of death after the proton magnetic resonance spectroscopy. During follow-up (18.5±14.4 months), 21 patients died and 15 underwent urgent heart transplantation. In the Cox proportional model, occipital metabolites (N-acetylaspartate, creatine, choline, and myoinositol), parietal N-acetylaspartate level, and the duration of CHF symptoms (>12 months) were validated as univariate predictors of death. In multivariate Cox analyses, however, the occipital N-acetylaspartate level was an independent predictor of death (hazard ratio, 0.52; 95% CI, 0.41 to 0.67;
P
<0.001). An analysis with respect to the combined end point of death or urgent transplantation showed similar results. The best cutoff value (9.0 mmol/kg) for occipital N-acetylaspartate level had 75% sensitivity and 67% specificity to predict mortality.

Conclusions
—The occipital N-acetylaspartate level is a powerful and independent predictor of CHF mortality, suggesting that cerebral metabolic abnormalities may be used as a new prognostic marker in the assessment of patients with CHF.
Low Circulating Vitamin B
6
Is Associated With Elevation of the Inflammation Marker C-Reactive Protein Independently of Plasma Homocysteine Levels
Authors: Friso Simonetta , Jacques Paul F. , Wilson Peter W.F. , Rosenberg Irwin H. , Selhub Jacob
Published: June 2012

Background
—Lower vitamin B
6
concentrations are reported to confer an increased and independent risk for cardiovascular disease (CVD). The mechanism underlying this relationship, however, remains to be defined. Other diseases, such as rheumatoid arthritis, are associated with reduced vitamin B
6
levels. Despite a clear distinction in pathophysiology, inflammatory reaction may be the major link between these diseases. We hypothesized a relationship between pyridoxal 5′-phosphate (PLP), the active form of vitamin B
6
, and the marker of inflammation C-reactive protein (CRP). We also evaluated whether total plasma homocysteine (tHcy), a well-defined risk factor for CVD and a major determinant of plasma PLP levels, had a possible role as a mediator of this hypothesized relationship.

Methods and Results
—Data from 891 participants from the population-based Framingham Heart Study cohort were analyzed. Subjects were divided into 2 groups according to normal or elevated CRP values: group 1, CRP <6 mg/L; group 2, CRP ≥6 mg/L. Plasma PLP levels were substantially lower in group 2 than in group 1 (mean values in group 2, 36.5 nmol/L versus 55.8 nmol/L in group 1,
P
<0.001). In a multiple logistic regression model adjusted for tHcy, the association of PLP with CRP remained highly significant (
P
=0.003).

Conclusions
—Low plasma PLP is associated with higher CRP levels independently of tHcy. This observation may reflect a vitamin B
6
utilization in the presence of an underlying inflammatory process and represent a possible mechanism to explain the decreased vitamin B
6
levels in CVD.
Autosomal Recessive Catecholamine- or Exercise-Induced Polymorphic Ventricular Tachycardia
Authors: Lahat Hadas , Eldar Michael , Levy-Nissenbaum Etgar , Bahan Tangiz , Friedman Eitan , Khoury Asad , Lorber Avraham , Kastner Daniel L. , Goldman Boleslaw , Pras Elon
Published: June 2012

Background
—Catecholaminergic polymorphic ventricular tachycardia (PVT) is characterized by episodes of syncope, seizures, or sudden death in response to physiological or emotional stress. In 2 families with autosomal dominant inheritance, the disease gene was mapped to chromosome 1q42-43. The objectives of this study were to characterize the clinical features of the disease in a Bedouin tribe from Israel and to map the disease gene.

Methods and Results
—In this Bedouin tribe, 9 children (age, 7±4 years) from 7 related families have died suddenly during the past decade, and 12 other children suffered from recurrent syncope and seizures starting at the age of 6±3 years. Parents of affected individuals were asymptomatic and were all related (first-, second-, or third-degree cousins). Segregation analysis suggested autosomal recessive inheritance. All 12 symptomatic patients and 1 asymptomatic sibling (mean age, 13±7 years) were found to have a relative resting bradycardia (64±13 bpm, versus 93±12 bpm in the unaffected siblings), as well as PVT induced by treadmill or isoproterenol infusion and appearing at a mean sinus rate of 110±10 bpm. Patients responded favorably to treatment with β-blockers. A genome-wide search using polymorphic DNA markers mapped the disease locus to a 16-megabase interval on chromosome 1p13-21. A maximal lod score of 8.24 was obtained with D1S189 at θ=0.00. Sequencing of
KCND3
, a gene that encodes an I
tO
potassium channel transporter, did not reveal any significant sequence alterations.

Conclusions
—This unique form of autosomal recessive PVT affects young children and may be lethal if left untreated. Linkage analysis maps this disorder to chromosome 1p13-21.
Combined Angiotensin II Receptor Antagonism and Angiotensin-Converting Enzyme Inhibition Further Attenuates Postinfarction Left Ventricular Remodeling
Authors: Mankad Sunil , d’Amato Thomas A. , Reichek Nathaniel , McGregor Walter E. , Lin Jeff , Singh Deepak , Rogers Walter J. , Kramer Christopher M.
Published: June 2012

Background
—ACE inhibition (ACEI) attenuates post–myocardial infarction (MI) LV remodeling, but the effects of angiotensin II type 1 receptor (AT
1
) antagonism alone or in combination with ACEI are unclear. Accordingly, we investigated the effects of AT
1
antagonism, ACEI, and their combination in a well-characterized ovine postinfarction model.

Methods and Results
—Beginning 2 days after transmural anteroapical MI, 62 sheep were treated with 1 of 5 treatment regimens: no therapy (control, n=12), standard-dose ACEI (sACEI; ramipril 10 mg/d, n=14), high-dose ACEI (hACEI; ramipril 20 mg/d, n=8), AT
1
blockade (losartan 50 mg/d, n=13), and combination therapy with sACEI+AT
1
blockade (CT; ramipril 10 mg/d+losartan 50 mg/d, n=15). MRI was performed before and 8 weeks after MI to quantify changes in LV end-diastolic and end-systolic volume indices (ΔEDVI, ΔESVI) and ejection fraction (ΔEF). Change in regional percent intramyocardial circumferential shortening in noninfarcted segments adjacent to the infarct (Adj Δ%S) was measured by tagged MRI. CT resulted in the most marked blunting of LV remodeling: ΔESVI (+1.0±0.4, +0.7±0.4, +0.6±0.3†, +0.9±0.5, and +0.4±0.2* mL/kg); ΔEDVI (+0.9±0.4, +0.7±0.5, +0.6±0.5, +0.9±0.5, and +0.4±0.3‡ mL/kg); ΔEF (−24±7, −18±6, −14±7†, −18±10, and −11±9* %); and Adj Δ%S (−8±4, −7±3, −5±3, −5±3, and −2±3* %) for Control, sACEI, hACEI, AT
1
blockade, and CT, respectively (*
P
<0.04 versus sACEI, AT
1
blockade, and control; †
P
<0.05 versus control; ‡
P
<0.002 versus AT
1
blockade and control). EDVI and ESVI at 8 weeks after MI were smallest with CT (
P
<0.02 versus all).

Conclusions
—Combination therapy with sACEI+AT
1
blockade shows promise in attenuating postinfarction LV remodeling but was not clearly superior to hACEI in the present study.
Responses of GLUT4-Deficient Hearts to Ischemia Underscore the Importance of Glycolysis
Authors: Tian Rong , Abel E. Dale
Published: June 2012

Background
—The ischemic heart is dependent on glycolysis for ATP generation, and therapies that increase glucose utilization during ischemia improve survival. Myocardial ischemia results in the translocation of the glucose transporter proteins GLUT1 and GLUT4 to the sarcolemma. The increased glucose entry via these transporters contributes to enhanced glycolysis during ischemia.

Methods and Results
—To determine the role of GLUT4 in mediating increased glycolytic flux during ischemia, hearts from mice with cardiac-selective GLUT4 deficiency (G4H−/−) were subjected to global low-flow ischemia. During normal perfusion, hearts from fed G4H−/− mice showed increased GLUT1-mediated glucose uptake, higher concentrations of glycogen and phosphocreatine, but delayed recovery after ischemia. When these compensatory changes were eliminated by a 20-hour fast, G4H−/− hearts exhibited depressed glucose utilization during ischemia and developed profound and irreversible systolic and diastolic dysfunction associated with accelerated ATP depletion during ischemia and diminished regeneration of high-energy phosphate compounds on reperfusion.

Conclusions
—GLUT4 is an important mediator of enhanced glycolysis during ischemia and represents an important protective mechanism against ischemic injury.
Differential Expression of Matrix Metalloproteinases After Stent Implantation and Balloon Angioplasty in the Hypercholesterolemic Rabbit
Authors: Feldman Laurent J. , Mazighi Mikael , Scheuble Aliocha , Deux Jean-François , De Benedetti Edoardo , Badier-Commander Cécile , Brambilla Elisabeth , Henin Dominique , Steg P. Gabriel , Jacob Marie-Paule
Published: June 2012

Background
—Intimal hyperplasia is the principal mechanism of in-stent restenosis. Matrix metalloproteinases (MMPs) play a key role in intimal growth after balloon angioplasty (BA). Little is known, however, about MMP expression after stent implantation (ST). We investigated whether MMP9 and MMP2 are differentially expressed after ST and BA.

Methods and Results
—Hypercholesterolemic rabbits underwent ST and BA in the right and left iliac arteries, respectively. The expression of MMPs and their inhibitors (TIMPs) was studied at various time points in the injured arteries by use of zymography, reverse transcription–polymerase chain reaction, and immunohistochemistry. MMP2, but not MMP9, was constitutively expressed in uninjured arteries. MMP9 expression was rapidly induced after injury, whereas the increase in MMP2 expression was delayed. At all time points, pro-MMP9 activity and MMP9 mRNA levels were ≥2-fold (ANOVA,
P
=0.002) and ≥3-fold (
P
<0.0001) higher after ST than after BA, respectively. Active MMP9 was detected only after ST. Although the increases in MMP2 mRNA levels were of similar magnitudes after ST and BA, pro-MMP2 activity was slightly higher 7 and 30 days after ST, and MMP2 activity was ≥2-fold higher 7 to 60 days after ST (
P
=0.002). No difference in TIMP expression was observed between stented and balloon-injured arteries. Cellular distributions of MMPs and TIMP1 were similar after ST and BA. Early inflammatory cell recruitment and 30-day intimal growth were more severe after ST.

Conclusions
—Stent implantation results in more intense and sustained expression of MMP9 and activation of MMP2 than balloon angioplasty.
Long-Term Effect of
N
-Acetyl-Seryl-Aspartyl-Lysyl-Proline on Left Ventricular Collagen Deposition in Rats With 2-Kidney, 1-Clip Hypertension
Authors: Rhaleb Nour-Eddine , Peng Hongmei , Yang Xiao-Ping , Liu Yun-He , Mehta Dharmesh , Ezan Eric , Carretero Oscar A.
Published: June 2012

Background
—
N
-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a natural inhibitor of pluripotent hematopoietic stem cell proliferation. Ac-SDKP plasma concentration is increased 5-fold after angiotensin-converting enzyme inhibition. Here we studied the effect of Ac-SDKP on monocyte/macrophage infiltration, fibroblast proliferation, and collagen deposition in the rat heart in renovascular hypertension.

Methods and Results
—We investigated whether long-term Ac-SDKP administration would prevent left ventricular (LV) hypertrophy and interstitial collagen deposition in rats with 2-kidney, 1-clip (2K-1C) hypertension. Ac-SDKP (400 μg · kg
−1
· d
−1
) did not affect development of hypertension. Mean blood pressure was similar in rats with 2K-1C hypertension whether they were given vehicle or Ac-SDKP and was higher than in controls. Both LV weight and cardiomyocyte size were significantly increased in rats with 2K-1C hypertension compared with controls and were unaffected by Ac-SDKP. Proliferating cell nuclear antigen- and monocyte/macrophage-positive cells were increased in the LV of 2K-1C hypertensive rats; this increase was significantly blunted by Ac-SDKP (
P
<0.001). LV interstitial collagen fraction was also increased in 2K-1C hypertensive rats given vehicle (10.1±0.8%) compared with sham (5.3±0.1%,
P
<0.0001), and this increase was prevented by Ac-SDKP (5.4±0.4%,
P
<0.001).

Conclusions
—Ac-SDKP inhibited monocyte/macrophage infiltration, cell proliferation, and collagen deposition in the LV of hypertensive rats without affecting blood pressure or cardiac hypertrophy, suggesting that it may be partly responsible for the cardioprotective effect of angiotensin-converting enzyme inhibitors.
Persistently Increased Serum Concentrations of Cardiac Troponin T in Patients With Idiopathic Dilated Cardiomyopathy Are Predictive of Adverse Outcomes
Authors: Sato Yukihito , Yamada Tasuku , Taniguchi Ryoji , Nagai Kozo , Makiyama Takeru , Okada Hideshi , Kataoka Kazuaki , Ito Haruyasu , Matsumori Akira , Sasayama Shigetake , Takatsu Yoshiki
Published: June 2012

Background
—The measurement of serum concentrations of cardiac troponin T (TnT) is a simple, useful method to detect myocyte injury that may be repeated multiple times to follow patients without interobserver variability.

Methods and Results
—Multiple measurements of TnT with a second-generation assay were performed in 60 patients with dilated cardiomyopathy confirmed by coronary angiography and endomyocardial biopsy between April 1996 and December 1999. Three evolutionary patterns of TnT concentrations were identified. Thirty-three patients had concentrations of TnT <0.02 ng/mL throughout the follow-up period (group 1). The remaining 27 patients had high initial serum concentrations of TnT (≥0.02 ng/mL). In 10 of these 27 patients, TnT decreased to <0.02 ng/mL during follow-up (group 2), whereas 17 had persistently high serum TnT concentrations despite being conventionally treated for chronic congestive heart failure (group 3). Although the initial echocardiographic left ventricular diastolic dimension (LVDd) and left ventricular ejection fraction (LVEF) were not significantly different among the 3 groups, follow-up echocardiography showed significantly decreased LVDd and increased LVEF in group 1 (each
P
<0.01) and group 2 (each
P
<0.05) compared with increased LVDd and decreased LVEF in group 3 (each
P
<0.05). The cardiac event-free rate was significantly lower in group 3 than in groups 1 and 2 (each
P
<0.001), and the survival rate was lower in group 3 than in group 1 (
P
<0.05).

Conclusions
—Persistently increased TnT concentrations in dilated cardiomyopathy suggest ongoing subclinical myocyte degeneration associated with deterioration of the patients’ clinical status.
Reduction of Stroke Events With Pravastatin
Authors: Byington Robert P. , Davis Barry R. , Plehn Jonathan F. , White Harvey D. , Baker Jennifer , Cobbe Stuart M. , Shepherd James
Published: June 2012

Background
—Stroke is a leading cause of death and disability. Although clinical trials of the early lipid-lowering therapies did not demonstrate a reduction in the rates of stroke, data from recently completed statin trials strongly suggest benefit.

Methods and Results
—The effect of pravastatin 40 mg/d on stroke events was investigated in a prospectively defined pooled analysis of 3 large, placebo-controlled, randomized trials that included 19 768 patients with 102 559 person-years of follow-up. In all, 598 participants had a stroke during ≈5 years of follow-up. The 2 secondary prevention trials (CARE [Cholesterol And Recurrent Events] and LIPID [Long-term Intervention with Pravastatin in Ischemic Disease]) individually demonstrated reductions in nonfatal and total stroke rates. When the 13 173 patients from CARE and LIPID were combined, there was a 22% reduction in total strokes (95% CI 7% to 35%,
P
=0.01) and a 25% reduction in nonfatal stroke (95% CI 10% to 38%). The beneficial effect of pravastatin on total stroke was observed across a wide range of patient characteristics. WOSCOPS (West of Scotland Coronary Prevention Study, a primary prevention trial in hypercholesterolemic men) exhibited a similar, although smaller, trend for a reduction in total stroke. Among the CARE/LIPID participants, pravastatin was associated with a 23% reduction in nonhemorrhagic strokes (95% CI 6% to 37%), but there was no statistical treatment group difference in hemorrhagic or unknown type.

Conclusions
—Pravastatin reduced the risk of stroke over a wide range of lipid values among patients with documented coronary disease. This effect was due to a reduction in nonfatal nonhemorrhagic strokes.
Structural Abnormalities of Great Arterial Walls in Congenital Heart Disease
Authors: Niwa Koichiro , Perloff Joseph K. , Bhuta Sunita M. , Laks Hillel , Drinkwater Davis C. , Child John S. , Miner Pamela D.
Published: June 2012

Background
—Great arteries in congenital heart disease (CHD) may dilate, become aneurysmal, or rupture. Little is known about medial abnormalities in these arterial walls. Accordingly, we studied 18 types of CHD in patients from neonates to older adults.

Methods and Results
—Intraoperative biopsies from ascending aorta, paracoarctation aorta, truncus arteriosus, and pulmonary trunk in 86 patients were supplemented by 16 necropsy specimens. The 102 patients were 3 weeks to 81 years old (average, 32±6 years). Biopsies were examined by light (LM) and electron (EM) microscopy; necropsy specimens by LM. Positive aortic controls were from 15 Marfan patients. Negative aortic controls were from 11 coronary artery disease patients and 1 transplant donor. Nine biopsies from acquired trileaflet aortic stenosis were compared with biopsies from bicuspid aortic stenosis. Negative pulmonary trunk controls were from 7 coronary artery disease patients. A grading system consisted of negative controls and grades 1, 2, and 3 (positive controls) based on LM and EM examination of medial constituents.

Conclusions
—Medial abnormalities in ascending aorta, paracoarctation aorta, truncus arteriosus, and pulmonary trunk were prevalent in patients with a variety of forms of CHD encompassing a wide age range. Aortic abnormalities may predispose to dilatation, aneurysm, and rupture. Pulmonary trunk abnormalities may predispose to dilatation and aneurysm; hypertensive aneurysms may rupture. Pivotal questions are whether these abnormalities are inherent or acquired, whether CHD plays a causal or facilitating role, and whether genetic determinants are operative.
Right Ventricular Hypertrophy Secondary to Pulmonary Hypertension Is Linked to Rat Chromosome 17
Authors: Zhao Lan , Sebkhi Abdelkrim , Nunez Derek J. R. , Long Lu , Haley Christopher S. , Szpirer Josiane , Szpirer Claude , Williams Alan J. , Wilkins Martin R.
Published: June 2012

Background
—Fischer 344 (F344) rats are relatively resistant to hypoxia-induced right ventricular (RV) hypertrophy compared with the Wistar-Kyoto (WKY) strain. These 2 strains were used to examine the genetic basis for the differential response.

Methods and Results
—Male F
2
offspring from an F344×WKY intercross were exposed to hypoxia (10% O
2
) for 3 weeks, and pulmonary artery pressure and cardiac chamber weights were measured. Genomic DNA was screened by use of polymorphic microsatellite markers across the whole genome (excluding the sex chromosomes). A quantitative trait locus (QTL) for RV weight was identified on rat chromosome 17 (lod score 6.5) that accounted for 22% of the total variance of RV weight in the F
2
population and was independent of pulmonary artery pressure. The peak was centered over marker D17Rat41, close to
Chrm3
, with a 1-lod support interval of 5 cM. Comparison of homologous regions in mice and humans suggested that Ryr2, the cardiac isoform of the ryanodine receptor, colocalizes with our QTL. A panel of somatic cell hybrids and fluorescence in situ hybridization mapped Ryr2 close to the gene
Chrm3
within our QTL. [
3
H]Ryanodine binding to cardiac membranes from the parental strains showed a 21% reduction in B
max
in the WKY compared with the F344 strain, with no difference in
K
d
.

Conclusions
—These data provide the first demonstration of a QTL linked to the RV response to hypoxia-induced pulmonary hypertension. The Ryr2 receptor gene lies within this QTL and merits further investigation as a candidate for this differential RV response.
Angiotensin II–Induced Hypertension Accelerates the Development of Atherosclerosis in ApoE-Deficient Mice
Authors: Weiss Daiana , Kools John J. , Taylor W. Robert
Published: June 2012

Background
—Angiotensin II may contribute to the development and progression of atherosclerotic lesions because of its growth and proinflammatory effects. We sought to determine whether angiotensin II–induced hypertension would augment and accelerate the development of atherosclerotic lesions in apoE-deficient mice.

Methods and Results
—Angiotensin II (0.7 mg · kg
−1
· d
−1
SC) was administered to apoE-deficient mice via osmotic minipumps. The animals were placed on either standard chow or an atherogenic diet. After 8 weeks, the mean atherosclerotic lesion area in the descending thoracic and abdominal aortas of animals on a standard chow diet was 0.4±0.1% compared with 5.2±1.2% in those animals maintained on an atherogenic diet (
P
<0.0001). In angiotensin II–treated animals on standard chow, the mean lesion area was increased to 11.0±2.3%, which was further increased to 69.9±9.4% (
P
<0.0001) in angiotensin II–treated animals on an atherogenic diet. Similar findings were obtained when tissues from the ascending aorta were analyzed. At 8 weeks in mice receiving a standard chow diet, angiotensin II dramatically increased the atherosclerotic lesion area by 840±83 μm
2
(
P
<0.0001). Animals on a high-fat diet had a similar marked increase in lesion area in response to angiotensin II (217±19 μm
2
,
P
<0.0001). In contrast, when hypertension was induced with norepinephrine, only a modest effect on the atherosclerotic lesion area was observed.

Conclusions
—Angiotensin II–induced hypertension specifically increased the development of atherosclerosis in apoE knockout mice. This response was seen in animals receiving either standard chow or an atherogenic diet. These studies demonstrate the profound effect of angiotensin II on the development of atherosclerosis.
Inhaled Nitric Oxide Versus Aerosolized Iloprost in Secondary Pulmonary Hypertension in Children With Congenital Heart Disease
Authors: Rimensberger Peter C. , Spahr-Schopfer Isabelle , Berner Michel , Jaeggi Edgar , Kalangos Afksendiyos , Friedli Beat , Beghetti Maurice
Published: June 2012

Background
—Inhaled nitric oxide (iNO) has been used to assess the vasodilator capacity of the pulmonary vascular bed in children with congenital heart disease and elevated pulmonary vascular resistance. Inhaled iloprost is a pulmonary vasodilator for the long-term treatment of pulmonary hypertension (PHT). Because these 2 vasodilators act through different pathways (release of cGMP or cAMP, respectively), we compared the pulmonary vasodilator capacity of each.

Methods and Results
—A total of 15 children with congenital heart disease and PHT who had elevated pulmonary vascular resistance (preoperative, n=10; immediately postoperative, n=5) were first given 20 ppm of iNO for 10 minutes; then, after baseline values were reached again, they were given aerosolized iloprost at 25 ng · kg
−1
· min
−1
for another 10 minutes. Finally, iNO and iloprost were given simultaneously for 10 minutes. With iNO, the pulmonary vascular resistance and systemic vascular resistance ratio decreased from 0.48±0.38 to 0.27±0.16 (
P
<0.001). Similarly, iloprost decreased the ratio from 0.49±0.38 to 0.26±0.11 (
P
<0.05). The combination had no additional effect on the resistance ratio. Plasma cGMP increased from 17.6±11.9 to 34.7±21.4 nmol/L during iNO (
P
<0.01), and plasma cAMP increased from 55.7±22.9 to 65.1±21.2 nmol/L during iloprost inhalation (
P
<0.05).

Conclusions
—In children with PHT and congenital heart disease, both iNO and aerosolized iloprost are equally effective in selectively lowering pulmonary vascular resistance through an increase in cGMP or cAMP, respectively. However, the combination of both vasodilators failed to prove more potent than either substance alone. Aerosolized iloprost might be an alternative to iNO for early testing of vascular reactivity and for the postoperative treatment of acute PHT.
Endothelial Cells Inhibit Flow-Induced Smooth Muscle Cell Migration
Authors: Redmond Eileen M. , Cullen John P. , Cahill Paul A. , Sitzmann James V. , Stefansson Steingrimur , Lawrence Daniel A. , Okada S. Steve
Published: June 2012

Background
—The endothelium may play a pivotal role in hemodynamic force–induced vascular remodeling. We investigated the role of endothelial cell (EC) plasminogen activator inhibitor-1 (PAI-1) in modulating flow-induced smooth muscle cell (SMC) migration.

Methods and Results
—Human SMCs cocultured with or without human ECs were exposed to static (0 mL/min) or flow (26 mL/min; shear stress 23 dyne/cm
2
) conditions for 24 hours in a perfused capillary culture system. SMC migration was then assessed with a Transwell migration assay. In the absence but not in the presence of ECs, pulsatile flow significantly increased the migration of SMCs (264±26%) compared with SMCs under static conditions, concomitant with a 3- and 4-fold increase in PAI-1 mRNA and protein, respectively, in cocultured ECs. In the presence of PAI-1−/− ECs, flow increased wild-type SMC migration (226±25%), an effect that was reversed by exogenous PAI-1. To determine whether the antimigratory activity of PAI-1 was dependent primarily on inhibition of PAs or its association with vitronectin, experiments were conducted with PAI-1R (a mutant PAI-1 that binds to vitronectin but does not inhibit PA) and PAI-1K (a mutant that inhibits PA but has reduced affinity for vitronectin). PAI-1R inhibited both basal and flow-induced migration, whereas PAI-1K inhibited flow-induced migration in the absence of any effect on baseline migration.

Conclusions
—Flow-induced EC PAI-1 inhibits flow-induced SMC migration in vitro. EC PAI-1 expression may be one of the predominant mechanisms responsible for controlling the process of vascular remodeling.
Postmenopausal Hormone Therapy and Risk of Stroke
Authors: Simon Joel A. , Hsia Judith , Cauley Jane A. , Richards Cynthia , Harris Fran , Fong Josephine , Barrett-Connor Elizabeth , Hulley Stephen B.
Published: June 2012

Background
—Observational studies have shown that postmenopausal hormone therapy may increase, decrease, or have no effect on the risk of stroke. To date, no clinical trial has examined this question. To investigate the relation between estrogen plus progestin therapy and risk of stroke among postmenopausal women, we analyzed data collected from the Heart & Estrogen-progestin Replacement Study (HERS), a secondary coronary heart disease prevention trial.

Methods and Results
—Postmenopausal women (n=2763) were randomly assigned to take conjugated estrogen plus progestin or placebo. Primary outcomes for these analyses were stroke incidence and stroke death during a mean follow-up of 4.1 years. The number of women with strokes was compared with the number of women without strokes. A total of 149 women (5%) had 1 or more strokes, 85% of which were ischemic, resulting in 26 deaths. Hormone therapy was not significantly associated with risk of nonfatal stroke (relative hazard [RH] 1.18; 95% CI 0.83 to 1.66), fatal stroke (RH 1.61; 95% CI 0.73 to 3.55), or transient ischemic attack (RH 0.90; 95% CI 0.57 to 1.42). Independent predictors of stroke events included increasing age, hypertension, diabetes, current cigarette smoking, and atrial fibrillation. Black women were at increased risk compared with white women, and unexpectedly, body mass index was inversely associated with stroke risk.

Conclusions
—Hormone therapy with conjugated equine estrogen and progestin had no significant effect on the risk for stroke among postmenopausal women with coronary disease.
Percutaneous Coronary Intervention After Subcutaneous Enoxaparin Pretreatment in Patients With Unstable Angina Pectoris
Authors: Collet J. Ph. , Montalescot G. , Lison L. , Choussat R. , Ankri A. , Drobinski G. , Sotirov I. , Thomas D.
Published: June 2012

Background
—Subcutaneous low-molecular-weight (LMW) heparins can effectively replace unfractionated heparin in patients with unstable angina or non–Q-wave myocardial infarction. However, the optimal anticoagulation strategy for these patients when they require cardiac catheterization is still unclear. Therefore, we evaluated a new and simple strategy of anticoagulation in these patients.

Methods and Results
—A total of 451 consecutive patients with unstable angina/non–Q-wave myocardial infarction were treated for at least 48 hours with subcutaneous injections of enoxaparin (1 mg [100 IU]/kg every 12 hours, cycled at 6 AM and 6 PM). Of this unselected population, 293 patients (65%) underwent a coronary angiography within 8 hours of the morning LMW heparin injection, followed by immediate percutaneous coronary intervention (PCI) in 132 patients (28%). PCI was performed without any additional bolus of unfractionated/LMW heparin and without coagulation monitoring. Anti-Xa activity at the time of catheterization was 0.98±0.03 IU/mL, was >0.5 IU/mL in 97.6% of patients, and did not relate to the LMW heparin injection-to-catheterization time. There were no in-hospital abrupt closures or urgent revascularizations after PCI. The death/myocardial infarction rate at 30 days was 3.0% in the PCI group (n=132) but 6.2% in the whole population (n=451) and 10.8% in the patients not undergoing catheterization (n=158). The 30-day major bleeding rate was 0.8% in the PCI group, which was comparable to that of patients without catheterization (1.3%).

Conclusions
—PCI within 8 hours of the last enoxaparin subcutaneous injection seems to be safe and effective. The safety of subcutaneous LMW heparin in combination with platelet glycoprotein IIb/IIIa blockade awaits further study.
Midwall Mechanics Are Improved After Regression of Hypertensive Left Ventricular Hypertrophy and Normalization of Chamber Geometry
Authors: Perlini Stefano , Muiesan Maria Lorenza , Cuspidi Cesare , Sampieri Lorena , Trimarco Bruno , Aurigemma Gerard P. , Agabiti-Rosei Enrico , Mancia Giuseppe
Published: June 2012

Background
—It is still unclear whether substantial regression of hypertensive left ventricular hypertrophy (LVH) and normalization of chamber geometry are associated with improved left ventricular (LV) myocardial function.

Methods and Results
—Midwall mechanics were evaluated in 152 patients undergoing 1 year of effective antihypertensive treatment. Two-dimensionally directed M-mode echocardiography was performed as follows: (1) after a 4-week placebo “run-in” period, (2) after 1 year of treatment with 20 mg/d lisinopril (alone or associated with 12.5 to 25 mg/d hydrochlorothiazide), and (3) after a final 1-month placebo period to allow blood pressure (24-hour average ambulatory monitoring) to return to pretreatment levels. Treatment-induced reductions in blood pressure (from 149±16/95±11 to 131±12/83±10 mm Hg,
P
<0.05) and circumferential end-systolic wall stress (from 84±22 to 72±19 g/cm
2
,
P
<0.05) were associated with a marked reduction in LV mass index (from 159±30 to 133±26 g/m
2
,
P
<0.05). LVH regression was accompanied by an increase in midwall fractional shortening (from 19.7±2.7% to 20.9±2.7%,
P
<0.05) and by a decrease in relative wall thickness (from 48.2±7.7% to 44.1±6.7%,
P
<0.05). The improvement in midwall function associated with afterload reduction and substantial LVH regression persisted after antihypertensive therapy withdrawal and restoration of the hypertensive state. Despite a significant increase in end-systolic wall stress, further LV chamber remodeling did not occur. The preservation of relative wall thickness was associated with a persistent improvement in midwall systolic function.

Conclusions
—Regression of concentric LVH is associated with an improvement of midwall systolic function, which is more dependent on the normalization of LV geometry than on the reduction in LV systolic stress.
Effects of Early Use of Atenolol or Captopril on Infarct Size and Ventricular Volume
Authors: Galcerá-Tomás José , Castillo-Soria Francisco José , Villegas-García Manuel , Florenciano-Sánchez Rafael , Sánchez-Villanueva José Ginés , de la Rosa José Antonio Nuño , Martínez-Caballero Antonio , Valentí-Aldeguer José Antonio , Jara-Pérez Pedro , Párraga-Ramírez Manuel , López-Martínez Iluminada , Iñigo-García Luis , Picó-Aracil Francisco
Published: June 2012

Background
—β-Blockers and ACE inhibitors reduce early mortality when either one is started in the first hours after myocardial infarction (MI). Considering the close correlation between morphological changes and prognosis, we aimed to investigate whether the benefit of both β-blockers and ACE inhibitors might reside in a similar protective effect on infarct size or ventricular volume.

Methods and Results
—In a randomized, double-blind comparison between early treatment with captopril or atenolol in 121 patients with acute anterior MI, both drugs showed a similar reduction in mean blood pressure. However, only the atenolol-treated patients showed a significant early reduction in heart rate. Infarct size, obtained from the perfusion defect in resting single photon emission imaging, was higher in captopril-treated patients than in atenolol-treated patients: 29.8±12% versus 20.8±12% (
P
<0.01) by polar map and 28.3±13% versus 20.0±13% (
P
<0.01) by tomography. Changes from baseline to 1 week and to 3 months in ventricular end-diastolic volume, assessed by echocardiography, were as follows: 58±14 versus 64±19 (
P
<0.05) and 65±21 mL/m
2
(
P
<0.05), respectively, with captopril, and 58±18 versus 64±18 (
P
<0.05) and 69±30 mL/m
2
(
P
<0.05), respectively, with atenolol. Neither group showed significant changes in end-systolic volume. Among patients with perfusion defect >18% (n=51), those treated with atenolol showed a significant increase of end-systolic and end-diastolic ventricular volumes, whereas captopril-treated patients did not.

Conclusions
—Although early treatment with atenolol or captopril results in similar overall short- and medium-term preservation of ventricular function and volumes, in patients with larger infarctions, a β-blocker alone does not adequately protect myocardium from ventricular dilatation.
The Gap-Junctional Protein Connexin40 Is Elevated in Patients Susceptible to Postoperative Atrial Fibrillation
Authors: Dupont Emmanuel , Ko Yu-Shien , Rothery Stephen , Coppen Steven R. , Baghai Max , Haw Marcus , Severs Nicholas J.
Published: June 2012

Background
—Atrial fibrillation (AF), a cardiac arrhythmia arising from atrial re-entrant circuits, is a common complication after cardiac surgery, but the proarrhythmic substrate underlying the development of postoperative AF remains unclear. This study investigated the hypothesis that altered expression of connexins, the component proteins of gap junctions, is a determinant of a predisposition to AF.

Methods and Results
—The expression of the 3 atrial connexins–connexins 43, 40, and 45—was analyzed at the mRNA and protein levels by Northern and Western blotting techniques and immunoconfocal microscopy in right atrial appendages from patients with ischemic heart disease who were undergoing coronary artery bypass surgery. Twenty percent of the patients subsequently developed AF, which allowed retrospective division of the samples into 2 groups, non-AF and AF. Connexin43 and connexin45 transcript and protein levels did not differ between the groups. However, connexin40 transcript and protein were expressed at significantly higher levels in the AF group. Connexin40 protein was markedly heterogeneous in distribution.

Conclusions
—Atrial myocardium susceptible to AF is distinguished from its nonsusceptible counterpart by elevated connexin40 expression. The heterogeneity of connexin distribution could give rise to different resistive properties and conduction velocities in spatially adjacent regions of tissue, which become enhanced and, hence, proarrhythmic the higher the overall level of connexin40.
Flow (Shear Stress)–Induced Endothelium-Dependent Dilation Is Altered in Mice Lacking the Gene Encoding for Dystrophin
Authors: Loufrani Laurent , Matrougui Khalid , Gorny Diane , Duriez Micheline , Blanc Isabelle , Lévy Bernard I. , Henrion Daniel
Published: June 2012

Background
—Dystrophin has a key role in striated muscle mechanotransduction of physical forces. Although cytoskeletal elements play a major role in the mechanotransduction of pressure and flow in vascular cells, the role of dystrophin in vascular function has not yet been investigated. Thus, we studied endothelial and muscular responses of arteries isolated from mice lacking dystrophin (mdx mice).

Methods and Results
—Carotid and mesenteric resistance arteries 120 μm in diameter were isolated and mounted in vitro in an arteriograph to control intraluminal pressure and flow. Blood pressure was not affected by the absence of dystrophin. Pressure-induced (myogenic), phenylephrine-induced, and KCl-induced forms of tone were unchanged. Flow (shear stress)–induced dilation in arteries isolated from mdx mice was decreased by 50% to 60%, whereas dilation to acetylcholine or sodium nitroprusside was unaffected. NG-nitro-L-arginine methyl ester–sensitive flow dilation was also decreased in arteries from mdx mice. Thus, the absence of dystrophin was associated with a defect in signal transduction of shear stress. Dystrophin was present in vascular endothelial and smooth muscle cells, as shown by immunolocalization, and localized at the level of the plasma membrane, as seen by confocal microscopy of perfused isolated arteries.

Conclusions
—This is the first functional study of arteries lacking the gene for dystrophin. Vascular reactivity was normal, with the exception of flow-induced dilation. Thus, dystrophin could play a specific role in shear-stress mechanotransduction in arterial endothelial cells. Organ damage in such diseases as Duchenne dystrophy might be aggravated by such a defective arterial response to flow.
Magnetic Resonance Characterization of the Peri-Infarction Zone of Reperfused Myocardial Infarction With Necrosis-Specific and Extracellular Nonspecific Contrast Media
Authors: Saeed Maythem , Lund Gunnar , Wendland Michael F. , Bremerich Jens , Weinmann Hanns-Joachim , Higgins Charles B.
Published: June 2012

Background
—Because ischemically injured myocardium is frequently composed of viable and nonviable portions, a method to discriminate the two is useful for clinical management.

Methods and Results
—Ischemically injured myocardium was characterized with extracellular nonspecific (Gd-DTPA) and necrosis-specific (mesoporphyrin) MR contrast media in rats. Relaxation rates (R1) were measured on day 1 and day 2 by inversion-recovery echoplanar imaging. Spin-echo imaging was used to define contrast-enhanced regions and regional wall thickening. Gadolinium concentration, area at risk, and infarct size were measured at postmortem examination. ΔR1 ratio (ΔR1
myocardium
/ΔR1
blood
) after administration of Gd-DTPA was greater in ischemically injured myocardium (1.20±0.15) than in normal myocardium (0.47±0.05,
P
<0.05), which was attributed to differences in gadolinium concentration and water content. The Gd-DTPA–enhanced region on day 2 was larger (32.8±0.9%) than true infarction as demonstrated by triphenyltetrazolium chloride (TTC) (24.6±1.4%,
P
<0.001,
r
=0.21). Bland-Altman analysis revealed that the Gd-DTPA–enhanced region overestimated true infarct size by 7.8±5.9%. On the other hand, the mesoporphyrin-enhanced region (26.9±1.8%,
P
=NS,
r
=0.87) and true infarct size were identical. The difference in the areas demarcated by the 2 agents is the peri-infarction. Systolic and diastolic MR images revealed no wall thickening in the mesoporphyrin-enhanced region (0.3±3.3%) but reduced thickening in the Gd-DTPA–enhanced rim (8.5±5.5%,
P
<0.05).

Conclusions
—The Gd-DTPA–enhanced region encompasses both viable and nonviable portions of the ischemically injured myocardium. The Gd-DTPA–enhanced area overestimated infarct size, but the mesoporphyrin-enhanced area matched true infarct size. The salvageable peri-infarction zone can be characterized with double-contrast–enhanced and functional MR imaging; the mismatched area of enhancement between the 2 agents shows residual wall thickening.
Augmentation of Postnatal Neovascularization With Autologous Bone Marrow Transplantation
Authors: Shintani Satoshi , Murohara Toyoaki , Ikeda Hisao , Ueno Takafumi , Sasaki Ken-ichiro , Duan Junli , Imaizumi Tsutomu
Published: June 2012

Background
—Endothelial progenitor cells (EPCs) have been identified in adult human peripheral blood. Because circulating EPCs should originate from bone marrow (BM), we examined whether BM mononuclear cells (BM-MNCs) can give rise to functional EPCs and whether transplantation of autologous BM-MNCs might augment angiogenesis and collateral vessel formation in a rabbit model of hindlimb ischemia.

Methods and Results
—Rabbit BM-MNCs were isolated by centrifugation through a Histopaque density gradient and cultured on fibronectin. EPCs developed from BM-MNCs in vitro, as assessed by acetylated LDL incorporation, nitric oxide (NO) release, and expression of von Willebrand factor and lectin binding. Unilateral hindlimb ischemia was surgically induced in rabbits (n=8), and fluorescence-labeled autologous BM-MNCs were transplanted into the ischemic tissues. Two weeks after transplantation, fluorescence microscopy revealed that transplanted cells were incorporated into the capillary network among preserved skeletal myocytes. In contrast, transplanted autologous BM-fibroblasts did not participate in EC capillary network formation (n=5). Then, in an additional 27 rabbits, saline (control; n=8), autologous BM-MNCs (n=13; 6.9±2.2×10
6
cells/animal), or BM-fibroblasts (n=6; 6.5±1.5×10
6
cells/animal) were injected into the ischemic tissues at postoperative day 7. Four weeks after transplantation, the BM-MNC–transplanted group had more angiographically detectable collateral vessels (angiographic score: 1.5±0.34 versus 0.94±0.26 and 1.1±0.14;
P
<0.05), a higher capillary density (23±5.8 versus 10±1.9 and 11±0.8 per field;
P
<0.001), and a greater laser Doppler blood perfusion index (505±155 versus 361±35 and 358±22 U;
P
<0.05) than the control and BM-fibroblast–transplanted groups.

Conclusions
—Direct local transplantation of autologous BM-MNCs seems to be a useful strategy for therapeutic neovascularization in ischemic tissues in adults, consistent with “therapeutic vasculogenesis.”
Pravastatin Treatment Increases Collagen Content and Decreases Lipid Content, Inflammation, Metalloproteinases, and Cell Death in Human Carotid Plaques
Authors: Crisby Milita , Nordin-Fredriksson Gunilla , Shah Prediman K. , Yano Juliana , Zhu Jenny , Nilsson Jan
Published: June 2012

Background
—The clinical benefits of lipid lowering with statins are attributed to changes in plaque composition leading to lesion stability, but supporting clinical data from human studies are lacking. Therefore, we investigated the effect of 3 months of pravastatin treatment on composition of human carotid plaques removed during carotid endarterectomy.

Methods and Results
—Consecutive patients with symptomatic carotid artery stenosis received 40 mg/d pravastatin (n=11) or no lipid-lowering therapy (n=13; control subjects) for 3 months before scheduled carotid endarterectomy. Carotid plaque composition was assessed with special stains and immunocytochemistry with quantitative image analysis. Plaques from the pravastatin group had less lipid by oil red O staining (8.2±8.4% versus 23.9±21.1% of the plaque area,
P
<0.05), less oxidized LDL immunoreactivity (13.3±3.6% versus 22.0±6.5%,
P
<0.001), fewer macrophages (15.0±10.2% versus 25.3±12.5%,
P
<0.05), fewer T cells (11.2±9.3% versus 24.3±13.4%,
P
<0.05), less matrix metalloproteinase 2 (MMP-2) immunoreactivity (3.6±3.9% versus 8.4±5.3%,
P
<0.05), greater tissue inhibitor of metalloproteinase 1 (TIMP-1) immunoreactivity (9.0±6.2% versus 3.1±3.9%,
P
<0.05), and a higher collagen content by Sirius red staining (12.4±3.1% versus 7.5±3.5%,
P
<0.005). Cell death by TUNEL staining was reduced in the pravastatin group (17.7±7.8% versus 32.0±12.6%,
P
<0.05).

Conclusions
—Pravastatin decreased lipids, lipid oxidation, inflammation, MMP-2, and cell death and increased TIMP-1 and collagen content in human carotid plaques, confirming its plaque-stabilizing effect in humans.
Results of Targeted Anti–Tumor Necrosis Factor Therapy With Etanercept (ENBREL) in Patients With Advanced Heart Failure
Authors: Bozkurt Biykem , Torre-Amione Guillermo , Warren Marshelle Smith , Whitmore James , Soran Ozlem Z. , Feldman Arthur M. , Mann Douglas L.
Published: June 2012

Background
—Previously, we showed that tumor necrosis factor (TNF) antagonism with etanercept, a soluble TNF receptor, was well tolerated and that it suppressed circulating levels of biologically active TNF for 14 days in patients with moderate heart failure. However, the effects of sustained TNF antagonism in heart failure are not known.

Methods and Results
—We conducted a randomized, double-blind, placebo-controlled, multidose trial of etanercept in 47 patients with NYHA class III to IV heart failure. Patients were treated with biweekly subcutaneous injections of etanercept 5 mg/m
2
(n=16) or 12 mg/m
2
(n=15) or with placebo (n=16) for 3 months. Doses of 5 and 12 mg/m
2
etanercept were safe and well tolerated for 3 months. Treatment with etanercept led to a significant dose-dependent improvement in left ventricular (LV) ejection fraction and LV remodeling, and there was a trend toward an improvement in patient functional status, as determined by clinical composite score.

Conclusion
—Treatment with etanercept for 3 months was safe and well-tolerated in patients with advanced heart failure, and it resulted in a significant dose-dependent improvement in LV structure and function and a trend toward improvement in patient functional status.