bluuebunny/crossref_metadata_2025 huggingface dataset:
Delayed Surgery of Traumatic Aortic Rupture
Authors: Fattori Rossella , Celletti Francesca , Bertaccini Paola , Galli Roberto , Pacini Davide , Pierangeli Angelo , Gavelli Giampaolo
Published: June 2012

Background
Traumatic aortic rupture (TAR) is a pathological entity with a high mortality, both spontaneous and perioperative. Delayed surgical repair has been proposed when associated lesions are stabilized. The aim of this study was to validate MRI for detecting both the presence and type of TAR and to monitor posttraumatic aneurysm and associated lesions.

Methods and Results
Twenty-four consecutive patients with acute chest trauma and suspected aortic rupture, as suggested by emergency CT or chest radiographs, were subjected to MRI and/or angiography in random order. Such parameters as the presence and type of lesion; presence of periaortic, pericardial, mediastinal, or pleural effusion; and presence of associated lesions were considered in every patient. Follow-up imaging was performed exclusively by MRI every 1 to 2 months. TAR was present in 20 patients. No patient underwent surgery in the acute phase; 14 patients underwent surgery at 6.8±2.7 months; 5 are waiting for surgery; and 1 healed spontaneously. There was no overall mortality. For detection of TAR, the accuracy of MRI was 100%; angiography, 84%; and CT, 69%. In detecting the type of lesion, the diagnostic accuracy of MRI was 92%. During follow-up, a significant increase in the posttraumatic aneurysm was observed in 2 patients, and surgical repair was initiated.

Conclusions
In chest trauma patients, MRI provides complete anatomic data to assess the severity of aortic and thoracic lesions. Moreover, along with the concept of delayed surgical repair of TAR, MRI is the ideal modality to monitor and follow TAR before surgical repair.
Body Height, Cardiovascular Risk Factors, and Risk of Stroke in Middle-aged Men and Women
Authors: Njølstad Inger , Arnesen Egil , Lund-Larsen Per G.
Published: June 2012

Background
Geographical differences in stroke mortality are not fully explained by population variations in blood pressure and antihypertensive treatment. Some studies have suggested that factors connected with health and nutrition in early life may be related to stroke morbidity and mortality. Body height is a sensitive marker for socioeconomic conditions, but results are conflicting as to whether height is associated with stroke.

Methods and Results
In a population-based study, we investigated stroke incidence in relation to height and classic cardiovascular risk factors. A total of 13 266 men and women 35 to 52 years of age were followed for 14 years, and 241 first events of stroke were registered. Stroke incidence was 36% higher in men. Height was inversely related to stroke in a dose-response manner. Per 5-cm increase in height, the age-adjusted risk of stroke was 25% lower in women (
P
<.0001) and 18% lower in men (
P
=.0007). Systolic blood pressure and daily smoking were positively associated with stroke in both sexes, while serum triglyceride level was a significant risk factor in women only (relative risk per 1 mmol/L, 1.3; 95% CI, 1.1 to 1.5). The associations remained after adjustment for possible confounders and were also observed in certain subtypes of stroke.

Conclusions
The results are consistent with the theory that factors influencing early growth as well as adult lifestyle factors contribute to cerebrovascular disease in adult age.
Virus-Encoded Serine Proteinase Inhibitor SERP-1 Inhibits Atherosclerotic Plaque Development After Balloon Angioplasty
Authors: Lucas Alexandra , Liu Li-ying , Macen Joanne , Nash Piers , Dai Erbin , Stewart Michael , Graham Kathryn , Etches Wai , Boshkov Lynn , Nation Patric N. , Humen Dennis , Hobman Marita Lundstrom , McFadden Grant
Published: June 2012

Background
Recurrent atherosclerotic plaque growth, restenosis, is a significant clinical problem after interventional procedures. Initiation of restenosis involves activation of inflammatory and thrombotic cascades, which are regulated by serine proteinase enzymes and inhibitors. We have investigated the use of a viral serine proteinase inhibitor, SERP-1, to reduce plaque development after primary balloon angioplasty. This is the first experimental report of the use of a viral anti-inflammatory protein for the prevention of atherosclerosis.

Methods and Results
Seventy-four cholesterol-fed rabbits were treated with either local or systemic infusions of SERP-1 protein (or control solutions) after balloon-mediated injury. Sites of SERP-1 infusion in rabbits had dramatically reduced plaque compared with control infusions at the 4-week follow-up. At low-dose infusions (30 to 300 pg), only the primary infusion site had a demonstrable decrease in plaque, whereas at higher-dose infusions (>3000 pg), a generalized reduction in plaque development was detected. An associated decrease in mononuclear cell infiltration of the arterial wall was detected after SERP-1 infusion within the first 24 hours. Infusion of an active-site mutant of SERP-1 (P
1
-P
1
′, ala-ala) lacking serine proteinase inhibitory activity failed to prevent plaque growth.

Conclusions
Purified SERP-1, a virus-encoded secreted glycoprotein, reduces plaque growth after primary balloon-mediated injury. Plaque development is decreased by inhibition of serine proteinase activity and is associated with a focal reduction in macrophage infiltration immediately after injury. Investigation of serine proteinase inhibitors may provide new insight into the regulation of arterial responses to injury.
Codon 102 of the Cardiac Troponin T Gene Is a Putative Hot Spot for Mutations in Familial Hypertrophic Cardiomyopathy
Authors: Forissier Jean-Franc¸ois , Carrier Lucie , Farza Hend , Bonne Gise`le , Bercovici Josiane , Richard Pascale , Hainque Bernard , Townsend Philip J. , Yacoub Magdi H. , Faure´ Sabine , Dubourg Olivier , Millaire Alain , Hage`ge Albert A. , Desnos Michel , Komajda Michel , Schwartz Ketty
Published: June 2012

Background
Familial hypertrophic cardiomyopathy is a phenotypically and genetically heterogeneous disease. In some families, the disease is linked to the CMH2 locus on chromosome 1q3, in which the cardiac troponin T gene (TNNT2) has been identified as the disease gene. The mutations found in this gene appear to be associated with incomplete penetrance and poor prognosis. Because mutational hot spots offer unique possibilities for analysis of genotype-phenotype correlations, new missense mutations that could define such hot spots in TNNT2 were looked for in unrelated French families with familial hypertrophic cardiomyopathy.

Methods and Results
Family members were genotyped with microsatellite markers to detect linkage to the four known disease loci. In family 715, analyses showed linkage to CMH2 only. To accurately position potential mutations on TNNT2, its partial genomic organization was established. Screening for mutations was performed by single-strand conformation polymorphism analysis and sequencing. A new missense mutation, Arg102Leu, was identified in affected members of family 715 because of a G→T transversion located in the 10th exon of the gene. Penetrance of this new mutation is complete; echocardiographic data show a wide range of hypertrophy; and there was no sudden cardiac death in this family.

Conclusions
The codon 102 of the TNNT2 gene is a putative mutational hot spot in familial hypertrophic cardiomyopathy and is associated with phenotypic variability. Analysis of more pedigrees carrying mutations in this codon is necessary to better characterize the clinical and prognostic implications of TNNT2 mutations.
Myocardial Involvement Is Very Frequent Among Patients Affected With Subclinical Becker's Muscular Dystrophy
Authors: Melacini P. , Fanin M. , Danieli G.A. , Villanova C. , Martinello F. , Miorin M. , Freda M.P. , Miorelli M. , Mostacciuolo M.L. , Fasoli G. , Angelini C. , Volta S. Dalla
Published: June 2012

Background
Several cases of Becker's muscular dystrophy (BMD) have been reported, which showed mild or subclinical skeletal muscle involvement with an overt dilated cardiomyopathy. Here, for the first time, a group of 28 patients with BMD who had a subclinical or benign myopathy have been studied through a thorough cardiological assessment.

Methods and Results
Each patient underwent ECG and echocardiographic examinations. Molecular analyses of the dystrophin gene and protein were performed. An unexpectedly high incidence of myocardial involvement was observed among patients affected with subclinical (72%) or benign (60%) BMD. The cardiac involvement appears to develop early from the right ventricle. Both the increase in left ventricular end-diastolic volume and the reduction in the ejection fraction appeared to be age related. Severe left ventricular dilation with reduced ejection fraction, which could be complicated by life-threatening arrhythmias, may occur. Contrary to previous reports, which indicated the involvement of 5′-end mutations in cardiomyopathies as a result of dystrophin gene alterations, this study shows that despite the apparent concentration of deletions in two regions (5′-end and exons 47 through 49), no general conclusions can be drawn regarding the involvement of specific gene mutations in the development of cardiomyopathy.

Conclusions
Cardiomyopathy is the main clinical feature and complication in patients affected by subclinical or mild BMD. The cardiac manifestation is characterized by early right ventricular involvement and is later associated with left ventricular impairment. In mild BMD, myocardial damage may develop because the patients, who are unaware of a possible cardiac involvement, are still able to perform strenuous muscle exercise and, through pressure or volume overload, may induce mechanical stress, which is harmful for dystrophin-deficient myocardial cells.
Higher Triglycerides, Lower High-Density Lipoprotein Cholesterol, and Higher Systolic Blood Pressure in Lipoprotein Lipase–Deficient Heterozygotes
Authors: Sprecher Dennis L. , Harris Betsy V. , Stein Evan A. , Bellet Paul S. , Keilson Leonard M. , Simbartl Loretta A.
Published: June 2012

Background
Heterozygous lipoprotein lipase (LPL) deficiency has been associated with familial hypertriglyceridemia and familial combined hyperlipidemia. Studies of heterozygotes with
LPL
gene defects at amino acid residues 188 and 207 showed higher triglycerides (TG) and lower HDL cholesterol (HDL-C), with no elevation in LDL cholesterol (LDL-C). Other
LPL
defects may reveal alternate clinical phenotypes.

Methods and Results
We evaluated three families with defects at amino acid residues 64, 194, and 188. Thirty-eight heterozygotes (8 with defect 64, 14 with defect 194, and 16 with defect 188) and 95 family members without defects were studied. Plasma lipid, lipoprotein, and apolipoprotein (apo) values were measured, as well as blood pressure. Pooled carriers demonstrated higher systolic blood pressure (SBP) (127 versus 116 mm Hg,
P
<.0001) and TG (160 versus 125 mg/dL,
P
=.004) and lower HDL-C (44 versus 52 mg/dL,
P
=.001) than did noncarriers. A comparison of the 188 carriers and noncarriers revealed the most striking phenotypic characteristics, with lower HDL-C (36 versus 51 mg/dL,
P
<.0001) and HDL-C/(apo A-I + apo A-II) (0.21 versus 0.24,
P
=.002) and higher TG (206 versus 123 mg/dL,
P
=.0003), SBP (132 versus 116 mm Hg,
P
=.0004), and apo B/LDL-C (1.12 versus 0.93,
P
<.0001).

Conclusions
These data confirm past observations that LPL deficient heterozygotes trend toward lower HDL-C and higher TG levels while potentially expressing higher SBP. These data also implicate the specific
LPL
gene defect as a contributing factor to the variable expression of HDL-C, TG, and SBP.
Accelerated Restitution of Endothelial Integrity and Endothelium-Dependent Function After phVEGF
165
Gene Transfer
Authors: Asahara Takayuki , Chen Donghui , Tsurumi Yukio , Kearney Marianne , Rossow Susan , Passeri Jonathan , Symes James F. , Isner Jeffrey M.
Published: June 2012

Background
Delinquent reendothelialization (rET) has been shown to have a permissive, if not facilitatory, impact on smooth muscle cell proliferation. This inverse relation has been attributed to certain functions of the endothelium, including barrier regulation of permeability, thrombogenicity, and leukocyte adherence, as well as production of growth-inhibitory molecules. Accordingly, the present investigation was designed to test the hypothesis that an endothelial cell (EC) mitogen could serve as the basis for a novel gene therapy strategy designed to facilitate EC regeneration, reduce neointimal thickening, and promote recovery of EC dysfunction after balloon injury.

Methods and Results
New Zealand White rabbits underwent simultaneous balloon injury and gene transfer of one femoral artery with phVEGF
165
, encoding the 165–amino acid isoform of vascular endothelial growth factor (VEGF), or pGSVLacZ. In each animal transfected with phVEGF
165
or pGSVLacZ, the contralateral femoral artery was also subjected to balloon injury but not to gene transfer. For pGSVLacZ, rET remained incomplete at 4 weeks after transfection; in contrast, phVEGF
165
produced prompt rET, which was 95% complete by 1 week. Furthermore, rET in the contralateral, balloon-injured, nontransfected limb of the VEGF group was similarly accelerated. Consequently, intimal thickening was diminished, thrombotic occlusion was less frequent, and recovery of EC-dependent vasomotor reactivity was accelerated in VEGF transfectants compared with control animals. A similar benefit was observed for the contralateral, balloon-injured, nontransfected limb.

Conclusions
Catheter-mediated, site-specific arterial gene transfer of phVEGF
165
can accelerate rET at local and remote sites, leading to inhibition of neointimal thickening, reduction in thrombogenicity, and restoration of endothelium-dependent vasomotor reactivity. These findings support the notion that gene transfer encoding for an EC-specific mitogen may be useful for preventing the complications, including restenosis, of balloon angioplasty.
Nitric Oxide Attenuates the Release of Endothelium-Derived Hyperpolarizing Factor
Authors: Bauersachs Johann , Popp Ru¨diger , Hecker Markus , Sauer Edith , Fleming Ingrid , Busse Rudi
Published: June 2012

Background
The contribution of the endothelium-derived hyperpolarizing factor (EDHF), proposed to be a cytochrome P450–derived metabolite of arachidonic acid, to endothelium-dependent dilatation under physiological conditions has yet to be established, because its effect can be detected only after inhibition of NO synthase and cyclooxygenase. The possibility that NO exerts a feedback inhibition on EDHF formation was studied in isolated perfused arterial segments.

Methods and Results
Under combined blockade of NO synthase and cyclooxygenase, the EDHF-mediated vasodilatation elicited by receptor-dependent agonists in rabbit carotid and porcine coronary arteries was significantly attenuated by the NO donors C87-3786 and CAS 1609. The endothelium-independent dilatation elicited by isoproterenol was not altered by either NO donor. In
N
G
-nitro-
l
-arginine–treated carotid artery segments, C87-3786 significantly attenuated the acetylcholine-induced increase in 6-keto-prostaglandin F
1α
release, which was taken as an index of arachidonic acid liberation. In parallel experiments using cultured human endothelial cells, C87-3786 attenuated the Ca
2+
response to bradykinin. The release of EDHF from a luminally perfused porcine coronary artery was detected by recording the membrane potential of downstream-situated cultured rat aortic smooth muscle cells. The NO donor C87-3786 had no effect on the hyperpolarization elicited by preformed EDHF but markedly inhibited its release from bradykinin-stimulated donor segments.

Conclusions
These findings indicate that under physiological conditions, the production of EDHF is damped by NO. Therefore, it follows that when NO synthesis is impaired, alleviation of this intrinsic inhibition may, at least in part, maintain endothelial vasodilator function.
Cost-effectiveness of a Coronary Care Unit Versus an Intermediate Care Unit for Emergency Department Patients With Chest Pain
Authors: Tosteson Anna N.A. , Goldman Lee , Udvarhelyi I. Steven , Lee Thomas H.
Published: June 2012

Background
Guidelines are not available for which patients with acute chest pain should be admitted to the coronary care unit and which patients can be reasonably triaged to monitored beds in lower levels of care.

Methods and Results
Clinical and resource utilization data from 12 139 emergency department patients with acute chest pain were used in a decision-analytic model to identify cost-effective guidelines for the admission to a coronary care unit versus an intermediate care unit for initially uncomplicated patients without other indications for intensive care. The probability of clinical complications and death were derived from data on age-specific subsets of the population. Resource utilization estimates were based on cost data from a subset of 901 patients and length of stay data for the entire cohort. The survival benefit associated with initial triage to the coronary care unit instead of an intermediate care unit was assumed to be 15%. In the baseline analysis for 55- to 64-year-old patients, the probability of acute myocardial infarction (AMI) at which the coronary care unit had an incremental cost-effectiveness below $50 000 per year-of-life-saved was 29%. Triage to the coronary care unit was somewhat more cost-effective in elderly patients because their higher early complication rate more than offset their shorter life expectancy.

Conclusions
This analysis indicates that the coronary care unit usually should be reserved for patients with a moderate (21% or more, depending on the patient's age) probability of AMI unless patients need intensive care for other reasons. Clinical data suggest that only patients with ECG changes of ischemia or infarction not known to be old have a probability of AMI this high. Intermediate care units are appropriate for patients whose risks are not high enough for a coronary care unit to be cost-effective but too high for other alternatives to be recommended for safety and effectiveness.
Altered Serotonin Receptor Subtypes Mediate Coronary Microvascular Hyperreactivityin Pigs With Chronic Inhibitionof Nitric Oxide Synthesis
Authors: Kadokami Toshiaki , Egashira Kensuke , Kuwata Kouichi , Fukumoto Yoshihiro , Kozai Toshiyuki , Yasutake Hiroshi , Kuga Takeshi , Shimokawa Hiroaki , Sueishi Katsuo , Takeshita Akira
Published: June 2012

Background
We previously reported that chronic inhibition of nitric oxide synthesis by administration of
N
ω
-nitro-
l
-arginine methyl ester (L-NAME) causes microvascular hyperreactivity to 5-hydroxytryptamine (5-HT) and vascular structural changes in pigs in vivo. In the present study, we investigated the relative contributions of 5-HT receptor subtypes to microvascular hyperreactivity in this animal model.

Methods and Results
Coronary vasomotor response was studied in 16 pigs treated with oral L-NAME for 4 weeks (L group) and in 11 control pigs (C group). Intracoronary administration of 5-HT at 30 μg/kg decreased coronary blood flow (CBF) in the two groups. The decrease in CBF by 5-HT was greater (
P
<.01) in the L group than in the C group. The decrease in CBF by 5-HT in the C group was blocked completely by pretreatment with ketanserin, a 5-HT
2
antagonist. In contrast, the augmented decrease in CBF by 5-HT in the L group was only partly inhibited by ketanserin alone and was blocked completely by ketanserin and methiothepin, a 5-HT
1
/5-HT
2
antagonist. The decrease in CBF caused by prostaglandin F
2α
and the increase in CBF caused by nitroglycerin were comparable between the two groups and were not affected by the 5-HT antagonists.

Conclusions
These results suggest that the 5-HT–induced microvascular hyperreactivity may be mediated by relative changes in affinity for 5-HT receptors or de novo expression of 5-HT
1
receptors in microvascular smooth muscle cells in our animal model.
Recombinant Staphylokinase Variants With Altered Immunoreactivity
Authors: Collen De´sire´ , Bernaerts Ria , Declerck Paul , De Cock Frans , Demarsin Edward , Jenne´ Stephane , Laroche Yves , Lijnen Henri R. , Silence Karen , Verstreken Maria
Published: June 2012

Background
Recombinant staphylokinase offers promise for thrombolytic therapy in acute myocardial infarction, but it is immunogenic. Although reduced immunogenicity of heterologous proteinaceous drugs by protein engineering has not previously been reported, an attempt was made to achieve this in staphylokinase by site-specific mutagenesis.

Methods and Results
Biospecific interaction analysis of a panel of 17 murine monoclonal antibodies against recombinant staphylokinase (SakSTAR variant) identified three nonoverlapping immunodominant epitopes, two of which could be eliminated by substitution mutagenesis of clusters of two or three charged amino acids with alanine. Circulating anti-staphylokinase antibodies elicited in patients by treatment with SakSTAR were incompletely (<90%) absorbed by these mutants. Therefore, the combination variants K35A,E38A,K74A,E75A,R77A (SakSTAR.M38) and K74A,E75A,R77A,E80A,D82A (SakSTAR.M89) were constructed, expressed in
Escherichia coli,
highly purified by ion-exchange and hydrophobic interaction chromatography, and characterized. These variants had specific activities that were approximately half that of SakSTAR, and they combined the reduced reactivity with the panels of monoclonal antibodies of their parent molecules. Absorption of circulating antibodies elicited in patients by treatment with SakSTAR was incomplete in 13 of 16 patients (median values, 68% and 65% with SakSTAR.M38 and SakSTAR.M89, respectively).

Conclusions
SakSTAR contains three immunodominant epitopes, two of which were eliminated by site-directed mutagenesis, yielding combination mutants with relatively maintained specific activities that were not recognized by a significant fraction of the antibodies elicited in patients by treatment with wild-type SakSTAR. These mutants appear to be suitable for more detailed investigation of their thrombolytic and antigenic properties.
Innervation of Human Atrioventricular and Arterial Valves
Authors: Marron Kevin , Yacoub Magdi H. , Polak Julia M. , Sheppard Mary N. , Fagan David , Whitehead Bruce F. , de Leval Marc R. , Anderson Robert H. , Wharton John
Published: June 2012

Background
Limited information exists on the innervation of human cardiac valves and the relationship of nerve fibers and terminals with functional elements within leaflets.

Methods and Results
We examined human AV and arterial valves, obtained postmortem and at surgery, using quantitative immunohistochemical, histochemical, and confocal microscopic techniques. Significant differences in nerve density and distribution were found both between and within cardiac valves. Nerve density within the anterior leaflet of the mitral valve, for example, was twofold greater than that in the posterior leaflet (
P
<.001). Nerves within the AV valves were situated in the atrial layer and extended over the proximal and medial portions of the leaflets, whereas those in the arterial valves were situated in the ventricular layer. No nerves reached either the free edge or the fibrous core of the leaflets. The arterial valves displayed a similar density of innervation, except for the noncoronary leaflet of the aortic valve in which the innervation was attenuated (
P
<.01). The innervation of aortic valvar leaflets was age dependent. Nerve terminal arborizations, arising from myelinated nerves and exhibiting variable morphology, were detected in all four cardiac valves and in some tendinous cords. Nerve terminals exhibited either acetylcholinesterase activity or tyrosine hydroxylase and neuropeptide Y immunoreactivity. Varicose nerve fibers occurred in close physical proximity to valvar endothelial, smooth muscle, and fibroblast cells.

Conclusions
Human cardiac valves have distinct patterns of innervation that comprise both primary sensory and autonomic components. The presence of distinct nerve terminals and the close association of varicose nerve fibers with endothelial, smooth muscle, and fibroblast cells suggest a possible neural involvement in the control of valvar function.
Elevated Basic Fibroblast Growth Factor in Pericardial Fluid of Patients With Unstable Angina
Authors: Fujita Masatoshi , Ikemoto Masaki , Kishishita Masamichi , Otani Hideo , Nohara Ryuji , Tanaka Terumitsu , Tamaki Shun-ichi , Yamazato Ario , Sasayama Shigetake
Published: June 2012

Background
Collateral growth is induced by chemical signals from the ischemic myocardium. We hypothesized that angiogenic growth factors are produced by cardiac tissue; they are diffusible, more concentrated in pericardial fluids, and are increased by myocardial ischemia.

Methods and Results
With the use of an enzyme-linked immunosorbent assay, we measured the concentrations of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) in pericardial fluids of 12 patients with unstable angina (group 1) and of 8 patients with nonischemic heart diseases (group 2). The levels of protein in pericardial fluids were quite comparable between the two groups (34±2 versus 32±4 mg/mL). The concentration of bFGF in pericardial fluids in group 1 was 2036±357 pg/mL, significantly (
P
<.001) higher than the 289±72 pg/mL in group 2. The amount of bFGF per milligram of protein was also significantly (
P
<.05) higher in group 1 than in group 2 (67±15 versus 12±4 pg/mg). The concentration of VEGF in pericardial fluids tended to be higher in group 1, but the difference was statistically insignificant (39±7 versus 22±6 pg/mL). The amount of VEGF per milligram of protein was 1.2±0.3 pg/mg in group 1, similar to the 0.8±0.4 pg/mg in group 2.

Conclusions
This finding provides new evidence that bFGF plays an important role in mediating collateral growth in humans.
Coronary Reserve Abnormalities in the Infarcted Myocardium
Authors: Villanueva Flordeliza S. , Camarano Gustavo , Ismail Suad , Goodman Norman C. , Sklenar Jiri , Kaul Sanjiv
Published: June 2012

Background
The aim of this study was to determine whether myocardial contrast echocardiography (MCE) during exogenous vasodilation can accurately delineate infarct size, and hence the extent of myocardial viability, both immediately (15 minutes) and late (3 hours) after reperfusion when postreflow coronary hyperemia is still present.

Methods and Results
Twenty-one open-chest anesthetized dogs underwent 3 to 6 hours of coronary occlusion followed by reperfusion. MCE was performed 15 minutes after reflow before and during infusion of 0.2 mg·kg
−1
·min
−1
adenosine IV. In 12 dogs, infarct size was measured at this time. In the remaining 9 dogs, reperfusion was continued for 3 hours, when MCE was repeated before and after an infusion of 0.56 mg·kg
−1
·min
−1
dipyridamole IV and infarct size was measured. In the absence of adenosine, MCE perfusion defect at 15 minutes underestimated infarct sizes at both 15 minutes and 3 hours, whereas in the presence of adenosine, the estimate of infarct size was more accurate. Similarly, in the absence of dipyridamole, although MCE perfusion defect underestimated infarct size (both measured 3 hours after reflow), in the presence of dipyridamole, the estimate of infarct size was more accurate.

Conclusions
By unmasking abnormalities in flow reserve within the infarct bed, MCE in conjunction with coronary vasodilators can accurately predict infarct size both 15 minutes and 3 hours after reperfusion. Thus, MCE can be used for assessing the extent of myocardial viability both immediately and late after reperfusion when postreflow coronary hyperemia is still present.
Short-term Hemodynamic Effects of Endothelin Receptor Blockade in Dogs With Chronic Heart Failure
Authors: Shimoyama Hisashi , Sabbah Hani N. , Borzak Steven , Tanimura Mitsuhiro , Shevlyagin Serguei , Scicli Gloria , Goldstein Sidney
Published: June 2012

Background
Plasma endothelin levels are increased in heart failure and may contribute to the increased peripheral vasoconstriction that characterizes this disease state. In the present study, we examined the effects of intravenous bosentan, a nonpeptide, competitive endothelin-1 receptor antagonist, on hemodynamics in dogs with chronic heart failure.

Methods and Results
Chronic heart failure was produced in 11 dogs by multiple sequential intracoronary microembolization. At the time of study, left ventricular (LV) ejection fraction was 25±2%. Hemodynamic and echocardiographic measurements were made at baseline and at 15, 30, and 60 minutes after a bolus injection of bosentan (10 mg/kg). Bosentan had no significant effect on heart rate or mean aortic blood pressure. At 60 minutes, bosentan reduced LV end-diastolic pressure (17±2 versus 11±2 mm Hg;
P
<.05) and systemic vascular resistance (3891±379 versus 3071±346 dyne·s·cm
−
5
;
P
<.05) compared with baseline and increased cardiac output (2.63±0.29 versus 3.33±0.46 L/min;
P
<.05), peak rate of change of LV pressure during isovolumic contraction and relaxation (1751±92 versus 2197±170 mm Hg/s;
P
<.05), and LV fractional shortening determined by echocardiography (30±2% versus 36±2%;
P
<.05).

Conclusions
Short-term intravenous bosentan reduced systemic vascular resistance and improved overall LV performance in dogs with chronic heart failure. These results suggest that endothelin-1 receptor antagonists may be useful therapeutic agents in the treatment of heart failure.
Contribution of Local Renin-Angiotensin System to Cardiac Hypertrophy, Phenotypic Modulation, and Remodeling in TGR(mRen2)27 Transgenic Rats
Authors: Ohta Kensuke , Kim Shokei , Wanibuchi Hideki , Ganten Detlev , Iwao Hiroshi
Published: June 2012

Background
The transgenic rat TGR(mRen2)27, carrying the mouse
Ren
-2 gene, is a new model to elucidate the role of the local renin-angiotensin system in vivo. However, the role of the local renin-angiotensin system in the heart remains to be determined in TGR(mRen2)27.

Methods and Results
TGR(mRen2)27 were treated with various antihypertensive drugs for 6 weeks to examine the effects on cardiac hypertrophy and gene expression. Cardiac mRNAs were examined by Northern blot analysis. In TGR(mRen2)27, left ventricular hypertrophy was associated with a decrease in α-myosin heavy chain expression of 31% and an increase in skeletal α-actin and atrial natriuretic polypeptide expression by 2.6- and 21-fold, respectively (
P
<.05), thereby showing the shift of myocardium to a fetal phenotype. Furthermore, cardiac collagen and laminin expressions were increased in TGR(mRen2)27 (
P
<.05), suggesting the occurrence of cardiac remodeling. Although treatment of TGR(mRen2)27 with a high dose of TCV-116 (angiotensin AT
1
receptor antagonist) or manidipine (calcium antagonist) combined with atenolol (β
1
-adrenergic receptor blocker) completely normalized blood pressure, TCV-116 regressed cardiac hypertrophy and suppressed the changes in cardiac mRNA levels of TGR(mRen2)27 much more potently than manidipine with atenolol. Furthermore, the inhibitory effects of a low dose of TCV-116 on cardiac hypertrophy and altered gene expressions of TGR(mRen2)27 were greater than those of doxazosin (α
1
-adrenergic receptor blocker) combined with atenolol, despite their similar hypotensive effects.

Conclusions
Our present observations provide evidence that the cardiac renin-angiotensin system in TGR(mRen2)27 is responsible for cardiac hypertrophy, phenotypic modulation, and remodeling.
Percutaneous Multielectrode Endocardial Mapping During Ventricular Tachycardia in the Swine Model
Authors: Eldar Michael , Fitzpatrick Adam P. , Ohad Dan , Smith Michael F. , Hsu Steve , Whayne James G. , Vered Zvi , Rotstein Zeev , Kordis Thomas , Swanson David K. , Chin Michael , Scheinman Melvin M. , Lesh Michael D. , Greenspon Arnold J.
Published: June 2012

Background
Identification of critical areas within the ventricular tachycardia circuit is a prerequisite for catheter ablation. Currently, mapping during ventricular tachycardia, usually performed with standard catheters, is difficult and time-consuming and can be used only in patients with hemodynamically stable tachycardia.

Methods and Results
A total of 43 pigs underwent closed-chest induction of myocardial infarction. A basket-shaped catheter carrying 64 electrodes was deployed in the left ventricle during normal sinus rhythm. Unipolar pacing at 3 mA was successful in 78% of the basket catheter electrodes, demonstrating good electrode-tissue contact. Hemodynamic and echocardiographic measurements did not reveal any significant interference with myocardial or valvular function during or after catheter deployment. One hundred eighteen episodes of monomorphic ventricular tachycardia were induced in 28 pigs through right ventricular stimulation, 81 of which were mapped and analyzed. Ventricular tachycardia mapping was rapid, requiring only several beats and <10 seconds to complete. Presystolic potentials, a possible target for ablation, were identified in 58% of the tachycardia episodes mapped. Pathological examination revealed only minor valvular and endocardial catheter–induced lesions immediately after mapping and none a month later.

Conclusions
The multielectrode catheter enables rapid and safe percutaneous endocardial mapping of ventricular tachycardia in the swine model. Exploration of the clinical potential of the multielectrode catheter seems warranted.
Oxidation-Specific Epitopes in Human Coronary Atherosclerosis Are Not Limited to Oxidized Low-Density Lipoprotein
Authors: O'Brien Kevin D. , Alpers Charles E. , Hokanson John E. , Wang Shari , Chait Alan
Published: June 2012

Background
Previous small studies have demonstrated positive immunohistochemical staining in rabbit and human atherosclerotic plaques by antibodies that recognize oxidized low-density lipoprotein (OxLDL), but none have examined a large number of human coronary arteries or evaluated whether epitopes recognized by these antibodies might be present on plaque proteins other than OxLDL.

Methods and Results
Immunohistochemistry was performed on atherosclerotic (n=87) and nonatherosclerotic (n=51) coronary arterial segments from 20 patients by use of monoclonal antibodies that recognize epitopes on macrophages, smooth muscle cells, apolipoprotein (apo) B, and OxLDL. Staining with the OxLDL antibody (Ox5) was much more prevalent in atherosclerotic than in control segments. Extracellular Ox5 staining colocalized with apo B, but cell-associated Ox5 staining occurred in the absence of cell-associated apo B staining, which suggests that cell-associated epitopes for Ox5 were on proteins other than LDL. Epitopes for Ox5 formed in vitro on two readily available non–apo B proteins, human serum albumin and apo A-I, when these proteins were incubated under conditions of oxidant stress with polyunsaturated but not monounsaturated fatty acids; furthermore, an antioxidant inhibited Ox5 epitope formation. Thus, epitopes for Ox5 can form on proteins other than apo B. Also, phorbol ester–treated macrophages cultured in apo B–free medium developed epitopes for Ox5.

Conclusions
These findings are consistent with the hypothesis that atherosclerosis is associated with oxidative modification of proteins in addition to LDL, particularly cell-associated proteins, and that the antiatherosclerotic effects of antioxidants seen in some studies may not be solely due to prevention of LDL oxidation.
Defective
l
-Arginine–Nitric Oxide Pathway in Offspring of Essential Hypertensive Patients
Authors: Taddei Stefano , Virdis Agostino , Mattei Paola , Ghiadoni Lorenzo , Sudano Isabella , Salvetti Antonio
Published: June 2012

Background
Essential hypertension is characterized by impaired endothelium-dependent vasodilation. The present study was designed to investigate whether this abnormality is a primary defect or a consequence of blood pressure increases.

Methods and Results
In offspring of essential hypertensive patients (n=34) and normotensive subjects (n=30), we evaluated forearm blood flow (strain-gauge plethysmography) modifications induced by intrabrachial acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 μg·100 mL
−
1
·min
−
1
), an endothelium-dependent vasodilator, and sodium nitroprusside (1, 2, and 4 μg·100 mL
−
1
·min
−
1
), an endothelium-independent vasodilator. Minimal forearm vascular resistances also were calculated as the ratio between mean intra-arterial pressure and maximal forearm blood flow induced by forearm ischemia and hand exercise. Vasodilation to acetylcholine was significantly (
P
<.01) blunted in offspring of hypertensive patients compared with offspring of normotensive subjects, whereas the responses to sodium nitroprusside and minimal forearm vascular resistances were similar. In two subgroups of 14 offspring of essential hypertensive patients but not in 10 offspring of normotensive subjects, vasodilation to acetylcholine was increased by intra-brachial
l
-arginine (1 μmol·100 mL
−
1
·min
−
1
), the substrate for nitric oxide synthesis, whereas in the other 10 and 8 offspring of essential hypertensive patients and normotensive subjects, respectively, cyclooxygenase blockade by intra-brachial indomethacin (50 μg·100 mL
−
1
·min
−
1
) was ineffective.

Conclusions
Offspring of essential hypertensive patients are characterized by a reduced response to acetylcholine linked to a defect in the nitric oxide pathway, suggesting that an impairment in nitric oxide production precedes the onset of essential hypertension.
Placebo-Controlled, Randomized, Double-Blind Study of Intravenous Enalaprilat Efficacy and Safety in Acute Cardiogenic Pulmonary Edema
Authors: Annane Djillali , Bellissant Eric , Pussard Eric , Asmar Roland , Lacombe Florence , Lanata Edouard , Madonna Olivier , Safar Michel , Giudicelli Jean-Franc¸ois , Gajdos Philippe
Published: June 2012

Background
Converting enzyme inhibitors meet most of the criteria required to be used in acute pulmonary edema. However, they could also induce deleterious effects on renal function and electrolytes. The purpose of this study was to evaluate the efficacy and safety of a single intravenous 2-hour infusion of enalaprilat (1 mg) after an acute pulmonary edema.

Methods and Results
This was a placebo-controlled, randomized, double-blind study performed in 20 congestive heart failure patients (New York Heart Association class III or IV). Systemic and regional hemodynamic parameters, biological parameters, and blood gases were measured before and repeatedly after the onset of infusion. Compared with placebo, enalaprilat decreased pulmonary capillary wedge pressure (−37% versus −10%,
P
=.001), diastolic and mean systemic blood pressures (−21% versus 0%,
P
=.009, and −18% versus −1%,
P
=.026, respectively), diastolic and mean pulmonary blood pressures (−21% versus −8%,
P
=.040; −18% versus −9%,
P
=.046), and brachial and renal resistances (−44% versus −14%,
P
=.017, and −22% versus −2%,
P
=.014, respectively); increased brachial and renal blood flows (+77% versus +8%,
P
=.036, and +12% versus 0%,
P
=.043, respectively), arterial oxygen tension (+2% versus −16%,
P
=.041), and arterial oxygen saturation (+1% versus −2%,
P
=.045); and tended to decrease rate-pressure product (−19% versus −7%,
P
=.076), increase brachial artery diameter (+13% versus 0%,
P
=.081), and improve intrapulmonary shunt (−18% versus +16%,
P
=.080). Enalaprilat did not affect cardiac output or carotid or hepatosplanchnic hemodynamics.

Conclusions
Early administration of enalaprilat is effective and well tolerated in acute pulmonary edema.
Increased Monday Incidence of Life-Threatening Ventricular Arrhythmias
Authors: Peters Robert W. , McQuillan Steve , Resnick Susan Kaye , Gold Michael R.
Published: June 2012

Background
Examination of the timing of cardiac events provides important pathophysiological information. Previous studies have shown that the onset of acute myocardial infarction occurs most frequently on Monday. The septadian (day of the week) pattern of occurrence of sudden cardiac death and lethal ventricular arrhythmias has not been examined previously.

Methods and Results
We examined the septadian distribution of life-threatening (cycle length <280 ms) ventricular arrhythmias in 683 consecutive patients receiving a Ventak PRx, a third-generation implantable defibrillator with an event recorder. There was a prominent Monday peak, with a midweek decline and a secondary peak later in the week. A marked trough is apparent on both weekend days. The observed pattern was independent of age, sex, ejection fraction, NYHA functional class, type of heart disease, and the use of antiarrhythmic drugs but was not observed in patients receiving β-blockers.

Conclusions
Potentially lethal arrhythmias are not random events but occur in a daily pattern suggesting a relationship to the beginning and end of the work week. The absence of a Monday peak in patients receiving β-blockers suggests that the pattern may be influenced by β-blockers. This information may be useful in devising strategies to prevent sudden cardiac death.
Differential Effects of Changes in Local Myocardial Refractoriness on Atrialand Ventricular Latency
Authors: Fananapazir Lameh , Packer Douglas , Prystowsky Eric N.
Published: June 2012

Background
Assessment of myocardial refractoriness and conduction properties, critical to development and propagation of reentrant arrhythmias, is an integral part of the investigation of atrial and ventricular tachycardias through the use of programmed electrical stimulation. Local conduction itself, however, may be affected by myocardial refractoriness.

Methods and Results
We studied the effects of changes in myocardial refractoriness on local conduction in right atrial and ventricular myocardium in 19 patients. Changes in effective, functional, and relative refractoriness were accomplished with the use of four pacing protocols, including drive train pacing cycle lengths (PCLs) of 600 and 400 milliseconds (ms) and drive train durations (DTDs) of 8 and 50 stimuli. Unipolar cathodal stimulation was performed from the distal electrode, and unipolar electrograms were recorded from the proximal three poles of quadripolar catheters with 5-mm interelectrode spaces. Atrial and ventricular effective and relative refractory periods (ERPs and RRPs) were significantly shortened by both the reduction in PCL and the increase in DTD. The reduction in the PCL shortened atrial and ventricular refractory periods significantly more than did the increase in the DTD. Changes in ventricular refractory periods were significantly greater compared with atrial refractory periods. The ratio of RRP to ERP was reduced in the atrium but significantly increased in the ventricle with reduction in PCL and increase in DTD. For all premature intervals, the conduction interval from stimulus to the first recording electrode pole was significantly greater than conduction intervals measured between subsequent electrode poles. The greatest increase in conduction interval with closely coupled premature complexes occurred between the stimulus artifact and the first recording electrode pole. Reduction in ventricular but not atrial ERP was associated with significantly increased local conduction interval.

Conclusions
First, most of the conduction delay after the stimulus artifact occurs within 5 mm from the pacing site. Second, closely coupled premature complexes delay conduction primarily by prolonging latency in the first 5 mm from the pacing site. Third, fundamental differences occur between the atrium and ventricle regarding changes in local conduction as a function of changes in ERP, suggesting that factors involved in sudden changes in refractoriness (eg, heart rate acceleration) could produce divergent effects on atrial and ventricular arrhythmogenesis.
Prospective Randomized Trial of Low-Saturated-Fat, Low-Cholesterol Diet During the First 3 Years of Life
Authors: Niinikoski Harri , Viikari Jorma , Ro¨nnemaa Tapani , Lapinleimu Helena , Jokinen Eero , Salo Pia , Seppa¨nen Ritva , Leino Aila , Tuominen Juhani , Va¨lima¨ki Ilkka , Simell Olli
Published: June 2012

Background
The long-term consequences of modified fat intake in early childhood are poorly known. The randomized prospective STRIP baby project evaluates the effects of repeated dietary counseling on nutrient intakes and serum lipid values in children 7 months to 3 years old.

Methods and Results
One thousand sixty-two infants were randomized to intervention and control groups at 7 months of age. The families of the 540 intervention children were counseled to reduce the child's intake of saturated fat and cholesterol but to ensure adequate energy intake. Five hundred twenty-two control children consumed an unrestricted diet. Food records were kept, and serum lipids were measured at 5- to 12-month intervals. Intakes of saturated fat, fat as proportion of energy (E%), and cholesterol were lower in the intervention children than in control children at 13, 24, and 36 months of age. Fat intake by the intervention children decreased from 29±5 E% at 8 months of age to 26±6 E% at 13 months and then increased to 30±5 E% at 24 months and to 31±5 E% at 36 months. The control children consumed 29±4 E%, 28±5 E%, 33±5 E%, and 33±5 E% of fat at 8, 13, 24, and 36 months, respectively. The ratio of dietary polyunsaturated to saturated fats of the intervention children was consistently higher than that of the control children (
P
<.0001). Baseline adjusted mean serum cholesterol concentration was lower in the intervention children than control children between 13 and 36 months (
P
<.0001; 95% confidence interval of the difference between the group means, −0.27 to −0.12 mmol/L). The effect was significant only in boys (95% confidence interval, −0.39 to −0.20 mmol/L in boys; −0.21 to 0.01 mmol/L in girls).

Conclusions
Repeated individualized dietary counseling markedly reduces the increase in serum cholesterol concentration that occurs in control children during the first years of life.
Enhanced Thrombolytic and Antithrombotic Potency of a Fibrin-Targeted Plasminogen Activator in Baboons
Authors: Runge Marschall S. , Harker Laurence A. , Bode Christoph , Ruef Johannes , Kelly Andrew B. , Marzec Ulla M. , Allen Elaine , Caban Rafael , Shaw Shyh-Yu , Haber Edgar , Hanson Stephen R.
Published: June 2012

Background
Thrombolytic therapy reduces mortality in patients with acute myocardial infarction, but significant limitations exist with the use of currently available agents. In the present report, we describe the thrombolytic and antithrombotic potencies of a hybrid recombinant plasminogen activator consisting of an antifibrin antibody 59D8 (AFA) and low-molecular-weight single-chain urokinase-type plasminogen activator (scuPA).

Methods and Results
A thrombolysis model in which thrombi are preformed in vivo in juvenile baboons was developed to compare the potencies of AFA-scuPA, recombinant tissue plasminogen activator (rTPA), and recombinant scuPA (rscuPA) in lysing nonocclusive
111
In-labeled platelet-rich arterial-type thrombi and
125
I-labeled fibrin-rich venous-type thrombi. Systemic infusion of 1.89 nmol/kg AFA-scuPA produced thrombolysis that was comparable to that obtained with much higher doses of TPA (14.2 nmol/kg) and rscuPA (28.5 nmol/kg). When steady-state plasma concentrations are normalized, AFA-scuPA lyses thrombi sixfold more rapidly than scuPA and TPA (
P
<.001) and reduces the rate of formation more than comparable doses of rscuPA (
P
<.0001). At equivalent thrombolytic doses, AFA-scuPA produced fewer antihemostatic effects than either rTPA or rscuPA. Template bleeding time measurements were shorter (3.5±0.12 minutes for AFA-scuPA versus 5.3±0.36 and 5.2±0.04 minutes for rTPA and rscuPA, respectively;
P
<.05), α
2
-antiplasmin consumption was less (
P
<.05), and
d
-dimer generation was lower (
P
<.05).

Conclusions
We conclude that antibody targeting of scuPA to fibrin increases thrombolytic and antithrombotic potencies with less impairment of hemostasis compared with rTPA and rscuPA.