bluuebunny/crossref_metadata_2025 huggingface dataset:
High Glucose Increases Nitric Oxide Synthase Expression and Superoxide Anion Generation in Human Aortic Endothelial Cells
Authors: Cosentino Francesco , Hishikawa Keiichi , Katusic Zvonimir S. , Lüscher Thomas F.
Published: June 2012

Background
Hyperglycemia is a primary cause of premature vascular disease. Endothelial cell dysfunction characterized by diminished endothelium-dependent relaxations is likely to be involved. Little is known about the molecular mechanisms of hyperglycemia-induced endothelial dysfunction.

Methods and Results
This study was designed to determine the effect of hyperglycemia on the
l
-arginine/nitric oxide (NO) pathway. Expression of endothelial nitric oxide synthase (eNOS) mRNA and production of NO were studied in human aortic endothelial cells exposed to control levels (5.5 mmol/L) and high levels (22.2 mmol/L) of glucose for 5 days. We examined the effect of glucose on NO release by measuring changes in nitrite (NO
2
−
) levels by Griess reaction. Superoxide anion (O
2
−
) production was also examined by the ferrocytochrome
c
assay. NOS mRNA and protein expression, which were evaluated by reverse transcription–polymerase chain reaction and Western blotting, were approximately twofold greater in endothelial cells exposed to high glucose. Elevated glucose levels increased NO
2
−
production by only 40% but increased the release of O
2
−
by more than threefold.

Conclusions
The present study demonstrates that prolonged exposure to high glucose increases eNOS gene expression, protein expression, and NO release. However, upregulation of eNOS and NO release is associated with a marked concomitant increase of O
2
−
production. These results provide the molecular basis for understanding how chronic exposure to elevated glucose leads to an imbalance between NO and O
2
−
. This may explain impaired endothelial function and be important for diabetic vascular disease.
Relationships Between Myocardial Bioenergetic and Left Ventricular Function in Hearts With Volume-Overload Hypertrophy
Authors: Zhang Jianyi , Toher Cynthia , Erhard Mark , Zhang Yi , Ugurbil Kamil , Bache Robert J. , Lange Thomas , Homans David C.
Published: June 2012

Background
Left ventricular (LV) hypertrophy secondary to volume overload can result in alterations in myocardial bioenergetics and LV dysfunction. This study examined whether bioenergetic abnormalities contribute to the pump dysfunction.

Methods and Results
Severe mitral regurgitation (MR) was produced in 10 dogs by disruption of the chordal apparatus. Hemodynamics and ventricular function were examined 11.7 months later under baseline conditions and during treadmill exercise. Myocardial high-energy phosphates were measured by using magnetic resonance spectroscopy at rest, during coronary vasodilation with adenosine, and during oxidative stress induced by rapid pacing and dobutamine. Chronic MR caused a 30% increase in LV mass and a 65% increase in LV volume. In MR animals, the hemodynamic and LV function were normal at rest, but abnormalities developed during β-blockade and exercise. Myocardial creatine phosphate–to-ATP ratios were significantly lower in each layer across the LV wall in MR hearts than normal hearts. Myocardial blood flow and coronary reserve were normal in MR hearts. Moreover, hyperperfusion did not correct the abnormal bioenergetics. Despite altered bioenergetics at rest, the MR hearts tolerated rapid pacing and dobutamine infusion well.

Conclusions
In volume-overloaded LV hypertrophied hearts, alterations in myocardial high-energy phosphate levels do not induce abnormal mechanical performance at rest but may be related to a decreased contractile reserve during exercise.
Left Ventricular Mechanics and Geometry in Patients With Congenital Complete Atrioventricular Block
Authors: Kertesz Naomi J. , Friedman Richard A. , Colan Steven D. , Walsh Edward P. , Gajarski Robert J. , Gray Portia S. , Shirley Ramona , Geva Tal
Published: June 2012

Background
Radiographic evidence of cardiomegaly is common in patients with congenital complete atrioventricular block (CCAVB). It has been speculated that left ventricular (LV) remodeling and increased stroke volume counteract the bradycardia, but the effects of slow heart rate and atrioventricular asynchrony on LV dimensions, geometry, wall stress, and function have not been examined in detail.

Methods and Results
Thirty patients with CCAVB without associated congenital heart disease (mean age, 8.5±5.3 years; range, 0.2 to 20 years) were included in a cross-sectional two-institution study. Thirty-five echocardiograms were performed using standard techniques. ECG and 24-hour ECG recordings were reviewed. Seven patients did not receive a pacemaker, whereas 23 patients underwent pacemaker implantation after the echocardiogram. Compared with normal control subjects, LV volume (Z score=1.5±1.3) and LV mass (Z=1.2±1.5) were significantly increased, whereas LV mass-to-volume ratio (1.1±0.3) and geometry (short-axis diameter/length ratio=0.65±0.09) were normal. LV end-systolic stress (ESS) (a measure of afterload) was normal (Z score=0.2±2.3), whereas shortening fraction (Z=3±2.9) and velocity of circumferential fiber shortening (VCF) (Z=3±3.1) were increased. The relationship between VCF and ESS (a preload-insensitive and afterload-adjusted index of contractility) was increased (Z=2.2±2) with only small increase in preload (Z=1.02±1.1). Regression analyses showed no significant change over age in LV mass, volume, geometry, loading conditions, or systolic function. Patients who ultimately met criteria for pacemaker implantation did not differ from those who did not in terms of heart rate or LV function but did have increased LV volume (Z score=1.8±1.4 versus 0.4±0.9,
P
=.03) and LV mass (Z score=1.7±1.2 versus 0.2±1.7,
P
=.001) compared to the unpaced group.

Conclusions
In most patients with CCAVB, the LV was enlarged with normal geometry and enhanced systolic function during the first two decades of life. The degree of LV dilation and enhanced function did not significantly change with age. In patients who ultimately underwent pacemaker implantation LV function did not differ from those who remained unpaced, but evidence of a slightly increased load manifested as increased end-diastolic volume and mass.
Pulsatile Stretch Stimulates Superoxide Production in Human Aortic Endothelial Cells
Authors: Hishikawa Keiichi , Lüscher Thomas F.
Published: June 2012

Background
Free radicals such as superoxide and nitric oxide (NO) play a key role in the pathophysiology of atherosclerosis. Mechanical forces such as pulsatile stretch may be involved in free radical production. We studied superoxide production by pulsatile stretch in human endothelial cells.

Methods and Results
Human cultured aortic endothelial cells were exposed to pulsatile stretch up to 24 hours, and superoxide production was examined. Short-term stretch for 1 hour (10% average elongation, 50 cycles per minute) increased superoxide production 2.2-fold. This effect was reduced by diphenyleneiodonium chloride, an NADPH oxidase inhibitor, but not by the xanthine oxidase inhibitor oxypurinol or the cyclooxygenase inhibitor indomethacin. Prolonged stretch up to 6 hours increased superoxide production, but it returned to near the control level after 24 hours of stretch. However, after blockade of NO production, 24 hours of stretch did increase superoxide production 2.4-fold compared with 24 hours of stretch alone. Moreover, 24-hour stretch doubled NO synthase (NOS) (III) protein and mRNA expression. The tetrahydrobiopterin synthesis inhibitor 2,4-diamino-6-hydroxypyrimidine had no effect on unstretched cells but doubled superoxide production compared with 24-hour stretch alone; this increase was halved by cotreatment with 6-methyl-5,6,7,8-tetrahydropterine, a lipid-soluble form of tetrahydrobiopterine.

Conclusions
Short-term stretch increased superoxide production from human aortic endothelial cells via NADPH oxidase and NOS (III), whereas prolonged stretch increased both superoxide and NO production. The increase in NOS (III) protein with prolonged stretch acts as a scavenger mechanism whereby NO inactivates superoxide. Tetrahydrobiopterin determines the balance of superoxide and NO production from NOS (III) after prolonged stretch in which NOS (III) level is upregulated.
Iridium Oxide–Coated Defibrillation Electrode
Authors: Niebauer Mark J. , Wilkoff Bruce , Yamanouchi Yoshio , Mazgalev Todor , Mowrey Kent , Tchou Patrick
Published: June 2012

Background
Transvenous implantable cardioverter-defibrillator (ICD) leads are designed to deliver electric shocks to the heart for termination of ventricular dysrhythmias. However, the efficiency of different lead materials has not been well studied. This study compares an ICD lead coated with iridium oxide (IROX), a material that reduces shock-induced polarization, with an otherwise identical, uncoated lead.

Methods and Results
The defibrillation threshold (DFT) was determined in 13 swine with both IROX-coated and uncoated ICD leads paired with an uncoated “can” electrode. The leads were exchanged through a Teflon sheath to reproduce the intracardiac position. The delivered energy DFT of the IROX-coated lead was 15.9±5.4 J and was significantly lower than the delivered energy DFT of the uncoated lead (19.1±5.1 J;
P
<.006). The initial lead impedance was equivalent in both leads (IROX, 41.7±5.8 Ω; uncoated, 41.3±4.7 Ω;
P
=NS) at DFT. However, the impedance rose by 7.3±2.0 Ω during the first phase and by 3.7±2 Ω during the second phase with the uncoated lead, whereas the corresponding impedance change was 1.0±0.3 Ω during phase 1 and 1.6±0.5 Ω during phase 2 (
P
<.01 each phase) when the IROX-coated lead was used.

Conclusions
This study shows that an IROX coating of this lead system significantly lowers the DFT energy in the swine model. The blunting of the impedance rise by the IROX coating that is seen is consistent with a reduction in electrode polarization.
Isolated Myocyte Contractile Function Is Normal in Postinfarct Remodeled Rat Heart With Systolic Dysfunction
Authors: Anand Inder S. , Liu Daosheng , Chugh Sumeet S. , Prahash Arun J.C. , Gupta Sudhir , John Rohan , Popescu F. , Chandrashekhar Y.
Published: June 2012

Background
Postinfarction ventricular remodeling is associated with lengthening and contractile dysfunction of the remote noninfarcted myocardium. Mechanisms underlying this phenomenon remain unclear.

Methods and Results
We studied serial changes in global left ventricular (LV) structure and function in infarcted (1, 2, 4, and 6 weeks after myocardial infarction) and sham-operated rat hearts and correlated them with structural and functional changes in myocytes isolated from the remote LV myocardium in the same hearts. Rats with myocardial infarction developed significant remodeling. The heart weight–to–body weight ratios were increased. LV volumes at filling pressure of 10 mm Hg were higher (305±28 versus 215±12 μL,
P
<.01). This was accompanied by global LV dysfunction (in vivo LV end-diastolic pressure, 4±1 versus 23±1.6 mm Hg; Langendorff LV developed pressure, 105±4 versus 62±9 mm Hg,
P
<.001 for both). Myocytes isolated from these hearts showed significant structural remodeling (LV myocytes, 24% longer and 15% wider; right ventricular myocytes, 38% longer and 31% wider, all
P
<.05). LV myocyte length correlated with changes in LV volume (
r
=.79) and function (LV developed pressure,
r
=−.81). However, LV myocytes from the same hearts showed normal contractile function and intracellular Ca
2+
transients at baseline and during inotropic stimulation with increasing extracellular Ca
2+
(1 to 6 mmol/L). The shortening-frequency relationship was also similar in myocytes from sham and myocardial infarction rats.

Conclusions
Postinfarct LV remodeling occurs predominantly by myocyte lengthening rather than by myocyte slippage. However, contractile function of the unloaded myocytes from the remote noninfarcted LV myocardium of the remodeled heart is normal. Therefore, myocyte contractile abnormalities may not contribute to global dysfunction of the remodeled heart. Reduced myocyte mass and nonmyocyte factors like increased wall stress, altered LV geometry, and changes in the myocardial interstitium may be more important in the genesis of postinfarct LV dysfunction in this model.
Remodeling and Neointimal Formation in the Carotid Artery of Normal and P-Selectin–Deficient Mice
Authors: Kumar Anjali , Hoover Jennifer L. , Simmons Carol A. , Lindner Volkhard , Shebuski Ronald J.
Published: June 2012

Background
Inflammatory reactions such as leukocyte activation with platelet adherence and release of inflammatory mediators occur after percutaneous transluminal coronary angioplasty and may play a role in restenosis. Vascular remodeling with neointimal formation was studied in normal C57Bl/J6 and P-selectin–deficient mice.

Methods and Results
The left common carotid artery was ligated just proximal to the carotid bifurcation. Four weeks later, left carotids and contralateral controls were snap-frozen. Computer-aided morphometry was performed to measure ratios of neointimal to medial area (NI/M) in 10 sections per animal as a measure of the thickness of the neointimal lesion. For normal mice, NI/M was 1.13±0.2 (n=20), whereas NI/M was reduced by 76% to 0.27±0.1 (n=19) in P-selectin knockout mice. Vascular constriction (as measured by the length of external elastic lamina) was the same in both groups, but the circumference of the lumen in knockout mice was 26% larger. Also, normal and P-selectin–deficient mice were killed at 3 and 7 days after ligation (n=6 for each group per time point). Histological staining and immunostaining for CD45 showed no inflammatory cell presence in P-selectin knockout mice. However, in normal mice, leukocyte infiltration was observed in the adventitia, media, and developing neointima. Also, P-selectin immunostaining was observed in media and developing neointima of normal mice.

Conclusions
These data suggest that P-selectin is involved in processes leading to cell migration and proliferation associated with vascular remodeling, presumably by mediating leukocyte recruitment and the interaction between platelets and leukocytes.
Effects of Adenovirus-Mediated Human Apo A-I Gene Transfer on Neointima Formation After Endothelial Denudation in Apo E–Deficient Mice
Authors: De Geest Bart , Zhao Zhian , Collen Désiré , Holvoet Paul
Published: June 2012

Background
Inactivation of apolipoprotein (apo) E genes in mice markedly increases β-VLDL levels and accelerates progression of complex atherosclerotic lesions. The present study investigated (1) the effect of apo E deficiency (apo E
-/-
) on neointima formation after endothelial denudation; and (2) the effect of increased HDL, induced by adenovirus-mediated transfer of a human apo A-I gene, on neointima formation.

Methods and Results
Guidewire-induced abrasion of the endothelium of the common carotid artery did not produce neointima formation within 18 days after injury in C57BL/6J mice (n=12) but was associated with an intima/media ratio of 0.82±0.25 in age-matched C57BL/6J apo E
−/−
mice (n=12). Neointima consisted primarily of smooth muscle α-actin positive cells. Injection in C57BL/6J apo E
−/−
mice of 2×10
9
(n=5) or 4×10
9
(n=7) plaque forming units (p.f.u.) of a recombinant human apo A-I adenovirus 3 days before injury resulted in an increase of HDL cholesterol from 36±5 to 75±3 mg/dL (
P
<.05) and to 96±13 mg/dL (
P
<.05), respectively, and of the HDL cholesterol/non–HDL cholesterol ratio from 0.063±0.003 to 0.15±0.01 (
P
<.05) and to 0.16±0.015 (
P
<.05), respectively. Intima/media ratio decreased to 0.28±0.06 (
P
=NS versus C57BL/6J apo E
−/−
mice) with 2×10
9
p.f.u. of apo A-I virus and to 0.03±0.01 with 4×10
9
p.f.u. (
P
<.01 versus C57BL/6J apo E
−/−
mice). Injection of 4×10
9
p.f.u. of RR5 (n=7) or tissue plasminogen activator (t-PA) control virus (n=6) did not result in a significant alteration of HDL cholesterol (44±11 and 26±4 mg/dL, respectively) nor in a reduction of intima/media ratio (0.81±0.35 and 0.86±0.23, respectively).

Conclusions
Apo E deficiency is associated with increased neointima formation after endothelial denudation. Gene transfer of apo A-I increases HDL cholesterol and significantly reduces neointima formation, which suggests a direct vascular protective effect of HDL.
Myocardial Infarction in Young Women in Relation to Plasma Total Homocysteine, Folate, and a Common Variant in the Methylenetetrahydrofolate Reductase Gene
Authors: Schwartz Stephen M. , Siscovick David S. , Malinow M. Rene , Rosendaal Frits R. , Beverly R. Kevin , Hess David L. , Psaty Bruce M. , Longstreth W. T. , Koepsell Thomas D. , Raghunathan T. E. , Reitsma Pieter H.
Published: June 2012

Background
In a population-based study, we examined the relationship between the risk of myocardial infarction (MI) among young women and plasma total homocysteine (tHCY), folate, vitamin B
12
, and a common cytosine (C) to thymine (T) polymorphism in the gene for 5,10-methylenetetrahydrofolate reductase (MTHFR).

Methods and Results
In-person interviews and nonfasting blood samples were obtained from 79 women <45 years old diagnosed with MI and 386 demographically similar control subjects living in western Washington state between 1991 and 1995. Compared with control subjects, case patients had higher mean tHCY concentrations (13.4±5.2 versus 11.1±4.4 μmol/L,
P
=.0004) and lower mean folate concentrations (12.4±13.4 versus 16.1±12.2 nmol/L,
P
=.018). There was no difference in vitamin B
12
concentrations between case patients and control subjects (346.8±188.4 versus 349.7±132.4 pmol/L,
P
=.90). After adjusting for cardiovascular risk factors, we found that women with tHCY ≥15.6 μmol/L were at approximately twice the risk of MI as women with tHCY <10.0 μmol/L (OR, 2.3; 95% CI, 0.94 to 5.64). Women with folate ≥8.39 nmol/L had an ≈50% lower risk of MI than women with folate <5.27 nmol/L (OR, 0.54; 95% CI, 0.23 to 1.28). There was no association with vitamin B
12
concentration. Among control subjects, 12.7% were homozygous for the
MTHFR T

677

allele, and these women had higher plasma tHCY and lower plasma folate than women with other genotypes. Ten percent of case patients were homozygous for

te T

677

allele, and there was no association of homozygosity for
T

677

with MI risk (OR, 0.90; 95% CI, 0.31 to 2.29).

Conclusions
These data support the hypothesis that elevated plasma tHCY and low plasma folate are risk factors for MI among young women. Although homozygosity for
MTHFR T

677

is related to increased plasma tHCY and low plasma folate, this genetic characteristic is not a risk factor for MI in this population.
Abnormal Epinephrine Release in Young Adults With High Personal and High Parental Blood Pressures
Authors: Harrap Stephen B. , Fraser Robert , Inglis Gordon C. , Lever Anthony F. , Beastall Graham H. , Dominiczak Marek H. , Foy Christopher J. W. , Watt Graham C. M.
Published: June 2012

Background
Increased activity of the sympathetic nervous system has been proposed as a cause of high blood pressure (BP) and may be related to diet and body weight. To determine the role of these factors in predisposition to high BP, we studied 100 young adults with high or low BP from families in which both parents had either high or low BP.

Methods and Results
Plasma catecholamine, glucose, and insulin levels were measured before and after an oral glucose load. There was a significant correlation between fasting plasma norepinephrine and mean arterial pressure (
P
=.001). Subjects with high BP, irrespective of parental BP, were heavier (
P
=.003) and fatter (
P
=.002) and had a greater rise in plasma insulin (
P
=.003) following glucose than those with low BP. Offspring with high BP whose parents also had high BP showed an unexpected rise in plasma epinephrine (
P
=.004) following glucose. This adrenal medullary response was not the result of high parental or high personal BP alone as it was not seen in offspring with low BP whose parents had high BP or in offspring with high BP whose parents had low BP.

Conclusions
Irrespective of family history, high BP is associated with increased body weight and hyperinsulinemia and reflects personal environment and behavior. However, abnormal epinephrine release is characteristic of the combination of genetic, environmental, and behavioral factors that is associated with high personal BP and a familial predisposition to high BP.
Prediction of Head-Up Tilt Test Result by Analysis of Early Heart Rate Variations
Authors: Mallat Ziad , Vicaut Eric , Sangaré Adama , Verschueren Jordanka , Fontaine Guy , Frank Robert
Published: June 2012

Background
Head-up tilt testing is a useful test for investigating vasovagal syncope. The determination of early, accurate, predictive criteria for a negative result would permit a reduction in the duration of the tilt test.

Methods and Results
Patients with no drug use and no illnesses other than recurrent unexplained syncope were recruited. In an initial study (110 consecutive patients), we aimed to determine a predictive criterion based on heart rate variations during the first minutes of upright tilting that could distinguish between patients with positive and negative tilt tests (patients with an early continual decrease in heart rate or blood pressure were excluded). Then we tested the predictive value of the established criterion in a second independent sample of patients with unexplained syncope (109 consecutive patients). An early sustained increase in heart rate ≤18 bpm during the first 6 minutes of upright tilting at a 60° angle allowed us to predict negative tilt tests with 100% specificity, 100% positive predictive value, and 88.6% sensitivity. This criterion was validated in the second, prospective arm of the study (96.4% specificity, 98.4% positive predictive value, and 87.3% sensitivity), even with subsequent use of isoproterenol in low doses.

Conclusions
In patients with no drug use and no illnesses other than recurrent unexplained syncope, a simple clinical criterion identifies patients who will not develop syncope during a prolonged upright tilt.
Infarct Size, Myocardial Hemorrhage, and Recovery of Function After Mechanical Versus Pharmacological Reperfusion
Authors: Pislaru Sorin V. , Barrios Laurentino , Stassen Tony , Jun Lin , Pislaru Cristina , Van de Werf Frans
Published: June 2012

Background
Whether myocardial reperfusion obtained with thrombolysis or primary angioplasty is associated with a similar recovery of function and with the same risk of hemorrhagic infarction is unknown. We evaluated the effects of mechanical and pharmacological reperfusion (with or without a plasma lytic state) on infarct size, myocardial hemorrhage, and left ventricular (LV) function in a canine model.

Methods and Results
Six groups of six dogs were subjected to balloon occlusion of the left anterior descending coronary artery (LAD) followed by 2 hours of reperfusion. The study had a two-by-three factorial design with two occlusion periods (90 and 240 minutes) and three different reperfusion strategies (placebo, 0.4 mg/kg recombinant tissue plasminogen activator, and 40 μg/kg recombinant staphylokinase). In a seventh control group, LAD occlusion was maintained without reperfusion. All dogs received aspirin and heparin. A systemic lytic state was present in staphylokinase-treated dogs. Planimetry of LV slices showed larger infarcts (percent of area at risk) and more hemorrhage (percent of IA) after 240 minutes of occlusion than after 90 minutes of occlusion (54±17% versus 37±18% and 52±27% versus 29±27%, respectively;
P
<.01 for both comparisons), with no significant difference among treatments. Hemorrhage was not observed in the control group without reperfusion. LV angiography showed no differences in global and regional LV function between mechanical and pharmacological reperfusion.

Conclusions
In this experimental model, hemorrhagic infarctions of similar extent were observed after both pharmacological and mechanical reperfusion. The extent of hemorrhage was increased by the delay in reperfusion but not by the presence of a lytic state.
High-Energy Defibrillation Increases the Severity of Postresuscitation Myocardial Dysfunction
Authors: Xie Jianlin , Weil Max Harry , Sun Shijie , Tang Wanchun , Sato Yoji , Jin Xiaohua , Bisera Joe
Published: June 2012

Background
The fatal outcome of victims after initially successful resuscitation from cardiac arrest has been attributed both to global myocardial ischemia during the interval of cardiac arrest and to the adverse effects of reperfusion. The present study was prompted by earlier experimental observation that the magnitude of myocardial dysfunction was in part related to the energy delivered during electrical defibrillation.

Methods and Results
Ventricular fibrillation (VF) was induced in 15 Sprague-Dawley rats. Precordial compression was begun together with mechanical ventilation after 4 minutes of untreated VF and continued for 6 minutes. Spontaneous circulation was restored in each animal after external defibrillation with a single stored 2-, 10-, or 20-J countershock. Cardiac index and the rate of left ventricular pressure rise at left ventricular pressure of 40 mm Hg (dP/dt
40
) and fall (negative dP/dt) during the 240-minute interval after successful resuscitation were decreased, and left ventricular diastolic pressure was increased. These decreases in myocardial function were closely related to the energy of electrical defibrillation. After a 20-J shock, animals survived for only 5±3 hours; after a 10-J shock, animals survived for 15±4 hours; and after a 2-J shock, all animals survived for >24 hours.

Conclusions
The severity of postresuscitation myocardial dysfunction is related, at least in part, to the magnitude of the electrical energy of the delivered shock.
Estrogen Effects on Insulin-Like Growth Factor-I (IGF-I)–Induced Cell Proliferation and IGF-I Expression in Native and Allograft Vessels
Authors: Lou Hong , Zhao Yejun , Delafontaine Patrick , Kodama Teruaki , Katz Nevin , Ramwell Peter W. , Foegh Marie L.
Published: June 2012

Background
Estrogen protects against cardiovascular disease in both patients and animal models and regulates insulin-like growth factor-I (IGF-I), an important cell-cycle progression factor.

Methods and Results
Smooth muscle cells and tissues were harvested from male recipient rabbits that 6 weeks earlier had received a cardiac allograft transplant consisting of a donor heart and ascending aorta. Segments of the ascending aorta from the native and allograft hearts from 9 placebo-treated and 8 estradiol-treated recipients were compared by using IGF-I–stimulated [
3
H]thymidine incorporation. The responses of the native vessel segments were similar (175.3±32% and 166.9±41%, respectively;
P
>.05) whether or not the recipients had been treated for 6 weeks with estradiol. In the grafts, however, estradiol markedly inhibited vascular cell thymidine incorporation (328.04±56% compared with 67.3±11%;
P
<.02). Smooth muscle cells were derived from the native aorta of the placebo-treated rabbits to study the effect of estradiol in vitro. IGF-I increased cell counts in a concentration-dependent manner. In serum-starved cells estradiol further decreased cell proliferation; this effect was blocked by the specific estrogen receptor antagonist ZK-119.010. Immunohistochemistry staining for IGF-I protein in the coronary arteries and ascending aorta of the cardiac allograft from the placebo-treated recipients revealed extensive IGF-I expression in the myointima. In contrast, IGF-I protein was not expressed in the coronary arteries and ascending aorta of the cardiac allograft from the estradiol-treated recipients. The IGF-I protein was extensively expressed only in the placebo-treated graft vessels. Myointimal thickening of the coronary arteries was significantly reduced by estradiol treatment (17.9±1.5% versus 44.3±3.7%;
P
<.02).

Conclusions
In vivo estradiol treatment abolishes both IGF-I mitogenic effects and IGF-I protein expression in the vascular wall, which may be causally related to the inhibitory effect of estradiol on transplant arteriosclerosis.
Lossy (15:1) JPEG Compression of Digital Coronary Angiograms Does Not Limit Detection of Subtle Morphological Features
Authors: Baker William A. , Hearne Steven E. , Spero Laurence A. , Morris Kenneth G. , Harrington Robert A. , Sketch Michael H. , Behar Victor S. , Kong Yihong , Peter Robert H. , Bashore Thomas M. , Harrison J. Kevin , Cusma Jack T.
Published: June 2012

Background
Development of the “all-digital” cardiac catheterization laboratory has been slowed by substantial computer archival and transfer requirements. Lossy data compression reduces this burden but creates irreversible changes in images, potentially impairing detection of clinically important angiographic features.

Methods and Results
Fifty image sequences from 31 interventional procedures were viewed both in the original (uncompressed) state and after 15:1 lossy Joint Photographic Expert’s Group (JPEG) compression. Experienced angiographers identified dissections, suspected thrombi, and coronary stents, and their results were compared with those from a consensus panel that served as a “gold standard.” The panel and the individual observers reviewed the same image sequences 4 months after the first session to determine intraobserver variability. Intraobserver agreement for original images was not significantly different from that for compressed images (89.8% versus 89.5% for 600 pairs of observations in each group). Agreement of individual observers with the consensus panel was not significantly different for original images from that for compressed images (87.6% versus 87.3%; CIs for the difference, −4.0%, 4.0%). Subgroup analysis for each observer and for each detection task (dissection, suspected thrombus, and stent) revealed no significant difference in agreement.

Conclusions
The identification of dissections, thrombi, and coronary stents is not substantially impaired by the application of 15:1 lossy JPEG compression to digital coronary angiograms. These data suggest that digital angiographic images compressed in this manner are acceptable for clinical decision-making.
Effects of Chronic ACE Inhibition on Sympathetic Nerve Traffic and Baroreflex Control of Circulation in Heart Failure
Authors: Grassi Guido , Cattaneo Bianca M. , Seravalle Gino , Lanfranchi Antonio , Pozzi Massimo , Morganti Alberto , Carugo Stefano , Mancia Giuseppe
Published: June 2012

Background
In congestive heart failure ACE inhibitors chronically reduce plasma norepinephrine. No information exists, however, on whether and to what extent this reduction reflects a true chronic inhibition of sympathetic outflow and which mechanisms may be responsible.

Methods and Results
In 24 patients aged 60.3±2.0 years (mean±SEM) affected by congestive heart failure (New York Heart Association class II) and treated with diuretics and digitalis, we measured mean arterial pressure (Finapres), plasma renin activity and angiotensin II levels (radioimmunoassay), plasma norepinephrine (high-performance liquid chromatography), and muscle sympathetic nerve activity (microneurography at a peroneal nerve) at rest and during baroreceptor stimulation and deactivation caused by stepwise intravenous infusions of phenylephrine and nitroprusside, respectively. In 12 patients measurements were repeated after a 2-month addition of the ACE inhibitor benazepril (10 mg/d PO), while in the remaining 12 patients they were performed again after 2 months without any treatment modifications. Benazepril did not alter mean arterial pressure, markedly increased plasma renin activity, reduced plasma angiotensin II, and caused a nonsignificant reduction in plasma norepinephrine. In contrast, muscle sympathetic nerve traffic was significantly reduced (−30.5±5.3%,
P
<.01). This reduction was accompanied by no change in the sympathoexcitatory responses to baroreceptor deactivation but by a marked enhancement of the sympathoinhibitory responses to baroreceptor stimulation (103.5±3.4%).

Conclusions
These results provide the first direct evidence that in congestive heart failure chronic ACE inhibitor treatment is accompanied by a marked reduction in central sympathetic outflow. This reduction may depend on a persistent restoration of baroreflex restraint on the sympathetic neural drive.
Safety of Transvenous Atrial Defibrillation
Authors: Sokoloski Mary C. , Ayers Gregory M. , Kumagai Koichiro , Khrestian Celeen M. , Niwano Shinichi , Waldo Albert L.
Published: June 2012

Background
It is recognized that a ventricular vulnerability period exists during which atrial shock delivery may induce a ventricular tachyarrhythmia. This study was designed to define the zone in which the ventricles are vulnerable to induction of ventricular tachyarrhythmia during delivery of atrial shocks in the sterile pericarditis canine model of atrial fibrillation.

Methods and Results
Two days after creation of sterile pericarditis, 24 dogs underwent either a four-part or five-part ventricular vulnerability protocol during which atrial shocks were delivered between transvenous catheters, one in the distal coronary sinus and one in the right atrial appendage. The protocol included part 1, shocks during induced atrial fibrillation; parts 2 through 4, shocks delivered synchronously with the last ventricular beat of one of the following three ventricular pacing protocols: constant ventricular rates (S
1
S
1
), short-long-short cycles (S
1
S
2
S
3
-V), and ventricular premature beats (S
1
); and part 5, shocks delivered synchronously with the last R wave resulting from an atrially paced short-long-short cycle (S
1
S
2
S
3
-A). Ventricular tachyarrhythmia was induced 122 times: 2 of 665 shocks in two dogs in part 1, 29 of 786 shocks in nine dogs in part 2, 67 of 734 shocks in 15 dogs in part 3, 24 of 919 shocks in five dogs in part 4, and none in part 5. All ventricular proarrhythmia resulted from shocks delivered during the T wave of a preceding ventricular beat. No episodes of ventricular tachyarrhythmia were induced by atrial shocks synchronized to R waves with the previous RR at intervals above the QT+60 ms interval (absolute interval >320 ms), with one exception, at the QT+100 ms interval (absolute interval 360 ms).

Conclusions
With transvenous electrode catheters used to deliver atrial shocks, life-threatening ventricular rhythms were induced but were limited to a specific zone defined by the QT interval.
Plasma Cholesterol Regulates Soluble Cell Adhesion Molecule Expression in Familial Hypercholesterolemia
Authors: Sampietro T. , Tuoni M. , Ferdeghini M. , Ciardi A. , Marraccini P. , Prontera C. , Sassi G. , Taddei M. , Bionda A.
Published: June 2012

Background
Hypercholesterolemia is associated with endothelial dysfunction. On the basis of the hypothesis that high plasma cholesterol per se may be a sufficient stimulus to upregulate endothelial adhesiveness and that this phenomenon might be reversible, soluble endothelial leukocyte adhesion molecules (sELAMs) were studied in patients with familial hypercholesterolemia undergoing LDL apheresis.

Methods and Results
Selective LDL absorption by dextran sulfate columns was used to treat plasma volumes of 6.5 to 9.2 L; after LDL apheresis, total cholesterol, LDL cholesterol, apolipoprotein B, triglycerides, and lipoprotein(a) levels were reduced by 74%, 82%, 79%, 56%, and 86%, respectively. Soluble intercellular adhesion molecule-1 (sICAM-1) and sELAM-1 were measured before, immediately after, and 2 and 6 days after LDL apheresis. Basal sICAM-1 and sELAM-1 values were higher than in healthy control subjects. After LDL apheresis, they decreased (
P
<.0001 and
P
<.0004, respectively); their removal by extracorporeal circulation components was excluded. Individual pretreatment and posttreatment values of sICAM-1 and sELAM-1 were positively correlated (
P
<.0001 and
P
<.001, respectively) with total cholesterol; their rebound curves showed patterns similar to the total cholesterol rebound curve but not to the triglyceride and lipoprotein(a) curves.

Conclusions
In the absence of changes in clinical chemical parameters, tumor necrosis factor-α, interleukin-6, and acute-phase reactant proteins, these results confirm in a clinical setting the upregulation of endothelial adhesiveness observed in experimental hypercholesterolemia and suggest a direct role for cholesterol in regulating this phenomenon, at least in familial hypercholesterolemia.
Cigarette Smoking, Weight Gain, and Coronary Mortality
Authors: Fulton Janet E. , Shekelle Richard B.
Published: June 2012

Background
Prospective studies of overweight and coronary heart disease (CHD) have presented inconsistent findings. Previous inconsistencies may be explained by the modifying effect of cigarette smoking on the association between weight gain and coronary mortality.

Methods and Results
We prospectively studied 1531 men 40 to 59 years of age who were employed at the Hawthorne Works of the Western Electric Company in Chicago, Ill. Information collected at the initial examination in 1958 included recalled weight at age 20, present weight, height, smoking status, and other CHD risk factors. Vital status was known for all men on the 25th anniversary: 257 CHD deaths occurred over 31 644 person-years of experience. Cox regression analysis was used to investigate risk of coronary mortality associated with change in body mass index (ΔBMI) and its modification by smoking status after adjustment for age, major organ system disease, family history of CHD, and BMI at age 20. Adjustment was not performed for blood pressure or serum total cholesterol because these are intervening variables. ΔBMI was positively associated with risk of coronary mortality in never-smokers but not in current-smokers (
P
for interaction=.088). For never-smokers with ΔBMI classified as stable, low gain, moderate gain, or high gain, adjusted relative risks of coronary mortality were 1.00, 1.75, 1.75, and 3.07, respectively (
P
for trend=.010). For current-smokers, the respective adjusted relative risks were 1.00, 0.78, 1.05, and 1.03 (
P
for trend=.344).

Conclusions
These results support the hypothesis that cigarette smoking modifies the association between weight gain and coronary mortality. Future investigations of weight gain and coronary mortality should account for the modifying effect of cigarette smoking.
Effect of Verapamil and Procainamide on Atrial Fibrillation–Induced Electrical Remodeling in Humans
Authors: Daoud Emile G. , Knight Bradley P. , Weiss Raul , Bahu Marwan , Paladino Walter , Goyal Rajiva , Man K. Ching , Strickberger S. Adam , Morady Fred
Published: June 2012

Background
Atrial fibrillation (AF) shortens the atrial effective refractory period (ERP) and predisposes to further episodes of AF. The purpose of this study was to determine the effect of verapamil and procainamide on these manifestations of AF-induced electrical remodeling.

Methods and Results
In adult patients without structural heart disease, the atrial ERP was measured before and after AF after pharmacological autonomic blockade and administration of verapamil (17 patients), procainamide (10 patients), or saline (20 patients). AF was then induced by rapid pacing. Immediately on AF conversion, the post-AF ERP was measured at alternating drive cycle lengths of 350 and 500 ms. In the saline group, the pre-AF and first post-AF ERPs at the 350-ms drive cycle length were 206±19 and 179±27 ms (
P
<.0001), respectively, and at the 500-ms drive cycle length, the values were 217±16 and 183±23 ms, respectively (
P
<.0001). There was a similar significant shortening of the first post-AF ERP in the procainamide group. In the verapamil group, however, there was no difference between the pre-AF and the first post-AF ERP at the 350-ms (226±15 versus 227±22 ms,
P
=.8) or 500-ms (230±17 versus 232±20 ms,
P
=.6) drive cycle length. During determinations of the post-AF ERP, 105 secondary episodes of AF were unintentionally induced in 12% of verapamil patients compared with 90% and 80% of saline and procainamide patients (
P
<.01 versus verapamil).

Conclusions
Pretreatment with the calcium channel antagonist verapamil, but not the sodium channel antagonist procainamide, markedly attenuates acute, AF-induced changes in atrial electrophysiological properties. These data suggest that calcium loading during AF may be at least partially responsible for AF-induced electrical remodeling.
Three-Dimensional Echocardiographic Estimation of Infarct Mass Based on Quantification of Dysfunctional Left Ventricular Mass
Authors: Yao Jiefen , Cao Qi-Ling , Masani Navroz , Delabays Alain , Magni Giuseppina , Acar Philippe , Laskari Cleo , Pandian Natesa G.
Published: June 2012

Background
Two-dimensional echocardiography is useful for estimating the extent of infarct-related wall motion abnormalities. Such estimation, however, is based on a few selected views and extrapolated for the whole left ventricle (LV). This approach does not provide us with the actual amount of dysfunctional myocardium. Volume-rendered three-dimensional echocardiography (3DE) might overcome these limitations. In this study we explored (1) how well volume-rendered 3DE delineates regional dysfunction of the infarcted LV and (2) how well dysfunctional myocardial mass quantified by 3DE reflects the actual anatomic infarct mass.

Methods and Results
3DE was performed before and 3 hours after coronary occlusion in 16 dogs. With the LV viewed in equidistant short-axis slices, the region of dysfunction was demarcated, and the dysfunctional myocardial mass was derived from this. With triphenyltetrazolium chloride staining, anatomic infarct regions were delineated, dissected, and weighed. The anatomic infarct mass was 16.3±7.7 g (mean±SD) (range, 6.4 to 31.4 g); the dysfunctional mass estimated by 3DE was 17.4±9.1 g (range, 5.2 to 39.0 g). The mean difference was 1.0 g. The correlation between dysfunctional mass (
y
) and infarct mass (
x
) was
y
=1.1
x
−0.6,
r
=.93 (
P
<.0001). The percentage of LV involved in infarction was 18.2±5.8% (range, 9.1% to 26.1%); the percentage of LV involved in regional dysfunction was 18.3±6.9% (range, 7.9% to 31.2%). The mean difference was 0.1%. The correlation between percentage of LV involved in infarction (
x
) and percentage of LV involved in dysfunction (
y
) was
y
=1.0
x
−1.1,
r
=.92 (
P
<.0001).

Conclusions
Volume-rendered 3DE crisply displays regional dysfunction of infarcted LV. 3DE-measured dysfunctional mass accurately reflects the anatomic infarct mass.
Bmx
Tyrosine Kinase Is Specifically Expressed in the Endocardium and the Endothelium of Large Arteries
Authors: Ekman Niklas , Lymboussaki Athina , Västrik Imre , Sarvas Krista , Kaipainen Arja , Alitalo Kari
Published: June 2012

Background
The growth and differentiation of endothelial cells are regulated by signal transduction through tyrosine protein kinases. Recently, a novel cytoplasmic tyrosine kinase gene,
Bmx
(

B

one

M

arrow tyrosine kinase gene in chromosome

X

), was identified in human bone marrow RNA and found to be expressed predominantly in myeloid hematopoietic cell lineages. Our preliminary analyses indicated that the
Bmx
gene was also highly expressed in human heart.

Methods and Results
Mouse
Bmx
cDNA was isolated, sequenced, and found to encode a polypeptide ≈91% identical to the human
Bmx
tyrosine kinase. Northern blotting and in situ hybridization of tissue sections indicated that
Bmx
mRNA is specifically expressed in the endocardium of the developing heart as well as in the endocardium of the left ventricle and in the endothelium of large arteries in adult mice. A weak signal was seen also in coronary arterial endothelium.

Conclusions Bmx
shows a unique specificity of expression among tyrosine kinase genes and may be involved in signal transduction in endocardial and arterial endothelial cells. The results suggest that specific signal transduction mechanisms are present in such endothelia.
Phasic Coronary Flow Characteristics in Patients With Constrictive Pericarditis
Authors: Akasaka Takashi , Yoshida Kiyoshi , Yamamuro Atushi , Hozumi Takeshi , Takagi Tsutomu , Morioka Shigefumi , Yoshikawa Junichi
Published: June 2012

Background
Phasic coronary flow characteristics have been reported in patients with aortic valve disease and hypertrophic cardiomyopathy. The purpose of this study was to assess the differences in coronary flow characteristics between patients with constrictive pericarditis and those with restrictive cardiomyopathy.

Methods and Results
The study populations consisted of 7 case patients with constrictive pericarditis, 8 with restrictive cardiomyopathy, and 11 control subjects with chest pain and normal coronary arteries. Five minutes after injection of 3 mg of isosorbide dinitrate, phasic coronary flow velocity patterns were analyzed in the proximal segment of the angiographically normal left anterior descending coronary artery at rest using a 0.014-in, 15-MHz Doppler guidewire. Coronary flow reserve was obtained from the ratio of adenosine-induced (0.14 mg · kg
−1
· min
−1
IV) hyperemic/baseline time-averaged peak velocity. Although in case patients with constrictive pericarditis and restrictive cardiomyopathy maximal hyperemic time-averaged peak velocity (21±8 and 31±17 versus 60±19 cm/s, respectively;
P
<.001) and coronary flow reserve (1.3±0.4 and 1.6±0.6 versus 3.6±0.4, respectively,
P
<.001) were significantly lower than in control subjects, there were no significant differences in these indexes between the two groups of case patients. Velocity half-time of diastolic flow velocity corrected by

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, which indicates deceleration of diastolic flow, in the groups of case patients with constrictive pericarditis and restrictive cardiomyopathy was significantly less than that in control subjects (6.2±2.6 and 10.6±1.5 versus 16.9±2.7, respectively;
P
<.001); this was also significantly smaller in constrictive pericarditis than restrictive cardiomyopathy (
P
<.001). This index <9.5 could distinguish constrictive pericarditis from restrictive cardiomyopathy with a sensitivity of 86% and a specificity of 88%. Furthermore, time from the beginning of diastole to diastolic peak velocity corrected by

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indicating acceleration of diastolic flow velocity in constrictive pericarditis was significantly less than that in restrictive cardiomyopathy and control subjects (2.8±1.2 versus 4.8±0.8 and 4.4±0.6, respectively;
P
<.001).

Conclusions
Although coronary flow reserve is limited in both constrictive pericarditis and restrictive cardiomyopathy because of restriction of hyperemic response, rapid acceleration and more rapid deceleration of diastolic flow velocity are more characteristic in constrictive pericarditis than in restrictive cardiomyopathy.