bluuebunny/crossref_metadata_2025 huggingface dataset:
Imaging and Sizing of Atrial Septal Defects by Magnetic Resonance
Authors: Holmvang Godtfred , Palacios Igor F. , Vlahakes Gus J. , Dinsmore Robert E. , Miller Stephen W. , Liberthson Richard R. , Block Peter C. , Ballen Barbara , Brady Thomas J. , Kantor Howard L.
Published: June 2012

Background
Development of techniques for percutaneous closure of atrial septal defects (ASDs) makes accurate noninvasive sizing of ASDs important for appropriate patient selection.

Methods and Results
Magnetic resonance (MR) images of ASDs were obtained in 30 patients (mean age, 41±16 years) by both spin-echo and phase-contrast cine MR imaging. Spin-echo images were obtained in two orthogonal views (short-axis and four-chamber) perpendicular to the plane of the ASD. Spin-echo major and minor diameters were measured, and spin-echo defect area was calculated. Phase-contrast cine MR images were obtained in the plane of the ASD, and cine major diameter and defect area were measured from the region of signal enhancement or phase change due to shunt flow across the defect. MR measurements were compared with templates cut during surgery to match the defect or with ASD diameter determined by balloon sizing at catheterization. ASD size measured from cine MR images (
y
) agreed closely with catheterization and template standards (
x
). For major diameter,
y
=0.78
x
+5.7,
r
=.93, and SEE=3.4 mm. On average, spin-echo measurements overestimated major diameter and area of secundum ASDs by 48% and 125%, respectively.

Conclusions
Phase-contrast cine MR images acquired in the plane of an ASD define the defect shape by the cross section of the shunt flow stream and allow noninvasive determination of defect size with sufficient accuracy to permit stratification of patients to closure of the defect by catheter-based techniques versus surgery. Spin-echo images, on the other hand, are not adequate for defining ASD size, because septal thinning adjacent to a secundum ASD may appear to be part of the defect.
Copper-Induced Tissue Factor Expression in Human Monocytic THP-1 Cells and Its Inhibition by Antioxidants
Authors: Crutchley David J. , Que Benito G.
Published: June 2012

Background
Transition metals such as copper are known to initiate free radical formation and lipid peroxidation. Recent reports suggest that intracellular reactive oxygen intermediates can induce the transcription of a number of important genes. The present study examines the effects of copper and iron on the ability of monocytic cells to synthesize and express tissue factor, the potent procoagulant factor.

Methods and Results
Exposure of human monocytic THP-1 cells to 5 to 10 μmol/L Cu
2+
led to cell damage and the expression of tissue factor activity to levels up to 70 times higher than control, as measured by a single-stage plasma coagulation assay. These effects were seen only in the presence of a lipophilic chelating agent, 8-hydroxyquinoline, suggesting that intracellular transport of Cu
2+
was required. The effects of Cu
2+
were mimicked by ceruloplasmin but not by Fe
3+
or hemin. The induction of tissue factor activity by Cu
2+
was slow in onset (6 hours) but sustained (24 hours) and was accompanied by increased tissue factor mRNA levels, measured by reverse transcription/polymerase chain reaction after annealing with oligomer primers. Increases in tissue factor protein, measured by a specific immunoassay, also occurred but were smaller than those in activity. Cu
2+
, therefore, appears to act at both the transcriptional and posttranslational levels. The effects of Cu
2+
were inhibited by a number of lipophilic antioxidants, including probucol, vitamin E, butylated hydroxytoluene, and a 21-aminosteroid, U74389G.

Conclusions
Exposure of monocytes to oxidizing conditions may lead to the expression of high levels of tissue factor activity, with accompanying risk for disseminated intravascular coagulation, and this may be inhibited by lipophilic antioxidants.
Growth Hormone Improves Cardiac Performance in Experimental Heart Failure
Authors: Yang Renhui , Bunting Stuart , Gillett Nancy , Clark Ross , Jin Hongkui
Published: June 2012

Background
Growth hormone has been shown to increase maximum isometric active force of the left ventricular papillary muscle of rats in vitro. Administration of growth hormone causes an increase in myocardial contractility in normal humans. Our preliminary study suggests that treatment with growth hormone results in increased ventricular contractility in rats with left ventricular dysfunction. In the present study, the effects of growth hormone on cardiac function, including cardiac output, stroke volume, and peripheral vascular resistance, were determined in a rat model of heart failure.

Methods and Results
Ligation of the left coronary artery or sham operation was performed; 4 weeks after surgery, recombinant human growth hormone (2 mg/kg per day SC) or vehicle then was administered for 15 days. The animals were catheterized after 13 days of the treatment. Cardiac output, measured by a thermodilution method, and other hemodynamic parameters were measured in the conscious animals 2 days after catheterization. The infarct sizes induced by left coronary ligation were comparable between growth hormone–treated and vehicle-treated rats. Six weeks after ligation, rats treated with vehicle exhibited significant decreases in cardiac index, stroke volume index, and left ventricular maximum dP/dt and increases in left ventricular end-diastolic pressure compared with sham rats. In the ligated rats, treatment with growth hormone increased cardiac index, stroke volume index, and left ventricular maximum dP/dt (
P
<.05) and reduced left ventricular end-diastolic pressure and systemic vascular resistance (
P
<.05). In sham rats, growth hormone slightly reduced arterial pressure but did not significantly alter cardiac performance. There was no significant difference in heart rate between the experimental groups.

Conclusions
These results suggest that growth hormone treatment may improve cardiac function by both increased myocardial contractility and decreased peripheral vascular resistance in heart failure.
Job Strain and the Prevalence and Outcome of Coronary Artery Disease
Authors: Hlatky Mark A. , Lam Lai Choi , Lee Kerry L. , Clapp-Channing Nancy E. , Williams Redford B. , Pryor David B. , Califf Robert M. , Mark Daniel B.
Published: June 2012

Background
It has been hypothesized that jobs that have both high psychological demands and low decision latitude (“job strain”) can lead to coronary disease. The objective of this study was to test whether job strain was correlated with the presence of coronary disease at angiography or with long-term outcome in patients with angiographic coronary disease.

Methods and Results
Employed patients under the age of 65 years undergoing diagnostic coronary angiography completed a self-administered questionnaire about their job duties and work environment. Job strain was measured by the method of Karasek. Patients were separated into three groups, based on extent of coronary disease: significant disease (≥75% stenosis), insignificant disease (>0% but <75% stenosis), and normal coronary arteries. Statistical analyses were performed using logistic regression and the Cox proportional hazards model. The 1489 patients enrolled had a median age of 52 years; 76% were male and 88% were white. By design, all patients were employed, 60% in white-collar jobs and only 16% in jobs requiring heavy labor. Traditional cardiac risk factors were most prevalent in the 922 patients with significant coronary artery disease, at intermediate levels in the 204 patients with insignificant disease, and least prevalent in the 363 patients with normal coronary arteries (all
P
<.01). Job strain was actually more common in patients with normal coronary arteries (35%) than in patients with insignificant (26%) or significant disease (25%,
P
<.002). In a multivariate analysis, job strain was not significantly correlated with the presence of coronary disease. Job strain was not correlated with angina frequency at the time of angiography. Job strain was not a predictor of cardiac events (cardiac death or nonfatal myocardial infarction) during follow-up.

Conclusions
Job strain was not correlated with the prevalence or severity of coronary artery disease in a cohort of patients undergoing coronary angiography. The outcome of patients with angiographically defined coronary disease was not affected by the level of job strain as measured by the method of Karasek.
Mechanism of Adenosine-Induced Elevation of Pulmonary Capillary Wedge Pressure in Humans
Authors: Nussbacher Amit , Ariê Sigemituzo , Kalil Roberto , Horta Pedro , Feldman Marc D. , Bellotti Giovanni , Pileggi Fulvio , Ellis Mark , Johnson William H. , Camarano Gustavo B. , Kass David A.
Published: June 2012

Background
Continuous intravenous administration of adenosine to humans often results in a paradoxical rise in pulmonary capillary wedge pressure (PCWP), whereas arterial resistance is lowered and cardiac output and heart rate increase. This is believed to be due to diastolic stiffening of the ventricle or to a negative inotropic effect. In the present study, we tested these and other mechanisms by using pressure–volume (PV) analysis and echocardiography.

Methods and Results
Fifteen patients with normal rest left ventricular function underwent cardiac catheterization and received adenosine at a rate of 140 μg/kg per minute IV for 6 to 10 minutes. PV relations were measured in 9 patients (without coronary artery disease) using the conductance catheter method. In 6 additional patients with coronary artery disease, echocardiograms were used to assess wall thickness and function, and aortic and coronary sinus blood, lactate, oxygen, and adenosine levels were measured. Adenosine increased PCWP by 19% (+2.6 mm Hg) in both patient groups while lowering arterial load by 30% and increasing cardiac output by 45% (all
P
<.001). There was no significant effect of adenosine on mean linear chamber compliance or monoexponential elastic stiffness, as the diastolic PV relation was unchanged in most patients. Diastolic wall thickness also was unaltered. Thus, the PCWP rise did not appear to be due to diastolic stiffening. Adenosine induced a rightward shift of the end-systolic PV relation (ESPVR) (+12.7±3.7 mL) without a slope change. This shift likely reflected effects of afterload reduction, as other indexes (stroke work–end-diastolic volume relation and dP/dt
max
at matched preload) were either unchanged or increased. Furthermore, this modest shift in ESPVR was more than compensated for by vasodilation and tachycardia, so reduced systolic function could not explain the increase in PCWP. There also was no net lactate production to suggest ischemia. Rather than arising from direct myocardial effects, PCWP elevation was most easily explained by a change in vascular loading, as both left ventricular end-diastolic volume and right atrial pressure increased (
P
<.05). This suggests that adenosine induced a redistribution of blood volume toward the central thorax.

Conclusions
PCWP elevation in response to adenosine primarily results from changes in vascular loading rather than from direct effects on cardiac diastolic or systolic function.
Upregulation and Modulation of Inducible Nitric Oxide Synthase in Rat Cardiac Allografts With Chronic Rejection and Transplant Arteriosclerosis
Authors: Russell Mary E. , Wallace Africa F. , Wyner Lauri R. , Newell John B. , Karnovsky Morris J.
Published: June 2012

Background
The Lewis-F344 rat cardiac transplantation model produces cardiac allografts with chronic rejection characterized by arteriosclerotic lesions composed of macrophages and smooth muscle cells. Modulation of the inflammatory response with a diet deficient in essential fatty acids protects against the development of intimal thickening. Little is known about the components of the inflammatory response mediating this process. The cytokine-inducible isoform of nitric oxide synthase (iNOS) regulates the high-output nitric oxide pathway that confers activation properties to macrophages and regulates vasomotion, monocyte adherence, and smooth muscle cell proliferation in the vasculature. The purpose of the present study was to determine whether the iNOS pathway was upregulated during the course of chronic cardiac rejection.

Methods and Results
We studied iNOS mRNA and protein expression patterns in a series of Lewis-F344 cardiac allografts with early and late chronic rejection and after modulation of the inflammatory response (in an effort to attenuate arteriosclerosis). Relative gene transcript levels were measured with a
32
P-dCTP reverse-transcriptase polymerase chain reaction assay designed to amplify iNOS mRNA. The distribution of the iNOS gene product was examined by immunocytochemistry with a polyclonal antibody against iNOS. NOS transcript levels increased significantly in cardiac allografts (days 7, 14, 28, and 75) compared with paired host hearts (exposed to the same circulation) and syngrafts (
P
<.003). Immunostaining localized the iNOS antigen within subpopulations of mononuclear inflammatory cells in cardiac allografts—presumably, activated macrophages. The number of iNOS-positive mononuclear cells was 25-fold higher in cardiac allografts compared with paired host hearts and syngrafts (
P
<.009). In cardiac allografts of 75 days or older, there also was striking iNOS staining within some medial and intimal smooth muscle cells in various vessels. Modulation of the inflammatory response (with a diet deficient in essential fatty acids) produced significant decreases in the intimal thickening score and in the percentage of diseased vessels in 28-day cardiac allografts compared with allografts from rats fed a control diet. There was a correlate decrease in iNOS transcript levels and in the number of iNOS-positive mononuclear cells in the 28-day cardiac allografts from rats fed the essential fatty acid-deficient diet.

Conclusions
The early and persistent upregulation of iNOS in chronic cardiac rejection and the coincident reduction in arteriosclerosis and downregulation of iNOS suggest that this inducible regulator may contribute to the inflammatory response mediating transplant arteriosclerosis.
Transient Outward Currents in Subendocardial Purkinje Myocytes Surviving in the Infarcted Heart
Authors: Jeck Cynthia , Pinto Judith , Boyden Penelope
Published: June 2012

Background
Altered electrical activity of subendocardial Purkinje fibers contributes to arrhythmias in the 48-hour infarcted canine heart. Changes in the transmembrane action potentials of these fibers include marked action potential prolongation. The ionic basis for these changes is unknown.

Methods and Results
We used whole-cell voltage-clamp techniques to study 4-aminopyridine (4-AP)–sensitive voltage-dependent transient outward currents (I
to1
) in Purkinje myocytes isolated from LV subendocardial (n=14) and free-running (n=15) bundles of the normal canine heart. I
to1
in these two groups of control cells (normal-zone Purkinje cells [NZPCS]) did not differ. NZPCS I
to1
was then compared with I
to1
of Purkinje myocytes dispersed from subendocardium of infarcted hearts 48 hours after total coronary artery occlusion (IZPC
48
, n=14). I
to1
amplitude and current density were significantly reduced (
P
<.01) in IZPC
48
s (1650±389 pA, 9±2 pA/pF) compared with NZPCS (2917±267 pA, 20.2±2 pA/pF) at V
t
=+55 mV, V
h
=−60 mV, where V
t
is test potential and V
h
is holding potential. Decay of I
to1
was biexponential in all NZPCS but monoexponential in 71% of IZPC
48
s. Both NZPCS and IZPC
48
s have a sustained 4-AP–sensitive component (at 250 ms, V
t
=+55 mV: 4±1 pA/pF, 3±1 pA/pF, respectively). I
to1
voltage dependence of inactivation did not differ between groups. In IZPC
48
s, recovery of I
to1
from inactivation was slowed significantly. Furthermore, significantly more I
to1
was seen with rapid pacing in NZPCS (cycle length [CL] 5000 ms=100%, CL 1300 ms=73%, CL 330 ms=46%) than in IZPC
48
s (CL 5000 ms=100%, CL 1300 ms=58%, CL 330 ms=31%). In three IZPC
48
s, no I
to1
was seen at CL 330 ms.

Conclusions
I
to1
plays a major role in normal Purkinje myocyte electrophysiology, contributing both a large transient and a sustained component that are 4-AP–sensitive. In subendocardial Purkinje myocytes that survive in the 48-hour infarcted heart, density of I
to1
is markedly reduced and the remaining I
to1
showed specific changes in kinetics. The alterations observed in both I
to1
density and function could contribute to abnormally long transmembrane action potentials of these arrhythmogenic Purkinje myocytes of the infarcted heart.
Glibenclamide, a Selective Inhibitor of ATP-Sensitive K
+
Channels, Attenuates Metabolic Coronary Vasodilatation Induced by Pacing Tachycardia in Dogs
Authors: Katsuda Yousuke , Egashira Kensuke , Ueno Hideki , Akatsuka Yutaka , Narishige Takahiro , Arai Yukinori , Takayanagi Tsuneo , Shimokawa Hiroaki , Takeshita Akira
Published: June 2012

Background
We previously reported that glibenclamide (a selective inhibitor of ATP-sensitive K
+
channels [K
+
ATP
channels]) inhibited metabolic coronary vasodilatation induced by β
1
-adrenoceptor stimulation. However, the role of K
+
ATP
channels in metabolic coronary vasodilatation induced by tachycardia is still unknown. This study aimed to determine whether glibenclamide attenuates metabolic coronary vasodilatation induced by pacing-induced tachycardia.

Methods and Results
In anesthetized dogs, increasing heart rate from 103±1 to 160 beats per minute with atrial pacing increased coronary blood flow without altering arterial pressure and left ventricular pressure. Intracoronary infusion of glibenclamide at 1.5 and 5.0 μg · kg
−1
· min
−1
did not alter basal coronary blood flow but significantly attenuated (
P
<.01) the tachycardia-induced coronary vasodilatation without altering the tachycardia-induced increase in myocardial oxygen consumption (MV̇
o
2
). In conscious dogs, intracoronary glibenclamide at 5.0 μg · kg
−1
· min
−1
attenuated (
P
<.05) coronary vasodilatation induced by ventricular pacing from 85±6 to 150 beats per minute. Glibenclamide markedly attenuated coronary vasodilatation evoked with the K
+
ATP
channel opener pinacidil.

Conclusions
These data indicate that blockade of coronary vascular K
+
ATP
channels with glibenclamide inhibited metabolic coronary vasodilatation induced by pacing tachycardia in dogs, suggesting that K
+
ATP
channels are involved in the mechanism mediating metabolic coronary vasodilatation associated with pacing tachycardia.
Pressure and Volume Loading of the Right Ventricle Have Opposite Effects on Left Ventricular Ejection Fraction
Authors: Louie Eric K. , Lin Steve S. , Reynertson Sandra I. , Brundage Bruce H. , Levitsky Sidney , Rich Stuart
Published: June 2012

Background
Left ventricular ejection fraction has been reported to be depressed in patients with right ventricular volume overload (RVVO) due to Ebstein’s anomaly and uncomplicated atrial septal defect, whereas it is usually preserved in right ventricular pressure overload (RVPO) due to congenital pulmonic stenosis. In the present study, we examined the hypothesis that the differential timing of active displacement of the ventricular septum into the left ventricle in RVPO (end systole) and RVVO (end diastole) results in opposite effects of RVPO and RVVO on left ventricular ejection fraction.

Methods and Results
Ten patients with severe tricuspid regurgitation after tricuspid valve resection for endocarditis and 10 patients with primary pulmonary hypertension were studied as models of isolated RVVO and RVPO, respectively. Left ventricular ejection fraction, end-diastolic volume, and regional systolic shortening were measured with the use of echocardiographic techniques in these 20 patients and 10 healthy control subjects. In RVPO, despite marked underfilling of the left ventricle relative to the healthy control subjects (end-diastolic volume, 48±26 versus 77±20 mL;
P
<.02), left ventricular ejection fraction was similar to that of the control subjects (56±5% versus 60±4%;
P
=.07) and only 1 of 10 RVPO patients had an ejection fraction of less than 50%. In contrast, in RVVO the left ventricle was volume replete (end-diastolic volume, 84±26 versus 77±20 mL;
P
=NS), but left ventricular ejection fraction was significantly depressed (51±4% versus 60±4%,
P
<.001) compared with the control subjects, and 4 of 10 RVVO patients had an ejection fraction of less than 50%. Analysis of systolic fractional shortening along two perpendicular short-axis diameters and the mutually orthogonal long axis demonstrated isolated augmentation of fractional shortening in the ventricular septal–to–posterolateral free wall dimension in RVPO (47.4±13.7% versus 34.2±13.1%,
P
<.05) and isolated depression of fractional shortening along that same dimension in RVVO (13.7±11.8% versus 34.2±13.1%,
P
<.001) compared with the control subjects.

Conclusions
End-systolic leftward ventricular septal shift in RVPO results in isolated augmentation of systolic shortening in the septal–to–free wall dimension, whereas end-diastolic leftward ventricular septal shift in RVVO results in isolated reduction in systolic shortening in the septal–to–free wall dimension. As a result, despite relative underfilling of the left ventricle in RVPO, resting left ventricular ejection fraction is preserved, whereas ejection fraction is depressed for the volume-replete left ventricle of patients with RVVO.
Infiltrates of Activated Mast Cells at the Site of Coronary Atheromatous Erosion or Rupture in Myocardial Infarction
Authors: Kovanen Petri T. , Kaartinen Maija , Paavonen Timo
Published: June 2012

Background
Erosion and rupture of coronary atheromas are the events preceding the vast majority of acute coronary syndromes. The shoulder regions of atheromas, the sites at which erosion or rupture is most likely to occur, are the sites at which mast cells accumulate. These cells are filled with neutral proteases capable of triggering extracellular matrix degradation via activation of matrix metalloproteinases. To obtain more direct evidence for the participation of mast cells in the acute coronary syndromes, we quantified the numbers of mast cells at eroded or ruptured sites of coronary atheromas in patients who died of myocardial infarction.

Methods and Results
In specimens of coronary arteries from 20 patients who had died of acute myocardial infarction, the site of atheromatous erosion or rupture was identified. The specimens were stained with monoclonal antibodies against the two major proteases of mast cells, tryptase and chymase, and against macrophages, T lymphocytes, and smooth muscle cells. At the immediate site of erosion or rupture, mast cells amounted to 6% of all nucleated cells, in the adjacent atheromatous area to 1%, and in the unaffected intimal area to 0.1%. The proportions of these mast cells that were activated, ie, had been stimulated to degranulate and release some of their tryptase and chymase contents, were 86% at the site of erosion or rupture, 63% in the adjacent atheromatous area, and 27% in the unaffected intima. At the site of erosion or rupture, the numbers of macrophages and T lymphocytes were also increased, but the number of smooth muscle cells was decreased.

Conclusions
The accumulation of activated mast cells (200-fold more than in the unaffected coronary intima) at the site of atheromatous erosion or rupture suggests that in thrombotic coronary occlusion the role played by mast cells is significant.
Acute Hypertension Induces Heat-Shock Protein 70 Gene Expression in Rat Aorta
Authors: Xu Qingbo , Li Ding-gang , Holbrook Nikki J. , Udelsman Robert
Published: June 2012

Background
Many factors cause acute systemic hypertension, which in turn can result in damage to the vessel wall and lead to vascular disease. In previous studies, we demonstrated that restraint, or immobilization stress, results in the induction of heat-shock protein 70 (hsp70) gene expression in the aorta of adult rat and showed that this response was markedly attenuated with age.

Methods and Results
Here we provide evidence that restraint-induced hsp70 expression occurs secondary to a rise in systemic blood pressure. Old rats were unable to mount a significant stress-induced hypertensive response, providing an explanation for the reduced hsp70 response in the old rats. A variety of vasoactive agents that induce acute hypertension through distinct signal transduction pathways, including phenylephrine, dopamine, vasopressin, angiotensin II, and endothelin-1, were found to result in hsp70 mRNA induction in the aorta. The magnitude of hsp70 expression achieved with these hypertensive agents was directly correlated with their relative effects on blood pressure. Rats were treated with the vasodilator sodium nitroprusside, which prevented an acute rise in blood pressure from the hypertensive agents tested and abolished induction of hsp70 expression.

Conclusions
These findings support the conclusion that hsp70 induction occurs as a physiological response to acute hypertension and suggest the possibility that hsp70 plays a role in the protecting the vasculature from damage during hemodynamic stress.
Effect of Left Ventricular Hypertrophy Secondary to Chronic Pressure Overload on Transmural Myocardial 2-Deoxyglucose Uptake
Authors: Zhang Jianyi , Duncker Dirk J. , Ya Xu , Zhang Yi , Pavek Todd , Wei Horan , Merkle Hellmut , Ugurbil Kâmil , From Arthur H. L. , Bache Robert J.
Published: June 2012

Background
This study tested the hypothesis that
31
P nuclear magnetic resonance (NMR)–detectable 2-deoxyglucose (2DG) uptake is increased in chronically pressure-overloaded hypertrophied left ventricular myocardium.

Methods and Results
31
P NMR spectroscopy was used to determine the transmural distribution of high-energy phosphate levels and 2-deoxyglucose-6-phosphate (2DGP) accumulation during intracoronary infusion of 2DG (15 μmol · kg body wt
−1
· min
−1
) in eight normal dogs and in eight dogs with severe left ventricular hypertrophy (LVH) produced by ascending aortic banding. The ratio of LV weight to body weight was 8.25±0.65 g/kg in the LVH group compared with 4.35±0.11 g/kg in the normal group (
P
<.01). Myocardial ATP content was decreased by ≈40% and phosphocreatine (PCr) by ≈60% in LVH hearts. ATP values were transmurally uniform in LVH and normal hearts, whereas PCr was lower in the subendocardium (Endo) than the subepicardium (Epi) of both groups. The PCr/ATP ratio was lower in LVH hearts (1.72±0.05, 1.64±0.07, and 1.53±0.10 in Epi, midwall, and Endo, respectively) compared with normal hearts (2.36±0.05, 2.09±0.06, and 1.96±0.06; each
P
<.01 normal versus LVH). Arterial blood levels of glucose, insulin, and free fatty acids were comparable between groups, whereas arterial lactate and norepinephrine levels were significantly higher in the LVH group. 2DG infusion did not affect systemic hemodynamics or myocardial high-energy phosphate or inorganic phosphate levels in either group. At the end of 60 minutes of 2DG infusion, there was no detectable accumulation of 2DGP in the normal hearts. However, seven of the eight LVH hearts showed time-dependent accumulation of 2DGP, which was linearly related to the severity of hypertrophy (
r
=.90 for subendocardial 2DGP versus LV weight/body weight). A transmural gradient of 2DGP was present, with greatest accumulation in the subendocardium (3.3±1.6, 5.8±2.3, and 7.9±2.2 μmol/g in Epi, midwall, and Endo of the LVH hearts, respectively;
P
<.05 Epi versus Endo).

Conclusions
The pressure-overloaded hypertrophied left ventricle demonstrated increased accumulation of 2DGP detected with
31
P NMR spectroscopy. Accumulation of 2DGP was positively correlated with the degree of hypertrophy and was most marked in the subendocardium.
Interstitial Collagenase (MMP-1) Expression in Human Carotid Atherosclerosis
Authors: Nikkari Seppo T. , O’Brien Kevin D. , Ferguson Marina , Hatsukami Thomas , Welgus Howard G. , Alpers Charles E. , Clowes Alexander W.
Published: June 2012

Background
In human atherosclerosis, most clinical events occur when plaque integrity is compromised and hemorrhage and thrombosis result. One mechanism for this might be the release by plaque cells of matrix-degrading proteases, such as interstitial collagenase (matrix metalloproteinase-1, MMP-1), which degrades two major plaque structural proteins, types I and III collagen. This study was undertaken to determine whether MMP-1 is expressed in human atherosclerotic plaques.

Methods and Results
To determine the cellular source and location of MMP-1 in human carotid atherosclerotic lesions, in situ hybridization and immunohistochemistry were performed on 20 endarterectomy specimens. Six nonatherosclerotic carotid arteries also were studied. Intense MMP-1 expression (mRNA and protein) was detected in a subset of plaque macrophages located at the borders of the lipid cores adjacent to fibrous caps and shoulder regions. Subsets of plaque smooth muscle cells and endothelial cells also expressed MMP-1. There was a strong correlation between the percentage of the lipid core occupied by hemorrhage and the percentage of the lipid core perimeter positive for MMP-1 (
r
=.823,
P
=.0001). MMP-1 was not detected in any cell type in nonatherosclerotic carotid arteries.

Conclusions
This study demonstrates that MMP-1 is expressed by several cell types in human carotid atherosclerosis and that there is a correlation between the expression of the protease and histopathological evidence of plaque instability. Since MMP-1 may degrade the major structural collagens of the plaque, expression of the protease by macrophages in regions critical to plaque integrity could contribute to plaque expansion, rupture, and hemorrhage.
Ischemia-Related Lesion Characteristics in Patients With Stable or Unstable Angina
Authors: de Feyter Pim J. , Ozaki Yukio , Baptista Jose , Escaned Javier , Di Mario Carlo , de Jaegere Peter P.T. , Serruys Patrick W. , Roelandt Jos R.T.C.
Published: June 2012

Background
Postmortem-derived findings support the common beliefs that lipid-rich coronary plaques with a thin, fibrous cap are prone to rupture and that rupture and superimposed thrombosis are the primary mechanisms causing acute coronary syndromes. In vivo imaging with intracoronary techniques may disclose differences in the characterization of atherosclerotic plaques in patients with stable or unstable angina and thus may provide clues to which plaques may rupture and whether rupture and thrombosis are active.

Methods and Results
We assessed the characteristics of the ischemia-related lesions with coronary angiography and intracoronary angioscopy and determined their compositions with intracoronary ultrasound in 44 patients with unstable and 23 patients with stable angina. The angiographic images were classified as noncomplex (smooth borders) or complex (irregular borders, multiple lesions, thrombus). Angioscopic images were classified as either stable (smooth surface) or thrombotic (red thrombus). The ultrasound characteristics of the lesion were classified as poorly echo-reflective, highly echo-reflective with shadowing, or highly echo-reflective without shadowing. There was a poor correlation between clinical status and angiographic findings. An angiographic complex lesion (n=33) was concordant with unstable angina in 55% (24 of 44); a noncomplex lesion (n=34) was concordant with stable angina in 61% (14 of 23). There was a good correlation between clinical status and angioscopic findings. An angioscopic thrombotic lesion (n=34) was concordant with unstable angina in 68% (30 of 44); a stable lesion (n=33) was concordant with stable angina in 83% (19 of 23). The ultrasound-obtained composition of the plaque was similar in patients with unstable and stable angina.

Conclusions
Angiography discriminates poorly between lesions in stable and unstable angina. Angioscopy demonstrated that plaque rupture and thrombosis were present in 17% of stable angina and 68% of unstable angina patients. Currently available ultrasound technology does not discriminate stable from unstable plaques.
Transhepatic Cardiac Catheterization in Children
Authors: Shim David , Lloyd Thomas R. , Cho Kyung J. , Moorehead Catherine P. , Beekman Robert H.
Published: June 2012

Background
In some children with congenital heart disease, conventional venous access is unavailable for cardiac catheterization. This study investigates a novel transhepatic venous approach to cardiac catheterization in children and evaluates its efficacy and safety.

Methods and Results
Percutaneous transhepatic puncture was performed using a 22-gauge Chiba needle under fluoroscopic guidance. After wire exchanges were performed, a 5F to 8F sheath was positioned in the low right atrium and cardiac catheterization was performed. On completion of the catheterization, the sheath was withdrawn and a 3-mm steel coil was placed in the parenchymal tract between the hepatic vein and liver capsule. Liver enzyme studies were obtained before and after transhepatic catheterization, and an abdominal ultrasound was performed to evaluate the liver 24 hours after the procedure. Percutaneous transhepatic cardiac catheterization was performed successfully in 17 of 18 children in whom it was attempted. Patient age was 30±8 months (mean±SEM; range, 1 day to 9 years), weight was 10.5±1.5 kg (3.1 to 27.5 kg), and mean right atrial pressure was 10±1 mm Hg (5 to 19 mm Hg). Time from initial needle puncture to right atrial entry was 6.2±1.2 minutes. Diagnostic catheterization was performed successfully in all 17 children, and additional interventional procedures were performed in 5 children. The total catheterization time was 2.0±0.2 hours. Serum aspartate aminotransferase increased from 57±15 to 78±8 IU/L (
P
=.06), but alanine aminotransferase and gamma-glutamyl transpeptidase did not change. Ultrasound was performed 24 hours after transhepatic catheterization, and no evidence was found in any patient of hemorrhage or subcapsular hematoma.

Conclusions
These data suggest that this novel transhepatic approach provides an effective and safe route for diagnostic and interventional cardiac catheterization in children.
Does Ischemic Preconditioning Trigger Translocation of Protein Kinase C in the Canine Model?
Authors: Przyklenk Karin , Sussman Mark A. , Simkhovich Boris Z. , Kloner Robert A.
Published: June 2012

Background
Brief episodes of ischemia protect or “precondition” the heart and reduce the size of infarcts caused by subsequent sustained coronary artery occlusion, yet the mechanisms responsible for this cardioprotection remain unresolved. We tested the theory that translocation of protein kinase C (PKC) to the myocyte membranes, initiated in response to brief preconditioning ischemia and manifest during the initial minutes of the sustained occlusion, mediates this phenomenon by attempting to (1) blunt the cardioprotective effects of preconditioning by administration of the PKC inhibitors H-7 and polymyxin B, (2) visualize by fluorescence staining and confocal microscopy changes in the amount or location of PKC, and (3) quantify by incorporation of
32
P into PKC-specific peptide changes in the subcellular distribution of PKC in preconditioned versus control hearts.

Methods and Results
In the first three limbs of this study, anesthetized open-chest dogs underwent four 5-minute episodes of preconditioning ischemia or a comparable control period before 1 hour of sustained occlusion and 4 to 5 hours of reperfusion. Collateral blood flow was assessed with radioactive microspheres; area at risk (AR) was delineated by injection of blue dye; and the area of necrosis (AN) was measured by tetrazolium staining. AN/AR was smaller in preconditioned versus control dogs that received no treatment (6±2% versus 19±3%,
P
<.01), H-7 (2±2% versus 14±5%,
P
<.02), or polymyxin B (10±3% versus 29±5%,
P
<.01) during the preconditioning or control period. Additional dogs underwent four 5-minute episodes of ischemia, with biopsies obtained at baseline and after the first and fourth occlusions. Frozen sections were stained with a fluorescent probe for active PKC and viewed with confocal microscopy. No differences in the intensity or distribution of fluorescence staining were observed after brief ischemia compared with baseline. Finally, myocardial samples were obtained from dogs subjected to four 5-minute episodes of preconditioning ischemia and time-matched sham-operated controls. Incorporation of
32
P into PKC-specific peptide revealed no quantitative difference in the subcellular distribution of PKC between control and preconditioned cohorts.

Conclusions
H-7 and polymyxin B did not blunt the reduction in infarct size achieved with ischemic preconditioning. Neither fluorescence staining and confocal microscopy nor biochemical quantification revealed evidence of preconditioning-induced translocation of PKC to the cell membranes. These results fail to support the hypothesis that translocation of PKC, triggered by preconditioning ischemia, is an important mechanism for the reduction in infarct size seen with preconditioning in the dog model.
Response of Failing Canine and Human Heart Cells to β
2
-Adrenergic Stimulation
Authors: Altschuld Ruth A. , Starling Randall C. , Hamlin Robert L. , Billman George E. , Hensley James , Castillo Lourdes , Fertel Richard H. , Hohl Charlene M. , Robitaille Pierre-Marie L. , Jones Larry R. , Xiao Rui-Ping , Lakatta Edward G.
Published: June 2012

Background
Failing human hearts lose β
1
- but not β
2
-adrenergic receptors. In canine hearts with tachypacing failure, the ratio of β
2
- to β
1
-adrenergic receptors is increased. The present study was designed to determine whether heart failure increases sensitivity to β
2
-adrenergic stimulation in isolated canine ventricular cardiomyocytes and to verify that myocytes from failing human ventricles contain functional β
2
-adrenergic receptors.

Methods and Results
Myocytes from healthy dogs, dogs with tachypacing failure, and human transplant recipients were loaded with fura 2-AM and subjected to electric field stimulation in the presence of zinterol, a highly selective β
2
-adrenergic agonist. Zinterol significantly increased [Ca
2+
]
i
transient amplitudes in all three groups. The failing canine myocytes were significantly more responsive than normal to β
2
-adrenergic stimulation. We also measured isotonic twitches, indo-1 fluorescence transients, and L-type Ca
2+
currents in healthy canine myocytes. Zinterol (10
−5
mol/L) elicited large increases in the amplitudes of simultaneously recorded twitches and [Ca
2+
]
i
transients. Zinterol also increased L-type Ca
2+
currents in the normal canine myocytes; this augmentation was abolished by 10
−7
mol/L ICI 118,551. cAMP production by suspensions of healthy and failing canine myocytes was not increased by zinterol (10
−9
to 10
−5
mol/L), nor did 10
−5
mol/L zinterol elicit phospholamban phosphorylation.

Conclusions
Failing human ventricular cardiomyocytes contain functional β
2
-adrenergic receptors. Canine myocytes also contain functional β
2
-adrenergic receptors. The canine ventricular response to β
2
-agonists is increased in tachypacing failure. Positive inotropic responses to β
2
-stimulation are not mediated by increases in cAMP or cAMP-dependent phosphorylation of phospholamban.
Differential Effects of Lidocaine on Defibrillation Threshold With Monophasic Versus Biphasic Shock Waveforms
Authors: Ujhelyi Michael R. , Schur Michael , Frede Thomas , Gabel Marjorie , Markel Michael L.
Published: June 2012

Background
Defibrillation waveforms and antiarrhythmic drugs have disparate effects on myocardial excitability and refractoriness, making it likely that antiarrhythmic drugs will interact with one waveform differently than with another. The aim of the present study was to determine if the increase in defibrillation threshold (DFT) induced by lidocaine is similar for electrical shocks with monophasic and biphasic waveforms.

Methods and Results
Twenty-six pentobarbital-anesthetized farm-raised pigs were instrumented with pacing catheters and epicardial defibrillation electrodes. Each pig was assigned to one of four groups: (1) monophasic shock waveform and placebo (5% dextrose in water [D
5
W]) (n=7), (2) monophasic shock waveform and lidocaine (n=7), (3) biphasic shock waveform and placebo (D
5
W) (n=5), or (4) biphasic shock waveform and lidocaine (n=7). DFT was measured at baseline and subsequently during treatment (D
5
W or lidocaine). In the monophasic waveform groups, DFT increased from baseline in response to lidocaine by 92% (
P
<.0001), whereas DFT values in response to D
5
W did not change. In the biphasic waveform groups, DFT values did not change from baseline in response to lidocaine (
P
=NS), whereas DFT values from baseline in response to D
5
W significantly decreased by 29% (
P
=.04). In the monophasic waveform groups, the change in DFT from baseline in response to lidocaine was significantly different than the change from baseline in response to D
5
W (92±29% versus −0.5±29%, respectively) (
P
<.0002). In the biphasic waveform groups, however, the change in DFT from baseline in response to lidocaine was similar to the change from baseline in response to D
5
W (−5.66±15% versus −29±17%, respectively) (
P
=.48). Furthermore, the change in DFT from baseline in response to lidocaine differed significantly between monophasic and biphasic waveform groups (92±29% versus −5.66±15%) (
P
<.0002), whereas the change from baseline in response to D
5
W did not differ between monophasic and biphasic waveforms (−0.5±29% versus −29±17%) (
P
=.34).

Conclusions
Compared with placebo groups, DFT values increased during lidocaine treatment to a much greater degree in the monophasic waveform group than in the biphasic waveform group receiving lidocaine. These data support our hypothesis that antiarrhythmic drugs can affect the defibrillation efficacy of monophasic waveforms differently than that of biphasic waveforms.
Kuopio Atherosclerosis Prevention Study (KAPS)
Authors: Salonen Riitta , Nyyssönen Kristiina , Porkkala Elina , Rummukainen Juha , Belder Rene , Park Jong-Soon , Salonen Jukka T.
Published: June 2012

Background
The atherosclerotic progression–reducing effect of LDL cholesterol (LDL-C) lowering has been established in subjects with severe atherosclerotic disease but not in persons with elevated LDL cholesterols without severe atherosclerosis. KAPS (Kuopio Atherosclerosis Prevention Study) is the first population-based trial in the primary prevention of carotid and femoral atherosclerosis.

Methods and Results
The eligibility requirements were serum LDL-C ≥4.0 mmol/L and total cholesterol <7.5 mmol/L. Out of a geographically defined population, 447 men aged 44 to 65 years (mean, 57) were randomized to pravastatin (40 mg/d) or placebo for 3 years. Less than 10% of the subjects had prior myocardial infarction. Thirty-nine men discontinued study medication; however, efficacy data were available for 424 men. The primary outcome was the rate of carotid atherosclerotic progression, measured as the linear slope over annual ultrasound examinations in the average of the maximum carotid intima-media thickness (IMT) of the far wall of up to four arterial segments (the right and left distal common carotid artery and the right and left carotid bulb). For the carotid arteries, at the overall mean baseline IMT of 1.66 mm, the rate of progression of carotid atherosclerosis was 45% (95% CI, 16 to 69%) less in the pravastatin (0.017 mm/y) than the placebo (0.031 mm/y) group (
P
=.005). In the common carotid artery there was a treatment effect of 66% (95% CI, 30 to 95%; pravastatin 0.010 mm/y; placebo 0.029 mm/y;
P
<.002) at the overall mean baseline IMT of 1.35 mm. A treatment effect of 30% (95% CI, −1% to 54%) was found for the carotid bulb (pravastatin, 0.028; placebo, 0.040;
P
=.056) at the overall mean baseline IMT of 2.0 mm. The treatment effect was larger in subjects with higher baseline IMT values, in smokers and in those with low plasma vitamin E levels. There was no significant treatment effect on atherosclerotic progression in the femoral arteries.

Conclusions
These data establish the antiatherogenic effect of LDL-C lowering by pravastatin in hypercholesterolemic men in a primary prevention setting and suggest a greater effect in smokers than in nonsmokers.
Accelerometer Systolic Time Intervals as Fast-Response Sensors of Upright Posture in the Young
Authors: Ovadia Marc , Gear Kathy , Thoele David , Marcus Frank I.
Published: June 2012

Background
Sensors of posture may improve rate-adaptive pacing in syndromes where syncope occurs in the upright posture, particularly in the young. No sensor of posture has been described to date. Previous studies suggest that two sensors currently under investigation (preejection period [PEP] and left ventricular ejection time [LVET] systolic time intervals [STIs] and accelerometers) may be affected by posture. A PEP-sensing pacemaker is available commercially in which heart rate (HR) decreases with an increase in PEP (∂[HR]/∂[PEP]<0). In patients with upright syncope, it is not known how such algorithms respond to posture. Also, it is not known whether STIs correlate with posture independent of autonomic tone.

Methods and Results
We studied accelerometer-derived STIs in head-upright tilt-testing with β-blockade and catecholamine stimulation in patients with syncope or presyncope using an ultra-low-frequency accelerometer placed on the chest. Thirty-two patients age 6 to 22 years with unexplained recurrent syncope or presyncope underwent tilt-testing involving two to four tilts (60°) at baseline, during esmolol infusion (500 μg/kg load, 50 to 140 μg/kg per minute), after esmolol withdrawal, and during isoproterenol infusion if not contraindicated. PEP, LVET, and other indexes were quantified, and their relations to posture and to autonomic state were determined. With tilt, PEP increased from 98.9±2.2 to 109.1±2.8 msec (
P
<.0001), and LVET decreased (supine-to-upright) from 295.5±4.5 to 247.2±4.7 msec (
P
<.0001). PEP/LVET changed from 0.337±0.01 to 0.45±0.02 (
P
<.0001). Similar postural changes were observed during tilt with β-blockade and esmolol withdrawal, and during isoproterenol infusion. STI changes occurred immediately on postural change and were stable. Postural change of PEP was greater than the β-adrenergic effect by 6:1. Postural change of STIs was independent of vagal tone.

Conclusions
First, accelerometer-derived STIs detect postural changes. Because these changes are independent of autonomic tone and are rapid and stable, they may be useful as fast-response sensors of upright posture in rate-adaptive pacemakers. Second, with postural change, HR increases when PEP increases. However, PEP-sensing pacemakers presently under investigation assume the opposite (inverse) mathematical relationship. Therefore, current PEP-sensing pacemakers use an incorrect algorithm for physiological postural responses in syncope patients. These data predict a paradoxical tachycardic response to the supine posture in patients implanted with these devices.