bluuebunny/crossref_metadata_2025 huggingface dataset:
Configuration of Unipolar Atrial Electrograms During Electrically Induced Atrial Fibrillation in Humans
Authors: Konings Karen T.S. , Smeets Joep L.R.M. , Penn Olaf C. , Wellens Hein J.J. , Allessie Maurits A.
Published: June 2012

Background
During atrial fibrillation (AF), the atrium is activated by multiple wavelets that continuously change in size and direction. The aim of this study was to correlate the temporal variation in AF electrogram configuration with the varying spatial patterns of activation.

Methods and Results
In a group of 25 Wolff-Parkinson-White patients undergoing cardiac surgery, the free wall of the right atrium was mapped (244 points) during electrically induced AF. The unipolar electrograms recorded during 4 seconds of AF were classified into four categories: (1) single deflections, (2) short-double potentials, (3) long-double potentials, and (4) fragmented potentials. The proportion of these four types of electrograms during AF was as follows: singles, 77±12%; short-doubles, 7±3%; long-doubles, 10±7%; and fragmented, 6±4%. Electrogram morphology was an indicator for rapid uniform conduction (single potentials; positive predictive value [PPV] of 0.96), collision (short-double potentials; PPV of 0.33), conduction block (long-double potentials; PPV of 0.84), and pivoting points or slow conduction (fragmented potentials; PPV of 0.87). In type I, II, and III AF, the proportion of long-double potentials was 4±2%, 12±3%, and 18±7% (
P
<.05); the proportion of fragmented complexes was 2±2%, 6±3%, and 10±4% (
P
<.05), respectively. During electrically induced and self-terminating episodes of AF, no preferential anatomic sites for double or fragmented potentials were found in the right atrium.

Conclusions
The morphology of single unipolar electrograms during AF reflects the occurrence of various specific patterns of conduction. This might be used to differentiate between different types of AF and to identify regions with structural conduction disturbances involved in perpetuation of chronic AF.
Prevalence of Heparin-Associated Antibodies Without Thrombosis in Patients Undergoing Cardiopulmonary Bypass Surgery
Authors: Bauer Thomas L. , Arepally Gowthami , Konkle Barbara A. , Mestichelli Bernadette , Shapiro Sandor S. , Cines Douglas B. , Poncz Mortimer , McNulty Stephen , Amiral Jean , Hauck Walter W. , Edie Richard N. , Mannion John D.
Published: June 2012

Background
Patients with cardiovascular disease almost invariably receive heparin before cardiopulmonary bypass surgery, which places them at risk of developing heparin-associated antibodies with a risk of thromboembolic complications. This study was designed to determine the prevalence of heparin-induced antibodies in patients before and after cardiopulmonary bypass surgery.

Methods and Results
Plasma from 111 patients was tested before surgery and 5 days after surgery for heparin-dependent platelet-reactive antibodies with a
14
C-serotonin–release assay (SRA) and for antibodies to heparin/platelet factor 4 complexes with an ELISA. Heparin exposure after surgery was minimized. Heparin-dependent antibodies were detected before surgery in 5% of patients with SRA and 19% of patients with ELISA. By the fifth postoperative day, there was a marked increase in patients positive on the SRA or ELISA (13% and 51%, respectively;
P
<.01 for each). Patients who had received heparin therapy earlier in their hospitalization were more likely to have a positive ELISA before surgery (35%;
P
=.017) and a positive ELISA (68%;
P
=.054) or SRA (30%;
P
=.002) after surgery. However, there was no difference in the prevalence of thrombocytopenia or thromboembolic events between the antibody-positive and -negative groups.

Conclusions
Approximately one fifth of patients undergoing cardiopulmonary bypass surgery have heparin-induced platelet antibodies detectable before the procedure as a result of prior heparin exposure, and many more develop antibodies after surgery. The absence of an association between these antibodies and thromboembolic complications in this study may be, in part, attributable to careful avoidance of heparin after surgery. The high prevalence of heparin-induced antibodies in this setting suggests that these patients may be at risk of developing thrombotic complications with additional heparin exposure.
Tumor Necrosis Factor-α Provokes a Hypertrophic Growth Response in Adult Cardiac Myocytes
Authors: Yokoyama Tomoyuki , Nakano Masayuki , Bednarczyk John L. , McIntyre Bradley W. , Entman Mark , Mann Douglas L.
Published: June 2012

Background
Tumor necrosis factor-α (TNF-α) is a pleiotropic cytokine with a broad range of concentration-dependent effects. The recent observation that TNF-α is expressed by the cardiac myocyte after certain forms of stress suggests that TNF-α might contribute to the maintenance of normal tissue homeostasis after environmental injury. Accordingly, the purpose of this study was to examine the effects of TNF-α on protein synthesis in cultured adult cardiac myocytes.

Methods and Results
Cultured adult feline cardiac myocytes were stimulated with 10 to 1000 U/mL TNF-α to examine the effects of this cytokine on the rate of protein synthesis and degradation. Stimulation with TNF-α led to an accelerated rate of general protein synthesis and a time-dependent decrease in protein degradation in adult cardiac myocytes. The specificity of these findings was demonstrated by studies in which the effects of TNF-α on protein synthesis were blocked by a neutralizing anti–TNF-α antibody as well as studies in which TNF-α–conditioned medium had no effect on protein synthesis in myocytes. In addition to the TNF-α–induced increase in the general protein synthesis, stimulation with TNF-α led to a 2.4-fold increase in net actin protein synthesis and a 3.3-fold increase in net myosin heavy chain synthesis. Finally, the effects of TNF-α on adult cardiac myocytes were shown to be dependent on cell-substrate interaction, suggesting that the cell signaling pathways used by TNF-α are dependent on a preserved interaction between cell integrins and the extracellular matrix.

Conclusions
The observation that TNF-α provokes a hypertrophic growth response in cardiac myocytes suggests that TNF-α may play an important role in myocardial homeostasis after environmental stress.
Dissociation of Left Ventricular Hypertrophy, β-Myosin Heavy Chain Gene Expression, and Myosin Isoform Switch in Rats After Ascending Aortic Stenosis
Authors: Wiesner Rudolf J. , Ehmke Heimo , Faulhaber Jo¨rg , Zak Radovan , Ru¨egg J. Caspar
Published: June 2012

Background
Reexpression of the fetal β-myosin heavy chain (β-MHC) gene was reported to be a marker for phenotypic reprogramming and cardiac hypertrophy in rats. Recent in vitro studies strongly suggested a role of angiotensin II for phenotypic reprogramming. In the present investigation, β-MHC gene expression was studied in an experimental model of pressure-overload hypertrophy that is not associated with a concurrent activation of the circulating renin-angiotensin system.

Methods and Results
Hypertrophy was induced in rats by ascending aortic banding (n=40). After 7 days, myosin contained 31% (
P
<.05) of the β-MHC isoform in banded but <5% in sham-operated animals. However, no specific elevation of β-MHC mRNA levels was found in banded animals. In contrast, hearts of rats with abdominal aortic banding displayed a marked increase in β-MHC mRNA levels (3-fold to 5-fold,
P
<.05). Both the left ventricular weight and left ventricular peak systolic pressure were significantly elevated compared with sham-operated animals (abdominal aortic banding, +13% and 164±7 mm Hg; ascending aortic banding, +27% and 191±9 mm Hg). Plasma renin activity was elevated in rats with abdominal aortic banding (2.5-fold,
P
<.05) but not in rats with ascending aortic banding.

Conclusions
The results of the present work do not support the concept that increased β-MHC gene expression is a general “stable late marker” of myocardial hypertrophy in rats. Our results suggest that the stimulation of the renin-angiotensin system is crucial for the activation of the β-MHC gene.
Blockade of Nitric Oxide Synthesis Reduces Myocardial Oxygen Consumption In Vivo
Authors: Sherman Andrew J. , Davis Cornelius A. , Klocke Francis J. , Harris Kathleen R. , Srinivasan Gopalakrishnan , Yaacoub Adel S. , Quinn Debra A. , Ahlin KaLee A. , Jang James J.
Published: June 2012

Background
Although cardiac myocytes and coronary vascular endothelium are known to express a constitutive form of NO synthase, the in vivo effects of tonic endogenous production of NO on myocardial O
2
consumption and contractile performance remain unclear.

Methods and Results
The effects of blockade of NO synthase were determined in intact dogs. Myocardial O
2
consumption decreased systematically over a wide range of hemodynamic demand after the systemic administration of
N
ω
-nitro-
l
-arginine methyl ester (L-NAME) or
N
ω
-nitro-
l
-arginine. Decreases after doses of 1 and 10 mg/kg L-NAME averaged 23±3.8% and 34±7.2% at a heart rate of 90 bpm in open-chest animals. Similar reductions occurred after the administration of L-NAME and
N
ω
-nitro-
l
-arginine in chronically instrumented animals and were unaffected by β-adrenergic blockade. Intracoronary infusion of L-NAME in chronically instrumented animals reduced both myocardial O
2
consumption and regional segment shortening, even at a dose that did not increase systemic arterial pressure.

Conclusions
The blockade of NO synthesis reduces myocardial O
2
consumption in vivo. The decrease in O
2
consumption is accompanied by a decrease in segment shortening. It involves a direct myocardial action of NO, is unaffected by β-blockade, and is consistent with in vitro studies indicating that low levels of NO augment contractile performance by inhibition of a cGMP-dependent phosphodiesterase.
Plasma Adenosine Levels Increase in Patients With Chronic Heart Failure
Authors: Funaya Hiroharu , Kitakaze Masafumi , Node Koichi , Minamino Tetsuo , Komamura Kazuo , Hori Masatsugu
Published: June 2012

Background
Adenosine is believed to be cardioprotective; however, it has not been elucidated whether the plasma adenosine level is increased in chronic heart failure.

Methods and Results
Seventy-one patients attending a specialized heart failure clinic during a 6-month period were grouped according to the cause of chronic heart failure and the New York Heart Association function class. There were 40 patients with chronic heart failure due to ischemic heart diseases and 31 patients with valvular heart diseases and dilated cardiomyopathy. Control subjects consisted of 64 healthy laboratory staff members and patients without chronic heart failure. We found that the plasma adenosine levels were increased in patients with ischemic and nonischemic heart failure (218±23 and 211±21 nmol/L, respectively, versus 62±3 nmol/L for healthy subjects) and that the extent of increases in adenosine levels correlated well with the severity of chronic heart failure.

Conclusions
We conclude that adenosine levels in the systemic blood increase in patients in ischemic and nonischemic chronic heart failure. Because adenosine counteracts catecholamine-, renin-angiotensin–, and cytokine-induced cellular injury, increased adenosine levels may be endogenous compensatory mechanisms for heart failure.
Antioxidant Protection of LDL by Physiological Concentrations of 17β-Estradiol
Authors: Shwaery Glenn T. , Vita Joseph A. , Keaney John F.
Published: June 2012

Background
Exposure to estrogens reduces the risk for coronary artery disease and associated clinical events; however, the mechanisms responsible for these observations are not clear. Supraphysiological levels of estrogens act as antioxidants in vitro, limiting oxidation of low-density lipoprotein (LDL), an event implicated in atherogenesis. We investigated the conditions under which physiological concentrations of 17β-estradiol (E
2
) inhibit oxidative modification of LDL.

Methods and Results
Plasma incubated with E
2
(0.1 to 100 nmol/L) for 4 hours yielded LDL that demonstrated a dose-related increase in resistance to oxidation by Cu
2+
as measured by conjugated diene formation. This effect was dependent on plasma, because incubation of isolated LDL with E
2
at these concentrations in buffered saline produced no effect on Cu
2+
-mediated oxidation. Incubation of plasma with E
2
had no effect on LDL α-tocopherol content or cholesteryl ester hydroperoxide formation during the 4-hour incubation. Plasma incubation with [
3
H]E
2
was associated with dose-dependent association of
3
H with LDL. High-performance liquid chromatographic analysis of LDL derived from plasma incubated with [
3
H]E
2
indicated that the majority of the associated species were not detectable as authentic E
2
but as nonpolar forms of E
2
that were susceptible to base hydrolysis consistent with fatty acid esterification of E
2
. Plasma-mediated association of E
2
and subsequent antioxidant protection was inhibited by 5,5′-dithio-bis(2-nitrobenzoic acid), an inhibitor of plasma acyltransferase activity.

Conclusions
Exposure of LDL to physiological levels of E
2
in a plasma milieu is associated with enhanced resistance to Cu
2+
-mediated oxidation and incorporation of E
2
derivatives into LDL. This antioxidant capacity may be another means by which E
2
limits coronary artery disease in women.
Assessment of Myocardial Viability by Use of
11
C-Acetate and Positron Emission Tomography
Authors: Wolpers H. Georg , Burchert Wolfgang , van den Hoff Jörg , Weinhardt Regina , Meyer Geert-J. , Lichtlen Paul R.
Published: June 2012

Background
Dual positron emission tomography (PET) imaging with a perfusion tracer and
18
F-fluorodeoxyglucose (FDG) can detect myocardial viability. This approach may be replaced by a single
11
C-acetate study, which enables quantification of both regional blood flow and oxidative metabolism. The significance of acetate-derived indexes for myocardial viability is examined.

Methods and Results
Thirty postinfarct patients with akinetic ventricular segments, a mean ejection fraction of 42±11%, and high-grade coronary obstructions were studied with serial
11
C-acetate PET scanning before and 7±5 months after coronary revascularization. Acetate PET was tested against FDG and serial assessments of segmental wall motion. Sixty of 155 severely dysfunctional LV segments improved postoperatively, and regional blood flow increased. Flow estimates after revascularization suggested little fibrosis in reversible segments. At baseline, blood flows differed between normal myocardium, reversible dysfunction, and irreversible dysfunction (1.04±0.27, 0.73±0.18, and 0.43±0.18 mL·min
−1
·g
−1
, respectively;
P
<.001). Oxidative metabolic rates were reduced only in irreversibly injured LV segments. Multivariate analysis identified the acetate perfusion index as the only independent predictor of postoperative recovery. Its predictive accuracy was similar to that of FDG imaging but superior to indexes of flow-metabolic mismatch or oxidative metabolism.

Conclusions
After myocardial infarction, quantitative indexes of perfusion and oxidative metabolism from acetate PET indicate a critical threshold beyond which tissue is irreversibly injured. Findings support the use of blood flow as a marker of myocardial viability in chronic postinfarct patients with modestly reduced ejection fractions.
Estrogen-Receptor–Mediated Inhibition of Human Endothelial Cell Apoptosis
Authors: Spyridopoulos Ioakim , Sullivan Alison B. , Kearney Marianne , Isner Jeffrey M. , Losordo Douglas W.
Published: June 2012

Background
A series of studies was performed to examine the ability of estradiol (E
2
) to protect endothelial cells from apoptosis.

Methods and Results
Light and transmission electron microscopy demonstrated typical features of apoptosis in human umbilical vein endothelial cells (HUVEC) exposed to tumor necrosis factor-α (TNF-α). Northern and Western blot analyses revealed induction of message and protein for the interleukin-1β converting enzyme (ICE), which has been shown to mediate apoptosis induced by TNF-α. Immunofluorescent staining of HUVEC colocalized ICE expression to apoptotic HUVEC. Direct cell counting demonstrated a significant decrease in total endothelial cell number after 24 hours of TNF-α exposure and a dose-dependent reversal of the effect of TNF-α with E
2
treatment. This protective effect was abrogated by an estrogen-receptor antagonist. Fluorescence-activated cell sorting analysis revealed 39.3% apoptosis after 24 hours of TNF-α exposure. Treatment with E
2
resulted in a 50% decrease in apoptosis. Similarly, viability assays revealed 35±4% cell death after TNF-α exposure. Simultaneous treatment with E
2
resulted in a dose-dependent reduction of cell death to a minimum of 18±2%. The protective effect of E
2
was nullified by a specific estrogen-receptor antagonist.

Conclusions
E
2
treatment resulted in a dose-dependent, receptor-mediated inhibition of TNF-α–induced endothelial cell apoptosis. These studies indicate that E
2
may also serve a maintenance function in preventing endothelial cell death after noxious stimuli and suggest that the ICE pathway may mediate cytokine-induced apoptosis in endothelial cells. Preservation of endothelial integrity represents another mechanism that may account for the atheroprotective effect of estrogen.
Blocking the Endogenous Increase in HSP 72 Increases Susceptibility to Hypoxia and Reoxygenation in Isolated Adult Feline Cardiocytes
Authors: Nakano Masayuki , Mann Douglas L. , Knowlton Anne A.
Published: June 2012

Background
Heat shock protein (HSP) 72 is a ubiquitous protein that is rapidly induced in response to stress and is thought to constitute an endogenous protective response. Previously, work has focused on the effect of overexpression of HSP 72 in various cell types. We were interested in testing the hypothesis that blocking the increase in HSP 72 that occurs in response to hypoxia or ischemia would be deleterious, thus showing that the endogenous response in cells, particularly cardiac cells, is an important line of defense against cell injury.

Methods and Results
Isolated adult feline cardiocytes were treated with a 14-mer phosphorothioate antisense (AS) to HSP 72 and then exposed to mild (8 hours) or severe (12 hours) hypoxia. With mild hypoxia, an increase in LDH release, a decrease in MTT uptake, and a decrease in live-to-dead ratios were seen in AS-treated cells compared with control cells and cells treated with the complementary sense sequence or with AS to major histocompatibility complex I. AS treatment converted mild hypoxic injury to a pattern of cell injury seen with severe injury. After severe hypoxia, all treatment groups showed an increase in LDH, a decrease in MTT uptake, and a decrease in live-to-dead ratios; AS-treated cells had the greatest increase in cell injury. AS treatment produced a 40% decrease in HSP 72 levels after hypoxia compared with control cells treated with hypoxia. A dose-response study showed inhibition of the increase in HSP 72 with as little as 5 μg (1.24 μmol/L) of AS.

Conclusions
(1) Blocking an increase in HSP 72 with AS increases the susceptibility of adult cardiac myocytes to hypoxic injury. (2) HSP 72 is an important part of the normal cell response to stress and is important in protecting cardiac myocytes from hypoxia and reoxygenation.
Tamoxifen Decreases Cholesterol Sevenfold and Abolishes Lipid Lesion Development in Apolipoprotein E Knockout Mice
Authors: Reckless Jill , Metcalfe James C. , Grainger David J.
Published: June 2012

Background
Apolipoprotein E (apo E) knockout mice develop severe vascular lipid lesions resembling human atherosclerotic plaques, irrespective of the fat content of their diet.

Methods and Results
Oral tamoxifen (TMX) at a dose of 1.9 mg·kg body wt
−1
·d
−1
abolished lipid lesion development, assayed by oil red O staining, whether the mice were fed a normal diet or a diet with high fat content. The TMX-treated mice showed a sevenfold decrease in total cholesterol. However, the proportion of plasma cholesterol present in VLDL remained unchanged, whereas the proportion in LDL decreased by 37%, and that in HDL increased by 64%. Consistent with the shift from LDL to HDL cholesterol, there was a 62% decrease in total triglycerides. The concentrations of active and acid-activatable latent plus active TGF-β in the aorta were substantially elevated by TMX (87% and 24% increase, respectively).

Conclusions
Although the mechanism of cardiovascular protection by TMX in apo E knockout mice is unknown, the inhibition of lipid lesion formation may be attributable to the changes in lipoprotein profile and the elevated levels of TGF-β, both of which are thought to be protective against atherosclerosis in humans and animal models.
Effects of
l
-Arginine and
N

ω

-Nitro-
l
-Arginine Methyl Ester on Cardiac Perfusion and Function After 1-Day Cold Preservation of Isolated Hearts
Authors: Stowe David F. , Boban Mladen , Roerig David L. , Chang David , Palmisano Barbara W. , Bosnjak Zeljko J.
Published: June 2012

Background
Coronary flow responses to endothelium-dependent (acetylcholine [ACh] or 5-hydroxytryptamine [5-HT]) and endothelium-independent (adenosine [ADE] or nitroprusside [NP]) vasodilators may be altered before and after 1-day hypothermia during the perfusion of arginine vasopressin (AVP),
d
-arginine (D-ARG),
l
-arginine (L-ARG), or nitro-
l
-arginine methyl ester (L-NAME).

Methods and Results
Four groups of guinea pig hearts (37.5°C [warm]) were perfused for 6 hours with AVP, L-ARG, L-NAME, or nothing (control). Five heart groups (cold) were perfused with AVP, D-ARG, L-ARG, L-NAME, or nothing (control), but after 2 hours they were perfused at low flow for 22 hours at 3.7°C and again for 3 hours at 37.5°C. ADE, butanedione monoxime, and NP were given for cardioprotection before, during, and after hypothermia. In warm groups, L-ARG did not alter basal flow or ADE, ACh, 5-HT, or NP responses, whereas L-NAME and AVP reduced basal flow and the ADE response, abolished ACh and 5-HT responses, and increased the NP response. In cold groups after hypothermia, L-ARG did not alter basal flow, but L-NAME, AVP, D-ARG, and control reduced flow. In the postcold L-ARG group, ACh increased peak flow, but NP did not increase flow in other cold groups. Effluent L-ARG and L-CIT in the cold control group fell from 64±9 and 9±1 μg/L at 1 hour to 36±5 and 5±1 μg/L at 25 hours, respectively. Left ventricular pressure and cardiac efficiency improved more in the postcold L-ARG group than in the postcold D-ARG, AVP, and L-NAME groups.

Conclusions
Endogenous effluent levels of L-ARG and L-CIT decrease after 24 hours in isolated hearts, whereas perfusion of L-ARG improves cardiac performance, basal coronary flow, and vasodilator responses. In contrast, L-NAME, L-ARG, and AVP limit flow and performance but maintain a partial vasodilatory response to NP. Sustained release of NO may account for improved performance after L-ARG after hypothermia.
Assisted Ventilation Does Not Improve Outcome in a Porcine Model of Single-Rescuer Bystander Cardiopulmonary Resuscitation
Authors: Berg Robert A. , Kern Karl B. , Hilwig Ronald W. , Berg Marc D. , Sanders Arthur B. , Otto Charles W. , Ewy Gordon A.
Published: June 2012

Background
Mouth-to-mouth rescue breathing is a barrier to the performance of bystander cardiopulmonary resuscitation (CPR). We evaluated the need for assisted ventilation during simulated single-rescuer bystander CPR in a swine model of prehospital cardiac arrest.

Methods and Results
Five minutes after ventricular fibrillation, swine were randomly assigned to 8 minutes of hand-bag-valve ventilation with 17% oxygen and 4% carbon dioxide plus chest compressions (CC+V), chest compressions only (CC), or no CPR (control group). Standard advanced life support was then provided. Animals successfully resuscitated received 1 hour of intensive care support and were observed for 24 hours. All 10 CC animals, 9 of the 10 CC+V animals, and 4 of the 6 control animals attained return of spontaneous circulation. Five of the 10 CC animals, 6 of the 10 CC+V animals, and none of the 6 control animals survived for 24 hours (CC versus controls,
P
=.058; CC+V versus controls,
P
<.03). All 24-hour survivors were normal or nearly normal neurologically.

Conclusions
In this model of prehospital single-rescuer bystander CPR, successful initial resuscitation, 24-hour survival, and neurological outcome were similar after chest compressions only or chest compressions plus assisted ventilation. Both techniques tended to improve outcome compared with no bystander CPR.
Restoration of Coronary Flow in Myocardial Infarction by Intravenous Chimeric 7E3 Antibody Without Exogenous Plasminogen Activators
Authors: Gold Herman K. , Garabedian Harry D. , Dinsmore Robert E. , Guerrero Luis J. , Cigarroa Joaquin E. , Palacios Igor F. , Leinbach Robert C.
Published: June 2012

Background
Coronary thrombus is composed of platelets and fibrin, and during thrombolytic treatment, reflow may be slowed by platelet deposition. It may be possible to initiate coronary reflow without exogenous plasminogen activators by blocking platelet aggregation while fibrin generation is impeded with heparin.

Methods and Results
In 14 dogs, left anterior descending coronary artery thrombosis was produced by endothelial trauma and thrombin instillation in the presence of stenosis distally. Reflow was monitored by flow probe during treatment with (1) heparin, (2) heparin and aspirin, and (3) heparin, aspirin, and intravenous 7E3. Eighty percent of dogs treated with the third combination showed stable reflow (≥25% of prestenotic flow) in 50±9 minutes. In addition, 13 patients were studied during intravenous administration of c7E3 10 minutes before primary angioplasty for acute myocardial infarction and Thrombolysis In Myocardial Infarction (TIMI) grade 0 or 1 flow. Pretreatment included heparin and oral aspirin. Flow increased during a 10-minute period by at least one TIMI grade in 11 (85%) of 13 and reached TIMI grade 2 or 3 in 7 (54%) of 13 patients. Average TIMI grade flow increased from 0.31±0.5 to 1.54±0.8 (
P
<.001). Thrombus length 10 minutes after c7E3 was 5.1±3.5 mm. All but 1 patient then underwent angioplasty. There were no complications.

Conclusions
Coronary reflow can be initiated by intravenous 7E3 administration in the presence of heparin and aspirin. In human patients, this flow can be observed in 10 minutes without exogenous thrombolytic agents.
Oxidized Low-Density Lipoprotein Induces Apoptosis of Human Endothelial Cells by Activation of CPP32-Like Proteases
Authors: Dimmeler Stefanie , Haendeler Judith , Galle Jan , Zeiher Andreas M.
Published: June 2012

Background
Oxidized LDL (oxLDL) is believed to play a key role as a triggering molecule that causes injury to the endothelium as an early event in atherogenesis. However, the mechanisms by which oxLDL injures endothelial cells are entirely unknown. We speculate that oxLDL may activate a cellular suicide pathway that leads to apoptosis.

Methods and Results
Human umbilical venous endothelial cells (HUVEC) were incubated with increasing doses of native or oxLDL for 18 hours. Apoptosis of HUVEC was measured with an ELISA specific for histone-associated DNA fragments and confirmed with DNA laddering. Native LDL had no effect, but incubation with oxLDL dose-dependently induced apoptosis of HUVEC. Induction of apoptosis by oxLDL was associated with increased CPP32-like protease activity, which is the major enzyme that initiates the proteolytical cascade leading to cell death. Specific inhibition of CPP32 activity completely abrogated oxLDL-induced apoptosis. The antioxidants
N
-acetylcysteine and the combination of vitamins C and E prevented oxLDL-induced apoptosis, abrogated the enhancement of CPP32-like protease activity, and inhibited the proteolytic cleavage of CPP32 into its active subunit p17.

Conclusions
oxLDL activates the suicide pathway leading to apoptosis of endothelial cells by enhancing CPP32-like protease activity. The oxLDL-mediated activation of CPP32 appears to involve the elaboration of reactive oxygen species. Activation of the cell death effector CPP32 by oxLDL may provide a mechanistic clue to the “response-to-injury” hypothesis of atherogenesis.
Estimation of Central Aortic Pressure Waveform by Mathematical Transformation of Radial Tonometry Pressure
Authors: Chen Chen-Huan , Nevo Erez , Fetics Barry , Pak Peter H. , Yin Frank C.P. , Maughan W. Lowell , Kass David A.
Published: June 2012

Background
Central aortic pressures and waveform convey important information about cardiovascular status, but direct measurements are invasive. Peripheral pressures can be measured noninvasively, and although they often differ substantially from central pressures, they may be mathematically transformed to approximate the latter. We tested this approach, examining intersubject and intrasubject variability and the validity of using a single averaged transformation, which would enhance its applicability.

Methods and Results
Invasive central aortic pressure by micromanometer and radial pressure by automated tonometry were measured in 20 patients at steady state and during hemodynamic transients (Valsalva maneuver, abdominal compression, nitroglycerin, or vena caval obstruction). For each patient, transfer functions (TFs) between aortic and radial pressures were calculated by parametric model and results averaged to yield individual TFs. A generalized TF was the average of individual functions. TFs varied among patients, with coefficients of variation for peak amplitude and frequency at peak amplitude of 24.9% and 16.9%, respectively. Intrapatient TF variance with altered loading (>20% variation in peak amplitude) was observed in 28.5% of patients. Despite this, the generalized TF estimated central arterial pressures to ≤0.2±3.8 mm Hg error, arterial compliance to 6±7% accuracy, and augmentation index to within −7% points (30±45% accuracy). Individual TFs were only marginally superior to the generalized TF for reconstructing central pressures.

Conclusions
Central aortic pressures can be accurately estimated from radial tonometry with the use of a generalized TF. The reconstructed waveform can provide arterial compliance estimates but may underestimate the augmentation index because the latter requires greater fidelity reproduction of the wave contour.
18
F-2-Deoxyglucose Deposition and Regional Flow in Pigs With Chronically Dysfunctional Myocardium
Authors: Fallavollita James A. , Perry Bryan J. , Canty John M.
Published: June 2012

Background
Hibernating myocardium in patients with collateral-dependent myocardium is characterized by relative reductions in resting flow and increases in the uptake of
18
F-2-deoxyglucose (FDG) in the fasting state. We performed the present study to examine whether these key physiological alterations could be produced in a porcine model of chronic coronary occlusion and to assess whether the adaptations consistent with hibernation varied across the myocardial wall.

Methods and Results
We chronically instrumented pigs (n=18) with a fixed occluder on the proximal left anterior descending coronary artery (LAD). Three months later, ventricular function, regional myocardial perfusion, and FDG deposition (by excised tissue counting or positron emission tomography) were assessed in pigs after an overnight fast in the closed-chest anesthetized state. Total LAD occlusion with angiographic collaterals was present in the majority of animals. Left ventriculography showed severe anterior hypokinesis, and resting perfusion was significantly reduced in the hibernating LAD region in comparison with the normal remote regions (subendocardium: 0.80±0.06 versus 1.07±0.06 mL·min
−1
·g
−1
,
P
<.001; full-thickness: 0.87±0.04 versus 0.99±0.06 mL·min
−1
·g
−1
,
P
<.01). There was a twofold increase in full-thickness fasting FDG uptake in the dysfunctional LAD region (1.8±0.2 by positron emission tomography versus 1.9±0.1 by ex vivo counting). Ex vivo tissue counting revealed a pronounced transmural variation in FDG uptake in the hibernating region (LAD/normal), which averaged 2.5±0.2 in the subendocardium, 1.9±0.2 in the midmyocardium, and 1.4±0.1 in the subepicardium.

Conclusions
These results demonstrate that pigs instrumented with a proximal LAD stenosis develop hibernating myocardium characterized by relative reductions in resting function and perfusion in association with increased uptake of FDG in the fasting state. The transmural variations in relative resting flow and FDG uptake suggest that myocardial adaptations consistent with hibernation are most pronounced in the subendocardial layers and vary in relation to local coronary flow reserve.
Short-term Hemodynamic Effects of Immunoadsorption in Dilated Cardiomyopathy
Authors: Dörffel Wolf V. , Felix Stephan B. , Wallukat Gerd , Brehme Stefan , Bestvater Knut , Hofmann Torsten , Kleber Franz X. , Baumann Gert , Reinke Petra
Published: June 2012

Background
Previous studies have shown that the sera of many patients with dilated cardiomyopathy (DCM) are positive for several antibodies directed against cardiac antigens. Anti–β
1
-adrenergic receptor antibodies occur in 70% to 90% of DCM patients. These antibodies are extractable by immunoadsorption (IA). In an investigation of the functional significance of antibodies for hemodynamics, IA was performed throughout 5 consecutive days on nine patients with severe DCM who were on stable drug therapy.

Methods and Results
Immunoglobulins were eliminated in nine patients with severe DCM (mean age, 43.5 years; range, 25 to 58 years; left ventricular ejection fraction, <25%). IA was performed over 5 consecutive days with an immunoadsorber for immunoglobulin. All patients were on stable medication, including ACE inhibitors, digitalis, and diuretics. All patients received β-blockers. During therapy, hemodynamic parameters (mean±SD) were monitored with a Swan-Ganz thermodilution catheter. IA elicited a decrease of anti–β
1
-adrenergic receptor antibodies from 6.4±1.3 to 1.0±0.5 relative units. During IA, cardiac output increased from 3.7±0.8 to 5.5±1.8 L/min,
P
<.01. Mean arterial pressure decreased from 76.0±9.9 to 65.0±11.2 mm Hg,
P
<.05; mean pulmonary arterial pressure, from 27.6±7.7 to 22.0±6.5 mm Hg,
P
<.05; left ventricular filling pressure, from 16.8±7.4 to 12.8±4.7 mm Hg,
P
<.05; and systemic vascular resistance, from 1465±332 to 949±351 dyne·s·cm
−5
,
P
<.01.

Conclusions
In addition to conventional medical treatment, IA may be an additional therapeutic possibility for acute hemodynamic stabilization of patients with severe DCM.
Nonsurgical Septal Reduction for Hypertrophic Obstructive Cardiomyopathy
Authors: Knight Charles , Kurbaan Arvinder S. , Seggewiss Hubert , Henein Michael , Gunning Mark , Harrington Derek , Fassbender Dieter , Gleichmann Ulrich , Sigwart Ulrich
Published: June 2012

Background
Some patients with hypertrophic obstructive cardiomyopathy may gain symptomatic relief from a reduction in the extent of obstruction to left ventricular outflow. We present the outcome of the first series of patients treated with an alternative method of gradient reduction using catheter techniques.

Methods and Results
Eighteen patients were treated with selective intracoronary alcohol injection to induce localized septal infarction. Patients underwent echocardiographic measurement of left ventricular dimensions and Doppler echocardiographic evaluation of left ventricular outflow tract gradients before the procedure, on the first postoperative day, and at a median follow-up of 3 months after the procedure. In addition, patients underwent exercise testing and symptom evaluation before and 3 months after nonsurgical septal reduction. There was a significant reduction in left ventricular outflow tract obstruction after the procedure (preprocedure, 67 mm Hg [95% CI, 48 to 87 mm Hg]; postprocedure, 25 mm Hg [95% CI, 16 to 34 mm Hg];
P
=.0006), which persisted at 3-month follow-up (22 mm Hg [95% CI, 12 to 32 mm Hg];
P
=.001). This was associated with a significant improvement in symptoms. There was a small but not significant increase in exercise capacity (n=10; preprocedure, 418 seconds [95% CI, 273 to 563 seconds]; postprocedure, 452 seconds [95% CI, 283 to 621 seconds). Left ventricular dimensions were not significantly altered by nonsurgical septal reduction.

Conclusions
Nonsurgical septal reduction significantly reduces left ventricular outflow tract obstruction and improves symptoms in some patients with hypertrophic obstructive cardiomyopathy. The technique may provide an alternative to surgical myomectomy in selected patients.
Cellular Graded Responses and Ventricular Vulnerability to Reentry by a Premature Stimulus in Isolated Canine Ventricle
Authors: Gotoh Masamichi , Uchida Takumi , Mandel William J. , Fishbein Michael C. , Chen Peng-Sheng , Karagueuzian Hrayr S.
Published: June 2012

Background
The cellular mechanism by which a point strong premature stimulus (S
2
) induces reentry is unknown. We hypothesized that cellular graded responses induced by an S
2
mediate and control tissue vulnerability to reentry.

Methods and Results
Reentry is induced in normal canine ventricular epicardial slices (30×38×2 mm, n=30) by an S
2
at intervals shorter than the effective refractory period. The S
1
is applied at the edge and the S
2
at the center of the tissue. The line connecting the S
1
-S
2
sites is parallel to the long axis of the fiber orientation. Isochronal activation maps were constructed with 56 to 480 bipolar electrodes, and the activation pattern was visualized dynamically. Reentry induced by an S
2
is mediated by the graded responses as follows: The induced graded responses propagate with decrement toward recovered cells. When the amplitude of the propagated depolarizing graded responses reaches threshold relative to the recovering cells, an action potential is initiated along the fiber 2 to 3 mm away from the cathode of the S
2
. The distally initiated activation wave front blocks near the S
2
site because the same S
2
-induced graded response prolongs the refractory period. The “broken” wave front then circulates around both sides of the block and reenters when the site of block recovers its excitability, completing the first figure-eight reentry cycle. Reentry cannot be induced when the S
2
strength is >72±21 mA (upper limit of vulnerability) because these strong S
2
-induced graded responses convert the unidirectional block to bidirectional block by excess prolongation of the refractoriness.

Conclusions
We conclude that the magnitude and the propagation of S
2
-induced cellular graded responses mediate and control vulnerability to reentry in the ventricular epicardium.
Correlation Between Left Ventricular Hypertrophy and GAA Trinucleotide Repeat Length in Friedreich's Ataxia
Authors: Isnard Richard , Kalotka Hanna , Dürr Alexandra , Cossée Mireille , Schmitt Michèle , Pousset Françoise , Thomas Daniel , Brice Alexis , Koenig Michel , Komajda Michel
Published: June 2012

Background
Friedreich's ataxia (FA), the most common inherited ataxia, is associated frequently with cardiac hypertrophy, and death is often cardiac related. Recently, the disease has been associated with a mutation that consists of an unstable expansion of GAA repeats in the first intron of the gene encoding frataxin on chromosome 9.

Methods and Results
We studied 44 consecutive patients with FA, determined the size of GAA expansions in the frataxin gene, and examined the relation between the genotype and cardiac phenotype assessed by M-mode and two-dimensional echocardiography. All the patients were homozygous for the mutation. The size of the GAA expansion on the smaller allele varied from 270 to 1200. We found a correlation between the size of GAA expansion and the left ventricular wall thickness (
r
=.51,
P
<.001) and the left ventricular mass index (
r
=.45,
P
=.002). Left ventricular hypertrophy was observed in 81% of patients with a number of GAA repeats above the median value of 770 compared with only 14% in the other group (
P
=.002).

Conclusions
These data demonstrate that in FA, the severity of left ventricular hypertrophy is related to the number of GAA repeats. These results suggest that abnormalities of the gene encoding frataxin, a protein of unknown function highly expressed in the normal heart, may play an important role in the modulation of cardiac hypertrophy.
Influence of Inhaled Nitric Oxide on Systemic Flow and Ventricular Filling Pressure in Patients Receiving Mechanical Circulatory Assistance
Authors: Hare Joshua M. , Shernan Stanton K. , Body Simon C. , Graydon Erin , Colucci Wilson S. , Couper Gregory S.
Published: June 2012

Background
In patients with left ventricular (LV) dysfunction, inhaled nitric oxide (NO) decreases pulmonary vascular resistance (PVR) but causes a potentially clinically significant increase in left atrial pressure (LAP). This has led to the suggestion that inhaled NO may reach the coronary circulation and have a negative inotropic effect. This study tested an alternative hypothesis that LAP increases because of volume shifts to the pulmonary venous compartment caused by NO-induced selective pulmonary vasodilation.

Methods and Results
The Thermo Cardiosystems Heartmate is an LV assist device (LVAD) that can be set (by controlling pump rate) to deliver fixed or variable systemic blood flow. Eight patients (between 1 and 11 days after LVAD implantation) were administered inhaled NO (20 and 40 ppm for 10 minutes), and LAP, systemic flow, and pulmonary arterial pressure were measured in both fixed and variable pump flow modes. In both modes, inhaled NO lowered PVR (by 25±6% in the fixed mode,
P
<.001, and by 21±5% in the variable mode,
P
<.003). With fixed pump flow, LAP rose from 12.5±1.2 to 15.1±1.4 mm Hg (
P
<.008). In the variable flow mode, LAP did not increase and the assist device output rose from 5.3±0.3 to 5.7±0.3 L/min (
P
<.008).

Conclusions
A selective reduction in PVR by inhaled NO can increase LAP if systemic flow cannot increase. These data support the hypothesis that with LV failure, inhaled NO increases LAP by increasing pulmonary venous volume and demonstrate that inhaled NO has beneficial hemodynamic effects in LVAD patients.
Prospective Study of Asymptomatic Valvular Aortic Stenosis
Authors: Otto Catherine M. , Burwash Ian G. , Legget Malcolm E. , Munt Brad I. , Fujioka Michelle , Healy Nancy L. , Kraft Carol D. , Miyake-Hull Carolyn Y. , Schwaegler Rebecca G.
Published: June 2012

Background
Only limited data on the rate of hemodynamic progression and predictors of outcome in asymptomatic patients with valvular aortic stenosis (AS) are available.

Methods and Results
In 123 adults (mean age, 63±16 years) with asymptomatic AS, annual clinical, echocardiographic, and exercise data were obtained prospectively (mean follow-up of 2.5±1.4 years). Aortic jet velocity increased by 0.32±0.34 m/s per year and mean gradient by 7±7 mm Hg per year; valve area decreased by 0.12±0.19 cm
2
per year. Kaplan-Meier event-free survival, with end points defined as death (n=8) or aortic valve surgery (n=48), was 93±5% at 1 year, 62±8% at 3 years, and 26±10% at 5 years. Univariate predictors of outcome included baseline jet velocity, mean gradient, valve area, and the rate of increase in jet velocity (all
P
≤.001) but not age, sex, or cause of AS. Those with an end point had a smaller exercise increase in valve area, blood pressure, and cardiac output and a greater exercise decrease in stroke volume. Multivariate predictors of outcome were jet velocity at baseline (
P
<.0001), the rate of change in jet velocity (
P
<.0001), and functional status score (
P
=.002). The likelihood of remaining alive without valve replacement at 2 years was only 21±18% for a jet velocity at entry >4.0 m/s, compared with 66±13% for a velocity of 3.0 to 4.0 m/s and 84±16% for a jet velocity <3.0 m/s (
P
<.0001).

Conclusions
In adults with asymptomatic AS, the rate of hemodynamic progression and clinical outcome are predicted by jet velocity, the rate of change in jet velocity, and functional status.
Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of AS-013, a Prostaglandin E
1
Prodrug, in Patients With Intermittent Claudication
Authors: Belch J.J.F. , Bell P.R.F. , Creissen D. , Dormandy J.A. , Kester R.C. , McCollum R.D. , Mizushima Y. , Ruckley C.V. , Scurr J.H. , Wolfe J.H.N.
Published: June 2012

Background
Intermittent claudication due to peripheral arterial occlusive disease (PAOD) is a common cause of pain and disability in the middle-aged. Clinical trials of the potent vasodilator prostaglandin E
1
have been disappointing. This is the first report of a controlled clinical trial of AS-013, a novel prodrug of prostaglandin E
1
incorporated into lipid microspheres that has been developed to improve delivery of the active compound to blood vessel walls.

Methods and Results
Eighty patients with stenosis or occlusion, symptoms of intermittent claudication, and maximum walking distance of ≥30 and ≤300 m on a standard treadmill test were randomized to placebo or one of three dosage regimens of AS-013. Drug was administered by intravenous injection 5 d/wk for 4 weeks. Treadmill tests and other assessments were completed at weeks 0, 4, and 8. A statistically significant increase in maximum walking distance was observed at 4 weeks (for placebo: median, 4.5 m; interquartile range [IQR], 20; for active treatment: median, 28.0 m; IQR, 81;
P
<.01, Mann-Whitney test). A similar response was seen at 8 weeks (for placebo: median, −11.2 m; IQR, 35; for active treatment: median, 35 m; IQR, 68;
P
<.01, Mann-Whitney test). Dose-related improvements in pain-free walking distance and quality of life were observed. No serious safety issues were noted.

Conclusions
These promising clinical data indicate that AS-013, a new prodrug of prostaglandin E
1
, could provide an effective and acceptable treatment for patients with intermittent claudication. Studies to investigate the optimal dosing regimen, duration of clinical benefit, and effects in more severe forms of peripheral arterial disease are warranted.
Chronic Variant of Myocarditis Associated With Hepatitis C Virus Infection
Authors: Okabe Masanori , Fukuda Keisuke , Arakawa Kikuo , Kikuchi Masahiro
Published: June 2012

Background
Although molecular biological studies suggest a pathogenic link between enterovirus infection and dilated cardiomyopathy (DCM), the frequency of detection of enteroviral RNA is not consistently high in myocardial tissue from patients with DCM. A recent study has suggested that hepatitis C virus (HCV) may also be involved in the development of DCM.

Methods and Results
We performed genomic analysis for HCV in three patients with chronic active myocarditis. In all three patients, serum aminotransferase activities remained within normal ranges until the terminal stage of heart failure. At necropsy, all three livers showed evidence of tissue damage caused by chronic congestion, and one liver had evidence of chronic hepatitis. Routinely processed, paraffin-embedded tissue blocks of myocardium and liver were analyzed. Renal specimens were also analyzed to exclude the possibility of myocardial contamination with HCV material from the circulating blood. RNA extracted from the heart, liver, and kidney was subjected to strand-specific reverse transcription and amplified by semi-nested polymerase chain reaction. The target nucleotide sequence was a 178-bp fragment of the highly conserved 5′-noncoding region. Both positive- (genomic) and negative-strand RNA (replicative intermediates) were present in myocardial and liver tissue samples from all three patients. However, negative-strand RNA was undetectable in renal tissue from one patient.

Conclusions
These findings suggest that HCV replicated in myocardial tissue of these patients with myocarditis. Thus, HCV infection may contribute to the development of this unusual form of myocarditis.