bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantification of Effects of Global Ischemia on Dynamics of Ventricular Fibrillation in Isolated Rabbit Heart
Authors: Mandapati Ravi , Asano Yukio , Baxter William T. , Gray Richard , Davidenko Jorge , Jalife José
Published: June 2012

Background
—Ventricular fibrillation (VF) leads to global ischemia of the heart. After 1 to 2 minutes of onset, the VF rate decreases and appears more organized. The objectives of this study were to determine the effects of no-flow global ischemia on nonlinear wave dynamics and establish the mechanism of ischemia-induced slowing of the VF rate.

Methods and Results
—Activation patterns of VF in the Langendorff-perfused rabbit heart were studied with the use of 2 protocols: (1) 15 minutes of no-flow global ischemia followed by reperfusion (n=7) and (2) decreased excitability induced by perfusion with 5 μmol/L of tetrodotoxin (TTX) followed by washout (n=3). Video imaging (≈7500 pixels per frame; 240 frames per second) with a voltage-sensitive dye, ECG, and signal processing (fast Fourier transform) were used for analysis. The dominant frequency of VF decreased from 13.5±1.3 during control to 9.3±1.4 Hz at 5 minutes of global ischemia (
P
<0.02). The dominant frequency decreased from 13.9±1.1 during control to 7.0±0.3 Hz at 2 minutes of TTX infusion (
P
<0.001). The rotation period of rotors on the epicardial surface (n=27) strongly correlated with the inverse dominant frequency of the corresponding episode of VF (
R
2
=0.93). The core area, measured for 27 transiently appearing rotors, was 5.3±0.7 mm
2
during control. A remarkable increase in core area was observed both during global ischemia (13.6±1.7 mm
2
;
P
<0.001) and TTX perfusion (16.8±3.6 mm
2
;
P
<0.001). Density of wave fronts decreased during both global ischemia (
P
<0.002) and TTX perfusion (
P
<0.002) compared with control.

Conclusions
—This study suggests that rotating spiral waves are most likely the underlying mechanism of VF and contribute to its frequency content. Ischemia-induced decrease in the VF rate results from an increase in the rotation period of spiral waves that occurs secondary to an increase in their core area. Remarkably, similar findings in the TTX protocol suggest that reduced excitability during ischemia is an important underlying mechanism for the changes seen.
Regulation of 6-Pyruvoyltetrahydropterin Synthase Activity and Messenger RNA Abundance in Human Vascular Endothelial Cells
Authors: Linscheid Philippe , Schaffner Andreas , Blau Nenad , Schoedon Gabriele
Published: June 2012

Background
—The nitric oxide synthase cofactor tetrahydrobiopterin (BH4) is involved in the regulation of endothelium-dependent vascular functions mediated by nitric oxide. Vascular endothelial cells synthesize and secrete large amounts of BH4 on cytokine activation. There is scant knowledge about molecular mechanisms of cytokine-triggered BH4 production in endothelial cells.

Methods and Results
—Pteridine production, mRNA expression of GTP cyclohydrolase (GTPCH) and 6-pyruvoyltetrahydropterin synthase (PTPS) (both key enzymes of BH4 biosynthesis), and PTPS activity were studied in human umbilical vein endothelial cells (HUVECs) exposed to inflammatory cytokines. BH4 levels were ≤140-fold enhanced on treatment of HUVECs with combined interferon-γ/tumor necrosis factor-α/interleukin-1 (IFN/TNF/IL-1). Specific PTPS activity was ≈3-fold higher in cytokine-treated HUVECs than in untreated cells. Reverse-transcription/limiting-dilution polymerase chain reaction analysis showed that in response to IFN/TNF/IL-1, mRNA abundance of GTPCH and PTPS was increased ≈64-fold and 10-fold, respectively.

Conclusions
—The present study demonstrates for the first time the cytokine-dependent regulation of PTPS, the second enzyme in BH4 synthesis. Although GTPCH is believed to be the rate-limiting step, control of endothelial PTPS expression by cytokines may play an important role in regulating BH4-dependent nitric oxide production in the vascular system.
Association of a G
994
→T Missense Mutation in the Plasma Platelet-Activating Factor Acetylhydrolase Gene With Genetic Susceptibility to Nonfamilial Dilated Cardiomyopathy in Japanese
Authors: Ichihara Sahoko , Yamada Yoshiji , Yokota Mitsuhiro
Published: June 2012

Background
—Although several genes or genetic loci that are responsible for or confer susceptibility to familial dilated cardiomyopathy (DCM) have been identified, genetic defects that underlie nonfamilial DCM remain to be characterized. Mice lacking manganese superoxide dismutase exhibit DCM, suggesting that impairment of the defense mechanisms against oxidative stress is an important susceptibility factor for DCM. Plasma platelet-activating factor (PAF) acetylhydrolase also acts as a key defense against oxidative stress by hydrolyzing PAF and oxidized phospholipids. Thus, abnormalities in the activity of this enzyme may result in predisposition to myocardial damage.

Methods and Results
—The possible association of a G
994
(
M
allele)→T (
m
allele) missense mutation in the plasma PAF acetylhydrolase gene with genetic susceptibility to nonfamilial DCM has now been investigated in 122 Japanese individuals with this condition and 226 healthy control subjects. PAF acetylhydrolase activity in plasma was significantly associated with plasma PAF acetylhydrolase genotype in both DCM patients and healthy control subjects. The frequency of the mutant
m
allele was significantly higher in DCM patients than in control subjects. Left ventricular mass (LVM) and the LVM index in DCM patients with
Mm
or
mm
genotypes were significantly greater than those in patients with the
MM
genotype.

Conclusions
—The G
994
→T mutation in the plasma PAF acetylhydrolase gene is associated with nonfamilial DCM in Japanese subjects. Although the mutation is unlikely to be a causative factor, it may contribute to genetic susceptibility to or progression of nonfamilial DCM.
Intensive Medical Therapy Versus Coronary Angioplasty for Suppression of Myocardial Ischemia in Survivors of Acute Myocardial Infarction
Authors: Dakik Habib A. , Kleiman Neal S. , Farmer John A. , He Zuo-Xiang , Wendt Juliet A. , Pratt Craig M. , Verani Mario S. , Mahmarian John J.
Published: June 2012

Background
—Patients who have inducible ischemia after acute myocardial infarction (AMI) generally undergo coronary angiography with the intent to revascularize. Whether this approach is superior to intensive treatment with anti-ischemic medications is unknown.

Methods and Results
—We performed a prospective, randomized pilot study comparing intensive medical therapy with coronary angioplasty (PTCA) for suppression of myocardial ischemia in 44 stable survivors of AMI. Myocardial ischemia was quantified with adenosine
201
Tl tomography (SPECT) performed 4.5±2.9 days after AMI. All patients at baseline had a large total (≥20%) and ischemic (≥10%) left ventricular perfusion defect size (PDS). SPECT was repeated at 43±26 days after therapy was optimized. The total stress-induced PDS was comparably reduced with medical therapy (from 38±13% to 26±16%;
P
<0.0001) and PTCA (from 35±12% to 20±16%;
P
<0.0001). The reduction in ischemic PDS was also similar (
P
=NS) in both groups. Cardiac events occurred in 7 of 44 patients over 12±5 months. Patients who remained clinically stable had a greater reduction in ischemic PDS (−13±9%) than those who had a recurrent cardiac event (−5±7%;
P
<0.02). Event-free survival was superior in the 24 patients who had a significant (≥9%) reduction in PDS (96%) compared with those who did not (65%;
P
=0.009).

Conclusions
—In this small pilot study, intensive medical therapy and PTCA were comparable at suppressing ischemia in stable patients after AMI. Sequential imaging with adenosine SPECT can track changes in PDS after anti-ischemic therapies and thereby predict subsequent outcome. Corroboration of these preliminary findings in a larger cardiac-event trial is warranted.
Nonsustained Ventricular Tachycardia in the Setting of Acute Myocardial Infarction
Authors: Cheema Asim N. , Sheu Kathleen , Parker Michele , Kadish Alan H. , Goldberger Jeffrey J.
Published: June 2012

Background
—Nonsustained ventricular tachycardia (NSVT) has significant prognostic implications in the setting of healing and healed myocardial infarction (MI), but only limited information is available on its importance in the setting of acute MI. We evaluated the prognostic significance of NSVT characteristics in the setting of acute MI.

Methods and Results
—A prospective database was used to identify 112 patients with NSVT within 72 hours of acute MI. A control group was identified matched for age, sex, type of MI, and thrombolytic treatment. Mean age was 64 to 65 years in the 2 groups with 71% to 72% men. Q-wave MI was noted in 52% to 53%, and thrombolytic therapy was administered to 31% to 32% of patients in each group. In-hospital ventricular fibrillation occurred more frequently in the NSVT group (9% versus 0% in the control group;
P
<0.001), but total in-hospital (10% versus 4%) and follow-up mortality (10% versus 17%) did not differ between the 2 groups. With a Cox regression model, specific NSVT characteristics were predictive of mortality. The strongest predictor was time from presentation to occurrence of NSVT. Shortest RR interval during NSVT was also a univariate predictor of mortality. Multivariate analysis identified time from presentation to occurrence of NSVT as the strongest predictor of mortality (
P
<0.0001). The increased relative risk of NSVT was first significant when it occurred 13 hours from presentation and continued to increase as the time from presentation to occurrence of NSVT increased, plateauing at ≈24 hours with a relative risk of 7.5.

Conclusions
—Contrary to prevailing clinical opinion, NSVT that occurs in the setting of acute MI does have important prognostic significance. Specifically, the currently accepted notion that NSVT that occurs within 48 hours of acute MI has no prognostic significance needs to be adjusted. Although NSVT that occurs within the first several hours of presentation does not have an associated adverse prognosis, NSVT that occurs beyond the first several hours after presentation is associated with significant increases in relative risk.
Induction of Cyclooxygenase-2 and Activation of Nuclear Factor-κB in Myocardium of Patients With Congestive Heart Failure
Authors: Wong Samuel C. Y. , Fukuchi Mitsumasa , Melnyk Peter , Rodger Ian , Giaid Adel
Published: June 2012

Background
—Chronic heart failure is associated with induction of secondary inflammatory mediators, including prostanoids. The latter exert diverse functional and morphological effects on cardiac myocytes. Induction of cyclooxygenase (COX), the enzyme responsible for generating prostanoids, requires activation of nuclear factor-κB (NF-κB). The aim of the present study was to determine the expression of COX-2 and activation of NF-κB in the failing human heart.

Methods and Results
—Myocardial tissue from 27 patients with end-stage heart failure (various etiologies: ischemic heart disease, n=16; idiopathic dilated cardiomyopathy, n=10; and valvular heart disease, n=1), 2 septic patients, and 8 normal control subjects was immunostained with antisera to COX-2 and NF-κB. Western blotting was performed and showed high anti–COX-2 antibody specificity and the presence of COX-2 protein in the sample tissues. In situ hybridization and immunohistochemistry showed little or no expression of COX-2 and NF-κB in the control hearts. In contrast, there was abundant expression of COX-2 mRNA and protein in myocytes and inflammatory cells in areas of fibrotic scar compared with regions of normal morphology in all cases of heart failure, except the cases with sepsis, which showed an abundance of COX-2 throughout the myocardium. Sites of NF-κB activation were associated with those of COX-2 expression.

Conclusions
—We demonstrate induction of COX-2 and activation of NF-κB in the myocardium of failing human hearts. Induction of both molecules appears to be associated with the presence of inflammation and scar formation.
Antihypertensive Treatment Improves Endothelium-Dependent Hyperpolarization in the Mesenteric Artery of Spontaneously Hypertensive Rats
Authors: Onaka Uran , Fujii Koji , Abe Isao , Fujishima Masatoshi
Published: June 2012

Background
—The vascular endothelium releases endothelium-derived hyperpolarizing factor (EDHF). The mesenteric arteries of 6- to 8-month-old spontaneously hypertensive rats (SHRs) exhibit an impairment of the hyperpolarization induced by acetylcholine via EDHF.

Methods and Results
—We determined whether antihypertensive treatment can improve EDHF-mediated responses in SHRs. Beginning at age 8 to 9 months, the animals were treated with either enalapril (40 mg · kg
−1
· d
−1
) (SHR-Es) or a combination of hydralazine (25 mg · kg
−1
· d
−1
) and hydrochlorothiazide (7.5 mg · kg
−1
· d
−1
) (SHR-Hs) for 3 months. The control groups were age-matched SHRs (SHR-Cs) and Wistar Kyoto rats (WKYs). The two treatments lowered the blood pressure to comparable extents. The acetylcholine-induced hyperpolarization in the mesenteric artery of treated SHRs improved to a level comparable to that in WKYs (acetylcholine 10
−5
mol/L with norepinephrine 10
−5
mol/L: SHR-E, −14.4±1.8; SHR-H, −12.0±1.3; SHR-C, −7.2±1.2; and WKY, −13.3±2.3 mV). EDHF-mediated relaxation, as assessed by relaxation to acetylcholine resistant to
N
G
-nitro-
l
-arginine in norepinephrine-contracted rings, was markedly improved in treated SHRs (maximal relaxation: SHR-E, 79.3±3.2%; SHR-H, 47.4±8.6%; SHR-C, 4.8±2.4%; and WKY, 45.1±6.0%). When the rings were contracted with 77 mmol/L KCl to eliminate EDHF response, no difference was found in relaxation to acetylcholine among the four groups. Similarly, the hyperpolarization and relaxation to levcromakalim, a K
+
channel opener, were comparable among the groups.

Conclusions
—Antihypertensive treatment improved EDHF-mediated hyperpolarization and relaxation in the mesenteric artery in SHRs, whereas NO-mediated relaxation did not appear to be modulated by drug therapy. Thus, alterations in the EDHF system may play a pivotal role in endothelial dysfunction and its improvement with drug therapy in SHRs.
Pitfalls in Clinical Recognition and a Novel Operative Approach for Hypertrophic Cardiomyopathy With Severe Outflow Obstruction Due to Anomalous Papillary Muscle
Authors: Maron Barry J. , Nishimura Rick A. , Danielson Gordon K.
Published: June 2012

Background
—Ventricular septal myotomy/myectomy (Morrow procedure) is the standard surgical option for severely symptomatic patients with hypertrophic cardiomyopathy (HCM) and marked basal obstruction to left ventricular outflow due to mitral valve systolic anterior motion. In some patients, however, congenital malformations of the mitral apparatus may be responsible for outflow obstruction; the failure to recognize this morphology before operation could have adverse consequences.

Methods and Results
—We recently evaluated 2 patients with obstructive HCM operated on at Mayo Medical Center in 1997 who demonstrated direct anomalous papillary muscle insertion into the anterior mitral leaflet, producing muscular midcavity obstruction. This anomaly is potentially identifiable with echocardiography by exaggerated anterior displacement of hypertrophied papillary muscles within the left ventricular cavity and the direct continuity between papillary muscle and anterior leaflet associated with a rigid motion pattern of the mitral apparatus. Echocardiographic diagnosis, however, was confused in both patients by the association of systolic anterior motion of the mitral valve, probably produced by freely mobile margins of the mitral leaflet unencumbered by papillary muscle insertion, and in 1 patient probably representing a second and more basal level of obstruction. Because outflow tract morphology was judged unsuitable for conventional myotomy/myectomy, a novel surgical strategy was designed to remove the outflow gradient in which an extensive myectomy trough (wider at its apical than basal extent) was created within the ventricular septum to papillary muscle level; also, in 1 patient, attachment of anterolateral papillary muscle with the lateral free wall was partially severed to increase mobility of the mitral apparatus. After surgery, both patients reported substantial relief of symptoms and improved exercise tolerance and also showed reduced or abolished basal outflow obstruction.

Conclusions
—In HCM, outflow obstruction due to anomalous papillary muscle insertion directly into anterior mitral leaflet is challenging to identify but should always be contemplated before operative intervention. This important (but often unsuspected) congenital malformation may require alternative surgical strategies to standard myotomy/myectomy, similar to those described here.
Enterovirus Infections as a Possible Risk Factor for Myocardial Infarction
Authors: Roivainen Merja , Alfthan Georg , Jousilahti Pekka , Kimpimäki Marko , Hovi Tapani , Tuomilehto Jaakko
Published: June 2012

Background
—An increasing body of evidence suggests that, in addition to the well-known classic risk factors, some microbial infections may be associated with the development of atherosclerosis and myocardial infarction (MI). The aim of our study was to evaluate the possible role of enteroviral infections in the pathogenesis of MI.

Methods and Results
—Stored sera, collected in Eastern Finland in 1977, from a set of 12 155 randomly selected men and women aged 25 to 64 years were used in prospective, nested case-control study. The study sample comprised 183 men and 81 women with MI and matched controls. The sera were tested for IgG antibodies to a newly identified enterovirus-common (EVC) antigen, to heat-denatured coxsackievirus B5 (CBV-5), and to adenovirus hexon protein. Raw data from enzyme immunoassays were converted to relative units before analysis. In univariate analysis, EVC antibodies were significantly associated with the risk of MI in men (
P
=0.009) but not in women. Men with MI had a significantly higher mean level of EVC antibodies than matched controls (
P
=0.014). High antibody levels to EVC were associated with an increased risk of MI in men aged 25 to 49 years (relative risk [RR] 4.34,
P
<0.001) but not in older men (>50 years of age). Women with MI also showed a trend toward higher antibody levels than control women, but the difference was not statistically significant. Antibody levels to whole CBV-5 or adenovirus hexon protein appeared to be no different among case patients versus control subjects.

Conclusions
—If we assume that a high level of EVC antibodies reflects a history of relatively frequent enterovirus infections, the present observation might suggest that enterovirus infections increase the risk of MI at least in middle-aged men. Further studies are needed to understand possible clinical significance of this observation.
Selective Vagal Denervation of the Atria Eliminates Heart Rate Variability and Baroreflex Sensitivity While Preserving Ventricular Innervation
Authors: Chiou Chuen-Wang , Zipes Douglas P.
Published: June 2012

Background
—The purpose of this study was to test whether radiofrequency catheter ablation (RFCA) of 3 epicardial fat pads that resulted in efferent vagal denervation of the atria and sinus and atrioventricular nodes also denervated the ventricles.

Methods and Results
—Vagal innervation of the ventricles was determined by measuring prolongation of ventricular effective refractory period induced by bilateral vagal stimulation (20 Hz, 10 V, 4 ms). Changes in heart rate variability (HRV) and baroreflex sensitivity (BRS) were also examined. We found that RFCA of the 3 epicardial fat pads vagally denervated the sinus and AV nodes and atria without affecting vagal innervation of the ventricles, indicating that efferent vagal fibers to the ventricles do not travel through the 3 epicardial fat pads. Parameters of time-domain variables decreased significantly; the total-power, high-frequency, and low-frequency components of frequency-domain variables decreased significantly; and the ratio of the low- and high-frequency components increased significantly after chronic vagal denervation. Vagally modulated sinus arrhythmia and BRS were also eliminated after chronic vagal denervation. These data also indicate that HRV and BRS represent vagal activity at the level of the sinus node and may not accurately reflect efferent vagal activity at the ventricular level.

Conclusions
—Selective vagal denervation of the sinus and AV nodes and atria decreased HRV and eliminated BRS while preserving ventricular innervation.
Estrogen Stimulates Delayed Mitogen-Activated Protein Kinase Activity in Human Endothelial Cells via an Autocrine Loop That Involves Basic Fibroblast Growth Factor
Authors: Kim-Schulze Seunghee , Lowe William L. , Schnaper H. William
Published: June 2012

Background
—Estrogen plays a significant role in protecting premenopausal women from cardiovascular disease. We have found that estradiol augments endothelial cell activities related to vascular healing and that human coronary artery and umbilical vein endothelial cells express estrogen receptors (ERs). Classically, the ER functions as a transcription factor, but the cytoplasmic targets of this genomic effect have not been defined for endothelial cells. In the present study, we examined the potential role of the mitogen-activated protein (MAP) kinases ERK1 and ERK2 as mediators of estrogen action.

Methods and Results
—Human umbilical vein endothelial cells were estrogen depleted by culturing in hormone-free medium for 48 hours before experiments. 17β-Estradiol (E2) stimulated a delayed (3 hours) 5- to 7-fold induction of ERK1/2 activity requiring activation of ER and new transcription/translation. Conditioned media from cells stimulated for 3 hours with E2 induced immediate ERK1/2 activation and phosphorylation of the basic fibroblast growth factor (bFGF) receptor. Moreover, ERK1/2 activation by E2 or by conditioned media was abrogated by treatment with neutralizing anti-bFGF antibody.

Conclusions
—These data describe an autocrine mechanism for E2 induction of ERK1/2 in HUVEC. Because our previous studies suggested that certain cardioprotective effects of estrogen are genomic in nature, the results are consistent with the hypothesis that autocrine stimulation of endothelial ERK1/2 activity by bFGF may play a role in the beneficial effects of estrogen on cardiovascular biology.
Hirudin Reduces Tissue Factor Expression in Neointima After Balloon Injury in Rabbit Femoral and Porcine Coronary Arteries
Authors: Gertz S. David , Fallon John T. , Gallo Richard , Taubman Mark B. , Banai Shmuel , Barry William L. , Gimple Lawrence W. , Nemerson Yale , Thiruvikraman Singanallore , Naidu Srihari S. , Chesebro James H. , Fuster Valentin , Sarembock Ian J. , Badimon Juan J.
Published: June 2012

Background
—Tissue factor (TF) is a transmembrane glycoprotein that, after binding to factor VII/VIIa, initiates the extrinsic coagulation pathway, resulting in thrombin generation and its sequelae. Thrombin has been shown to induce TF mRNA in endothelium, monocytes, and smooth muscle cells, further perpetuating the thrombogenic cycle. This study was designed to determine the effect of specific inhibition of thrombin by recombinant hirudin (r-hirudin) on TF distribution after balloon angioplasty in the cholesterol-fed rabbit femoral artery and porcine coronary artery models.

Methods and Results
—Thirty-five femoral arteries from 32 cholesterol-fed New Zealand White rabbits and 84 coronary arteries from 55 Yorkshire-Albino swine were studied by use of a recently developed in situ method of TF localization based on digoxigenin labeling of recombinant factor VIIa (Dig-VIIa), with correlative studies of TF immunoreactivity by use of anti-rabbit (AP-1) or anti-human (sTF) antibodies. At sites of balloon angioplasty in rabbit femoral or pig coronary arteries (double or single injury), TF-antibody and Dig-VIIa staining were noted in association with endothelial cells, smooth muscle cells, and foam cells and within the fibrous tissue matrix primarily of the adventitia and neointima. Staining was significantly greater after balloon angioplasty than in vessels that had not undergone angioplasty but was similar after single and double balloon injury. Animals treated with r-hirudin (rabbits, 1 mg/kg bolus plus 2-hour infusion; pigs, 1 mg/kg bolus plus 0.7 mg · kg
−1
· d
−1
infusion for 14 days with implantable pump) had diminished TF-antibody and Dig-VIIa staining 28 days after balloon angioplasty compared with controls (bolus heparin only). This effect was more prominent on the neointima and was more striking in the porcine than the rabbit model.

Conclusions
—TF expression, persistent 1 month after balloon angioplasty in rabbit femoral arteries and porcine coronary arteries, is attenuated by specific thrombin inhibition with hirudin. These results suggest that thrombin inhibition, in addition to its effect on acute thrombus formation and its effect on luminal narrowing by plaque in experimental animals, may result in a prolonged reduction in thrombogenicity of the restenotic plaque through this effect on TF expression.
Resident Cardiac Mast Cells Degranulate and Release Preformed TNF-α, Initiating the Cytokine Cascade in Experimental Canine Myocardial Ischemia/Reperfusion
Authors: Frangogiannis Nikolaos G. , Lindsey Merry L. , Michael Lloyd H. , Youker Keith A. , Bressler Robert B. , Mendoza Leonardo H. , Spengler Robert N. , Smith C. Wayne , Entman Mark L.
Published: June 2012

Background
—Neutrophil-induced cardiomyocyte injury requires the expression of myocyte intercellular adhesion molecule (ICAM)-1 and ICAM-1–CD11b/CD18 adhesion. We have previously demonstrated interleukin (IL)-6 activity in postischemic cardiac lymph; IL-6 is the primary stimulus for myocyte ICAM-1 induction. Furthermore, we found that induction of IL-6 mRNA occurred very early on reperfusion of the infarcted myocardium. We hypothesized that the release of a preformed upstream cytokine induced IL-6 in leukocytes infiltrating on reperfusion.

Methods and Results
—Constitutive expression of TNF-α and not IL-1β was demonstrated in the normal canine myocardium and was localized predominantly in cardiac mast cells. Mast cell degranulation in the ischemic myocardium was documented by demonstration of a rapid release of histamine and TNF-α in the cardiac lymph after myocardial ischemia. Histochemical studies with FITC-labeled avidin demonstrated degranulating mast cells only in ischemic samples of canine myocardium. Immunohistochemistry suggested that degranulating mast cells were the primary source of TNF-α in the ischemic myocardium. In situ hybridization studies of reperfused myocardium localized IL-6 mRNA in infiltrating mononuclear cells and in mononuclear cells appearing in the postischemic cardiac lymph within the first 15 minutes of reperfusion. Furthermore, isolated canine mononuclear cells incubated with postischemic cardiac lymph demonstrated significant induction of IL-6 mRNA, which was partially blocked with a neutralizing antibody to TNF-α.

Conclusions
—Cardiac mast cells degranulate after myocardial ischemia, releasing preformed mediators, such as histamine and TNF-α. We suggest that mast cell–derived TNF-α may be a crucial factor in upregulating IL-6 in infiltrating leukocytes and initiating the cytokine cascade responsible for myocyte ICAM-1 induction and subsequent neutrophil-induced injury.
Cellular Mechanisms of Atrial Contractile Dysfunction Caused by Sustained Atrial Tachycardia
Authors: Sun Hui , Gaspo Rania , Leblanc Normand , Nattel Stanley
Published: June 2012

Background
—Transient atrial contractile dysfunction (“atrial stunning”) follows conversion of atrial fibrillation (AF) to sinus rhythm and has significant clinical implications; however, the underlying mechanisms are poorly understood. We investigated the hypothesis that rapid atrial activation (as during AF) impairs cellular contractility and affects cellular Ca
2+
handling.

Methods and Results
—Edge detection and indo 1 fluorescence techniques were used to measure unloaded cell shortening and intracellular Ca
2+
transients in atrial myocytes from control (Ctl) dogs and dogs subjected to atrial pacing at 400 bpm for 7 (P7) or 42 (P42) days. Atrial tachycardia reduced fractional cell shortening (0.1 Hz) from 7.3±0.4% (Ctl) to 4.3±0.3% and 2.0±0.3% in P7 and P42 dogs, respectively (
P
<0.01 for each). Resting [Ca
2+
]
i
was not altered in paced dogs, but the systolic Ca
2+
transient was significantly reduced. Furthermore, cells from paced dogs showed slowed relaxation and use-dependent decreases of Ca
2+
transients and cell shortening compared with cells from Ctl dogs. To determine whether changes in Ca
2+
transients account fully for alterations in contractility, we varied [Ca
2+
]
o
to evaluate the relation between Ca
2+
transients and cell shortening. Reductions in Ca
2+
transients in Ctl cells reduced shortening to the level of paced cells; however, when Ca
2+
transients in P42 cells were elevated to the range of Ctl cells, a significant reduction in cell shortening remained. Similar results were obtained in dogs that maintained 1:1 capture throughout the monitoring period and dogs that developed sustained AF over the course of the study.

Conclusions
—Sustained atrial tachycardia causes important reductions in cellular contractility, in part by impairing cellular Ca
2+
handling and decreasing systolic Ca
2+
transients. These results provide direct evidence for the concept that AF induces atrial contractile dysfunction by causing a tachycardia-induced atrial cardiomyopathy.
Randomized, Placebo-Controlled Trial of Platelet Glycoprotein IIb/IIIa Blockade With Primary Angioplasty for Acute Myocardial Infarction
Authors: Brener Sorin J. , Barr Lawrence A. , Burchenal J. E. B. , Katz Stanley , George Barry S. , Jones Ancil A. , Cohen Eric D. , Gainey Phillip C. , White Harvey J. , Cheek H. Barrett , Moses Jeffrey W. , Moliterno David J. , Effron Mark B. , Topol Eric J.
Published: June 2012

Background
—The benefit of catheter-based reperfusion for acute myocardial infarction (MI) is limited by a 5% to 15% incidence of in-hospital major ischemic events, usually caused by infarct artery reocclusion, and a 20% to 40% need for repeat percutaneous or surgical revascularization. Platelets play a key role in the process of early infarct artery reocclusion, but inhibition of aggregation via the glycoprotein IIb/IIIa receptor has not been prospectively evaluated in the setting of acute MI.

Methods and Results
—Patients with acute MI of <12 hours’ duration were randomized, on a double-blind basis, to placebo or abciximab if they were deemed candidates for primary PTCA. The primary efficacy end point was death, reinfarction, or any (urgent or elective) target vessel revascularization (TVR) at 6 months by intention-to-treat (ITT) analysis. Other key prespecified end points were early (7 and 30 days) death, reinfarction, or urgent TVR. The baseline clinical and angiographic variables of the 483 (242 placebo and 241 abciximab) patients were balanced. There was no difference in the incidence of the primary 6-month end point (ITT analysis) in the 2 groups (28.1% and 28.2%,
P
=0.97, of the placebo and abciximab patients, respectively). However, abciximab significantly reduced the incidence of death, reinfarction, or urgent TVR at all time points assessed (9.9% versus 3.3%,
P
=0.003, at 7 days; 11.2% versus 5.8%,
P
=0.03, at 30 days; and 17.8% versus 11.6%,
P
=0.05, at 6 months). Analysis by actual treatment with PTCA and study drug demonstrated a considerable effect of abciximab with respect to death or reinfarction: 4.7% versus 1.4%,
P
=0.047, at 7 days; 5.8% versus 3.2%,
P
=0.20, at 30 days; and 12.0% versus 6.9%,
P
=0.07, at 6 months. The need for unplanned, “bail-out” stenting was reduced by 42% in the abciximab group (20.4% versus 11.9%,
P
=0.008). Major bleeding occurred significantly more frequently in the abciximab group (16.6% versus 9.5%,
P
=0.02), mostly at the arterial access site. There was no intracranial hemorrhage in either group.

Conclusions
—Aggressive platelet inhibition with abciximab during primary PTCA for acute MI yielded a substantial reduction in the acute (30-day) phase for death, reinfarction, and urgent target vessel revascularization. However, the bleeding rates were excessive, and the 6-month primary end point, which included elective revascularization, was not favorably affected.
Improved Internal Defibrillation Success With Shocks Timed to the Morphology Electrogram
Authors: Hsu William , Lin Yayun , Lang Douglas J. , Jones Janice L.
Published: June 2012

Background
—A previous retrospective study by our group suggested that shocks timed to the upslope of the shocking lead electrogram improved defibrillation efficacy. The goal of this study was to prospectively determine whether defibrillation threshold could be reduced by use of an algorithm that timed shocks to the upslope of coarse ventricular fibrillation (test treatment) compared with shocks delivered asynchronously after 10 seconds of fibrillation (control treatment).

Methods and Results
—Ten pigs were instrumented with a 3-lead system for internal defibrillation. Initial estimates of the energy required to achieve defibrillation E
50
for both treatments were made by an up/down method. Subsequently, additional shocks at V
50
±10% and V
50
±20% were given for each treatment to obtain data points at higher and lower intensities. Probability-of-success curves were estimated for both treatments by the best-fit method. Energies required were significantly lower for the timed shocks than for the asynchronous shocks (
P
<0.001). E
80
was reduced 15.5%, from 27.1±2.5 to 22.9±1.8 J (
P
<0.002). The width of the probability-of-success curve (E
80
−E
20
) for the test treatment was also significantly narrower than that for the control treatment (7.1±0.9 versus 10.8±1.7,
P
<0.01). Normalized curve width (E
80
−E
20
)/E
50
was decreased from 51±5% of E
50
for control shocks to 37±4% of E
50
for synchronous shocks (
P
<0.02).

Conclusions
—In this model, defibrillation threshold is lower and more deterministic when shocks are timed to the upslope of the shocking lead electrogram. If a similar reduction is observed in humans, shock timing may lower defibrillation threshold and simplify programming of shock intensity.
Fostriecin, an Inhibitor of Protein Phosphatase 2A, Limits Myocardial Infarct Size Even When Administered After Onset of Ischemia
Authors: Weinbrenner Christof , Baines Christopher P. , Liu Guang-Shung , Armstrong Stephen C. , Ganote Charles E. , Walsh Aimée H. , Honkanen Richard E. , Cohen Michael V. , Downey James M.
Published: June 2012

Background
—The role of protein phosphatases (PPs) during ischemic preconditioning in the rabbit heart was examined.

Methods and Results
—Fostriecin, a potent inhibitor of PP2A, was administered to isolated rabbit hearts starting either 15 minutes before or 10 minutes after the onset of a 30-minute period of regional ischemia and continuing until the onset of reperfusion. After 2 hours of reperfusion, infarct size was measured with triphenyltetrazolium chloride. In a second study with isolated rabbit cardiomyocytes, the effect of fostriecin pretreatment was assessed by measuring changes in cell osmotic fragility during simulated ischemia. PP1 and PP2A activities of isolated control and ischemically preconditioned cells were also measured. In a third series of experiments, left ventricular biopsies of isolated rabbit hearts were obtained before and at selected times during 60 minutes of global ischemia, and the tissue was assayed for PP1 and PP2A activities. In isolated hearts pretreated with fostriecin, only 8% of the ischemic zone infarcted, significantly less than that in untreated control hearts (33%;
P
<0.001) but comparable to that in ischemically preconditioned hearts (9%;
P
<0.001 versus control). Significant protection was also observed in the hearts treated only after the onset of ischemia (18% infarction;
P
<0.05 versus control). In isolated myocytes, fostriecin also provided protection comparable to that produced by metabolic preconditioning. Preconditioning had no apparent effect on the activity of either PP1 or PP2A in isolated ventricular myocytes or ventricular tissue obtained from heart biopsies.

Conclusions
—Fostriecin, a potent inhibitor of PP2A, can protect the rabbit heart from infarction even when administered after the onset of ischemia. But inhibition of either PP1 or PP2A does not appear to be the mechanism of protection from ischemic preconditioning.
Longitudinal Dissociation Within the Posterior AV Nodal Input of the Rabbit
Authors: Patterson Eugene , Scherlag Benjamin J.
Published: June 2012

Background
—Longitudinal dissociation of an anatomic pathway into 2 electrophysiologically distinct pathways has been hypothesized as a basis for localized AV nodal reentry and supraventricular arrhythmias.

Methods and Results
—Extracellular bipolar and intracellular microelectrodes were used to record activation in the superfused rabbit AV junction. A subset of rabbit hearts (n=19 of 72) demonstrated dissociation of the posterior AV nodal input into ≥2 functional pathways. Antegrade AH conduction was maintained by a pathway just inferior to the tendon of Todaro. Rate-dependent conduction block was observed in a second pathway just superior to the tricuspid annulus, allowing retrograde activation of the distal portion of the inferior posterior AV nodal input and leading to the formation of apparent “dead-end” pathways. The superior (antegrade) and inferior (retrograde) pathways were separated by a band of well-polarized but poorly excitable transitional cells. Additional decreases in the atrial cycle length progressively increased the AH interval, further delaying retrograde activation of the inferior pathway, and progressively moved the site of conduction block in the inferior pathway proximally, thus extending the length of the retrograde conduction pathway and allowing circus movement within the transitional cells of the posterior AV nodal connection.

Conclusions
—Longitudinal dissociation within the posterior AV nodal input can give rise to localized reentry and AV nodal reentrant tachycardia.
Global Biventricular Dysfunction in Patients With Asymptomatic Coronary Artery Disease May Be Caused by Myocarditis
Authors: Frustaci Andrea , Chimenti Cristina , Maseri Attilio
Published: June 2012

Background
—The causal role of asymptomatic critical coronary artery obstruction in patients presenting with severe global biventricular dysfunction but no evidence of myocardial infarction is uncertain.

Methods and Results
—Among 291 patients aged >40 years undergoing a noninvasive (2-dimensional echocardiography) and invasive (catheterization, coronary angiography, and biventricular endomyocardial biopsy, 6 to 8 samples/patient) cardiac study because of progressive heart failure (New York Heart Association functional class III or IV) with global biventricular dysfunction and no history of myocardial ischemic events, 7 patients (2.4%; 7 men; mean age, 49±6.9 years) had severe coronary artery disease (3 vessels in 4 patients; 2 vessels in 1 patient, proximal occlusion of left anterior descending coronary artery in 2 patients). Left ventricular end-diastolic diameter and ejection fraction by 2-dimensional echocardiography were 73±10.5 mm and 23±6.5%, respectively, and right ventricular end-diastolic diameter and ejection fraction were 39±7 mm and 29±7.2%, respectively. Biopsy specimens showed extensive lymphocytic infiltrates with focal myocytolysis meeting the Dallas criteria for myocarditis in all patients (in 5 patients with and 2 patients without fibrosis). Cardiac autoantibodies were detected with indirect immunofluorescence in the serum of 2 patients with active myocarditis. The 2 patients with active inflammation received prednisone (1 mg · kg
−1
· d
−1
for 4 weeks followed by 0.33 mg · kg
−1
· d
−1
for 5 months) and azathioprine (2 mg · kg
−1
· d
−1
for 5 months) in addition to conventional drug therapy for heart failure. At 8-month overall follow-up, cardiac volume and function improved considerably in immunosuppressed patients but remained unchanged in conventionally treated patients, of whom 1 died.

Conclusions
—Global biventricular dysfunction in patients with severe asymptomatic coronary artery disease and no evidence of previous myocardial infarction may be caused by myocarditis. Histologic findings may influence the treatment.
Intimal Tear Without Hematoma
Authors: Svensson Lars G. , Labib Sherif B. , Eisenhauer Andrew C. , Butterly John R.
Published: June 2012

Background
—The modern imaging techniques of transesophageal echocardiography, CT, and MRI are reported to have up to 100% sensitivity in detecting the classic class of aortic dissection; however, anecdotal reports of patient deaths from a missed diagnosis of subtle classes of variants are increasingly being noted.

Methods and Results
—In a series of 181 consecutive patients who had ascending or aortic arch repairs, 9 patients (5%) had subtle aortic dissection not diagnosed preoperatively. All preoperative studies in patients with missed aortic dissection were reviewed in detail. All 9 patients (2 with Marfan syndrome, 1 with Takayasu’s disease) with undiagnosed aortic dissection had undergone ≥3 imaging techniques, with the finding of ascending aortic dilatation (4.7 to 9 cm) in all 9 and significant aortic valve regurgitation in 7. In 6 patients, an eccentric ascending aortic bulge was present but not diagnostic of aortic dissection on aortography. At operation, aortic dissection tears were limited in extent and involved the intima without extensive undermining of the intima or an intimal “flap.” Eight had composite valve grafts inserted, and all survived. Of the larger series of 181 patients, 98% (179 of 181) were 30-day survivors.

Conclusions
—In patients with suspected aortic dissection not proven by modern noninvasive imaging techniques, further study should be performed, including multiple views of the ascending aorta by aortography. If patients have an ascending aneurysm, particularly if eccentric on aortography and associated with aortic valve regurgitation, an urgent surgical repair should be considered, with excellent results expected.
Detection of Adenoviral Genome in the Myocardium of Adult Patients With Idiopathic Left Ventricular Dysfunction
Authors: Pauschinger Matthias , Bowles Neil E. , Fuentes-Garcia F. Javier , Pham Vanlinh , Kühl Uwe , Schwimmbeck Peter L. , Schultheiss Heinz-Peter , Towbin Jeffrey A.
Published: June 2012

Background
—The use of molecular biological techniques has demonstrated the importance of enteroviral infection of the myocardium in the pathogenesis of myocarditis and dilated cardiomyopathy in adults and adenovirus and enterovirus infection in children. The aim of this study was to determine the frequency of adenoviral infection of the myocardium of adults with impaired left ventricular function of unknown origin.

Methods and Results
—Nested polymerase chain reaction (nPCR) was used to determine the frequency of detection of adenoviral DNA and enteroviral RNA in myocardial tissue samples from 94 adult patients with idiopathic left ventricular dysfunction and 14 control patients. Histological and immunohistological analyses were performed to detect myocardial inflammation. Adenoviral genomic DNA was detected by nPCR in 12 of the 94 patients with left ventricular dysfunction (in each case, adenovirus type 2), whereas enteroviral RNA was detected in another 12 patients. All control samples were negative for both viruses. In all patients, active myocarditis was excluded according to the Dallas criteria. However, there was significantly decreased CD2, CD3, and CD45RO T lymphocyte counts in the adenovirus-positive group compared with the adenovirus-negative group
(P
<0.05), whereas no differences were associated with enterovirus infection.

Conclusions
—Although enteroviruses are an important causative agent in the pathogenesis of myocarditis and dilated cardiomyopathy, this study shows that adenovirus infection is also important in the pathogenesis of left ventricular failure in adults. However, the pathogenetic basis of disease associated with adenovirus infection may be different than that after infection with other agents, particularly with respect to activation of the host immune response.
Antioxidants Improve Impaired Insulin-Mediated Glucose Uptake and Prevent Migration and Proliferation of Cultured Rabbit Coronary Smooth Muscle Cells Induced by High Glucose
Authors: Yasunari Kenichi , Kohno Masakazu , Kano Hiroaki , Yokokawa Koji , Minami Mieko , Yoshikawa Junichi
Published: June 2012

Background
—To explore the role of intracellular oxidative stress in high glucose–induced atherogenesis, we examined the effect of probucol and/or α-tocopherol on the migration and growth characteristics of cultured rabbit coronary vascular smooth muscle cells (VSMCs).

Methods and Results
—Chronic high-glucose-medium (22.2 mmol/L) treatment increased platelet-derived growth factor (PDGF)-BB–mediated VSMC migration, [
3
H]thymidine incorporation, and cell number compared with VSMCs treated with normal-glucose medium (5.6 mmol/L+16.6 mmol/L mannose). Probucol and α-tocopherol significantly suppressed high glucose–induced increase in VSMC migration, cell number, and [
3
H]thymidine incorporation. Probucol and α-tocopherol suppressed high glucose–induced elevation of the cytosolic ratio of NADH/NAD
+
, phospholipase D, and membrane-bound protein kinase C activation. Probucol, α-tocopherol, and calphostin C improved the high glucose–induced suppression of insulin-mediated [
3
H]deoxyglucose uptake. Chronic high-glucose treatment increased the oxidative stress, which was significantly suppressed by probucol, α-tocopherol, suramin, and calphostin C.

Conclusions
—These findings suggest that probucol and α-tocopherol may suppress high glucose–induced VSMC migration and proliferation via suppression of increases in the cytosolic ratio of free NADH/NAD
+
, phospholipase D, and protein kinase C activation induced by high glucose, which result in reduction in intracellular oxidative stress.
Common Variant in
AMPD1
Gene Predicts Improved Clinical Outcome in Patients With Heart Failure
Authors: Loh Evan , Rebbeck Timothy R. , Mahoney Paul D. , DeNofrio David , Swain Judith L. , Holmes Edward W.
Published: June 2012

Background
—This study was undertaken to identify gene(s) that may be associated with improved clinical outcome in patients with congestive heart failure (CHF). The adenosine monophosphate deaminase locus (AMPD1) was selected for study. We hypothesized that inheritance of the mutant AMPD1 allele is associated with increased probability of survival without cardiac transplantation in patients with CHF.

Methods and Results
—AMPD1 genotype was determined in 132 patients with advanced CHF and 91 control reference subjects by use of a polymerase chain reaction–based, allele-specific oligonucleotide detection assay. In patients with CHF, those heterozygous (n=20) or homozygous (n=1) for the mutant AMPD1 allele (AMPD1 +/− or −/−, respectively) experienced a significantly longer duration of heart failure symptoms before referral for transplantation evaluation than CHF patients homozygous for the wild-type allele (AMPD1 +/+; n=111; 7.6±6.5 versus 3.2±3.6 years;
P
<0.001). The OR of surviving without cardiac transplantation ≥5 years after initial hospitalization for CHF symptoms was 8.6 times greater (95% CI: 3.05, 23.87) in those patients carrying ≥1 mutant AMPD1 allele than in those carrying 2 wild-type AMPD1 +/+ alleles.

Conclusions
—After the onset of CHF symptoms, the mutant AMPD1 allele is associated with prolonged probability of survival without cardiac transplantation. The mechanism by which the presence of the mutant AMPD1 allele may modify the clinical phenotype of heart failure remains to be determined.