bluuebunny/crossref_metadata_2025 huggingface dataset:
Graft Permeabilization Facilitates Gene Therapy of Transplant Arteriosclerosis in a Rabbit Model
Authors: Rekhter Mark D. , Shah Nikhil , Simari Robert D. , Work Carolyn , Kim Jong-Seung , Nabel Gary J. , Nabel Elizabeth G. , Gordon David
Published: June 2012

Background
—Smooth muscle cell (SMC) replication plays a central role in the pathogenesis of transplant arteriosclerosis. One strategy to eliminate dividing cells is to express a herpesvirus thymidine kinase (
tk
) gene that phosphorylates the nucleoside analogue ganciclovir into a toxic form leading to cell killing. However, medial SMCs are resistant to gene transfer unless the artery undergoes deendothelialization. We hypothesized that manipulations that increase the “porosity” of the artery can make SMCs prone to gene transfer without denudation.

Methods and Results
—In organ culture of rabbit aorta, longitudinal stretch and supraphysiological pressure applied for 3 hours during incubation with adenoviral vector facilitated gene transfer into medial SMCs without denudation. Of the SMCs, 10.2±3.8% expressed a reporter gene of human placental alkaline phosphatase (hpAP), whereas SMCs in control arteries did not express hpAP. To evaluate the feasibility of transgene expression in arterial grafts, we performed such permeabilization-assisted reporter gene transfer into aortas of donor Dutch Belted rabbits and transplanted them into carotid arteries of recipient New Zealand White rabbits. Unstretched transfected grafts were used as a control. SMCs expressed hpAP (7.3±2.4% of cells in 2 days and 4.2±1.9% in 2 weeks) in stretched grafts only. In the next series of experiments, we transfected stretched grafts with ADV-
tk
and combined transplantation with systemic administration of ganciclovir. Stretched ADV-hpAP grafts were used as a control. In 2 weeks, the formation of intimal thickening in
tk
-expressing grafts was significantly reduced (
P
<0.01) because of a decrease in proliferating SMCs.

Conclusions
—Manipulations within target tissues can enhance the efficiency of gene transfer into SMCs. Although mechanical permeabilization is clinically problematic, in principle, targeting SMC replication may provide a genetic approach to the treatment of transplant arteriosclerosis.
Reciprocal In Vivo Regulation of Myocardial G Protein–Coupled Receptor Kinase Expression by β-Adrenergic Receptor Stimulation and Blockade
Authors: Iaccarino Guido , Tomhave Eric D. , Lefkowitz Robert J. , Koch Walter J.
Published: June 2012

Background
—Impaired myocardial β-adrenergic receptor (βAR) signaling, including desensitization and functional uncoupling, is a characteristic of congestive heart failure. A contributing mechanism for this impairment may involve enhanced myocardial β-adrenergic receptor kinase (βARK1) activity because levels of this βAR-desensitizing G protein–coupled receptor kinase (GRK) are increased in heart failure. An hypothesis has emerged that increased sympathetic nervous system activity associated with heart failure might be the initial stimulus for βAR signaling alterations, including desensitization. We have chronically treated mice with drugs that either activate or antagonize βARs to study the dynamic relationship between βAR activation and myocardial levels of βARK1.

Methods and Results
—Long-term in vivo stimulation of βARs results in the impairment of cardiac βAR signaling and increases the level of expression (mRNA and protein) and activity of βARK1 but not that of GRK5, a second GRK abundantly expressed in the myocardium. Long-term β-blocker treatment, including the use of carvedilol, improves myocardial βAR signaling and reduces βARK1 levels in a specific and dose-dependent manner. Identical results were obtained in vitro in cultured cells, demonstrating that the regulation of GRK expression is directly linked to βAR signaling.

Conclusions
—This report demonstrates, for the first time, that βAR stimulation can significantly increase the expression of βARK1, whereas β-blockade decreases expression. This reciprocal regulation of βARK1 documents a novel mechanism of ligand-induced βAR regulation and provides important insights into the potential mechanisms responsible for the effectiveness of β-blockers, such as carvedilol, in the treatment of heart failure.
Effect of Single-Drug Therapy on Reduction of Left Atrial Size in Mild to Moderate Hypertension
Authors: Gottdiener John S. , Reda Domenic J. , Williams David W. , Materson Barry J. , Cushman William , Anderson Robert J.
Published: June 2012

Background
—Cardiac effects of hypertension include increased left ventricular (LV) mass and LV hypertrophy, as well as increased left atrial size, a predictor of stroke and atrial fibrillation. Although literature on reduction of LV mass with antihypertensive therapy is extensive, little information is available on effects of treatment on left atrial size.

Methods and Results
—Patients with mild to moderate hypertension (diastolic blood pressure 95 to 109 mm Hg) were randomly allocated to treatment with atenolol, captopril, clonidine, diltiazem, hydrochlorothiazide, or prazosin in a double-masked trial. Two-dimensional targeted M-mode echocardiography was used to assess left atrial size and LV mass at baseline, 8 weeks, and 1 and 2 years. Longitudinal analysis examined changes in left atrial size from the baseline study, statistically adjusting for age, race, pretreatment left atrial size and LV mass, and serial measurements of systolic blood pressure, body weight, urinary sodium excretion, and physical activity score. Without adjustment for covariates, only hydrochlorothiazide was associated with decreases in left atrial size from baseline at 8 weeks (−1.0±5.2 mm;
P
=0.052), 1 year (−2.0±5.1 mm;
P
=0.02), and 2 years (4.6±7.2 mm;
P
=0.002). After adjustment for effects of covariates, patients with normal left atrial size had greater reduction (−3.3 mm) in left atrial size at 2 years with hydrochlorothiazide than with any other drug. For patients with left atrial enlargement, left atrial size decreased significantly with hydrochlorothiazide, atenolol, clonidine, and diltiazem at 1 year and with all treatments at 2 years. However, reduction at 2 years was greater with hydrochlorothiazide than with captopril or prazosin.

Conclusions
—Antihypertensive drugs differ in their effects on left atrial size. Hydrochlorothiazide was associated with greater overall reduction of left atrial size than other drugs effective for the treatment of hypertension. Reduction of left atrial size with therapy is in part independent of factors known to influence left atrial size, including LV mass and reduction of LV mass with treatment. The clinical benefit of reducing left atrial size with antihypertensive treatment remains to be determined.
Vascular Endothelial Growth Factor (VEGF) Expression in Human Coronary Atherosclerotic Lesions
Authors: Inoue Mayumi , Itoh Hiroshi , Ueda Makiko , Naruko Takahiko , Kojima Akiko , Komatsu Ryushi , Doi Kentaro , Ogawa Yoshihiro , Tamura Naohisa , Takaya Kazuhiko , Igaki Toshio , Yamashita Jun , Chun Tae-Hwa , Masatsugu Ken , Becker Anton E. , Nakao Kazuwa
Published: June 2012

Background
—Vascular endothelial growth factor (VEGF) is an important angiogenic factor reported to induce migration and proliferation of endothelial cells, enhance vascular permeability, and modulate thrombogenicity. VEGF expression in cultured cells (smooth muscle cells, macrophages, endothelial cells) is controlled by growth factors and cytokines. Hence, the question arises of whether VEGF could play a role in atherogenesis.

Methods and Results
—Frozen sections from 38 coronary artery segments were studied. The specimens were characterized as normal with diffuse intimal thickening, early atherosclerosis with hypercellularity, and advanced atherosclerosis (atheromatous plaques, fibrous plaques, and totally occlusive lesions). VEGF expression as well as the expression of 2 VEGF receptors, flt-1 and Flk-1, were studied with immunohistochemical techniques in these samples at the different stages of human coronary atherosclerosis progression. The expression of VEGF mRNA was also studied with reverse transcription–polymerase chain reaction. Normal arterial segments showed no substantial VEGF expression. Hypercellular and atheromatous lesions showed distinct VEGF positivity of activated endothelial cells, macrophages, and partially differentiated smooth muscle cells. VEGF positivity was also detected in endothelial cells of intraplaque microvessels within advanced lesions. In totally occlusive lesions with extensive neovascularization, intense immunostaining for VEGF was observed in accumulated macrophages and endothelial cells of the microvessels. Furthermore, VEGF mRNA expression was detected in atherosclerotic coronary segments but not in normal coronary segments. The immunostainings for flt-1 and Flk-1 were detected in aggregating macrophages in atherosclerotic lesions and also in endothelial cells of the microvessels in totally occlusive lesions.

Conclusions
—These results demonstrate distinct expression of VEGF and its receptors (flt-1 and Flk-1) in atherosclerotic lesions in human coronary arteries. Considering the multipotent actions of VEGF documented experimentally in vivo and in vitro, our findings suggest that VEGF may have some role in the progression of human coronary atherosclerosis, as well as in recanalization processes in obstructive coronary diseases.
Relative Efficacy of Monophasic and Biphasic Waveforms for Transthoracic Defibrillation After Short and Long Durations of Ventricular Fibrillation
Authors: Walcott Gregory P. , Melnick Sharon B. , Chapman Fred W. , Jones Janice L. , Smith William M. , Ideker Raymond E.
Published: June 2012

Background
—Recently, interest has arisen in using biphasic waveforms for external defibrillation. Little work has been done, however, in measuring transthoracic defibrillation efficacy after long periods of ventricular fibrillation. In protocol 1, we compared the efficacy of a quasi-sinusoidal biphasic waveform (QSBW), a truncated exponential biphasic waveform (TEBW), and a critically damped sinusoidal monophasic waveform (CDSMW) after 15 seconds of fibrillation. In protocol 2, we compared the efficacy of the more efficacious biphasic waveform from protocol 1, QSBW, with CDSMW after 15 seconds and 5 minutes of fibrillation.

Methods and Results
—In protocol 1, 50% success levels, ED
50
, were measured after 15 seconds of fibrillation for the 3 waveforms in 6 dogs. In protocol 2, defibrillation thresholds were measured for QSBW and CDSMW after 15 seconds of fibrillation and after 3 minutes of unsupported fibrillation followed by 2 minutes of fibrillation with femoral-femoral cross-circulation. In protocol 1, QSBW had a lower ED
50
, 16.0±4.9 J, than TEBW, 20.3±4.4 J, or CDSMW, 27.4±6.0 J. In protocol 2, QSBW had a lower defibrillation threshold after 15 seconds, 38±10 J, and after 5 minutes, 41.5±5 J, than CDSMW after 15 seconds, 54±19 J, and 5 minutes, 80±30 J, of fibrillation. The defibrillation threshold remained statistically the same for QSBW for the 2 fibrillation durations but rose significantly for CDSMW.

Conclusions
—In this animal model of sudden death and resuscitation, these 2 biphasic waveforms are more efficacious than the CDSMW at short durations of fibrillation. Furthermore, the QSBW is even more efficacious than the CDSMW at longer durations of fibrillation.
High Plasminogen Activator Inhibitor and Tissue Plasminogen Activator Levels in Plasma Precede a First Acute Myocardial Infarction in Both Men and Women
Authors: Thögersen Anna M. , Jansson Jan-Håkan , Boman Kurt , Nilsson Torbjörn K. , Weinehall Lars , Huhtasaari Fritz , Hallmans Göran
Published: June 2012

Background
—In patients with established ischemic heart disease, prospective cohort studies have indicated that plasminogen activator inhibitor (PAI-1), the inhibitor of the fibrinolytic system, may predict cardiovascular events. So far, there have been no primary prospective studies of PAI-1.

Methods and Results
—The aim of the present study was to test whether plasma levels of PAI-1, tissue-type plasminogen activator (tPA), von Willebrand factor (vWF), and thrombomodulin (TM) could predict the occurrence of a first acute myocardial infarction (AMI) in a population with high prevalence of coronary heart disease by use of a prospective nested case-control design. Mass concentrations of PAI-1 and tPA were significantly higher for the 78 subjects who developed a first AMI compared with the 156 references matched for age, sex, and sampling time; for tPA, this increase was independent of smoking habits, body mass index, hypertension, diabetes, cholesterol, and apolipoprotein A-I. The ratio of quartile 4 to 1 for tPA was 5.9 for a patient to develop a first AMI. The association between tPA and AMI was seen in both men and women. Increased levels of vWF were associated with AMI in a univariate analysis. High levels of TM were associated with AMI in women but not in men.

Conclusions
—The plasma levels of PAI-1, tPA, and vWF are associated with subsequent development of a first AMI; for PAI-1 and tPA, this relation was found in both men and women. For tPA but not for PAI-1 and vWF, this association is independent of established risk factors.
Endothelin A Receptor Blockade Causes Adverse Left Ventricular Remodeling but Improves Pulmonary Artery Pressure After Infarction in the Rat
Authors: Nguyen Quang Trinh , Cernacek Peter , Calderoni Angelino , Stewart Duncan J. , Picard Pierre , Sirois Pierre , White Michel , Rouleau Jean L.
Published: June 2012

Background
—Endothelin A (ET
A
) receptor antagonists have been shown to improve ventricular remodeling and survival in rats when started 10 days after infarction. Whether starting them earlier would have a more or less beneficial effect is uncertain.

Methods and Results
—Rats surviving an acute myocardial infarction (MI) for 24 hours (n=403) were assigned to saline or the ET
A
receptor antagonist LU 127043 or its active enantiomer LU 135252 for 4 weeks. Chronic LU treatment had no effect on survival, with 46% of LU rats and 47% of saline-treated rats with large MI surviving to the end of the study. LU treatment led to scar thinning, further left ventricular (LV) dilatation, an increase in LV end-diastolic pressure, and an increase in wet lung weight (
P
<0.05). Despite this detrimental effect on LV function, LU led to a significant decrease in RV systolic (50±2 to 44±2 mm Hg,
P
<0.05 vs saline) and right atrial pressures. LU treatment also prevented the increase in pulmonary ET-1 found in saline-treated rats with large MI but did not modify the increase in cardiac ET-1 in hearts with large MI.

Conclusions
—The early use of the ET
A
receptor antagonists LU 127043 or its active enantiomer LU 135252 after infarction in the rat leads to impaired scar healing and LV dilatation and dysfunction. This is accompanied by a decrease in RV systolic and right atrial pressures and a decrease in pulmonary but not cardiac ET-1 levels. It would thus appear that the early use of ET
A
receptor antagonists after infarction may be detrimental.
Optimal Small-Capacitor Biphasic Waveform for External Defibrillation
Authors: Yamanouchi Yoshio , Brewer James E. , Mowrey Kent A. , Donohoo Ann M. , Wilkoff Bruce L. , Tchou Patrick J.
Published: June 2012

Background
—Biphasic waveforms have been reported to be more efficacious than monophasic waveforms for external defibrillation. This study examined the optimal phase-1 tilts and phase-2 leading-edge voltages with small capacitors (60 and 20 μF) for external defibrillation. We also assessed the ability of the “charge-burping” model to predict the optimal waveforms.

Methods and Results
—Two groups of studies were performed. In group 1, 9 biphasic waveforms from a combination of 3 phase-1 tilt values (30%, 50%, and 70%) and 3 phase-2 leading-edge voltage values (0.5, 1.0, and 1.5 times the phase-1 leading-edge voltage, V
1
) were tested. Phase-2 pulse width was held constant at 3 ms in all waveforms. Two separate 60-μF capacitors were used in each phase. The energy value that would produce a 50% likelihood of successful defibrillation (E
50
) decreased with increasing phase-1 tilt and increased with increasing phase-2 leading-edge voltage except for the 30% phase-1 tilt waveforms. In group 2, 9 waveforms were identical to the waveforms in group 1, except for a 20-μF capacitor for phase 2. E
50
decreased with increasing phase-1 tilt. Phase-2 leading-edge voltage of 1.0 to 1.5 V
1
appeared to minimize E
50
for phase-1 tilt of 50% and 70% but worsened E
50
for phase-1 tilt of 30%. There was a significant correlation between E
50
and residual membrane voltage at the end of phase 2, as calculated by the charge-burping model in both groups (group 1,
R
2
=0.47,
P
<0.001; group 2,
R
2
=0.42,
P
<0.001).

Conclusions
—The waveforms with 70% phase-1 tilt were more efficacious than those with 30% and 50%. The relationship of phase-2 leading-edge voltage to defibrillation efficacy depended on phase-2 capacitance. The charge-burping model predicted the optimal external biphasic waveform.
Central Serotonergic Responsiveness in Neurocardiogenic Syncope
Authors: Theodorakis George N. , Markianos Manolis , Livanis Efthimios G. , Zarvalis Elias , Flevari Panagiota , Kremastinos Dimitrios T.
Published: June 2012

Background
—Central serotonergic mechanisms appear to participate in the pathogenesis of recurrent neurally mediated syncope. The aim of the study was to investigate the responsiveness of the central serotonergic system by measuring the prolactin and cortisol responses to intravenous administration of the serotonin reuptake inhibitor clomipramine.

Methods and Results
—Twenty subjects free of any medical treatment were tested. Twelve had a history of recurrent syncopal attacks and positive tilt test (patient group, mean age 47±18 years, 8 men); 8 subjects without syncope and a negative tilt test result served as control subjects (mean age 49±10 years, 5 men). Twenty-five milligrams of clomipramine was administered intravenously within 15 minutes, and blood samples were taken at 0, 15, 30, 45, and 60 minutes. Two days later, a tilt test was performed at 60 degrees for 30 minutes and blood samples were taken at 0, 10, 20, and 30 minutes. During the clomipramine challenge, plasma prolactin levels increased in both groups. The levels at 30 minutes were higher in the patient group compared with the control group (17.3±7.2 vs 9.3±7.6 ng/mL,
P
=0.05). Similar results were observed for cortisol at 30 minutes (172±15 vs 118±21 ng/mL
P
=0.04) and at 45 minutes (189±20 vs 116±23 ng/mL,
P
=0.03). The tilt test was positive in 8 (67%) out of 12 of the patient group and negative in all control subjects. In the samples taken during the tilt test, significant increases in prolactin and cortisol were observed only in the subjects with positive tilt test results.

Conclusions
—Patients with a history of neurocardiogenic syncope show a higher responsiveness of the central serotonergic system to clomipramine challenge. The results support the view that central serotonergic mechanisms are involved in the pathophysiology of the syndrome.
Increased QT Dispersion in Patients With Vasospastic Angina
Authors: Suzuki Makoto , Nishizaki Mitsuhiro , Arita Masataka , Ashikaga Takashi , Yamawake Noriyoshi , Kakuta Tsunekazu , Numano Fujio , Hiraoka Masayasu
Published: June 2012

Background
—The risk factors for ventricular arrhythmias in patients with coronary vasospasm have not been identified. We evaluated QT dispersion in patients with vasospastic angina and its relation to susceptibility to ventricular arrhythmias during myocardial ischemia and reperfusion.

Methods and Results
—We assessed the corrected QT (QTc) dispersion before induction of coronary artery spasm by intracoronary injection of acetylcholine (baseline) and 30 minutes after administration of isosorbide dinitrate in 50 patients with vasospastic angina and 50 patients with atypical chest pain. The baseline QTc dispersion was significantly greater in patients with vasospastic angina than in patients with atypical chest pain (mean±SD: 69±24 versus 44±19 ms, 95% confidence interval of mean difference [CI]: 16 to 33 ms;
P
<0.001). QTc dispersion decreased significantly, to 48±15 ms (CI: 15 to 26 ms;
P
<0.001 versus baseline), after administration of isosorbide dinitrate in patients with vasospastic angina but did not change significantly in patients with atypical chest pain (mean±SD: 41±17 ms, CI: −3 to 9 ms). During the provocation test, 24 of 50 patients with vasospastic angina experienced ventricular arrhythmias. The baseline QTc dispersion was significantly greater in patients with than without ventricular arrhythmias (mean±SD: 77±23 versus 61±19 ms, CI: 4 to 26 ms;
P
<0.05).

Conclusions
—Patients with vasospastic angina exhibited an increased baseline QTc dispersion compared with patients with atypical chest pain, which suggests that inhomogeneity of repolarization and susceptibility to ventricular arrhythmias are increased in patients with vasospastic angina, even when asymptomatic. The association between increased QTc dispersion and ventricular arrhythmias during the provocation test suggests that measurement of QT dispersion may help predict which patients with vasospastic angina are at high risk for ventricular arrhythmias during ischemia.
Comparison of Apolipoprotein and Proteoglycan Deposits in Human Coronary Atherosclerotic Plaques
Authors: O’Brien Kevin D. , Olin Katherine L. , Alpers Charles E. , Chiu Winnie , Ferguson Marina , Hudkins Kelly , Wight Thomas N. , Chait Alan
Published: June 2012

Background
—Because the content of specific proteoglycans and apolipoproteins is increased in atherosclerotic plaques and in vitro studies have suggested a role for proteoglycans in mediating plaque apolipoprotein (apo) retention, immunohistochemistry was performed to systematically examine the relative locations of proteoglycans and apolipoproteins in human atherosclerosis.

Methods and Results
—The spatial relationships of versican, biglycan, and apoE were compared on 68 human coronary artery segments; apoA-I and apoB also were evaluated on an additional 20 segments. Nonatherosclerotic intima contained extensive deposits of versican, whereas deposits of apoE, apoB, and apoA-I were much less prevalent. In contrast, nearly all atherosclerotic segments contained substantial deposits of biglycan, apoE, apoA-I, and apoB. There was a high degree of colocalization of apoE and biglycan deposits. ApoA-I, the major apolipoprotein of HDL, and apoB also were detected in regions with apoE and biglycan deposition. Exceptions to the localization of biglycan with apolipoproteins were found in regions that lacked intact extracellular matrix because of necrosis or dense macrophage accumulation. In vitro studies demonstrated that biglycan binds apoE-containing but not apoE-free HDL and that biglycan also binds LDL.

Conclusions
—These results suggest that biglycan may bind apoE and apoB in atherosclerotic intima. They also raise the possibility that apoE may act as a “bridging” molecule that traps apoA-I–containing HDL in atherosclerotic intima. Taken together, these findings are consistent with the hypothesis that biglycan may contribute to the pathogenesis of atherosclerosis by trapping lipoproteins in the artery wall.
Cigarette Smoking Increases Sympathetic Outflow in Humans
Authors: Narkiewicz Krzysztof , van de Borne Philippe J.H. , Hausberg Martin , Cooley Ryan L. , Winniford Michael D. , Davison Diane E. , Somers Virend K.
Published: June 2012

Background
—It is generally accepted that smoking increases blood pressure and inhibits muscle sympathetic nerve activity (SNA). The decrease in muscle SNA with cigarette smoking might be secondary to baroreflex responses to the pressor effect of smoking, thus obscuring a sympathetic excitatory effect of smoking. We tested the hypothesis that smoking increases sympathetic outflow.

Methods and Results
—We examined the effects of sham smoking, cigarette smoking, and cigarette smoking in combination with nitroprusside on muscle (baroreflex-dependent) SNA in 10 healthy habitual smokers. The 3 sessions were performed in random order, each study on a separate day. In an additional study, we also investigated the effects of sham smoking and cigarette smoking on skin (baroreflex-independent) SNA in 9 subjects. Compared with sham smoking, cigarette smoking alone increased blood pressure and decreased muscle SNA. When the blood pressure increase in response to smoking was blunted by nitroprusside infusion, there was a striking increase in muscle SNA. Muscle SNA increased up to 3-fold the levels seen before smoking (
P
<0.001), accompanied by an increase in heart rate of up to 37±4 bpm. Cigarette smoking also induced a 102±22% increase in skin SNA (
P
=0.03).

Conclusions
—These data provide the first direct evidence that cigarette smoking increases sympathetic outflow.
Constitutive Properties of Adult Mammalian Cardiac Muscle Cells
Authors: Zile Michael R. , Richardson Kendrick , Cowles Monica Kelly , Buckley J. Michael , Koide Masaaki , Cowles Bradford A. , Gharpuray Vasanti , Cooper George
Published: June 2012

Background
—The purpose of this study was to determine whether changes in the constitutive properties of the cardiac muscle cell play a causative role in the development of diastolic dysfunction.

Methods and Results
—Cardiocytes from normal and pressure-hypertrophied cats were embedded in an agarose gel, placed on a stretching device, and subjected to a change in stress (σ), and resultant changes in cell strain (ε) were measured. These measurements were used to examine the passive elastic spring, viscous damping, and myofilament activation. The passive elastic spring was assessed in protocol A by increasing the σ on the agarose gel at a constant rate to define the cardiocyte σ-versus-ε relationship. Viscous damping was assessed in protocol B from the loop area between the cardiocyte σ-versus-ε relationship during an increase and then a decrease in σ. In both protocols, myofilament activation was minimized by a reduction in [Ca
2+
]
i
. Myofilament activation effects were assessed in protocol C by defining cardiocyte σ versus ε during an increase in σ with physiological [Ca
2+
]
i
. In protocol A, the cardiocyte σ-versus-ε relationship was similar in normal and hypertrophied cells. In protocol B, the loop area was greater in hypertrophied than normal cardiocytes. In protocol C, the σ-versus-ε relation in hypertrophied cardiocytes was shifted to the left compared with normal cells.

Conclusions
—Changes in viscous damping and myofilament activation in combination may cause pressure-hypertrophied cardiocytes to resist changes in shape during diastole and contribute to diastolic dysfunction.
First Postpacing Interval Variability During Right Ventricular Stimulation
Authors: Arenal Angel , Almendral Jesus , Villacastin Julian , Morris Raimundo , Castellanos Eduardo , Delcan Juan Luis
Published: June 2012

Background
—Failure to differentiate supraventricular from ventricular arrhythmias is the most frequent cause of inappropriate implantable cardioverter-defibrillator therapies. Although a sudden-onset criterion is available to differentiate sustained monomorphic ventricular tachycardias (SMVTs) and sinus tachycardias (STs), SMVTs arising during ST and SMVTs gradually accelerating above the cutoff rate can remain undetected. Regular paroxysmal atrial tachycardias (ATs) also can be undetected by onset and stability algorithms. We hypothesized that the first postpacing interval (FPPI) variability after overdrive right ventricular pacing may differentiate SMVTs from STs and ATs.

Methods and Results
—FPPI variability was measured in 23 SMVTs (cycle length [CL] 366±50 ms [VT group]), 27 supraventricular tachycardias, 15 episodes of induced or simulated ATs (CL 376±29 ms [AT group]), and 12 exercise-related STs (CL 381±24 [ST group]). Sequences of trains of 5, 10, and 15 beats were delivered with a CL 40 ms shorter than the tachycardia CL. An FPPI absolute mean difference between consecutive trains of 5 and 10 beats (ΔFPPI) ≤25 ms identified all VTs (mean difference 5±7 ms). In the AT group, the ΔFPPI was >25 ms in all sequences (mean difference 129±60 ms,
P
<0.01). In the ST group, the ΔFPPI was >50 ms in all STs (mean difference 118±47 ms,
P
<0.01).

Conclusions
—FPPI variability may differentiate SMVT from AT and ST. This criterion is potentially useful in implantable devices that use a single ventricular lead.
Protective Effect of Oral Xemilofiban in Arterial Thrombosis in Dogs
Authors: Frederick Leo G. , Suleymanov Osman D. , Szalony James A. , Taite Beatrice B. , Salyers Anita K. , King Lucy W. , Feigen Larry P. , Nicholson Nancy S.
Published: June 2012

Background
—Inhibition of platelet aggregation by preventing the binding of fibrinogen to glycoprotein (GP) IIb/IIIa on activated platelets results in antithrombotic activity. We report on the antithrombotic effect of xemilofiban (SC-54684A), an oral GP IIb/IIIa antagonist, administered alone or with aspirin (ASA) in an acute thrombosis model.

Methods and Results
—Conscious dogs were treated with xemilofiban (1.25, 2.5, 5.0, or 6 mg/kg, n=6); low-dose (LD, 81 mg) ASA, n=7; high-dose (HD, 162 mg) ASA, n=6; xemilofibran 1.25 mg/kg plus LD ASA, n=6; xemilofibran 1.25 mg/kg plus HD ASA, n=6; or placebo, n=7. Dogs were anesthetized 60 minutes later, and the effects of the treatments were evaluated after electrolytic injury (250 μA for 180 minutes) in the left circumflex coronary artery. Bleeding time (BT) was assessed in a separate study. Incidence of thrombosis was reduced (
P
<0.05) by xemilofiban ≥2.5 mg/kg, HD ASA, or xemilofiban 1.25 mg/kg plus HD ASA compared with placebo. Xemilofiban ≥2.5 mg/kg or xemilofiban 1.25 mg/kg plus HD ASA significantly increased time to occlusion, inhibited ex vivo platelet aggregation to collagen >90%, and prevented or decreased (
P
<0.05) cyclic flow variations (CFVs) compared with placebo. BT was increased (
P
<0.05) with xemilofiban ≥2.5 mg/kg but not with xemilofiban 1.25 mg/kg plus HD ASA.

Conclusions
—Xemilofiban ≥2.5 mg/kg, HD ASA, or xemilofiban 1.25 mg/kg plus HD ASA significantly reduced the incidence of thrombosis. These doses of xemilofiban or xemilofiban 1.25 mg/kg plus HD ASA increased time to occlusion, inhibited ex vivo platelet aggregation by >90%, and prevented or reduced CFVs. Xemilofiban ≥2.5 mg/kg but not xemilofiban 1.25 mg/kg plus HD ASA significantly increased BT.
Venous Levels of Shear Support Neutrophil-Platelet Adhesion and Neutrophil Aggregation in Blood via P-Selectin and β
2
-Integrin
Authors: Konstantopoulos Konstantinos , Neelamegham Sriram , Burns Alan R. , Hentzen Eric , Kansas Geoffrey S. , Snapp Karen R. , Berg Ellen L. , Hellums J. David , Smith C. Wayne , McIntire Larry V. , Simon Scott I.
Published: June 2012

Background
—After activation, platelets adhere to neutrophils via P-selectin and β
2
-integrin. The molecular mechanisms and adhesion events in whole blood exposed to venous levels of hydrodynamic shear in the absence of exogenous activation remain unknown.

Methods and Results
—Whole blood was sheared at ≈100 s
−1
. The kinetics of neutrophil-platelet adhesion and neutrophil aggregation were measured in real time by flow cytometry. P-selectin was upregulated to the platelet surface in response to shear and was the primary factor mediating neutrophil-platelet adhesion. The extent of neutrophil aggregation increased linearly with platelet adhesion to neutrophils. Blocking either P-selectin, its glycoprotein ligand PSGL-1, or both simultaneously by preincubation with a monoclonal antibody resulted in equivalent inhibition of neutrophil-platelet adhesion (≈30%) and neutrophil aggregation (≈70%). The residual amount of neutrophil adhesion was blocked with anti-CD11b/CD18. Treatment of blood with prostacyclin analogue ZK36374, which raises cAMP levels in platelets, blocked P-selectin upregulation and neutrophil aggregation to baseline. Complete abrogation of platelet-neutrophil adhesion required both ZK36374 and anti-CD18. Electron microscopic observations of fixed blood specimens revealed that platelets augmented neutrophil aggregation both by forming bridges between neutrophils and through contact-mediated activation.

Conclusions
—The results are consistent with a model in which venous levels of shear support platelet adherence to neutrophils via P-selectin binding PSGL-1. This interaction alone is sufficient to mediate neutrophil aggregation. Abrogation of platelet adhesion and aggregation requires blocking Mac-1 in addition to PSGL-1 or P-selectin. The described mechanisms are likely of key importance in the pathogenesis and progression of thrombotic disorders that are exacerbated by leukocyte-platelet aggregation.
Low-Energy Cardioversion With Epicardial Wire Electrodes: New Treatment of Atrial Fibrillation After Open Heart Surgery
Authors: Liebold Andreas , Wahba Alexander , Birnbaum Dietrich E.
Published: June 2012

Background
—Atrial fibrillation (AF) is the most common arrhythmia after open heart surgery. Traditional treatment with a range of antiarrhythmic drugs and electrical cardioversion is associated with considerable side effects. The aim of this study was to examine the feasibility and efficacy of low-energy atrial defibrillation with temporary epicardial defibrillation wire electrodes.

Methods and Results
—Epicardial defibrillation wire electrodes were placed at the left and right atria during open heart surgery in 100 consecutive patients (age 65±9 years; male to female ratio 67:23). Electrophysiological studies performed postoperatively revealed a test shock (0.3 J) impedance of 96±12 Ω (monophasic) and 97±13 Ω (biphasic). During their hospital stay, AF occurred in 23 patients (23%) at 2.1±1.3 days postoperatively. Internal atrial defibrillation was performed in 20 patients. Of these patients, 80% (16/20) were successfully cardioverted with a mean energy of 5.2±3 J. Early recurrence of AF (≤60 seconds after defibrillation) developed in 8 patients. Five patients had multiple episodes of AF. In total, 35 episodes of AF were treated, with an 88% success rate. Only 6 patients (30%) required sedation. No complications were observed with shock application or with lead extraction.

Conclusions
—Atrial defibrillation with temporary epicardial wire electrodes can be performed safely and effectively in patients after cardiac operations. The shock energy required to restore sinus rhythm is low. Thus, patients can be cardioverted without anesthesia.
Noninvasive, In Utero Imaging of Mouse Embryonic Heart Development With 40-MHz Echocardiography
Authors: Srinivasan Shardha , Baldwin H. Scott , Aristizabal Orlando , Kwee Lia , Labow Mark , Artman Michael , Turnbull Daniel H.
Published: June 2012

Background
—The increasing number of transgenic and targeted mutant mice with embryonic cardiac defects has resulted in the need for noninvasive techniques to examine cardiac structure and function in early mouse embryos. We report the first use of a novel 40-MHz ultrasound imaging system in the study of mouse cardiac development in utero.

Methods and Results
—Transabdominal scans of mouse embryos staged between 8.5 and 13.5 days of gestation (E8.5 to E13.5) were obtained in anesthetized mice. Atrial and ventricular contractions could be discerned from E9.5, and changes in cardiac morphology were observed from E9.5 to E13.5. Hyperechoic streaming patterns delineated flow through the umbilical, vitelline, and other major blood vessels. Diastolic and systolic ventricular areas were determined by planimetry of the epicardial borders, and fractional area change was measured as an index of contractile function. Significant increases in ventricular size were documented at each stage between E10.5 and E13.5, and the ability to perform serial imaging studies over 3 days of embryonic development is described. Finally, the detection of vascular cell adhesion molecule 1 (VCAM-1) homozygous null mutant embryos demonstrates the first example of noninvasive, in utero analysis of cardiac structure and function in a targeted mouse mutant.

Conclusions
—We used 40-MHz echocardiography to identify key elements of the early mouse embryonic cardiovascular system and for noninvasive dimensional analysis of developing cardiac ventricles. The ability to perform serial measurements and to detect mutant embryos with cardiac defects highlights the usefulness of the technique for investigating normal and abnormal cardiovascular development.
Clinical Application of an Integrated 3-Phase Mapping Technique for Localization of the Site of Origin of Idiopathic Ventricular Tachycardia
Authors: Peeters Heidi A. P. , SippensGroenewegen Arne , Wever Eric F. D. , Ramanna Hemanth , Linnenbank André C. , Potse Mark , Grimbergen Cornelis A. , van Hemel Norbert M. , Hauer Richard N. W. , Robles de Medina Etienne O.
Published: June 2012

Background
—Radiofrequency (RF) catheter ablation provides curative treatment for idiopathic ventricular tachycardia (VT).

Methods and Results
—Nineteen consecutive patients with an idiopathic VT underwent RF catheter ablation. An integrated 3-phase mapping approach was used, consisting of the successive application of online 62-lead body surface QRS integral mapping, directed regional paced body surface QRS integral mapping, and local activation sequence mapping. Mapping phase 1 was localization of the segment of VT origin by comparing the VT QRS integral map with a database of mean paced QRS integral maps. Mapping phase 2 was body surface pace mapping during sinus rhythm in the segment localized in phase 1 until the site at which the paced QRS integral map matched the VT QRS integral map was identified (ie, VT exit site). Mapping phase 3 was local activation sequence mapping at the circumscribed area identified in phase 2 to identify the site with the earliest local endocardial activation (ie, site of VT origin). This site became the ablation target. Ten VTs were ablated in the right ventricular outflow tract, 2 at the basal LV septum, and 7 at the midapical posterior left ventricle. A high long-term ablation success (mean follow-up duration, 14±9 months) was achieved in 17 of the 19 patients (89%) with a low number of RF pulses (mean, 3.3±2.2 pulses per patient).

Conclusions
—This prospective study shows that integrated 3-phase mapping for localization of the site of origin of idiopathic VT offers efficient and accurate localization of the target site for RF catheter ablation.
Reduction of Serum Cholesterol and Hypercholesterolemic Atherosclerosis in Rabbits by Secoisolariciresinol Diglucoside Isolated From Flaxseed
Authors: Prasad Kailash
Published: June 2012

Background
—Secoisolariciresinol diglucoside (SDG) is a plant lignan isolated from flaxseed. Lignans are platelet-activating factor–receptor antagonists that would inhibit the production of oxygen radicals by polymorphonuclear leukocytes. SDG is an antioxidant. Antioxidants studied thus far are known to reduce hypercholesterolemic atherosclerosis. The objective of this study was to determine the effect of SDG on various blood lipid and aortic tissue oxidative stress parameters and on the development of atherosclerosis in rabbits fed a high-cholesterol diet.

Methods and Results
—Rabbits were assigned to 4 groups: group 1, control; group 2, SDG control (15 mg · kg body wt
−1
· d
−1
PO); group 3, 1% cholesterol diet; and group 4, same as group 3 but with added SDG (15 mg · kg body wt
−1
· d
−1
PO). Blood samples were collected before (time 0) and after 4 and 8 weeks of experimental diets for measurement of serum triglycerides, total cholesterol (TC), and LDL, HDL, and VLDL cholesterol (LDL-C, HDL-C, and VLDL-C). The aorta was removed at the end of the protocol for assessment of atherosclerotic plaques; malondialdehyde, an aortic tissue lipid peroxidation product; and aortic tissue chemiluminescence, a marker for antioxidant reserve. Serum TC, LDL-C, and the ratios LDL-C/HDL-C and TC/HDL-C increased in groups 3 and 4 compared with time 0, the increase being smaller in group 4 than in group 3. Serum HDL-C decreased in group 3 and increased in group 4 compared with time 0, but changes were lower in group 3 than in group 4. SDG reduced TC and LDL-C by 33% and 35%, respectively, at week 8 but increased HDL-C significantly, by>140%, as early as week 4. It also decreased TC/LDL-C and LDL-C/HDL-C ratios by ≈64%. There was an increase in aortic malondialdehyde and chemiluminescence in group 3, and they were lower in group 4 than in group 3. SDG reduced hypercholesterolemic atherosclerosis by 73%.

Conclusions
—These results suggest that SDG reduced hypercholesterolemic atherosclerosis and that this effect was associated with a decrease in serum cholesterol, LDL-C, and lipid peroxidation product and an increase in HDL-C and antioxidant reserve.
Recombinant Soluble Form of PSGL-1 Accelerates Thrombolysis and Prevents Reocclusion in a Porcine Model
Authors: Kumar Anjali , Villani Mario P. , Patel Umesh K. , Keith James C. , Schaub Robert G.
Published: June 2012

Background
—We investigated whether administration of a soluble recombinant P-selectin glycoprotein ligand-1 chimera (rPSGL-Ig) in conjunction with thrombolytic therapy would enhance thrombolysis by preventing ongoing interactions of leukocytes with platelets and the injured arterial wall.

Methods and Results
—An occlusive thrombus was formed in an internal iliac artery of Yorkshire pigs by placement of a copper coil in the artery under fluoroscopic guidance. Pigs then received heparin and, 15 minutes later, either vehicle or rPSGL-Ig followed by infusion with 25 mg tissue plasminogen activator according to the 90-minute regimen. Blood flow through the artery was monitored by angiography and scored on a scale of 0 to 3. Lysis of the thrombus was accelerated by 70% in pigs treated with rPSGL-Ig 250 μg/kg compared with control (13.3±5.0 versus 44.4±13.3 minutes; n=9 each). Eight of 9 control pigs reoccluded in 13.8±16.9 minutes after the end of tissue plasminogen activator infusion, whereas no reocclusion was observed in 8 of 9 pigs in the rPSGL-Ig group. When the dose of rPSGL-Ig was increased to 500 μg/kg, time to lysis was shortened by 61% from control (18.0±8.4 versus 46.0±8.9 minutes). Reocclusion occurred in 6.0±15.2 minutes in control but not in any rPSGL-Ig–treated pig (n=5 each). In addition, near-normal flow (score 2 or 3) after thrombolysis was achieved 59% and 58% faster in the 2 rPSGL-Ig groups than in their respective controls.

Conclusions
—Inhibition of leukocyte accumulation at the site of thrombosis with rPSGL-Ig may represent a safe therapeutic intervention that could be important in accelerating thrombolysis, achieving optimal reperfusion, and reducing incidence of acute reocclusion.
Treatment of
Helicobacter pylori
and
Chlamydia pneumoniae
Infections Decreases Fibrinogen Plasma Level in Patients With Ischemic Heart Disease
Authors: Torgano Giuseppe , Cosentini Roberto , Mandelli Clara , Perondi Rodolfo , Blasi Francesco , Bertinieri Giovanni , Van Tien Tu , Ceriani Giuliana , Tarsia Paolo , Arosio Cristina , Ranzi Maria Luisa
Published: June 2012

Background
—Chronic
Chlamydia pneumoniae
and
Helicobacter pylori
infections could be a risk factor for ischemic heart disease (IHD), possibly by increasing fibrinogen levels. The aim of our study was to evaluate changes in fibrinogen level in patients with IHD and
H pylori
and/or
C pneumoniae
positivity randomly assigned to antibiotic treatment.

Methods and Results
—Eighty-four patients with chronic IHD,
H pylori
and/or
C pneumoniae
antibodies, and normal acute-phase reactants were randomly assigned to treatment or no treatment. Treatment consisted of omeprazole, clarithromycin, and tinidazole in
H pylori
–positive patients and clarithromycin alone in
C pneumoniae
–positive patients. The effect of treatment and other baseline variables on fibrinogen levels, determined at 6 months, was evaluated by multivariate analysis. Treatment significantly reduced fibrinogen level at 6 months in the overall study population and in the groups of patients divided according to
H pylori
or
C pneumoniae
positivity. In the 43 treated patients, mean (±SD) basal fibrinogen was 3.65±0.58 g/L, and mean final fibrinogen was 3.09±0.52 g/dL (
P
<0.001), whereas in the 41 untreated patients, mean basal and final fibrinogen levels were 3.45±0.70 and 3.61±0.71 g/L, respectively. The largest decrease was observed in patients with both infections. Fibrinogen changes were also significantly and negatively correlated with age.

Conclusions
—Our data suggest that a short, safe, and effective course of antibiotic therapy might be suggested as a means of interacting with an “emerging” risk factor.
Sympathetic Rhythmicity in Cardiac Transplant Recipients
Authors: van de Borne Philippe , Montano Nicola , Narkiewicz Krzysztof , Degaute Jean P. , Oren Ron , Pagani Massimo , Somers Virend K.
Published: June 2012

Background
—Variability of R-R interval and muscle sympathetic nerve activity (MSNA) occurs predominantly at a low frequency (LF, ±0.1 Hz) and a high frequency (HF, ±0.25 Hz) in normal humans. Increased sympathetic drive in normal humans is associated with an increased LF component of the R-R interval and MSNA. Patients with severe heart failure have high sympathetic activity but decreased or absent LF power of both R-R and MSNA. We tested the hypothesis that this dysfunction in autonomic modulation in heart failure can be reversed by heart transplantation.

Methods and Results
—We performed spectral analysis of resting MSNA, R-R interval, and respiration in 9 patients with heart transplants, 9 chronic heart failure patients, and 9 normal control subjects, all closely matched for age, sex, and body mass index. MSNA (bursts per minute) was higher in patients with heart transplants (74±3) than either patients with heart failure (56±6) or normal subjects (40±4) (
P
<0.001). LF variability in the R-R interval was reduced in both heart transplant recipients and heart failure patients compared with the control subjects (
P
<0.01). The LF variability in MSNA was also nearly absent in the heart failure patients (
P
<0.01). However, the LF and HF oscillations in MSNA in patients with heart transplants were comparable to those evident in the control subjects.

Conclusions
—Cardiac transplantation does not reduce MSNA. However, LF oscillations in sympathetic activity are restored after transplantation such that the MSNA oscillatory profile is similar to that observed in normal subjects.