bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment of Aortocoronary Vein Graft Lesions With Membrane-Covered Stents
Authors: Baldus Stephan , Köster Ralf , Elsner Mathias , Walter Dirk H. , Arnold Roman , Auch-Schwelk Wolfgang , Berger Jürgen , Rau Mathias , Meinertz Thomas , Zeiher Andreas M. , Hamm Christian W.
Published: June 2012

Background
—Stent implantation in lesions of degenerated aortocoronary vein grafts is associated with a high risk of periprocedural thrombus embolization and in-stent restenosis.

Methods and Results
—In a multicenter study, we followed up 109 consecutive patients (mean age 66±8 years, 12% female) who received polytetrafluoroethylene (PTFE) membrane–covered stents for 125 de novo stenoses in vein grafts 11±5 years after bypass surgery. Stent deployment was successful in all but 1 patient; 1 patient suffered from subacute stent thrombosis. Six-month cardiac mortality was 7% (8 patients), 3 patients (3%) underwent repeat bypass surgery, and 9 patients (8%) required target-lesion PTCA. Repeat angiography revealed vessel occlusions in 9% and in-stent restenosis in 8% of patients by the end of follow-up.

Conclusions
—Membrane-covered stents appear to be a safe and efficient treatment strategy associated with a low incidence of restenosis and target-vessel revascularization. Compared with previous studies, the investigated device is not associated with an increase in mortality or late vessel occlusions.
Considerable Time From the Onset of Plaque Rupture and/or Thrombi Until the Onset of Acute Myocardial Infarction in Humans
Authors: Ojio Shinsuke , Takatsu Hisato , Tanaka Tsutomu , Ueno Katsumi , Yokoya Koichi , Matsubara Tetsuo , Suzuki Takahiko , Watanabe Sachiro , Morita Norihiko , Kawasaki Masanori , Nagano Toshihiko , Nishio Itsuki , Sakai Kazuyoshi , Nishigaki Kazuhiko , Takemura Genzou , Noda Toshiyuki , Minatoguchi Shinya , Fujiwara Hisayoshi
Published: June 2012

Background
—It has been thought that the thrombi and bleeding in plaques that occur after plaque rupture or endothelial damage from vessels with mild stenosis suddenly occlude the lumen and cause acute myocardial infarction (AMI). However, our hypothesis is that thrombi and bleeding may not suddenly occlude the lumen.

Methods and Results
—The study group consisted of 20 patients who had coronary angiograms performed within 1 week (3±3 days) before AMI and 20 control patients who had coronary angiograms performed 6 to 18 months (282±49 days) before AMI. The features of infarct-related coronary segments (IRCS) at 3 days before AMI were the presence of a significant stenosis of >50% (95% in incidence and 71±12% diameter stenosis) and Ambrose’s type II eccentric lesions (plus multiple irregularities), an indicator of plaque rupture and/or thrombi (60% [70%]), and the features at 1 year before AMI were mild stenosis of <50% (95% incidence and 30±18% diameter stenosis) with rare Ambrose’s type II eccentric lesions (plus multiple irregularities) (10% [10%]). The same relation was observed in each of the 4 subgroups with Q-wave infarction, non–Q-wave infarction, preceding effort angina within 1 month before AMI, and no preceding effort angina.

Conclusions
—The appearance of marked progression and Ambrose’s type II eccentric lesion on coronary angiograms 3 days before AMI suggests the presence of a considerable time from the onset of plaque rupture and/or thrombi until the onset of AMI. These features may be predictors of AMI. The concept provides new insight into the mechanism and prevention of human AMIs.
Adriamycin-Induced Early Changes in Myocardial Antioxidant Enzymes and Their Modulation by Probucol
Authors: Li Timao , Singal Pawan K.
Published: June 2012

Background
—The clinical usefulness of adriamycin is restricted by the development of congestive heart failure. It has been suggested that probucol, a strong antioxidant, completely prevents adriamycin-induced cardiomyopathy without interfering with its antitumor properties. The present study investigated the effects of adriamycin and probucol on myocardial antioxidant enzyme activities and immunoreactive protein levels in rats.

Methods and Results
—Activities and protein levels of glutathione peroxidase (GSHPx) were significantly decreased from 2 to 24 hours, and those of manganese superoxide dismutase were decreased at 1 and 2 hours after adriamycin treatment. These changes were prevented by probucol. Catalase activity was increased from 2 to 24 hours after adriamycin treatment, but its protein levels were not significantly changed. Copper zinc superoxide dismutase activity and protein level were not changed at any time. Myocardial lipid peroxidation was found to be significantly higher at all time points, and this change was also prevented by probucol. Treatment with probucol alone increased GSHPx activity at 2 weeks, and in these hearts, lipid peroxidation was lower than the control value. Within 24 hours, there was no mortality in any of the groups.

Conclusions
—It is suggested that an early and persistent decrease in GSHPx activity and protein may play an important role in the pathogenesis of adriamycin-induced cardiomyopathy, worsening heart failure and mortality.
Evidence for Oxidative Activation of c-Myc–Dependent Nuclear Signaling in Human Coronary Smooth Muscle Cells and in Early Lesions of Watanabe Heritable Hyperlipidemic Rabbits
Authors: de Nigris Filomena , Youssef Tammam , Ciafré SilviaAnna , Franconi Flavia , Anania Vittorio , Condorelli GianLuigi , Palinski Wulf , Napoli Claudio
Published: June 2012

Background
—Oxidized LDL (oxLDL) promotes atherogenesis, and antioxidants reduce lesions in experimental models. OxLDL-mediated effects on c-Myc are poorly characterized, and those on c-Myc nuclear pathways are completely unknown. c-Myc stimulates smooth muscle cell (SMC) proliferation and could be involved in atherosclerosis. We investigated the early effects of oxLDL and α-tocopherol on c-Myc, its binding partner Max, and the carboxy-terminal domain–binding factors activator protein-2 and elongation 2 factor in human coronary SMCs. We also investigated whether 9-week treatment of Watanabe heritable hyperlipidemic (WHHL) rabbits with diet-enriched α-tocopherol reduces c-Myc expression and oxLDL in the left coronary artery.

Methods and Results
—OxLDL enhanced c-Myc/Max expression and transcription by cotransfection assay and the nuclear activities of E2F and activator protein-2 by binding shift and supershift in coronary SMCs. α-Tocopherol significantly reduced these molecular events. Furthermore, α-tocopherol reduced early lesions, SMC density, and the immunohistochemical presence of c-Myc, which colocalized with oxLDL/foam cells in the coronaries of WHHL rabbits.

Conclusions
—We provide the first evidence that oxLDL and α-tocopherol may influence c-Myc activation and several c-Myc–dependent signaling pathways in human coronary SMCs. The observation that in vivo, an antioxidant reduces both c-Myc and oxLDL in early coronary lesions of rabbits is consistent with, but does not prove, the hypothesis that c-Myc–dependent factors activated by oxidative processes contribute to atherogenesis and coronary heart disease.
A Noninvasive Imaging Modality for Cardiac Arrhythmias
Authors: Burnes John E. , Taccardi Bruno , Rudy Yoram
Published: June 2012

Background
—The last decade witnessed an explosion of information regarding the genetic, molecular, and mechanistic basis of heart disease. Translating this information into clinical practice requires the development of novel functional imaging modalities for diagnosis, localization, and guided intervention. A noninvasive modality for imaging cardiac arrhythmias is not yet available. Present electrocardiographic methods cannot precisely localize a ventricular tachycardia (VT) or its key reentrant circuit components. Recently, we developed a noninvasive electrocardiographic imaging modality (ECGI) that can reconstruct epicardial electrophysiological information from body surface potentials. Here, we extend its application to image reentrant arrhythmias.

Methods and Results
—Epicardial potentials were recorded during VT with a 490 electrode sock during an open chest procedure in 2 dogs with 4-day-old myocardial infarctions. Body surface potentials were generated from these epicardial potentials in a human torso model. Realistic geometry errors and measurement noise were added to the torso data, which were then used to noninvasively reconstruct epicardial isochrones, electrograms, and potentials with excellent accuracy. ECGI reconstructed the reentry pathway and its key components, including (1) the central common pathway, (2) the VT exit site, (3) lines of block, and (4) regions of slow and fast conduction. This allowed for detailed characterization of the reentrant circuit morphology.

Conclusions
—ECGI can noninvasively image arrhythmic activation on the epicardium during VT to identify and localize key components of the arrhythmogenic pathway that can be effective targets for antiarrhythmic intervention.
Nitric Oxide Inhibits Dystrophin Proteolysis by Coxsackieviral Protease 2A Through
S
-Nitrosylation
Authors: Badorff Cornel , Fichtlscherer Birgit , Rhoads Robert E. , Zeiher Andreas M. , Muelsch Alexander , Dimmeler Stefanie , Knowlton Kirk U.
Published: June 2012

Background
—Infection with enteroviruses like coxsackievirus B3 (CVB3) as well as genetic dystrophin deficiency can cause dilated cardiomyopathy. We recently identified cleavage and functional impairment of dystrophin by the viral protease 2A during CVB3-infection as a molecular mechanism that may contribute to the pathogenesis of enterovirus-induced cardiomyopathy. Nitric oxide (NO) is elevated in human dilated cardiomyopathy, but the relevance of this finding is unknown. In mice, NO inhibits CVB3 myocarditis. Therefore, we investigated the effects of NO on the coxsackieviral protease 2A.

Methods and Results
—In vitro, NO donors like PAPA-NONOate inhibited the cleavage of human and mouse dystrophin by recombinant coxsackievirus B protease 2A in a dose-dependent manner (IC
50
, 51 μmol/L). In CVB3-infected HeLa cells, addition of the NO donor SNAP inhibited protease 2A catalytic activity on dystrophin. Because this inhibitory effect was reversed by the thiol-protecting agent DTT, we investigated whether NO
S
-nitrosylates the protease 2A. In vitro, NO nitrosylated the active-site cysteine (C110) of the coxsackieviral protease 2A, as demonstrated by site-directed mutagenesis. Within living COS-7 cells, SNAP-induced
S
-nitrosylation of this site was confirmed with electron spin resonance spectroscopy.

Conclusions
—These data demonstrate inactivation of a coxsackieviral protease 2A by NO through active-cysteine
S
-nitrosylation in vitro and intracellularly. Given that the enteroviral protease 2A cleaves mouse and human dystrophin, NO may be protective in human heart failure with an underlying enteroviral pathogenesis through inhibition of dystrophin proteolysis.
Ultrasound-Guided Thrombin Injection for the Treatment of Postcatheterization Pseudoaneurysms
Authors: La Perna Lucy , Olin Jeffrey W. , Goines Debbie , Childs Mary Beth , Ouriel Kenneth
Published: June 2012

Background
—This prospective study was designed to assess the safety and efficacy of using bovine thrombin injection to treat pseudoaneurysms.

Methods and Results
—From April 1998 through December 1999, 70 pseudoaneurysm were injected with bovine thrombin under the guidance of color duplex ultrasound. The most superficial pseudoaneurysm chamber was entered with a 1.5-inch, 19- to 22-gauge or spinal needle. Bovine thrombin, in a 1000 U/cc solution, was injected into the chamber. A total of 36 women and 34 men underwent ultrasound-guided thrombin injection (UGTI). Their mean age was 69.5 years. Most pseudoaneurysms were associated with diagnostic cardiac catheterization or percutaneous coronary intervention (80%). Two pseudoaneurysms arose from the brachial artery; the remainder were in the groin. Twenty-one patients were being treated with either heparin or warfarin, and the majority of the others were on antiplatelet therapy with aspirin or clopidogrel. UGTI was successful in 66 of the 70 patients (94%). The first patient in the series had 2 attempts at thrombin injection and refused further attempts. Two patients had undergone stent graft placement and had short, wide tracts. Both of these patients required surgical repair of their pseudoaneurysms. The fourth patient had a nearly complete pseudoaneurysm thrombosis and was lost to follow-up on discharge. No arterial thrombotic events occurred. One patient had a soleal vein thrombosis in the ipsilateral leg.

Conclusions
—UGTI was safe and effective in 94% of patients with postcatheterization pseudoaneurysms. Anticoagulant use did not hinder successful thrombosis. UGTI should be the initial treatment of choice for patients with postcatheterization pseudoaneurysms.
New Mechanism of Antiarrhythmic Drug Action
Authors: Cabo Candido , Schmitt Heiko , Wit Andrew L.
Published: June 2012

Background
—We studied whether increasing L-type calcium current has antiarrhythmic effects.

Methods and Results
—Reentrant circuits in the epicardial border zone (EBZ) of healing canine infarcts were mapped during sustained ventricular tachycardia. The cardiac-specific L-type calcium current enhancer Bay Y5959 prevented initiation of sustained ventricular tachycardia in 7 of 14 experiments. Bay Y5959 caused slowing of conduction in areas of slow nonuniform conduction in reentrant circuits; block eventually occurred. Conduction was not affected in other regions of the circuits or in more normal areas of the EBZ, nor was the EBZ effective refractory period changed. Bay Y5959 also improved conduction of premature impulses so that lines of unidirectional block necessary for VT initiation were not formed, an effect not related to a change in the effective refractory period at the site of block.

Conclusions
—Block of conduction caused by enhanced L-type calcium current in reentrant circuits may result from a decreased gap junctional conductance consequent to an increase in intracellular calcium. An increase in L-type calcium current may improve conduction of premature impulses.
Vascular Endothelial Growth Factor-A–Induced Chemotaxis of Monocytes Is Attenuated in Patients With Diabetes Mellitus
Authors: Waltenberger Johannes , Lange Juliane , Kranz Andrea
Published: June 2012

Background
—Vascular endothelial growth factor-A (VEGF-A) acts on endothelial cells and monocytes, 2 cell types that participate in the angiogenic and arteriogenic process in vivo. Thus far, it has not been possible to identify differences in individual responses to VEGF-A stimulation because of the lack of an ex vivo assay.

Methods and Results
—We report a chemotaxis assay using isolated monocytes from individual diabetic patients and from healthy, age-matched volunteers. The chemotactic response of individual monocyte preparations to VEGF-A, as mediated via Flt-1, was quantitatively assessed using a modified Boyden chamber. Although the migration of monocytes from healthy volunteers could be stimulated with VEGF-A (1 ng/mL) to a median of 148.4% of the control value (25th and 75th percentiles, 136% and 170%), monocytes from diabetic patients could not be stimulated with VEGF-A (median, 91.1% of unstimulated controls; 25th and 75th percentiles, 83% and 98%;
P
<0.0001). In contrast, the response of monocytes to the chemoattractant formylMetLeuPhe remained intact in diabetic patients. The VEGF-A–inducible kinase activity of Flt-1, as assessed by in vitro kinase assays, remained intact in monocytes from diabetic patients. Moreover, the serum level of VEGF-A, as assessed by immunoradiometric assay, was significantly elevated in diabetic patients.

Conclusions
—The cellular response of monocytes to VEGF-A is attenuated in diabetic patients because of a downstream signal transduction defect. These data suggest that monocytes are important in arteriogenesis and that their ability to migrate might be critical to the arteriogenic response. Thus, we resolved a fundamental mechanism involved in the problem of impaired collateral formation in diabetic patients.
Host Response to Cytomegalovirus Infection as a Determinant of Susceptibility to Coronary Artery Disease
Authors: Zhu Jianhui , Shearer Gene M. , Norman James E. , Pinto Ligia A. , Marincola Francesco M. , Prasad Abhiram , Waclawiw Myron A. , Csako Gyorgy , Quyyumi Arshed A. , Epstein Stephen E.
Published: June 2012

Background
—Positive and negative associations between cytomegalovirus (CMV) infection and coronary artery disease (CAD) have been reported. We postulated that the susceptibility to CMV-induced CAD might relate to patterns of inflammatory and immune responses to CMV infection and that sex might have an effect on these responses.

Methods and Results
—In 151 men and 87 women being evaluated for CAD, blood samples were tested for humoral (Ab+) and cellular (Tc+) responses to CMV and for C-reactive protein (CRP). In men, an elevated CRP level was a significant determinant of CAD even after adjustment for CAD risk factors (OR, 3.1; 95% CI, 1.21 to 7.97). CMV seropositivity was associated with elevated CRP levels on multivariate analysis (
P
=0.006). In contrast, in women, CMV seropositivity was independently predictive of CAD (OR, 41.8; 95% CI, 4.12 to 423.74). CRP level in women with CAD was >25% higher than those without CAD, but the difference did not reach statistical significance. Importantly, compared with CMV Ab−/Tc− women, CAD prevalence was higher in Ab+/Tc− and Ab+/Tc+ (13% versus 68% and 64%, both
P
<0.005) but not in Ab−/Tc+ women (25%). There were no differences in age, smoking, diabetes, hypertension, and hypercholesterolemia among women with different types of immune responses to CMV infection.

Conclusions
—The mechanisms by which CMV predisposes to CAD in men and women may be different. In men, CMV appears to contribute to CAD risk, insofar as it predisposes to inflammation. In women, other mechanisms, possibly related to the type of immune response generated by the host, appear to be responsible for the proatherogenic effects of CMV.
Regulated Expression of the BTEB2 Transcription Factor in Vascular Smooth Muscle Cells
Authors: Hoshino Yoichi , Kurabayashi Masahiko , Kanda Tsugiyasu , Hasegawa Akira , Sakamoto Hironosuke , Okamoto Ei-ichi , Kowase Keiko , Watanabe Noboru , Manabe Ichiro , Suzuki Toru , Nakano Akihiko , Takase Shin-ichi , Wilcox Josiah N. , Nagai Ryozo
Published: June 2012

Background
—We have previously shown BTEB2, a Krüppel-like zinc finger transcription factor, to regulate expression of the SMemb/NMHC-B gene, which has been implicated in phenotypic modulation of smooth muscle cells (SMCs). The present study was done to assess the developmental and pathological expression profiles of BTEB2 and to further evaluate the clinical relevance of BTEB2 expression in human coronary artery disease.

Methods and Results
—Immunohistochemistry showed developmentally regulated expression of BTEB2 with abundant expression in fetal but not in adult aortic SMCs of humans and rabbits. In balloon-injured aortas, predominant expression of BTEB2 was seen in neointimal SMCs. Atherectomy specimens obtained from primary and restenotic lesions showed predominant expression of BTEB2 to stellate SMCs. The incidence of restenosis in primary lesions was significantly higher in lesions containing BTEB2-positive cells than in lesions without (55.6% versus 25.0%,
P
=0.01).

Conclusions
—The present study shows that BTEB2 expression is developmentally and pathologically regulated. BTEB2 is preferentially expressed in dedifferentiated or activated SMCs. Examination of human coronary artery specimens suggests that primary lesions containing BTEB2-positive cells are associated with higher risk of restenosis than BTEB2-negative lesions. These results suggest that BTEB2 can serve as a molecular marker for phenotypic modulation of vascular SMCs.
Isolation and Characterization of Coenzyme A Glutathione Disulfide as a Parathyroid-Derived Vasoconstrictive Factor
Authors: Jankowski Joachim , Schröter Anna , Tepel Martin , van der Giet Markus , Stephan Nina , Luo Jiankai , Zidek Walter , Schlüter Hartmut
Published: June 2012

Background
—Coenzyme A glutathione disulfide (CoA-SSG) was recently isolated from bovine adrenal glands and was shown to be a renal vasoconstrictor. The identification of CoA-SSG in human parathyroid glands and its action on cultured vascular smooth muscle cells (VSMCs) are described here.

Methods and Results
—After purification to homogeneity by several chromatographic steps, CoA-SSG was identified by matrix-assisted laser desorption/ionization mass spectrometry and enzymatic analysis. The dose-dependent growth-stimulating effect of CoA-SSG on VSMCs, measured by the [
3
H]thymidine method, is characterized by a threshold of 10
−
8
mol/L and a maximum effect of 10 μmol/L, increasing VSMC proliferation 254±21% above control. A dose of 10 μmol/L methylmalonyl-CoA and 10 μmol/L CoA increased the rate of proliferation of VSMCs only by 178±43% and 50±42% above control, respectively. Glutathione has no proliferative effect on VSMCs. The growth-stimulating effect of CoA-SSG (1 μmol/L) was decreased by the antagonists 3,7-dimethyl-1-propargylxanthine (DMPX; 11 μmol/L) (38% compared with CoA-SSG without antagonist) and pyridoxal-phosphate-6-azophenyl-2,4-disulfonic acid (PPADS; 10 μmol/L) (48% compared with CoA-SSG without antagonist; each
P
<0.05 versus control), indicating that the effect is mediated partly via A
2
and partly via P
2
Y
1
and/or P
2
Y
4
receptor.

Conclusions
—CoA-SSG may play a regulatory role in VSMC growth as a progression factor and thereby could play an important role in development of hypertension.
Altered Adrenergic Receptor Density in Myocardial Hibernation in Humans
Authors: Shan Kesavan , Bick Roger J. , Poindexter Brian J. , Nagueh Sherif F. , Shimoni Sarah , Verani Mario S. , Keng Felix , Reardon Michael J. , Letsou George V. , Howell Jimmy F. , Zoghbi William A.
Published: June 2012

Background
—Alterations in adrenergic receptor densities can potentially contribute to myocardial dysfunction. Their relevance to myocardial hibernation in humans is unknown.

Methods and Results
—Accordingly, 22 transmural myocardial biopsies were obtained in 11 patients with ischemic ventricular dysfunction during bypass surgery, guided by transesophageal echocardiography. Patients underwent dobutamine echocardiography (DE) and rest scintigraphic studies before revascularization and DE at 3 to 4 months. α- and β-receptor density (ARD and BRD) and extent of fibrosis were quantified from the myocardial biopsies. Of the 22 segments, 16 had abnormal rest function and 6 were normal. Severely hypokinetic or akinetic segments showed a 2.4-fold increase in ARD with a concomitant 50% decrease in BRD compared with normal segments. An increase in ARD, a decrease in BRD to a lesser extent, and thus an increase in ARD/BRD ratio were seen in dysfunctional segments with contractile reserve compared with normal segments and were most pronounced in those without contractile reserve (
P
<0.001). Similar findings were observed if recovery of function or scintigraphic uptake was analyzed as a marker for viability. No significant relation between either ARD or BRD and percent myocardial fibrosis was noted (
r
=0.37 and −0.39, respectively).

Conclusions
—Thus, graded and reciprocal changes in α- and β-adrenergic receptor densities occur in viable, hibernating myocardium and may account in part for the observed depression in resting myocardial function and preserved contractile reserve in this entity.
Lack of Direct Role for Calcium in Ischemic Diastolic Dysfunction in Isolated Hearts
Authors: Eberli Franz R. , Strömer Hinrik , Ferrell Margaret A. , Varma Niraj , Morgan James P. , Neubauer Stefan , Apstein Carl S.
Published: June 2012

Background
—Ischemia is characterized by an increase in intracellular calcium and occurrence of diastolic dysfunction. We investigated whether the myocyte calcium level is an important direct determinant of ischemic diastolic dysfunction.

Methods and Results
—We exposed isolated, perfused isovolumic (balloon in left ventricle) rat and rabbit hearts to low-flow ischemia and increased extracellular calcium (from 1.5 to 16 mmol/L) for brief periods. Intracellular calcium was measured by aequorin. Low-flow ischemia resulted in a 270% increase (
P
<0.05) in diastolic intracellular calcium, a 50% (
P
<0.05) calcium transient amplitude decrease, and a 52% (
P
<0.05) slowing of calcium transient decline. Diastolic pressure increased by 6±2 mm Hg (
P
<0.05), and rate of systolic pressure decay decreased by 65% (
P
<0.05). Experimentally increasing extracellular calcium doubled both intracellular diastolic calcium and calcium transient amplitude, concomitant with a developed pressure increase; however, there was no increase in ischemic diastolic pressure, slowing of the calcium transient decay, or further slowing of systolic pressure decay. Similarly, after 45 minutes of low-flow ischemia, after diastolic pressure had increased from 8.5±0.6 to 19.7±3.5 mm Hg (
P
<0.001), intracoronary high-molar calcium chloride infusion increased systolic pressure from 36±4 to 63±11 mm Hg (
P
<0.001), indicating an increase in intracellular calcium, but it decreased diastolic pressure from 19.7±3.5 to 17.5±3.7 mm Hg (
P
<0.01). Conversely, EGTA infusion decreased systolic pressure, indicating a decrease in intracellular calcium, but did not decrease diastolic pressure.

Conclusions
—When calcium availability was experimentally altered during ischemia, there was no alteration in left ventricular diastolic pressure, suggesting that ischemic diastolic dysfunction is not directly mediated by a calcium activated tension.
Dual-Chamber Pacing in the Treatment of Neurally Mediated Tilt-Positive Cardioinhibitory Syncope
Authors: Sutton Richard , Brignole Michele , Menozzi Carlo , Raviele Antonio , Alboni Paolo , Giani Paolo , Moya Angel
Published: June 2012

Background
—This study was performed to compare implantation of a DDI pacemaker with rate hysteresis with no implant in respect to syncopal recurrences in patients with severe cardioinhibitory tilt-positive neurally mediated syncope.

Methods and Results
—Forty-two patients from 18 European centers were randomized to receive a DDI pacemaker programmed to 80 bpm with hysteresis of 45 bpm (19 patients) or no pacemaker (23 patients). Inclusion criteria were ≥3 syncopes over the last 2 years and a positive cardioinhibitory (Vasovagal Syncope International Study types 2A and 2B) response to tilt testing. The median number of previous syncopal episodes was 6; asystolic response to tilt testing was present in 36 patients (86%) (mean asystole, 13.9±10.2 seconds). All patients were followed up for a minimum of 1.0 years and a maximum of 6.7 years (mean, 3.7±2.2). One patient (5%) in the pacemaker arm experienced recurrence of syncope compared with 14 patients (61%) in the no-pacemaker arm (
P
=0.0006). In the no-pacemaker arm, the median time to first syncopal recurrence was 5 months, with a rate of 0.44 per year. On repeated tilt testing performed within 15 days after enrollment, positive responses were observed in 59% of patients with pacemakers and in 61% of patients without pacemakers (
P
=NS).

Conclusions
—In a limited, select group of patients with tilt-positive cardioinhibitory syncope, DDI pacing with hysteresis reduced the likelihood of syncope. The benefit of the therapy was maintained over the long term. Even in untreated patients, the syncopal recurrence burden was low. A negative result of tilt testing was not a useful means to evaluate therapy efficacy.
Tumor Necrosis Factor-α Is Expressed in Donor Heart and Predicts Right Ventricular Failure After Human Heart Transplantation
Authors: Birks Emma J. , Owen Virginia J. , Burton Paul B. J. , Bishop Anne E. , Banner Nicholas R. , Khaghani Asghar , Polak Julia M. , Yacoub Magdi H.
Published: June 2012

Background
—Myocardial failure is an important problem after heart transplantation. Right ventricular (RV) failure is most common, although its mechanisms remain poorly understood. Inflammatory cytokines play an important role in heart failure. We studied the expression of tumor necrosis factor (TNF)-α and other cytokines in donor myocardium and their relationship to the subsequent development of RV failure early after transplantation.

Methods and Results
—Clinical details were obtained, and ventricular function was assessed by transesophageal echocardiography in 26 donors before heart retrieval. A donor RV biopsy was obtained immediately before transplantation, and each recipient was followed for the development of RV failure. Reverse transcriptase–polymerase chain reaction was performed to detect TNF-α, interleukin-2, interferon-γ, and inducible nitric oxide synthase expression. Eight of 26 recipients (30.8%) developed RV failure. Seven of these 8 (87.5%) expressed TNF-α, but only 4 of the 18 (22.2%) who did not develop RV failure expressed TNF-α (
P
<0.005). As a predictor of RV failure, TNF-α mRNA had a sensitivity of 87.5%, a specificity of 83.3%, a positive predictive value of 70%, and a negative predictive value of 93.7%. Western blotting demonstrated more TNF-α protein in the myocardium of donor hearts that developed RV failure (658±60 versus 470±57 optical density units,
P
<0.05). Immunocytochemistry localized TNF-α expression to cardiac myocytes. Reverse transcriptase–polymerase chain reaction detected interferon-γ in 2 (7.7%), interleukin-2 in 1 (3.8%), and inducible nitric oxide synthase mRNA in 1 (3.8%) of the 26 donor hearts, none of which developed RV failure.

Conclusions
—TNF-α expression in donor heart cardiac myocytes seems to predict the development of RV failure in patients early after heart transplantation.
Thrombomodulin Overexpression to Limit Neointima Formation
Authors: Waugh J. M. , Li-Hawkins J. , Yuksel E. , Kuo M. D. , Cifra P. N. , Hilfiker P. R. , Geske R. , Chawla M. , Thomas J. , Shenaq S. M. , Dake M. D. , Woo S. L. C.
Published: June 2012

Background
—These studies were initiated to confirm that high-level thrombomodulin overexpression is sufficient to limit neointima formation after mechanical overdilation injury.

Methods and Results
—An adenoviral construct expressing thrombomodulin (Adv/RSV-THM) was created and functionally characterized in vitro and in vivo. The impact of local overexpression of thrombomodulin on neointima formation 28 days after mechanical overdilation injury was evaluated. New Zealand White rabbit common femoral arteries were treated with buffer, viral control, or Adv/RSV-THM and subjected to mechanical overdilation injury. The treated vessels (n=4 per treatment) were harvested after 28 days and evaluated to determine intima-to-media (I/M) ratios. Additional experiments were performed to determine early (7-day) changes in extracellular elastin and collagen content; local macrophage, T-cell, and neutrophil infiltration; and local thrombus formation as potential contributors to the observed impact on 28-day neointima formation. The construct significantly decreased neointima formation after mechanical dilation injury in this model. By histological analysis, buffer controls exhibited mean I/M ratios of 0.76±0.06%, whereas viral controls reached 0.77±0.08%; in contrast, Adv/RSV-THM reduced I/M ratios to 0.47±0.06%. Local inflammatory infiltrate decreased in the Adv/RSV-THM group relative to controls, whereas matrix remained relatively preserved. Rates of early thrombus formation also decreased in Adv/RSV-THM animals.

Conclusions
—This construct thus offers a viable technique for promoting a locally neointima-resistant small-caliber artery via decreased thrombus bulk, normal matrix preservation, and decreased local inflammation without the inflammatory damage that has limited many other adenoviral applications.
Selective Endothelin-A Versus Combined Endothelin-A/Endothelin-B Receptor Blockade in Rat Chronic Heart Failure
Authors: Mulder Paul , Boujedaini Houssaine , Richard Vincent , Derumeaux Genevieve , Henry Jean Paul , Renet Sylvanie , Wessale Jerry , Opgenorth Terry , Thuillez Christian
Published: June 2012

Background
—The relative efficacy of endothelin-A (ET
A
) receptor blockade versus combined ET
A
-ET
B
receptor blockade in chronic heart failure (CHF) is still largely unknown.

Methods and Results
—We compared, in a rat model of CHF (coronary ligation), the hemodynamic and structural effects of 1 month of treatment with the ET
A
antagonist ABT-627 (5 mg · kg
−1
· d
−1
), the ET
B
antagonist A-192621 (30 mg · kg
−1
· d
−1
) or a combination of the 2 drugs. Doses were chosen for their capacity to block the pressor response to ET-1 (for ET
A
blockade) or the depressor responses to sarafotoxin S6c or ET-1 (for ET
B
blockade). ET
A
and combined ET
A
-ET
B
blockade reduced systolic blood pressure to the same extent, whereas ET
B
blockade had no effect. In contrast, only combined ET
A
-ET
B
blockade significantly reduced heart rate. Both ET
A
and combined ET
A
-ET
B
blockade, but not ET
B
blockade alone, increased left ventricular (LV) fractional shortening and wall thickening and reduced LV end-diastolic pressure, as well as LV end-diastolic and end-systolic volumes. However, all treatments (including ET
B
blockade) decreased LV collagen accumulation.

Conclusions
—The chronic blockade of both ET
A
and ET
B
receptors improved systemic hemodynamics, as well as LV function and remodeling, to the same extent as ET
A
receptor blockade alone. However, only combined ET
A
-ET
B
receptor blockade decreased heart rate. Whether this differential effect on heart rate affects the long-term outcome after treatment with ET
A
or mixed ET
A
-ET
B
antagonists in CHF remains to be determined.
Noradrenergic Vascular Hyper-Responsiveness in Human Hypertension Is Dependent on Oxygen Free Radical Impairment of Nitric Oxide Activity
Authors: Lembo Giuseppe , Vecchione Carmine , Izzo Raffaele , Fratta Luigi , Fontana Dario , Marino Gennaro , Pilato Giovanni , Trimarco Bruno
Published: June 2012

Background
—Noradrenergic vascular hyper-responsiveness is a hallmark of essential hypertension. To evaluate whether nitric oxide plays a role in the enhanced vascular response to norepinephrine in hypertension, we examined 32 hypertensives and 28 normotensives who were distributed in 3 experimental series.

Methods and Results
—In the first series, we measured the forearm blood flow (FBF) response to a norepinephrine infusion under control conditions and during the infusion of
l
-N-monomethylarginine (L-NMMA). Norepinephrine evoked dose-dependent vasoconstriction that was greater in hypertensives than in normotensives (maximum FBF, −61±1 versus −51±1%;
P
<0.01). During L-NMMA infusion, norepinephrine vasoconstriction was not modified in hypertensives; however, it was potentiated in normotensives (maximum FBF, −64±2%;
P
<0.01). In the second series, we tested whether norepinephrine vasoconstriction could be affected by an antioxidant such as ascorbic acid. Norepinephrine vasoconstriction was blunted by ascorbic acid administration only in hypertensives (maximum FBF, −49±3 versus −63±2%;
P
<0.01); the vasoconstriction became similar to that observed in normotensives. During ascorbic acid plus L-NMMA administration, the vascular response to norepinephrine increased to a similar extent in both study groups. To rule out the possibility that the effect of ascorbic acid on norepinephrine vasoconstriction could depend on adrenergic receptor–induced nitric oxide release, in the last series we inhibited endogenous nitric oxide and replaced it with an exogenous nitric oxide donor (sodium nitroprusside). Even in these conditions, ascorbic acid attenuated norepinephrine vasoconstriction only in hypertensives (maximum FBF, −50±2 versus −62±1%;
P
<0.01).

Conclusions
—Our data demonstrate that noradrenergic vascular hyper-responsiveness in hypertension is dependent on an impairment of nitric oxide activity that is realized through norepinephrine-induced oxygen free radical production.
Does Folic Acid Decrease Plasma Homocysteine and Improve Endothelial Function in Patients With Predialysis Renal Failure?
Authors: Thambyrajah J. , Landray M. J. , McGlynn F. J. , Jones H. J. , Wheeler D. C. , Townend J. N.
Published: June 2012

Background
—Considerable evidence suggests that hyperhomocysteinemia is an independent vascular risk factor that promotes atherosclerosis by inducing endothelial dysfunction. Although folic acid reduces hyperhomocysteinemia, the effect on adverse vascular events is unknown. We hypothesized that in patients with chronic renal failure, a condition associated with both hyperhomocysteinemia and atherosclerosis, treatment with folic acid would improve endothelial function.

Methods and Results
—In a prospective, double-blind protocol, 100 patients (mean age 62 years, 67 men) with predialysis chronic renal failure were randomized to 5 mg folic acid or placebo daily for 12 weeks. Endothelial function was assessed by measuring (1) endothelium-dependent dilation of the brachial artery, (2) combined serum nitrite/nitrate concentrations, and (3) plasma von Willebrand factor concentration. Baseline characteristics of the 2 groups were similar. At the end of the study, both serum and red cell folate concentrations were greater in the folic acid group than the placebo group [mean (95% CI) 39.0 (29.8 to 51.0) versus 7.7 (6.6 to 8.9) μg/L and 739 (613 to 891) versus 220 (184 to 262) μg/L, respectively; both
P
<0.001]. Despite a reduction in hyperhomocysteinemia in the folic acid group compared with the placebo group [15.1 (14.1 to 16.2) versus 20.1 (18.2 to 22.2) μmol/L;
P
<0.001], there were no significant differences in endothelium-dependent dilation, combined serum nitrite/nitrate concentrations, or plasma von Willebrand factor concentration between the 2 groups.

Conclusions
—High-dose folic acid lowers but fails to normalize hyperhomocysteinemia in patients with predialysis chronic renal failure. This was not accompanied by an improvement of endothelial function and suggests that treatment with folic acid may not reduce the burden of vascular disease in uremia.
Role of Calcium-Sensitive K
+
Channels and Nitric Oxide in In Vivo Coronary Vasodilation From Enhanced Perfusion Pulsatility
Authors: Paolocci Nazareno , Pagliaro Pasquale , Isoda Takayoshi , Saavedra Federico W. , Kass David A.
Published: June 2012

Background
—In vitro studies support K
+
Ca
channel–induced smooth muscle hyperpolarization as underlying acetylcholine-mediated (or bradykinin-mediated) vasodilation that persists despite combined nitric oxide (NO) and PGI
2
inhibition. We tested the hypothesis that these channels are activated by enhanced pulsatile perfusion in vivo and contribute substantially to vasodilation from this stimulus.

Methods and Results
—The canine left descending coronary artery was perfused with whole blood at constant mean pressure, and physiological flow pulsatility was set at 40 or 100 mm Hg by computer servo-pump. Cyclooxygenase was inhibited by indomethacin. Mean flow increased +18±2% (
P
<0.0001) with enhanced pulsatility. This response declined ≈50% by blocking NO synthase (L-NMMA) or K
+
Ca
[charybdotoxin (CbTX)+apamin (AP)]. Combining both inhibitors virtually eliminated the flow rise. Inhibiting either or both pathways minimally altered basal coronary flow, whereas agonist-stimulated flow was blocked. Bradykinin-induced dilation declined more with CbTX+AP than with L-NMMA (−66% versus −46%,
P
=0.03) and was fully blocked by their combination. In contrast, acetylcholine-induced dilation was more blunted by L-NMMA than by CbTX+AP (−71% versus −44%,
P
<0.002) and was not fully prevented by the combination. Substituting iberiotoxin (IbTX) for CbTX greatly diminished inhibition of pulse pressure and agonist flow responses (with or without NOS inhibition). Furthermore, blockade by IbTX+AP was identical to that by AP alone, supporting a minimal role of IbTX-sensitive large-conductance K
+
Ca
channels.

Conclusions
—K
+
Ca
activation and NO comodulate in vivo pulsatility-stimulated coronary flow, supporting an important role of a hyperpolarization pathway in enhanced mechanovascular signaling. Small- and intermediate-conductance K
+
Ca
channels are the dominant species involved in modulating both pulse pressure– and bradykinin-induced in vivo coronary dilation.
Effects of Combination of ACE Inhibitor and Angiotensin Receptor Blocker on Cardiac Remodeling, Cardiac Function, and Survival in Rat Heart Failure
Authors: Kim Shokei , Yoshiyama Minoru , Izumi Yasukatsu , Kawano Hitomi , Kimoto Manabu , Zhan Yumei , Iwao Hiroshi
Published: June 2012

Background
—The mechanism and treatment of diastolic heart failure are poorly understood. We compared the effects of an ACE inhibitor, an angiotensin receptor blocker (ARB), and their combination on diastolic heart failure in Dahl salt-sensitive (DS) rats.

Methods and Results
—DS rats fed an 8% NaCl diet from 7 weeks of age were treated with benazepril 10 mg/kg alone, valsartan 30 mg/kg alone, or combined benazepril and valsartan at 5 and 15 mg/kg, respectively, or at 1 and 3 mg/kg, respectively. At 16 weeks of age, DS rats exhibited prominent concentric left ventricular (LV) hypertrophy and diastolic dysfunction with preserved systolic function, as estimated by echocardiography. Despite comparable hypotensive effects among all drug treatments, the combination of benazepril 5 mg/kg and valsartan 15 mg/kg improved diastolic dysfunction and survival in DS rats more effectively than ACE inhibitor or ARB alone. Furthermore, the increase in LV endothelin-1 levels and hydroxyproline contents in DS rats was significantly suppressed only by combined benazepril and valsartan, and LV atrial natriuretic peptide mRNA upregulation in DS rats was suppressed to a greater extent by the combination therapy than monotherapy.

Conclusions
—The combination of ACE inhibitor and ARB, independently of the hypotensive effect, improved LV phenotypic change and increased LV endothelin-1 production and collagen accumulation, diastolic dysfunction, and survival in a rat heart failure model more effectively than either agent alone, thereby providing solid experimental evidence that the combination of these 2 agents is more beneficial than monotherapy for treatment of heart failure.
Effects of Urotensin II in Human Arteries and Veins of Varying Caliber
Authors: Hillier Chris , Berry Colin , Petrie Mark C. , O’Dwyer Patrick J. , Hamilton Carlene , Brown Amanda , McMurray John
Published: June 2012

Background
—Urotensin II (UII) is the ligand for the GPR14 receptor and the most potent vasoconstrictor in the cynomolgus monkey. UII also contracts rat thoracic aorta. We studied the effect of human UII (hUII) in human blood vessels

Methods and Results
—Small subcutaneous resistance arteries, internal mammary arteries, saphenous veins, and small subcutaneous veins were studied using standard techniques. Subcutaneous resistance arteries constricted in response to norepinephrine (maximum tension, 2.84±0.38 mN/mm; the concentration required to produce 50% of the maximum response [EC
50
], 0.52±0.07 μmol/L) and endothelin-1 (maximum tension, 4.19±0.93 mN/mm; EC
50
, 1.6±0.1 nmol/L). hUII did not contract these arteries, internal mammary arteries, or either type of vein, but it was a potent vasoconstrictor in rat thoracic aorta (maximum tension, 2.36±0.2 mN/mm; EC
50
, 1.13±0.36 nmol/L).

Conclusions
—hUII has no vasoconstrictor action in human arteries and veins of different sizes and vascular beds. Marked species differences in the actions of UII question its importance in human cardiovascular regulation.
Human Tissue Valves in Aortic Position
Authors: Willems Tineke P. , Takkenberg Johanna J. M. , Steyerberg Ewout W. , Kleyburg-Linkers Veronica E. , Roelandt Jos R. T. C. , Bos Egbert , van Herwerden Lex A.
Published: June 2012

Background
—Human tissue valves for aortic valve replacement have a limited durability that is influenced by interrelated determinants. Hierarchical linear modeling was used to analyze the relation between these determinants of durability and valve regurgitation measured by serial echocardiography.

Methods and Results
—In adult patients, 218 cryopreserved aortic allografts were implanted with the subcoronary (85) or the root replacement technique (133), and 81 patients had root replacement with a pulmonary autograft. Mean follow-up was 4.2 years (SD 2.7; range, 0 to 10.5). Patient age, operator experience with subcoronary implantation, and allograft diameter were independent predictors for reoperation. With repeated color Doppler echocardiography, the severity of aortic regurgitation was assessed by the jet length method and the jet diameter ratio. Multilevel hierarchical linear modeling was used to estimate initial aortic regurgitation (intercept), its change over time (slope), and the effect of 11 potential determinants of durability on aortic regurgitation. With the jet length method, the intercept was 0.94 grade and the slope was 0.11 grade per year. With the jet diameter ratio, the intercept was 0.34 and the annual increase was 0.01. Subcoronary implanted valves had more initial aortic regurgitation, but progression of aortic valve regurgitation did not differ from root replacement. At midterm follow-up, recipient age <40 years was the only independent predictor of aortic regurgitation.

Conclusions
—Subcoronary implantation has a learning curve, resulting in more initial aortic regurgitation and early reoperation compared with root replacement. In both techniques, progression of aortic regurgitation over time is small but accelerated in young adults.
Endothelin-1 Has a Unique Oxygen-Saving Effect by Increasing Contractile Efficiency in the Isolated Rat Heart
Authors: Takeuchi Yuzo , Kihara Yasuki , Inagaki Koichi , Yoneda Takeshi , Sasayama Shigetake
Published: June 2012

Background
—The effect of endothelin (ET)-1 on cardiac energetics is not fully understood.

Methods and Results
—In isolated, coronary-perfused rat hearts, we measured left ventricular contractility index (E
max
), pressure-volume area (PVA), and myocardial oxygen consumption (MV̇
o
2
) before and after administration of ET-1 (1×10
−
9
mol/L). ET-1 increased E
max
by 48±16% (
P
<0.01) and the total MV̇
o
2
by 24±11% (
P
<0.01). The MV̇
o
2
-PVA relations were linear both before and after ET-1 (
r
>0.99). ET-1 shifted MV̇
o
2
-PVA upward, increasing the MV̇
o
2
intercept by 24±13%. At the same time, ET-1 decreased the slope (S), with 1/S (contractile efficiency) being 46±5% before and 56±5% after ET-1 (
P
<0.01). ET-1–induced increases in E
max
and in contractile efficiency were abolished by an ET
A
receptor blocker (S-0139) but not by an ET
B
blocker (BQ-788). Although high [Ca
2+
] perfusion increased E
max
and the intercept to the same extent as ET-1, it did not change S.
N
G
-Nitro-
l
-arginine (an inhibitor of nitric oxide synthase) increased the coronary perfusion pressure as much as ET-1, but S again remained unchanged. Dimethylamyloride (Na
+
/H
+
exchanger inhibitor) partially blocked the positive inotropic effect of ET-1 but not the ET-1–induced increase in the contractile efficiency.

Conclusions
—Agonistic effects of ET-1 on the ET
A
receptor economized the chemomechanical conversion efficiency of the left ventricular unit myocardium by a mechanism independent of the Na
+
/H
+
exchanger. This unique oxygen-saving effect of ET-1 may play an adaptive role in the failing myocardium, in which local accumulation of ET-1 is present.