bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential Effects of Eicosapentaenoic Acid and Docosahexaenoic Acid on Vascular Reactivity of the Forearm Microcirculation in Hyperlipidemic, Overweight Men
Authors: Mori Trevor A. , Watts Gerald F. , Burke Valerie , Hilme Elisabet , Puddey Ian B. , Beilin Lawrence J.
Published: June 2012

Background
—Recent evidence supports differential effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the 2 major ω3 fatty acids of marine origin, on blood pressure in humans and vascular reactivity in adult spontaneously hypertensive rats. We investigated possible differences in the effects of purified EPA or DHA on forearm vascular reactivity in overweight hyperlipidemic men that might contribute to the blood pressure–lowering effects of fish oils.

Methods and Results
—With a double-blind, placebo-controlled trial of parallel design, 59 overweight, mildly hyperlipidemic men were randomized to receive 4 g/d purified EPA, DHA, or olive oil (placebo) capsules while continuing their usual diets for 6 weeks. Forearm blood flow (FBF) was measured with venous occlusion, strain-gauge plethysmography during the sequential intra-arterial administration of acetylcholine (7.5, 15, and 30 μg/min), sodium nitroprusside (1.5, 3, and 10 μg/min), norepinephrine (10, 20, and 40 ng/min), a single-dose infusion of
N
G
-monomethyl-
l
-arginine (L-NMMA) (1 mg/min), and coinfusion of acetylcholine (7.5, 15, and 30 μg/min) and L-NMMA. Forty of the 56 subjects who completed the study underwent FBF measurements. Plasma phospholipid EPA levels increased significantly (
P
<0.0001) after supplementation with EPA, and DHA composition increased with DHA supplementation (
P
<0.0001). Relative to placebo, DHA, but not EPA, supplementation significantly improved FBF in response to acetylcholine infusion (
P
=0.040) and coinfusion of acetylcholine with L-NMMA (
P
=0.040). Infusion of L-NMMA alone showed no group differences. DHA significantly enhanced dilatory responses to sodium nitroprusside (
P
<0.0001) and attenuated constrictor responses to norepinephrine (
P
=0.017).

Conclusions
—Relative to placebo, DHA, but not EPA, enhances vasodilator mechanisms and attenuates constrictor responses in the forearm microcirculation. Improvements in endothelium-independent mechanisms appear to be predominant and may contribute to the selective blood pressure–lowering effect observed with DHA compared with EPA in humans.
Monocyte Chemoattractant Protein-1 is Upregulated in Rats With Volume-Overload Congestive Heart Failure
Authors: Behr Thomas M. , Wang Xinkang , Aiyar Nambi , Coatney Robert W. , Li Xiang , Koster Paul , Angermann Christiane E. , Ohlstein Eliot , Feuerstein Giora Z. , Winaver Joseph
Published: June 2012

Background
—Chemokines are potent proinflammatory and immune modulators. Increased expression of chemokines, eg, monocyte chemoattractant protein-1 (MCP-1), has recently been described in clinical and experimental heart failure. The present report is aimed at exploring the expression, localization, and binding site regulation of MCP-1, a member of the C-C chemokine family, in a rat model of volume-overload congestive heart failure (CHF).

Methods and Results
—An aortocaval fistula was surgically created between the abdominal aorta and inferior vena cava. Rats with CHF were further subdivided into compensated and decompensated subgroups. Northern blot analysis and real-time quantitative polymerase chain reaction demonstrated upregulation of MCP-1 mRNA expression correlating with the severity of CHF (288±22, 502±62, and 826±138 copies/ng total RNA for sham, compensated, and decompensated animals, respectively; n=5,
P
<0.05). MCP-1 protein was localized by immunohistochemistry in cardiomyocytes, vascular endothelium and smooth muscle cells, infiltrating leukocytes, and interstitial fibroblasts, and its intensity increased with severity of CHF. In addition, rats with CHF displayed a significant decrease of
125
I-labeled MCP-1 binding sites to myocardium-derived membranes (384.3±57.0, 181.3±8.8, and 123.3±14.1 fmol/mg protein for sham, compensated, and decompensated animals, respectively).

Conclusions
—Volume-overload CHF in rats is associated with alterations in the expression, immunohistochemical localization, and receptor binding of the MCP-1 chemokine in the myocardium. These changes were more pronounced in rats with decompensated CHF. The data suggest that activation of the MCP-1 system may contribute to the progressive cardiac decompensation and development of CHF in rats with aortocaval fistula.
Positive Geometric Vascular Remodeling Is Seen After Catheter-Based Radiation Followed by Conventional Stent Implantation but Not After Radioactive Stent Implantation
Authors: Kay I. Patrick , Sabaté Manel , Costa Marco A. , Kozuma Ken , Albertal Mariano , van der Giessen Willem J. , Wardeh Alexander J. , Ligthart Jurgen M. R. , Coen Veronique M. A. , Levendag Peter C. , Serruys Patrick W.
Published: June 2012

Background
—Recent reports demonstrate that intracoronary radiation affects not only neointimal formation but also vascular remodeling. Radioactive stents and catheter-based techniques deliver radiation in different ways, suggesting that different patterns of remodeling after each technique may be expected.

Methods and Results
—We analyzed remodeling in 18 patients after conventional stent implantation, 16 patients after low-activity radioactive stent implantation, 16 patients after higher activity radioactive stent implantation, and, finally, 17 patients who underwent catheter-based radiation followed by conventional stent implantation. Intravascular ultrasound with 3D reconstruction was used after stent implantation and at the 6-month follow-up to assess remodeling within the stent margins and at its edges. Preprocedural characteristics were similar between groups. In-stent neointimal hyperplasia (NIH) was inhibited by high-activity radioactive stent implantation (NIH 9.0 mm
3
) and by catheter-based radiation followed by conventional stent implantation (NIH 6.9 mm
3
) compared with low-activity radioactive stent implantation (NIH 21.2 mm
3
) and conventional stent implantation (NIH 20.8 mm
3
) (
P
=0.008). No difference in plaque or total vessel volume was seen behind the stent in the conventional, low-activity, or high-activity stent implantation groups. However, significant increases in plaque behind the stent (15%) and in total vessel volume (8%) were seen in the group that underwent catheter-based radiation followed by conventional stent implantation. All 4 groups demonstrated significant late lumen loss at the stent edges; however, edge restenosis was seen only in the group subjected to high-activity stent implantation and appeared to be due to an increase in plaque and, to a lesser degree, to negative remodeling.

Conclusions
—Distinct differences in the patterns of remodeling exist between conventional, radioactive, and catheter-based radiotherapy with stenting.
Differential Pacing for Distinguishing Block From Persistent Conduction Through an Ablation Line
Authors: Shah Dipen , Haïssaguerre Michel , Takahashi Atsushi , Jaïs Pierre , Hocini Mélèze , Clémenty Jacques
Published: June 2012

Background
—Because complete linear conduction block is necessary to minimize the recurrence of reentrant tachycardias such as typical atrial flutter, we investigated a simple technique to recognize a persistent gap or complete linear block.

Methods and Results
—We prospectively evaluated cavotricuspid isthmus conduction in 50 patients (age 63±8 years, 43 men) after radiofrequency ablation. The distal and proximal bipoles of a quadripolar catheter placed close to the ablation line were successively stimulated during recording from the ablation line. We hypothesized that because the initial and terminal components of local potentials reflected activation at the ipsilateral and contralateral borders of the ablation lesion, a change to a more proximal pacing site without moving the catheter would prolong the stimulus to the initial component timing, whereas the response of the terminal component would depend on the presence of block or persistent conduction. A shortening or no change in timing of the terminal component would indicate block, whereas lengthening would indicate persistent gap conduction. The results were compared with previously described criteria for isthmus block. Ninety-two sites were assessed: 17 before and 75 after the achievement of complete isthmus block. The timing of the initial component was delayed by 19±9 ms, and the terminal component was advanced by 13±8 ms after block and delayed by 12±9 ms in case of persisting conduction. The sensitivity, specificity, and positive and negative predictive values for linear block were 100%, 75%, 94%, and 100%, respectively.

Conclusions
—An accurate assessment of isthmus block or persistent isthmus conduction is possible with this technique of differential pacing.
Angiotensin-Converting Enzyme Inhibition and Angiotensin II Type 1 Receptor Blockade Prevent Cardiac Remodeling in Pigs After Myocardial Infarction
Authors: van Kats Jorge P. , Duncker Dirk J. , Haitsma David B. , Schuijt Martin P. , Niebuur Remko , Stubenitsky René , Boomsma Frans , Schalekamp Maarten A. D. H. , Verdouw Pieter D. , Danser A. H. Jan
Published: June 2012

Background
—The mechanisms behind the beneficial effects of renin-angiotensin system blockade after myocardial infarction (MI) are not fully elucidated but may include interference with tissue angiotensin II (Ang II).

Methods and Results
—Forty-nine pigs underwent coronary artery ligation or sham operation and were studied up to 6 weeks. To determine coronary angiotensin I (Ang I) to Ang II conversion and to distinguish plasma-derived Ang II from locally synthesized Ang II,
125
I-labeled and endogenous Ang I and II were measured in plasma and in infarcted and noninfarcted left ventricle (LV) during
125
I-Ang I infusion. Ang II type 1 (AT
1
) receptor–mediated uptake of circulating
125
I-Ang II was increased at 1 and 3 weeks in noninfarcted LV, and this uptake was the main cause of the transient elevation in Ang II levels in the noninfarcted LV at 1 week. Ang II levels and AT
1
receptor–mediated uptake of circulating Ang II were reduced in the infarct area at all time points. Coronary Ang I to Ang II conversion was unaffected by MI. Captopril and the AT
1
receptor antagonist eprosartan attenuated postinfarct remodeling, although both drugs increased cardiac Ang II production. Captopril blocked coronary conversion by >80% and normalized Ang II uptake in the noninfarcted LV. Eprosartan did not affect coronary conversion and blocked cardiac Ang II uptake by >90%.

Conclusions
—Both circulating and locally generated Ang II contribute to remodeling after MI. The rise in tissue Ang II production during angiotensin-converting enzyme inhibition and AT
1
receptor blockade suggests that the antihypertrophic effects of these drugs result not only from diminished AT
1
receptor stimulation but also from increased stimulation of growth-inhibitory Ang II type 2 receptors.
Intrapericardial Paclitaxel Delivery Inhibits Neointimal Proliferation and Promotes Arterial Enlargement After Porcine Coronary Overstretch
Authors: Hou Dongming , Rogers Pamela I. , Toleikis Philip M. , Hunter William , March Keith L.
Published: June 2012

Background
—Catheter-based intrapericardial (IPC) delivery of therapeutic agents has recently been demonstrated. Paclitaxel is known to inhibit vascular smooth muscle cell proliferation. This study examined the effect of IPC instillation of paclitaxel on neointimal proliferation after balloon overstretch of porcine coronary arteries.

Methods and Results
—Overstretch injury of coronary arteries was followed by IPC administration of micellar paclitaxel at low dose (LD, 10 mg; n=6) or high dose (HD, 50 mg; n=7) or of control micelles (50 mg, n=5). Animals were euthanized 28 days after balloon dilation. Arterial injury indices were no different among the groups. The neointimal area, maximal intimal thickness, and adventitial thickness were significantly reduced in both LD (0.47±0.04 mm
2
, 0.43±0.03 mm, and 0.35±0.02 mm, respectively) and HD (0.51±0.06 mm
2
, 0.42±0.03 mm, and 0.38±0.03 mm, respectively) paclitaxel groups compared with the control group (0.79±0.07 mm
2
, 0.56±0.02 mm, and 0.47±0.02 mm, respectively;
P
<0.001). Meanwhile, the vessel circumference measured at the external elastic lamina of paclitaxel-treated vessels was significantly larger than the control circumference. Apoptotic cells were found in the neointima. The apoptotic cell percentage was not different between the control (1.72%) and LD (2.31%) groups but was higher in the HD group (7.07%,
P
<0.0001 versus control and LD groups). Immunostaining for matrix metalloproteinase-2 revealed concurrent reduction in the HD group compared with the control and LD groups.

Conclusions
—IPC space delivery of a single dose of paclitaxel significantly reduces vessel narrowing in this balloon-overstretch model. This effect is mediated by reduction of neointimal mass as well as positive vascular remodeling.
Association of Fibrinogen With Cardiovascular Risk Factors and Cardiovascular Disease in the Framingham Offspring Population
Authors: Stec James J. , Silbershatz Halit , Tofler Geoffrey H. , Matheney Travis H. , Sutherland Patrice , Lipinska Izabela , Massaro Joseph M. , Wilson Peter F.W. , Muller James E. , D’Agostino Ralph B.
Published: June 2012

Background
—Fibrinogen has been identified as an independent risk factor for cardiovascular disease and associated with traditional cardiovascular risk factors. Also, the role of elevated fibrinogen in thrombosis suggests that it may be on the causal pathway for certain risk factors to exert their effect. These associations remain incompletely characterized. Moreover, the optimal fibrinogen assay for risk stratification is uncertain.

Methods and Results
—In 2632 subjects from cycle 5 of the Framingham Offspring Population, fibrinogen levels were determined with a newly developed immunoprecipitation test (American Biogenetic Sciences) and the functional Clauss method. With the immunoprecipitation method, there were significant linear trends across fibrinogen tertiles (
P
<0.001) for age, body mass index, smoking, diabetes mellitus, total cholesterol, HDL cholesterol, and triglycerides in men and women. The Clauss method had significant results (
P
<0.030), except for triglycerides in men. Fibrinogen levels were higher for those with compared with those without cardiovascular disease. After covariate adjustment, fibrinogen remained significantly higher in those with cardiovascular disease with the use of the immunoprecipitation test (
P
=0.035 and
P
=0.018 for men and women, respectively) but not with the Clauss method.

Conclusions
—Fibrinogen was associated with traditional cardiovascular risk factors. Elevation of fibrinogen may provide a mechanism for risk factors to exert their effect. Also, fibrinogen levels were higher among subjects with cardiovascular disease compared with those without disease. The immunoprecipitation test showed a stronger association with cardiovascular disease than the Clauss method, suggesting that it may be a useful screening tool to identify individuals at increased thrombotic risk.
Early Assessment of Myocardial Salvage by Contrast-Enhanced Magnetic Resonance Imaging
Authors: Hillenbrand Hanns B. , Kim Raymond J. , Parker Michele A. , Fieno David S. , Judd Robert M.
Published: June 2012

Background
—Myocardial salvage after acute myocardial infarction is defined clinically by early restoration of flow and long-term improvement in contractile function. We hypothesized that contrast-enhanced magnetic resonance imaging (MRI), performed early after myocardial infarction, indexes myocardial salvage. We studied the relationship between the transmural extent of hyperenhancement by contrast-enhanced MRI, restoration of flow, and recovery of function.

Methods and Results
—The left anterior descending coronary artery was occluded in dogs (n=15) for either 45 minutes, 90 minutes, or permanently. Cine and contrast-enhanced MRI were performed 3 days after the procedure; cine MRI was also done 10 and 28 days after the procedure. The transmural extent of hyperenhancement and wall thickening were determined using a 60-segment model. The mean transmural extent of hyperenhancement for the 45-minute occlusion group was 22% of the 90-minute group and 18% of the permanent occlusion group (
P
<0.05 for both). The transmural extent of hyperenhancement on day 3 was related to future improvement in both wall thickening score and absolute wall thickening at 10 and 28 days (
P
<0.0001 for each). For example, of the 415 segments on day 3 that were dysfunctional and had <25% transmural hyperenhancement, 362 (87%) improved by day 28. Conversely, no segments (0 of 9) with 100% hyperenhancement improved. The transmural extent of hyperenhancement on day 3 was a better predictor of improvement in contractile function than occlusion time (
P
<0.0001).

Conclusions
—A reduction in the transmural extent of hyperenhancement by contrast-enhanced MRI early after myocardial infarction is associated with an early restoration of flow and future improvement in contractile function.
VLDL, Apolipoproteins B, CIII, and E, and Risk of Recurrent Coronary Events in the Cholesterol and Recurrent Events (CARE) Trial
Authors: Sacks Frank M. , Alaupovic Petar , Moye Lemuel A. , Cole Thomas G. , Sussex Bruce , Stampfer Meir J. , Pfeffer Marc A. , Braunwald Eugene
Published: June 2012

Background
—Plasma triglyceride concentration has been an inconsistent independent risk factor for coronary heart disease, perhaps because of the metabolic heterogeneity among VLDL particles, the main carriers of triglycerides in plasma.

Methods and Results
—We conducted a prospective, nested case-control study in the Cholesterol and Recurrent Events (CARE) trial, a randomized placebo-controlled trial of pravastatin in 4159 patients with myocardial infarction and average LDL concentrations at baseline (115 to 174 mg/dL, mean 139 mg/dL). Baseline concentrations of VLDL–apolipoprotein (apo) B (the VLDL particle concentration), VLDL lipids, and apoCIII and apoE in VLDL+LDL and in HDL were compared in patients who had either a myocardial infarction or coronary death (cases, n=418) with those in patients who did not have a cardiovascular event (control subjects, n=370) in 5 years of follow-up. VLDL-cholesterol, VLDL-triglyceride, VLDL-apoB, apoCIII and apoE in VLDL+LDL and apoE in HDL were all interrelated, and each was a univariate predictor of subsequent coronary events. The significant independent predictors were VLDL-apoB (relative risk [RR] 3.2 for highest to lowest quintiles,
P
=0.04), apoCIII in VLDL+LDL (RR 2.3,
P
=0.04), and apoE in HDL (RR 1.8,
P
=0.02). Plasma triglycerides, a univariate predictor of coronary events (RR 1.6,
P
=0.03), was not related to coronary events (RR 1.3,
P
=0.6) when apoCIII in VLDL+LDL was included in the model, whereas apoCIII remained significant. Adjustment for LDL- and HDL-cholesterol did not affect these results.

Conclusions
—The plasma concentrations of VLDL particles and apoCIII in VLDL and LDL are more specific measures of coronary heart disease risk than plasma triglycerides perhaps because their known metabolic properties link them more closely to atherosclerosis.
Modifications of Cardiac Autonomic Profile Associated With a Shift Schedule of Work
Authors: Furlan Raffaello , Barbic Franca , Piazza Simona , Tinelli Mauro , Seghizzi Paolo , Malliani Alberto
Published: June 2012

Background
—Shift work is associated with an increased rate of cardiovascular diseases and accidents. Discordance between circadian rhythms of stress-related biological variables and the work-sleep schedule might explain the reduced efficiency of work. It is not clear whether a shift schedule of work may induce similar discordance in the 24-hour oscillatory pattern of the cardiac autonomic control in respect to the work-sleep periods.

Methods and Results
—Twenty-two healthy male blue-collar shift workers underwent 24-hour ECG recordings during each of the 3 different shifts (first, 6
am
to 2
pm
; second, 2 to 10
pm
; third, 10
pm
to 6
am
). Spectral analysis of heart rate variability over 24 hours provided the normalized markers of cardiac sympathetic (LF
nu
) and vagal (HF
nu
) modulation of the sinoatrial node activity and of the sympathovagal balance (LF/HF). LF
nu
and LF/HF exhibited 24-hour oscillations with different times of maximum and minimum in accordance with the working and sleeping periods, respectively. Lower values of LF
nu
and LF/HF suggestive of a reduced cardiac sympathetic modulation were present when the job task was performed at night compared with the values observed when the work was performed during morning and evening.

Conclusions
—Continuous weekly changes of time of maximum and minimum in the cardiac sympathetic and vagal autonomic control may play a role in the excessive rate of cardiovascular diseases in shift workers. The reduced values of the indexes of cardiac sympathetic modulation during night work might be related to the presence of sleepiness or diminished alertness, which in turn could facilitate errors and accidents.
Risk Stratification in Patients With Inferior Acute Myocardial Infarction Treated by Percutaneous Coronary Interventions
Authors: Giannitsis Evangelos , Lehrke Stephanie , Wiegand Uwe K. H. , Kurowski Volkhard , Müller-Bardorff Margit , Weidtmann Britta , Richardt Gert , Katus Hugo A.
Published: June 2012

Background
—Cardiac troponin T (cTnT) elevations on admission indicate a high-risk subgroup of patients with ST-segment elevation acute myocardial infarction (AMI). This finding has been attributed to less effective reperfusion after thrombolytic therapy. The aim of this study was to determine the role of admission cTnT on the efficacy of percutaneous coronary interventions (PCIs) in inferior AMI.

Methods and Results
—One hundred fifty-nine consecutive patients with inferior ST-segment AMI were enrolled and followed up for a mean of 448 days. Patients were stratified by cTnT on admission. A cTnT ≥0.1 μg/L was found in 58% of patients. These patients had longer time intervals from onset of symptoms to therapy (
P
<0.001) and higher 30-day (10.8% versus 1.5%,
P
=0.027) and long-term (17.2% versus 4.5%,
P
=0.023) cardiac mortalities. Rates of the combined end point of death, nonfatal reinfarction, and need for repeated target vessel revascularization procedures were not different in cTnT groups (log rank, 0.69;
P
=0.41). PCI was attempted in 93.3% of cTnT-positive and 98.5% cTnT-negative patients (
P
=0.24) but was less frequently successful in patients with cTnT ≥0.1 μg/L (77.9% versus 96.9%,
P
<0.001). Coronary stenting reduced 30-day and long-term cardiac mortality, particularly among cTnT-positive patients. In a multivariate analysis, cTnT indicated an ≈5-fold-higher risk (adjusted OR, 4.6; 95% CI, 0.79 to 27.11;
P
=0.089) and was a strong albeit not independent risk predictor.

Conclusions
—In inferior AMI, a positive admission cTnT is associated with lower success rates of direct PCI and higher rates of cardiac events over the short and long term. These patients benefit from coronary stenting.
Electromagnetic Versus Fluoroscopic Mapping of the Inferior Isthmus for Ablation of Typical Atrial Flutter
Authors: Kottkamp Hans , Hügl Burkhardt , Krauss Beate , Wetzel Ulrike , Fleck Anne , Schuler Gerhard , Hindricks Gerhard
Published: June 2012

Background
—Radiofrequency catheter ablation within the tricuspid annulus–inferior caval vein isthmus can cure typical atrial flutter. The target for ablation, nonetheless, is relatively wide, and standard ablation procedures may require significant exposure to radiation.

Methods and Results
—A total of 50 patients (mean age, 58±11 years) with typical atrial flutter were prospectively randomized to receive isthmus ablation using conventional fluoroscopy for catheter navigation (group I, n=24) or electromagnetic mapping (group II, n=26). Complete bidirectional isthmus block was verified with double potential mapping. If complete isthmus block could not be achieved after 20 radiofrequency pulses or 25 minutes of fluoroscopy, the patients were switched to the other group. Eight patients from group I (33%) but only 1 patient from group II (4%) were switched. Overall, complete isthmus block was achieved in 47 of 50 patients (94%). The overall fluoroscopy time, including the placement of the diagnostic catheters, was 22.0±6.3 minutes in group I and 3.9±1.5 minutes in group II (
P
<0.0001). The fluoroscopy time needed for isthmus mapping was 17.7±6.5 minutes in group I and 0.2±0.3 minutes in group II (
P
<0.0001).

Conclusions
—Electromagnetic mapping during the induction of linear lesions for the ablation of atrial flutter permitted a highly significant reduction in exposure to fluoroscopy while maintaining high efficacy, and it allowed the time required for fluoroscopy to be reduced to levels anticipated for diagnostic electrophysiological studies.
Elevated Levels of Plasma C-Reactive Protein Are Associated With Decreased Graft Survival in Cardiac Transplant Recipients
Authors: Eisenberg Marc S. , Chen Hong Jun , Warshofsky Mark K. , Sciacca Robert R. , Wasserman Hal S. , Schwartz Allan , Rabbani LeRoy E.
Published: June 2012

Background
—Inflammation may be involved in the origin of transplant coronary artery disease. We hypothesized that plasma levels of C-reactive protein (CRP) and interleukin-6 (IL-6), markers for systemic inflammation, would correlate with cardiac transplant graft survival.

Methods and Results
—We studied 99 consecutive cardiac transplant recipients who were referred for routine endomyocardial biopsy and/or surveillance coronary angiography. Plasma levels of CRP and IL-6 were measured by their respective ELISAs. Patients were divided into 2 groups: those who died or required retransplantation and those who survived without the need for retransplantation. During the follow-up period of 5.0±2.7 years (range, 0.2 to 15.1 years) after transplant, 20 patients died and 9 required retransplantation. There was no significant difference in age, race, sex, cause of native myopathy, presence of diabetes, or use of aspirin, statins, or calcium channel blockers between the 2 groups. Although IL-6 did not relate to graft failure, CRP level was predictive of allograft failure (
P
=0.003). The risk of allograft failure increased 36% for every 2-fold increase in CRP level. Moreover, CRP levels also correlated significantly with the frequency of grade 3 rejection (
P
=0.02). In multivariate analysis, when combined with other significant predictors such as donor age and sex mismatching of the graft, CRP still significantly predicted graft failure (
P
=0.025) with a 32% increase in the risk of graft failure for every 2-fold increase in CRP level.

Conclusions
—These findings suggest that elevated plasma levels of CRP are associated with subsequent allograft failure in cardiac transplant recipients.
Chronic α-Adrenergic Receptor Stimulation Modulates the Contractile Phenotype of Cardiac Myocytes In Vitro
Authors: Satoh Naoya , Suter Thomas M. , Liao Ronglih , Colucci Wilson S.
Published: June 2012

Background
—Heart failure is characterized by contractile dysfunction of the myocardium and elevated sympathetic activity. We tested the hypothesis that chronic α-adrenergic (α-ADR) stimulation modifies the molecular and contractile phenotype of cardiac myocytes.

Methods and Results
—Adult rat ventricular myocytes in culture were exposed to α-ADR stimulation (norepinephrine + propranolol) for 48 hours. α-ADR stimulation decreased the mRNAs for sarcoplasmic reticulum Ca
2+
-ATPase and Ca
2+
release channel by 56% and 52%, respectively, and increased mRNA and protein for the Na
+
-Ca
2+
exchanger by 70% and 39%, respectively. After washout of the α-ADR agonist, simultaneous measurement of [Ca
2+
]
i
transients with fura 2 and myocyte shortening by video edge-detection showed that [Ca
2+
]
i
amplitude and myocyte shortening were decreased in α-ADR–treated myocytes, and the time to peak and time from peak to 80% decline of both [Ca
2+
]
i
and myocyte shortening were increased. The concentration-response curve for myocyte shortening by the Na
+
channel activator veratridine was shifted leftward in α-ADR–stimulated myocytes (EC
50
, 21.6±4.6 versus 105.8±10.5 nmol/L,
P
<0.001).

Conclusions
—Chronic α-ADR stimulation of cardiac myocytes causes decreases in the expression of sarcoplasmic reticulum Ca
2+
-ATPase and the Ca
2+
release channel that are associated with decreases in [Ca
2+
]
i
and contractility. α-ADR stimulation simultaneously increases Na
+
-Ca
2+
exchanger expression, thereby increasing sensitivity to intracellular Na
+
.
Intravascular Adenovirus-Mediated VEGF-C Gene Transfer Reduces Neointima Formation in Balloon-Denuded Rabbit Aorta
Authors: Hiltunen Mikko O. , Laitinen Marja , Turunen Mikko P. , Jeltsch Michael , Hartikainen Juha , Rissanen Tuomas T. , Laukkanen Johanna , Niemi Mari , Kossila Maija , Häkkinen Tomi P. , Kivelä Antti , Enholm Berndt , Mansukoski Hannu , Turunen Anna-Mari , Alitalo Kari , Ylä-Herttuala Seppo
Published: June 2012

Background
—Gene transfer to the vessel wall may provide new possibilities for the treatment of vascular disorders, such as postangioplasty restenosis. In this study, we analyzed the effects of adenovirus-mediated vascular endothelial growth factor (VEGF)-C gene transfer on neointima formation after endothelial denudation in rabbits. For comparison, a second group was treated with VEGF-A adenovirus and a third group with
lacZ
adenovirus. Clinical-grade adenoviruses were used for the study.

Methods and Results
—Aortas of cholesterol-fed New Zealand White rabbits were balloon-denuded, and gene transfer was performed 3 days later. Animals were euthanized 2 and 4 weeks after the gene transfer, and intima/media ratio (I/M), histology, and cell proliferation were analyzed. Two weeks after the gene transfer, I/M in the
lacZ
-transfected control group was 0.57±0.04. VEGF-C gene transfer reduced I/M to 0.38±0.02 (
P
<0.05 versus
lacZ
group). I/M in VEGF-A–treated animals was 0.49±0.17 (
P
=NS). The tendency that both VEGF groups had smaller I/M persisted at the 4-week time point, when the
lacZ
group had an I/M of 0.73±0.16, the VEGF-C group 0.44±0.14, and the VEGF-A group 0.63±0.21 (
P
=NS). Expression of VEGF receptors 1, 2, and 3 was detected in the vessel wall by immunocytochemistry and in situ hybridization. As an additional control, the effect of adenovirus on cell proliferation was analyzed by performing gene transfer to intact aorta without endothelial denudation. No differences were seen in smooth muscle cell proliferation or I/M between
lacZ
adenovirus and 0.9% saline–treated animals.

Conclusions
—Adenovirus-mediated VEGF-C gene transfer may be useful for the treatment of postangioplasty restenosis and vessel wall thickening after vascular manipulations.
Alcohol Consumption Raises HDL Cholesterol Levels by Increasing the Transport Rate of Apolipoproteins A-I and A-II
Authors: De Oliveira e Silva Elizabeth R. , Foster David , McGee Harper Monnie , Seidman Cynthia E. , Smith Jonathan D. , Breslow Jan L. , Brinton Eliot A.
Published: June 2012

Background
—Moderate alcohol intake is associated with lower atherosclerosis risk, presumably due to increased HDL cholesterol (HDL-C) concentrations; however, the metabolic mechanisms of this increase are poorly understood.

Methods and Results
—We tested the hypothesis that ethanol increases HDL-C by raising transport rates (TRs) of the major HDL apolipoproteins apoA-I and -II. We measured the turnover of these apolipoproteins in vivo in paired studies with and without alcohol consumption in 14 subjects. The fractional catabolic rate (FCR) and TR of radiolabeled apoA-I and -II were determined in the last 2 weeks of a 4-week Western-type metabolic diet, without (control) or with alcohol in isocaloric exchange for carbohydrates. Alcohol was given as vodka in fixed amounts ranging from 0.20 to 0.81 g · kg
−1
· d
−1
(mean±SD 0.45±0.19) to reflect the usual daily intake of each subject. HDL-C concentrations increased 18% with alcohol compared with the control (Wilcoxon matched-pairs test,
P
=0.002). The apoA-I concentrations increased by 10% (
P
=0.048) and apoA-II concentrations increased by 17% (
P
=0.005) due to higher apoA-I and -II TRs, respectively, whereas the FCR of both apoA-I and -II did not change. The amount of alcohol consumed correlated with the degree of increase in HDL-C (Pearson’s
r
=0.66,
P
=0.01) and apoA-I TR (
r
=0.57,
P
=0.03). The increase in HDL-C also correlated with the increase in apoA-I TR (
r
=0.61,
P
=0.02).

Conclusions
—Alcohol intake increases HDL-C in a dose-dependent fashion, associated with and possibly caused by an increase in the TR of HDL apolipoproteins apoA-I and -II.
Oral Glycoprotein IIb/IIIa Inhibition With Orbofiban in Patients With Unstable Coronary Syndromes (OPUS-TIMI 16) Trial
Authors: Cannon Christopher P. , McCabe Carolyn H. , Wilcox Robert G. , Langer Anatoly , Caspi Abraham , Berink Peter , Lopez-Sendon Jose , Toman Jiri , Charlesworth Andrew , Anders Robert J. , Alexander John C. , Skene Allan , Braunwald Eugene
Published: June 2012

Background
—Although intravenous glycoprotein IIb/IIIa inhibitors are beneficial in patients with acute coronary syndromes, prolonged oral IIb/IIIa inhibition might provide an additional reduction in recurrent events.

Methods and Results
—Investigators at 888 hospitals in 29 countries enrolled 10 288 patients with acute coronary syndromes, which was defined as ischemic pain at rest within 72 hours of randomization, associated with positive cardiac markers, electrocardiographic changes, or prior cardiovascular disease. Patients received aspirin and were randomized to receive, for the duration of the trial, (1) 50 mg of orbofiban twice daily (50/50 group), (2) 50 mg of orbofiban twice daily for 30 days followed by 30 mg of orbofiban twice daily (50/30 group), or (3) a placebo. The primary composite end point was death, myocardial infarction, recurrent ischemia requiring rehospitalization, urgent revascularization, or stroke. The trial was terminated prematurely because of an unexpected increase in 30-day mortality in the 50/30 orbofiban group. Mortality through 10 months was 3.7% for the placebo group versus 5.1% in the 50/30 group (
P
=0.008) and 4.5% in the 50/50 group (
P
=0.11). There were no differences in the primary end point (22.9%, 23.1%, and 22.8%, for the placebo, 50/30, and 50/50 groups, respectively). Major or severe bleeding (but not intracranial hemorrhage) was higher with orbofiban; it occurred in 2.0%, 3.7% (
P
=0.0004), and 4.5% (
P
<0.0001) of patients, respectively. Exploratory subgroup analyses found that patients who underwent percutaneous coronary intervention had a lower mortality and a significant reduction in the composite end point (
P
=0.001) with orbofiban.

Conclusions
—Fixed-dose orbofiban failed to reduce major cardiovascular events and was associated with increased mortality in this broad population of patients with acute coronary syndromes; however, a benefit was observed among patients who underwent percutaneous coronary intervention.
Low-Density Lipoprotein Postsecretory Modification, Monocyte Function, and Circulating Adhesion Molecules in Type 2 Diabetic Patients With and Without Macrovascular Complications
Authors: Devaraj S. , Jialal I.
Published: June 2012

Background
—Although diabetes confers an increased propensity toward accelerated atherogenesis, data are lacking on monocyte activity in type 2 diabetic patients with (DM2-MV) and without (DM2) macrovascular disease compared with control subjects. Thus, we tested whether (1) postsecretory modifications of LDL (glycation and oxidation), monocyte proatherogenic activity, and circulating levels of soluble cell adhesion molecules (sCAMs) are more pronounced in DM2-MV than in DM2 and control subjects and (2) RRR-α-tocopherol (AT) therapy, 1200 IU/d for 3 months, has a similar effect in the 3 groups (n=25 per group).

Methods and Results
—Although LDL glycation was increased in both diabetic groups compared with control subjects, AT therapy had no significant effect on glycation. AT therapy significantly decreased LDL oxidizability in all 3 groups. Diabetic monocytes released significantly more superoxide anion (O
2
−
) and interleukin-1β (IL-1β) and exhibited greater adhesion to endothelium than control subjects. AT therapy significantly decreased the release of O
2
−
, IL-1β, tumor necrosis factor-α, and monocyte-endothelium adhesion in all 3 groups. There was no significant difference between the 2 diabetic groups for any of the above parameters. sICAM levels were significantly elevated in both diabetic groups compared with controls. AT therapy resulted in a significant decrease in sCAMs.

Conclusions
—This is the first demonstration of increased IL-1β secretion and increased adhesion of monocytes to endothelium from normotriglyceridemic diabetic subjects and of decreased monocyte activity and sCAMs with AT therapy in diabetic subjects with and without macrovasculopathy.
Independent Prognostic Value of Cardiac Troponin T in Patients With Confirmed Pulmonary Embolism
Authors: Giannitsis Evangelos , Müller-Bardorff Margit , Kurowski Volkhard , Weidtmann Britta , Wiegand Uwe , Kampmann Markus , Katus Hugo A.
Published: June 2012

Background
—Cardiac troponin T (cTnT) is a sensitive and specific marker, allowing the detection of even minor myocardial cell injury. In patients with severe pulmonary embolism (PE), myocardial ischemia may lead to progressive right ventricular dysfunction. It was therefore the purpose of this study to test the presence of cTnT and its prognostic implications in patients with confirmed PE.

Methods and Results
—Fifty-six consecutive patients with confirmed PE were enrolled in this prospective study. PE was confirmed by pulmonary angiography, lung scan, or echocardiography and subsidiary analyses. Severity of PE was assessed by a clinical scoring system, and cTnT was measured within 12 hours after admission. cTnT was elevated (≥0.1 μg/L) in 18 (32%) patients with massive and moderate PE but not in patients with small PE. In-hospital death (odds ratio 29.6, 95% CI 3.3 to 265.3), prolonged hypotension and cardiogenic shock (odds ratio 11.4, 95% CI 2.1 to 63.4), and need for resuscitation (odds ratio 18.0, 95% CI 2.6 to 124.3) were more prevalent in patients with elevated cTnT. cTnT-positive patients more often needed inotropic support (odds ratio 37.6, 95% CI 5.8 to 245.6) and mechanical ventilation (odds ratio 78.8, 95% CI 9.5 to 653.2). After adjustment, cTnT remained an independent predictor of 30-day mortality (odds ratio 15.2, 95% CI 1.22 to 190.4).

Conclusions
—cTnT may improve risk stratification in patients with PE and may aid in the identification of patients in whom a more aggressive therapy may be warranted.
Effects of Digoxin on Acute, Atrial Fibrillation–Induced Changes in Atrial Refractoriness
Authors: Sticherling Christian , Oral Hakan , Horrocks Julie , Chough Steven P. , Baker Robert L. , Kim Michael H. , Wasmer Kristina , Pelosi Frank , Knight Bradley P. , Michaud Gregory F. , Strickberger S. Adam , Morady Fred
Published: June 2012

Background
—Atrial fibrillation (AF) shortens the atrial effective refractory period (ERP) and predisposes to further episodes of AF. The acute changes in atrial refractoriness may be related to tachycardia-induced intracellular calcium overload. The purpose of this study was to determine whether digoxin, which increases intracellular calcium, potentiates the acute effects of AF on atrial refractoriness in humans.

Methods and Results
—In 38 healthy adults, atrial ERP was measured at basic drive cycle lengths (BDCLs) of 350 and 500 ms after autonomic blockade. Nineteen patients had been treated with digoxin for 2 weeks. After a several-minute episode of AF, atrial ERP was measured serially at alternating BDCLs. Compared with pre-AF ERPs, the first post-AF ERPs were significantly shorter in both the digoxin and the control groups (
P
<0.001). The post-AF ERP at a BDCL of 350 ms shortened to a greater degree in the digoxin group (37±16 ms) than in the control group (20±13 ms,
P
<0.001); similar changes occurred at a BDCL of 500 ms. During post-AF determinations of the atrial ERP, secondary AF episodes occurred significantly more often in the digoxin group (32% versus 16%;
P
<0.04).

Conclusions
—After a brief episode of AF, digoxin augments the shortening that occurs in atrial refractoriness and predisposes to the reinduction of AF. These effects occur in the setting of autonomic blockade and therefore are more likely to be due to the effects of digoxin on intracellular calcium than to its vagotonic effects.
Hypoxia/Reoxygenation Stimulates Intracellular Calcium Oscillations in Human Aortic Endothelial Cells
Authors: Hu Qinghua , Ziegelstein Roy C.
Published: June 2012

Background
—We have previously shown that hydrogen peroxide stimulates endothelial [Ca
2+
]
i
oscillations. This study was performed to determine whether posthypoxic reoxygenation stimulates [Ca
2+
]
i
oscillations in vascular endothelial cells.

Methods and Results
—Hypoxia (glucose-free 95% N
2
/5% CO
2
bicarbonate buffer for 60 minutes) stimulated an increase in [Ca
2+
]
i
from 111.9±7.9 to 161.7±17.7 nmol/L (n=12,
P
<0.01) in indo 1–loaded human aortic endothelial cells. On reoxygenation (glucose-containing 95% air/5% CO
2
bicarbonate buffer), 13 of 16 cells responded with repetitive [Ca
2+
]
i
oscillations with an average amplitude of 570.6±59.3 nmol/L, occurring at a mean interval of 0.28±0.04/min and persisting for ≥60 minutes. [Ca
2+
]
i
oscillations were still observed in 4 of 7 cells studied in Ca
2+
-free buffer but did not occur when the intracellular Ca
2+
store was first depleted during hypoxia by either 1 μmol/L thapsigargin or by 10 mmol/L caffeine (n=6 for each). Reoxygenation-induced [Ca
2+
]
i
oscillations were abolished by 10 μmol/L diphenyleneiodonium, an inhibitor of NAD(P)H oxidase (n=7), and by polyethylene glycol (PEG)–catalase (5000 U/mL, n=4) but were not prevented by inhibitors of xanthine oxidase (n=5), cyclooxygenase (n=4), nitric oxide synthase (n=5), the mitochondrial electron transport chain (n=4), or by PEG–superoxide dismutase (n=5).

Conclusions
—Posthypoxic reoxygenation stimulates repetitive [Ca
2+
]
i
oscillations that are dependent on Ca
2+
release from an intracellular pool and require extracellular Ca
2+
to be maintained. These oscillations may be initiated by NAD(P)H oxidase–derived hydrogen peroxide and may play a role in signal transduction during ischemia/reperfusion in vivo.
Efficacy and Safety of an Irrigated-Tip Catheter for the Ablation of Accessory Pathways Resistant to Conventional Radiofrequency Ablation
Authors: Yamane Teiichi , Jaïs Pierre , Shah Dipen C. , Hocini Mélèze , Peng Jing Tian , Deisenhofer Isabel , Clémenty Jacques , Haïssaguerre Michel
Published: June 2012

Background
—Radiofrequency catheter ablation of accessory pathways (APs) is very effective in all but a minority of patients. We examined the usefulness and safety of irrigated-tip catheters in treating patients with APs resistant to conventional catheter ablation.

Methods and Results
—Among 314 APs in 301 consecutive patients, conventional ablation failed to eliminate AP conduction in 18 APs in 18 patients (5.7%), 6 of which were located in the left free wall, 5 in the middle/posterior-septal space, and 7 inside the coronary sinus (CS) or its tributaries. Irrigated-tip catheter ablation was subsequently performed with temperature control mode (target temperature, 50°C), a moderate saline flow rate (17 mL/min), and a power limit of 50 W (outside CS) or 20 to 30 W (inside CS) at previously resistant sites. Seventeen of the 18 resistant APs (94%) were successfully ablated with a median of 3 applications using irrigated-tip catheters. A significant increase in power delivery was achieved (20.3±11.5 versus 36.5±8.2 W;
P
<0.01) with irrigated-tip catheters, irrespective of the AP location, particularly inside the CS or its tributaries. No serious complications occurred.

Conclusions
—Irrigated-tip catheter ablation is safe and effective in eliminating AP conduction resistant to conventional catheters, irrespective of the location.
Effects of a Residential Exercise Training on Baroreflex Sensitivity and Heart Rate Variability in Patients With Coronary Artery Disease
Authors: Iellamo Ferdinando , Legramante Jacopo M. , Massaro Michele , Raimondi Gianfranco , Galante Alberto
Published: June 2012

Background
—Myocardial ischemia and infarction impair baroreflex sensitivity (BRS), which when depressed is predictive of future cardiac events after myocardial infarction (MI). The main objective of this study was to determine whether exercise training improves BRS in patients with coronary artery disease.

Methods and Results
—Ninety-seven male patients with and without a previous MI were recruited after myocardial revascularization surgery and randomized into trained (TR) or untrained (UTR) groups. TR patients underwent a residential exercise program at 85% of maximum heart rate (HRmax) consisting of 2 daily sessions 6 times a week for 2 weeks. Eighty-six patients (45 TR and 41 UTR) completed the study. BRS was assessed at baseline and at the end of the protocol by the spontaneous baroreflex method. The standard deviation of mean R-R interval (RRSD) was also assessed as a measure of heart rate variability. At baseline, there were no significant differences between TR and UTR patients in any variable. In TR patients, BRS increased from 3.0±0.3 to 5.3±0.7 ms/mm Hg (
P
<0.001), RRSD from 18.7±1.4 to 23.6±1.6 ms (
P
<0.01), and R-R interval from 792.0±15.5 to 851.3±20.5 ms (
P
<0.001). No significant changes occurred in UTR patients. Increases in BRS and RRSD were significant in patients either with or without a previous MI.

Conclusions
—Exercise training increases BRS and heart rate variability in patients with coronary artery disease. Improved cardiac autonomic function might add to the other benefits of exercise training in secondary prevention of ischemic heart disease.
Circumferential Radiofrequency Ablation of Pulmonary Vein Ostia
Authors: Pappone Carlo , Rosanio Salvatore , Oreto Giuseppe , Tocchi Monica , Gugliotta Filippo , Vicedomini Gabriele , Salvati Adriano , Dicandia Cosimo , Mazzone Patrizio , Santinelli Vincenzo , Gulletta Simone , Chierchia Sergio
Published: June 2012

Background
—The pulmonary veins (PVs) and surrounding ostial areas frequently house focal triggers or reentrant circuits critical to the genesis of atrial fibrillation (AF). We developed an anatomic approach aimed at isolating each PV from the left atrium (LA) by circumferential radiofrequency (RF) lesions around their ostia.

Methods and Results
—We selected 26 patients with resistant AF, either paroxysmal (n=14) or permanent (n=12). A nonfluoroscopic mapping system was used to generate 3D electroanatomic LA maps and deliver RF energy. Two maps were acquired during coronary sinus and right atrial pacing to validate the lateral and septal PV lesions, respectively. Patients were followed up closely for ≥6 months. Procedures lasted 290±58 minutes, including 80±22 minutes for acquisition of all maps, and 118±16 RF pulses were deployed. Among 14 patients in AF at the beginning of the procedure, 64% had sinus rhythm restoration during ablation. PV isolation was demonstrated in 76% of 104 PVs treated by low peak-to-peak electrogram amplitude (0.08±0.02 mV) inside the circular line and by disparity in activation times (58±11 ms) across the lesion. After 9±3 months, 22 patients (85%) were AF-free, including 62% not taking and 23% taking antiarrhythmic drugs, with no difference (
P
=NS) between paroxysmal and permanent AF. No thromboembolic events or PV stenoses were observed by transesophageal echocardiography.

Conclusions
—Radiofrequency PV isolation with electroanatomic guidance is safe and effective in either paroxysmal or permanent AF.