bluuebunny/crossref_metadata_2025 huggingface dataset:
Catheter Stimulation of Cardiac Parasympathetic Nerves in Humans
Authors: Schauerte Patrick , Mischke Karl , Plisiene Jurgita , Waldmann Matthias , Zarse Markus , Stellbrink Christoph , Schimpf Thomas , Knackstedt Christian , Sinha Anil , Hanrath Peter
Published: September 2007

Background

Cardiac parasympathetic nerves run alongside the superior vena cava (SVC) and accumulate particularly epicardially adjacent to the orifice of the coronary sinus (CS). In animals, these nerves can be electrically stimulated inside the SVC or CS, which results in negative chronotropic/dromotropic effects and negative inotropic effects in the atria but not the ventricles. Parasympathetic nerve stimulation (PS) with 20 Hz in the CS, however, also excites the atria, thereby inducing atrial fibrillation. The present study overcomes this limitation by applying high-frequency nerve stimuli within the atrial refractory period. Using this technique, we investigated for the first time whether neurophysiological effects similar to those in animals can be obtained in humans.

Methods and Results

In 25 patients, parasympathetic nerves were stimulated via a multipolar electrode catheter placed in the SVC (stimulation with 20 Hz; n=14) or CS (pulsed 200-Hz stimuli; n=11). A significant sinus rate decrease and prolongation of the antegrade Wenckebach period was achieved during PS in the SVC. During PS in the CS, a graded-response prolongation of the antegrade Wenckebach interval was observed with increasing PS voltage until third-degree AV block occurred in 8 of 11 patients. The negative chronotropic/dromotropic effects started and terminated immediately after the onset and termination of PS, respectively. Atropine abolished these effects (n=11).

Conclusions

Human parasympathetic efferent nerve stimulation induces reversible negative chronotropic and dromotropic effects. PS may serve as an adjunctive tool for the diagnosis/treatment of supraventricular tachycardias and may be beneficial for ventricular rate slowing during tachycardic atrial fibrillation in patients with congestive heart failure.
Impact of Atrial Fibrillation on the Clinical Course of Hypertrophic Cardiomyopathy
Authors: Olivotto Iacopo , Cecchi Franco , Casey Susan A. , Dolara Alberto , Traverse Jay H. , Maron Barry J.
Published: September 2007

Background

Clinical impact of atrial fibrillation (AF) in hypertrophic cardiomyopathy (HCM) is largely unresolved. Thus, we analyzed the prognostic implications of AF in a large, community-based HCM population assembled from Italian and US cohorts.

Methods and Results

Occurrence of AF and outcome were assessed in 480 consecutive HCM patients (age at diagnosis, 45±20 years; 61% male) who were followed up for 9.1±6.4 years. AF occurred in 107 patients (22%; incidence, 2%/y) and was independently predicted by advancing age, congestive symptoms, and increased LA size at diagnosis. Patients with AF had increased risk for HCM-related death (OR, 3.7;
P
<0.002) because of excess heart failure–related mortality but not sudden, unexpected death. This risk associated with AF was substantially greater in patients with outflow obstruction or with earlier development of AF (≤50 years of age). AF patients were also at increased risk for stroke (OR, 17.7;
P
=0.0001) and severe functional limitation (OR for NYHA class III or IV, 2.8;
P
<0.0001). Compared with those with exclusively paroxysmal AF, patients developing chronic AF showed higher combined probability of HCM-related death, functional impairment, and stroke (
P
<0.0001). In a subgroup of 37 patients with AF (35%), the clinical course was largely benign in the absence of stroke and severe symptoms.

Conclusions

In a community-based HCM population, AF (1) was common, with 22% prevalence over 9 years; (2) was associated with substantial risk for heart failure–related mortality, stroke, and severe functional disability, particularly in patients with outflow obstruction, those ≤50 years of age, or those developing chronic AF; and (3) was nevertheless compatible with benign outcome in 35% of patients.
Transplant Coronary Artery Disease
Authors: Cantin Bernard , Wen Peizhong , Zhu Dening , Dai Michelle , Panchal Shyam N. , Billingham Margaret E. , Gwathmey Judith K. , Valantine Hannah A.
Published: September 2007

Background

Allograft coronary atherosclerosis (TxCAD) is the leading cause of death after the first year after transplantation. TxCAD is believed to be a form of chronic rejection of the cardiac allografts. This study was undertaken to determine whether TxCAD could develop in the absence of a cellular alloimmune response.

Methods and Results

Inbred lean Zucker rats (>26 generations) served as donors and recipients of the cardiac grafts. Donor hearts were explanted at 60 or 90 days. Explanted hearts were processed for coronary artery histological analysis. Cytokine expression was determined by reverse transcription–polymerase chain reaction, and the presence of T cells within the explanted hearts was evaluated by immunohistochemistry. Forty-six transplantations were made, and TxCAD developed in all but one of the transplanted hearts. Overall, one third of the vessels examined were affected by TxCAD, and in roughly half of these vessels, the disease was severe. Native hearts were free of atherosclerosis. Interleukin-2 was absent from the transplanted hearts, and T cells were present in minimal amounts (<1 per low-power field).

Conclusions

TxCAD developed in the absence of a cellular alloimmune response in these genetically similar donors and recipients. The observed TxCAD was significant and comparable to what is found in rat allografting models.
In Vivo Myocardial Protection From Ischemia/Reperfusion Injury by the Peroxisome Proliferator–Activated Receptor-γ Agonist Rosiglitazone
Authors: Yue Tian-li , Chen Jun , Bao Weike , Narayanan Padma K. , Bril Antoine , Jiang Wen , Lysko Paul G. , Gu Juan-Li , Boyce Rogely , Zimmerman Dawn M. , Hart Timothy K. , Buckingham Robin E. , Ohlstein Eliot H.
Published: September 2007

BackgroundDiabetes is associated with increased risk of mortality as a consequence of acute myocardial infarction. This study determined whether rosiglitazone (ROSI) could reduce myocardial infarction after ischemia/reperfusion injury.

Methods and ResultsMale Lewis rats were anesthetized, and the left anterior descending coronary artery was ligated for 30 minutes. After reperfusion for 24 hours, the ischemic and infarct sizes were determined. ROSI at 1 and 3 mg/kg IV reduced infarct size by 30% and 37%, respectively (P<0.01 versus vehicle). Pretreatment with ROSI (3 mg · kg−1· d−1PO) for 7 days also reduced infarct size by 24% (P<0.01). ROSI also improved ischemia/reperfusion-induced myocardial contractile dysfunction. Left ventricular systolic pressure and positive and negative maximal values of the first derivative of left ventricular pressure (dP/dt) were significantly improved in ROSI-treated rats. ROSI reduced the accumulation of neutrophils and macrophages in the ischemic heart by 40% and 43%, respectively (P<0.01). Ischemia/reperfusion induced upregulation of CD11b/CD18 and downregulation of L-selectin on neutrophils and monocytes; these effects were significantly attenuated in ROSI-treated animals. Likewise, intercellular adhesion molecule-1 expression in ischemic hearts was markedly diminished by ROSI, as was the ischemia/reperfusion-stimulated upregulation of monocyte chemoattractant protein-1.

ConclusionsROSI reduced myocardial infarction and improved contractile dysfunction caused by ischemia/reperfusion injury. The cardioprotective effect of ROSI was most likely due to inhibition of the inflammatory response.
Transvenous Biventricular Defibrillation Halves Energy Requirements in Patients
Authors: Butter Christian , Meisel Eckhard , Tebbenjohanns Juergen , Engelmann Lothar , Fleck Eckart , Schubert Bernd , Hahn Stephen , Pfeiffer Dietrich
Published: September 2007

Background

Defibrillation thresholds (DFT) with standard implantable cardioverter-defibrillator leads in the right ventricle (RV) may be determined by weak shock field intensity in the myocardium of the left ventricle (LV). Adding a shocking electrode in a coronary vein on the middle of the LV free wall, thereby establishing biventricular defibrillation, substantially reduced defibrillation requirements in animals. We investigated the feasibility of this approach in 24 patients receiving an implantable cardioverter-defibrillator using a prototype over-the-wire temporary LV defibrillation lead.

Methods and Results

The LV lead was inserted through the coronary sinus, using a guide catheter and guidewire, into a posterior or lateral coronary vein whose location was determined by retrograde venography. Paired DFT testing compared a standard system (RV to superior vena cava plus can emulator [SVC+Can], 60% tilt biphasic shock) to a system including the LV lead. The biventricular system was tested with a dual-shock waveform (20% tilt monophasic shock from LV→SVC+Can, then 60% tilt biphasic shock from RV→SVC+Can). Twenty patients completed DFT testing. Venography and LV lead insertion time was 46±40 minutes. The biventricular system reduced mean DFT by 45% (8.9±1.1 J versus 4.9±0.5 J,
P
<0.001). Twelve patients (60%) had a standard system DFT ≥8 J, and the biventricular system gave a lower DFT in all patients. There were no adverse events related to the use of the LV lead, which was removed after testing.

Conclusions

Internal defibrillation using a transvenously inserted LV lead is feasible, produces significantly lower DFTs, and seems safe under the conditions tested. Biventricular defibrillation may be a useful option for reducing DFTs or could be added to an LV pacing lead for heart failure.
Ionic Mechanism of Delayed Afterdepolarizations in Ventricular Cells Isolated From Human End-Stage Failing Hearts
Authors: Verkerk Arie O. , Veldkamp Marieke W. , Baartscheer Antonius , Schumacher Cees A. , Klöpping Corinne , van Ginneken Antoni C.G. , Ravesloot Jan H.
Published: September 2007

Background

Animal studies have shown that the Ca
2+
-activated Cl
−
current (
I
Cl(Ca)
) and the Na
+
/Ca
2+
exchange current (
I
Na/Ca
) contribute to the transient inward current (
I
ti
).
I
ti
is responsible for the proarrhythmic delayed afterdepolarizations (DADs). We investigated the ionic mechanism of
I
ti
and DADs in human cardiac cells.

Methods and Results

Human ventricular cells were enzymatically isolated from explanted hearts of patients with end-stage heart failure and studied with patch-clamp methodology.
I
ti
s were elicited in the presence of 1 μmol/L norepinephrine by trains of repetitive depolarizations from −80 to +50 mV. DADs were induced in the presence of 1 μmol/L norepinephrine at a stimulus frequency of 1 Hz.
I
ti
currents were inwardly directed over the voltage range between −110 and + 50 mV. Neither the Cl
−
channel blocker 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid nor changes in [Cl
−
]
i
affected
I
ti
or DAD amplitude. This excludes an important role for
I
Cl(Ca)
. Blockade of Na
+
/Ca
2+
exchange by substitution of all extracellular Na
+
by Li
+
, conversely, completely inhibited
I
ti
. In rabbit,
I
Cl(Ca)
density in ventricular cells isolated from control hearts did not differ significantly from that in ventricular cells isolated from failing hearts.

Conclusions

In contrast to many animal species,
I
ti
and DADs in human ventricular cells from failing hearts consist only of
I
Na/Ca
. In rabbits, heart failure per se does not alter
I
Cl(Ca)
density, suggesting that
I
Cl(Ca)
may also be absent during DADs in nonfailing human ventricular cells.
β-Blockers Before Percutaneous Coronary Intervention Do Not Attenuate Postprocedural Creatine Kinase Isoenzyme Rise
Authors: Ellis Stephen G. , Brener Sorin J. , Lincoff A. Michael , Moliterno David J. , Whitlow Patrick L. , Schneider Jakob P. , Topol Eric J.
Published: September 2007

Background

β-blocker (BB) use reduces infarct size in spontaneously occurring nonreperfused infarcts but probably does not change infarct size in patients treated with reperfusion therapy. A recent observational study suggested that BB use concurrent with percutaneous coronary intervention (PCI) decreased the risk of creatine kinase (CK)-MB elevation. The cogency of such a conclusion is dependent on the ability to risk-adjust for the multiple differences in patients treated with and without BBs.

Methods and Results

Using propensity score and multivariate regression analyses, 6200 consecutive patients were analyzed to assess the relationship between BB use before PCI and per protocol-measured CK and CK-MB rise. There were several highly significant (
P
<0.001) differences between patients with and without BB treatment (eg, age, prior infarction, unstable angina). Maximum CK and CK-MB levels were higher in patients taking BBs (CK median, 95 U [interquartile range: 61, 175]; CK-MB, 3 U [2, 5]) than in patients not taking BBs (CK, 91 U [60, 157]; CK-MB, 3 U [2, 4]) (
P
=0.011 and
P
=0.021 for CK and CK-MB, respectively). After adjustment for significant differences in baseline characteristics there was no difference in either maximum CK rise (
P
=0.21) or maximum CK-MB rise (
P
=0.99).

Conclusions

The results of this large observation study do not support the contention that BB use before PCI decreases myocardial injury.
Incidence, Predictors, and Significance of Abnormal Cardiac Enzyme Rise in Patients Treated With Bypass Surgery in the Arterial Revascularization Therapies Study (ARTS)
Authors: Costa Marco A. , Carere Ronald G. , Lichtenstein Samuel V. , Foley David P. , de Valk Vincent , Lindenboom Wietze , Roose Paul C.H. , van Geldorp Theo R. , Macaya Carlos , Castanon José L. , Fernandez-Avilèz Francisco , Gonzáles Jesús Herreros , Heyer Günter , Unger Felix , Serruys Patrick W.
Published: September 2007

Background

Although it has been suggested that elevation of CK-MB after percutaneous coronary intervention is associated with adverse clinical outcomes, limited data are available in the setting of coronary bypass grafting. The aim of the present study was to determine the incidence, predictors, and prognostic significance of CK-MB elevation following multivessel coronary bypass grafting (CABG).

Methods and Results

The population comprises 496 patients with multivessel coronary disease assigned to CABG in the Arterial Revascularization Therapies Study (ARTS). CK-MB was prospectively measured at 6, 12, and 18 hours after the procedure. Thirty-day and 1-year clinical follow-up were performed. Abnormal CK-MB elevation occurred in 61.9% of the patients. Patients with increased cardiac-enzyme levels after CABG were at increased risk of both death and repeat myocardial infarction within the first 30 days (
P
=0.001). CK-MB elevation was also independently related to late adverse outcome (
P
=0.009, OR=0.64).

Conclusions

Increased concentrations of CK-MB, which are often dismissed as inconsequential in the setting of multivessel CABG, appear to occur very frequently and are associated with a significant increase in both repeat myocardial infarction and death beyond the immediate perioperative period.
Memories of Patients With a Giant Left Atrium
Authors: Hurst J. Willis
Published: September 2007

This article emphasizes that the abnormalities noted on chest x-ray films of the chest can be diagnostic of giant left atrium. It also points out that a giant left atrium that occasionally occurs in patients with rheumatic mitral valve regurgitation does not occur in patients with mitral regurgitation due to other causes.
Effects of Rapid Atrial Pacing on the Arrhythmogenic Activity of Single Cardiomyocytes From Pulmonary Veins
Authors: Chen Yi-Jen , Chen Shih-Ann , Chen Yao-Chang , Yeh Hung-I , Chan Paul , Chang Mau-Song , Lin Cheng-I
Published: September 2007

Background

Pulmonary veins (PVs) are important sources of paroxysmal atrial fibrillation. Long-term rapid atrial pacing (RAP) changes atrial electrophysiology and facilitates the maintenance of atrial fibrillation. It is not clear whether RAP alters the arrhythmogenic activity of PVs. The purpose of this study was to isolate single PV cardiomyocytes from control and RAP dogs and evaluate their electrophysiological characteristics.

Methods and Results

The action potential and ionic currents were investigated in PV cardiomyocytes from control and long-term (6 to 8 weeks) RAP (780 bpm) dogs by use of the whole-cell clamp technique. Dissociation of PVs yielded rod-shaped single cardiomyocytes without (n=91, 60%) or with (n=60, 40%) pacemaker activity. Compared with the control group, the RAP dog PV cardiomyocytes had faster beating rates (0.86±0.28 versus 0.45±0.07 Hz,
P
<0.05) and shorter action potential duration. The RAP dog PV cardiomyocytes with pacemaker activity have a higher incidence of delayed (59% versus 7%,
P
<0.001) or early (24% versus 0%,
P
<0.005) afterdepolarization. The RAP dog PV cardiomyocytes with pacemaker activity had smaller slow inward and transient outward but larger transient inward (0.017±0.004 versus 0.009±0.002 pA/pF,
P
<0.05) and pacemaker (0.111±0.019 versus 0.028±0.008 pA/pF,
P
<0.001) currents. The RAP dog PV cardiomyocytes without pacemaker activity had only smaller slow inward and transient outward and larger pacemaker currents.

Conclusions

PVs contain multiple cardiomyocytes with distinct electrophysiological characteristics. RAP changes the electrophysiological characteristics and arrhythmogenic activity of PVs.
Antithrombin III Prevents Early Pulmonary Dysfunction After Lung Transplantation in the Dog
Authors: Salvatierra Angel , Guerrero Rafael , Rodriguez Mariano , Alvarez Antonio , Soriano Fuensanta , Lopez-Pedrera Rosario , Ramirez Rafael , Carracedo Julia , Lopez-Rubio Fernando , Lopez-Pujol Javier , Velasco Francisco
Published: September 2007

Background
—

Ischemia-reperfusion injury with the resulting inflammatory response is a devastating complication of lung transplantation; much of the tissue damage could be diminished by control of the inflammatory response. Recent studies have show that antithrombin III (AT III) has an anti-inflammatory effect in addition to its established role in the regulation of blood coagulation. Thus, we hypothesized that the administration of AT III might help to prevent ischemia-reperfusion injury after lung transplantation.

Methods and Results
—

The study was performed in a dog model of orthotopic lung transplantation. Dogs were randomly assigned to receive either vehicle (controls) or AT III. We observed that in control dogs, during the 180-minute period after lung transplantation, the arterial O
2
partial pressure decreased and both the alveolar-arterial O
2
difference and the pulmonary vascular resistance increased. By contrast, these parameters remained unchanged in the group of dogs receiving AT III. Dogs with transplants receiving AT III did not show an increase in cell adhesion molecules, and histological examination revealed almost an absence of inflammatory response. The administration of AT III produced a marked increase in serum prostacyclin (PGI
2
) levels, whereas in control dogs, the PGI
2
levels did not change. The beneficial effect of AT III was not observed when dogs received indomethacin to prevent the stimulation of PGI
2
release by AT III.

Conclusions
—

Our results demonstrate that AT III prevents ischemia-reperfusion injury in a dog model of lung transplantation and that this effect is conditioned by an increase in PGI
2
production.
Protection Against Oxidized Low-Density Lipoprotein–Induced Vascular Endothelial Cell Death by Integrin-Linked Kinase
Authors: Zhang Xiuwu , Hu Kang , Li Chuan-Yuan
Published: September 2007

Background

Integrin-linked kinase (ILK) is a protein that plays important roles in extracellular matrix-mediated signaling. It has been shown that ILK is expressed preferentially in cardiac and skeletal muscles. Evidence points to its role as an upstream regulator of protein kinase B, a critical player in apoptosis. Because oxidized LDL (oxLDL) is thought to promote atherogenesis by causing the apoptosis of endothelial cells, we investigated the potential roles that ILK may play in oxLDL-induced apoptosis in vascular endothelial cells.

Methods and Results

Transcriptional and translational levels of ILK were investigated with reverse-transcriptase polymerase chain reaction and Western analysis. oxLDL treatment induced both the transcription and the translation of the ILK gene in endothelial cells. A recombinant adenovirus vector encoding the ILK gene was constructed to investigate its potential role in oxLDL-induced apoptosis in human umbilical vein endothelial cells and mouse lymphoid vein endothelial cells transformed by simian virus 40. In both types of cells, overexpression of the ILK gene significantly prevented oxLDL-induced apoptosis or cell death, as evaluated by 2 independent assay methods. Furthermore, we showed that ILK could inhibit oxLDL-induced upregulation of the kinase activity of p38 mitogen-activated protein kinase, which is often associated with stress-induced pro-apoptotic signal transduction. Finally, examination of other factors, such as bcl-2, bcl-xl, caspase 3, and caspase 9, demonstrated significant changes that were correlated with oxLDL treatment and ILK overexpression.

Conclusion

ILK may be an important factor involved in the regulation of oxLDL-induced apoptosis in vascular endothelial cells. Modifying its activity may be a useful approach for prevention of endothelial cell injury in oxLDL-induced atherosclerosis.
Myocardial Muscarinic Receptor Upregulation and Normal Response to Isoproterenol in Denervated Hearts by Familial Amyloid Polyneuropathy
Authors: Delahaye Nicolas , Le Guludec Dominique , Dinanian Sylvie , Delforge Jacques , Slama Michel S. , Sarda Laure , Dollé Frédéric , Mzabi Hichem , Samuel Didier , Adams David , Syrota André , Merlet Pascal
Published: September 2007

Background
—

Patients with familial amyloid polyneuropathy, a rare hereditary form of amyloidosis, have progressive autonomic neuropathy. The disease usually does not induce heart failure but is associated with sudden death, conduction disturbances, and an increased risk of complications during anesthesia. Although cardiac sympathetic denervation has been clearly demonstrated, the postsynaptic status of the cardiac autonomic nervous system remains unelucidated.

Methods and Results
—

Twenty-one patients were studied (age, 39±11 years; normal coronary arteries; left ventricular ejection fraction 68±9%). To evaluate the density and affinity constants of myocardial muscarinic receptors, PET with
11
C-MQNB (methylquinuclidinyl benzilate), a specific hydrophilic antagonist, was used. Cardiac β-receptor functional efficiency was studied by the heart rate (HR) response to intravenous infusion of isoproterenol (5 minutes after 2 mg of atropine, 5, 10, and 15 ng/kg per minute during 5 minutes per step). The mean muscarinic receptor density was higher in patients than in control subjects (B′
max
, 35.5±8.9 versus 26.1±6.7 pmol/mL,
P
=0.003), without change in receptor affinity. The increase in HR after injection of atropine as well as of MQNB was lower in patients compared with control subjects despite a similar basal HR (ΔHR after atropine, 11±21% versus 62±17%;
P
<0.001), consistent with parasympathetic denervation. Incremental infusion of isoproterenol induced a similar increase in HR in patients and control subjects.

Conclusions
—

Cardiac autonomic denervation in familial amyloid polyneuropathy results in an upregulation of myocardial muscarinic receptors but without change in cardiac β-receptor responsiveness to catecholamines.
Impaired Endothelial Regulation of Ventricular Relaxation in Cardiac Hypertrophy
Authors: MacCarthy Philip A. , Grieve David J. , Li Jian-Mei , Dunster Christina , Kelly Frank J. , Shah Ajay M.
Published: September 2007

Background
—

Endothelium-derived nitric oxide (NO) selectively enhances myocardial relaxation. In experimental left ventricular hypertrophy (LVH), this endothelium-dependent LV relaxant response is impaired despite a preserved response to exogenous NO. We investigated the potential role of reactive oxygen species (ROS) in this defect.

Methods and Results
—

Short-term treatment with the antioxidants vitamin C (10 μmol/L) or deferoxamine (500 μmol/L) restored LV relaxant responses to the NO agonists bradykinin (10 nmol/L) and substance P (100 nmol/L) in isolated ejecting hearts of aortic-banded guinea pigs. Substance P decreased the time to onset of LV relaxation (tdP/dt
min
) by −6.8±1.7 ms in the presence of vitamin C and by −8.9±2.2 ms in the presence of deferoxamine compared with −0.8±2.2 ms in the absence of antioxidants (
P
<0.05 either antioxidant versus control). A similar restoration of relaxant response to substance P was observed in the presence of the superoxide dismutase mimetic, Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (10 μmol/L), but not with tetrahydrobiopterin or
l
-arginine. Protein expression of the NADPH oxidase subunits gp91-
phox
and p67-
phox
and myocardial NADPH oxidase activity were significantly increased (
P
<0.05) in the banded group compared with shams.

Conclusions
—

An increase in ROS, most likely derived at least in part from NADPH oxidase, is responsible for the impaired endothelial regulation of LV relaxation in LVH. These are the first data to potentially link increased NADPH oxidase-derived ROS with a defect in cardiac contractile function in a pathological setting.
Blood Lipids and First-Ever Ischemic Stroke/Transient Ischemic Attack in the Bezafibrate Infarction Prevention (BIP) Registry
Authors: Tanne David , Koren-Morag Nira , Graff Eran , Goldbourt Uri
Published: September 2007

Background
—

Despite unclear associations between blood lipids, including fractionated cholesterol and triglycerides, and stroke, recent evidence demonstrates that lipid-modifying agents decrease the risk of stroke in patients with coronary heart disease (CHD).

Methods and Results
—

Patients with documented CHD who were screened for but not included in the Bezafibrate Infarction Prevention study and had no history of stroke or transient ischemic attack (TIA) (n=11 177) were followed up. At baseline, medical histories were obtained and blood lipids assessed at a central study laboratory. During a 6- to 8-year follow-up period, 941 patients were identified as having nonhemorrhagic cerebrovascular disease, of whom 487 had verified ischemic stroke (per clinical findings and brain CT) or TIA. Patients experiencing an ischemic stroke/TIA had higher mean levels of triglycerides, lower levels of HDL cholesterol, and lower percentages of cholesterol contained in the HDL cholesterol moiety (%HDL;
P
<0.01 for all). In a logistic regression model, the adjusted ORs for developing an ischemic stroke/TIA were 1.27 (95% CI 1.01 to 1.60) associated with triglycerides >200 mg/dL and 0.87 (95% CI 0.78 to 0.97) associated with a 5% decrease in %HDL. The increased risk associated with high triglycerides was found across subgroups of age, sex, patient characteristics, and cholesterol fractions.

Conclusions
—

High triglycerides constitute an independent risk factor for ischemic stroke/TIA across subgroups of age, sex, patient characteristics, and cholesterol fractions, whereas high %HDL was an independent protective factor among patients with CHD. These findings support the role of blood lipids, including triglycerides, as important modifiable stroke risk factors.
C-Reactive Protein Elevation in Patients With Atrial Arrhythmias
Authors: Chung Mina K. , Martin David O. , Sprecher Dennis , Wazni Oussama , Kanderian Anne , Carnes Cynthia A. , Bauer John A. , Tchou Patrick J. , Niebauer Mark J. , Natale Andrea , Van Wagoner David R.
Published: September 2007

Background

Atrial fibrillation (AF) may persist due to structural changes in the atria that are promoted by inflammation. C-reactive protein (CRP), a marker of systemic inflammation, predicts cardiovascular events and stroke, a common sequela of AF. We hypothesized that CRP is elevated in patients with atrial arrhythmias.

Methods and Results

Using a case-control study design, CRP in 131 patients with atrial arrhythmias was compared with CRP in 71 control patients. Among arrhythmia patients, 6 had frequent atrial ectopy or tachycardia, 86 had paroxysmal AF, 39 had persistent AF lasting >30 days, and 70 had lone arrhythmias. CRP was higher in arrhythmia than in control patients (median, 0.21 versus 0.096 mg/dL;
P
<0.001). Arrhythmia patients in AF within 24 hours before sampling had higher CRP than those in sinus rhythm (0.30 versus 0.15 mg/dL;
P
<0.001). CRP in controls was not different than in patients with atrial ectopy or tachycardia. Lone arrhythmia patients had a CRP of 0.21 mg/dL, which was not significantly lower than arrhythmia patients with structural heart disease (CRP, 0.23 mg/dL) but higher than controls (
P
=0.002). Persistent AF patients had a higher CRP (0.34 mg/dL) than paroxysmal AF patients (0.18 mg/dL;
P
=0.008); both groups had higher CRP levels than controls (
P
≤0.005).

Conclusions

CRP is elevated in AF patients. This study is the first to document elevated CRP in non-postoperative arrhythmia patients. These findings are reinforced by stepwise CRP elevation with higher AF burden. Although the cause of elevated CRP levels in AF patients remains unknown, elevated CRP may reflect an inflammatory state that promotes the persistence of AF.
Toll-Like Receptor-4 Is Expressed by Macrophages in Murine and Human Lipid-Rich Atherosclerotic Plaques and Upregulated by Oxidized LDL
Authors: Xu Xiaoou Helen , Shah Prediman K. , Faure Emmanuelle , Equils Ozlem , Thomas Lisa , Fishbein Michael C. , Luthringer Daniel , Xu Xiao-Ping , Rajavashisth Tripathi B. , Yano Juliana , Kaul Sanjay , Arditi Moshe
Published: September 2007

Background
—

Inflammation is implicated in atherogenesis and plaque disruption. Toll-like receptor 2 (TLR-2) and TLR-4, a human homologue of drosophila Toll, play an important role in the innate and inflammatory signaling responses to microbial agents. To investigate a potential role of these receptors in atherosclerosis, we assessed the expression of TLR-2 and TLR-4 in murine and human atherosclerotic plaques.

Methods and Results
—

Aortic root lesions of high-fat diet-fed apoE-deficient mice (n=5) and human coronary atherosclerotic plaques (n=9) obtained at autopsy were examined for TLR-4 and TLR-2 expression by immunohistochemistry. Aortic atherosclerotic lesions in all apoE-deficient mice expressed TLR-4, whereas aortic tissue obtained from control C57BL/6J mice showed no TLR-4 expression. All 5 lipid-rich human plaques expressed TRL-4, whereas the 4 fibrous plaques and 4 normal human arteries showed no or minimal expression. Serial sections and double immunostaining showed TLR-4 colocalizing with macrophages both in murine atherosclerotic lesions and at the shoulder region of human coronary artery plaques. In contrast to TLR-4, none of the plaques expressed TLR-2. Furthermore, basal TLR-4 mRNA expression by human monocyte-derived macrophages was upregulated by ox-LDL in vitro.

Conclusions
—

Our study demonstrates that TLR-4 is preferentially expressed by macrophages in murine and human lipid-rich atherosclerotic lesions, where it may play a role to enhance and sustain the innate immune and inflammatory responses. Moreover, upregulation of TLR-4 in macrophages by oxidized LDL suggests that TLR-4 may provide a potential pathophysiological link between lipids and infection/inflammation and atherosclerosis.
Activation of Cardiac Endothelium as a Compensatory Component in Endotoxin-Induced Cardiomyopathy
Authors: Mebazaa Alexandre , De Keulenaer Gilles W. , Paqueron Xavier , Andries Luc J. , Ratajczak Philippe , Lanone Sophie , Frelin Christian , Longrois Dan , Payen Didier , Brutsaert Dirk L. , Sys Stanislas U.
Published: September 2007

Background
—

In view of growing evidence of an important endothelial paracrine regulation of cardiac function, the present study investigated the role of cardiac endothelium-derived endothelin-1 (ET-1), prostaglandins, and nitric oxide (NO) during endotoxin-induced cardiomyopathy in rabbits.

Methods and Results
—

Immunohistochemical studies showed a marked transient coinduction of the inducible isoforms of NO synthase (NOS-2) and cyclooxygenase (COX-2) in endocardial endothelium and coronary arteriolar endothelium of hearts 12 hours after intravenous administration of lipopolysaccharide (LPS+12h); staining for both isoforms was much weaker 24 hours later (LPS+36h). Nitrotyrosine localization was similar to that of NOS-2, suggesting a NOS-2–related endothelial formation of peroxynitrite in septic hearts. Contractile performance of papillary muscles was depressed in both LPS-treated groups. In the LPS+12h group, however, isometric twitches were significantly prolonged (482±14 versus 420±14 ms in the saline-treated group,
P
<0.005). This twitch prolongation was completely reversed by simultaneous administration of BQ-123 and indomethacin to block endogenous ET-1 and prostaglandins, respectively. In addition, in the LPS+12h group, myocardial inotropic responsiveness to exogenous ET-1 was enhanced (
P
<0.01).

Conclusions
—

Cardiac endothelial activation and myocardial sensitization to endothelium-derived mediators may be part of an adaptive response in the early (12 hours) stages of septic cardiomyopathy.
Low Hepatic Lipase Activity Is a Novel Risk Factor for Coronary Artery Disease
Authors: Dugi Klaus A. , Brandauer Karin , Schmidt Nikolaus , Nau Barbara , Schneider Jochen G. , Mentz Stefani , Keiper Tanja , Schaefer Juergen R. , Meissner Christoph , Kather Horst , Bahner Malte L. , Fiehn Walter , Kreuzer Joerg
Published: September 2007

Background
—

The crucial function of hepatic lipase (HL) in lipid metabolism has been well established, but the relationship between HL activity and coronary artery disease (CAD) is disputed.

Methods and Results
—

We measured HL activity in the postheparin plasma of 200 consecutive men undergoing elective coronary angiography and determined the degree of CAD with the extent score, which has been shown to be better correlated with known risk factors than other measures of CAD extent. We found a significant inverse correlation between HL activity and the extent of CAD (
r
=−0.19,
P
<0.01). This association was mainly due to patients with HDL levels >0.96 mmol/L (n=94,
r
=−0.30,
P
<0.005). HL activity was lower in 173 patients with CAD than in 40 controls with normal angiograms (286±106 versus 338±108 nmol · mL
−1
· min
−1
,
P
<0.01). To correct for potential confounding factors, we performed multivariate analyses that confirmed the independent association of HL activity with CAD extent. In addition, the presence of the T allele at position −514 in the HL promoter, which leads to a reduced HL promoter activity, was associated with lower HL activity (
r
=0.30,
P
<0.001) and higher CAD extent (42.2±20.8 versus 35.3±23.6 [extent score],
P
<0.05). In patients with heterozygous familial hypercholesterolemia, calcified lesions in ECG-gated spiral computed tomography were higher in patients with low HL activity (6.3±6.8 versus 1.5±3.1,
P
=0.01).

Conclusions
—

Our data show that low HL activity is associated with CAD. Therefore, HL might be useful for CAD risk estimation and might be a target for pharmacological intervention.
Heterogeneity of Myocardial Sleeve Morphology and Gap Junctions in Canine Superior Vena Cava
Authors: Yeh Hung-I , Lai Yu-Jun , Lee Shih-Huang , Lee Yi-Nan , Ko Yu-Shien , Chen Shih-Ann , Severs Nicholas J. , Tsai Cheng-Ho
Published: September 2007

Background
—

The myocardial sleeve of the superior vena cava (SVC) has been identified as a potential initiating focus in atrial fibrillation, but information on cell-to-cell linkage at this site is lacking.

Methods and Results
—

We examined the SVC in 8 dogs by immunoconfocal and electron microscopy. Cardiomyocytes outlined with vinculin and bearing striations positive for α-actinin are found in the proximal segment of the SVC. These cells, grouped in bundles of various orientations according to location, extend cephalically as far as 3 cm from the right atrium (RA)-SVC junction. Comparison between the junctional level and the level 2 cm distal shows that the myocardial layer in the latter is thinner and not as compact and is composed of longer cells (87.3±15.7 versus 71.6±14.4 μm,
P
<0.01). Gap junctions made of connexin43 (Cx43), Cx40, and Cx45 are aggregated mainly at the intercalated disks, and colocalization of connexins is a common feature throughout the myocardial sleeve. Areas of atypical expression exist, however, characterized by a center of abundant Cx43 labels surrounded by a periphery of scattered tiny Cx40-labeled spots. Although in the ventral subluminal compact myocardial layer, individual cells at both levels are surrounded by similar numbers of cells, the number of aggregation of labeled gap junctions at the distal level is less (2.3±0.6 versus 3.7±0.9,
P
<0.01). In addition, electron-microscopic examination demonstrates that the gap junctions at the distal level are smaller in size (0.37±0.30 versus 0.55±0.34 μm,
P
<0.01).

Conclusions
—

The myocardial sleeve in the canine SVC is a heterogeneous structure, which could potentially form a substrate for heterogeneity of electrical coupling.
Oral Heparin Prevents Neointimal Hyperplasia After Arterial Injury
Authors: Welt Frederick G.P. , Woods T. Cooper , Edelman Elazer R.
Published: September 2007

Background
—

In animal models, heparin delivered as a continuous intravenous infusion or via frequent (BID) subcutaneous dosing inhibits neointimal hyperplasia after balloon injury or stent implantation. However, human trials of subcutaneous heparin after percutaneous intervention have proven ineffective against restenosis. It may be that these failures are due to unfavorable heparin pharmacokinetics. Recently, the drug delivery agent sodium
N
-[8-(2-hydroxybenzoyl)amino] caprylate (SNAC) has been found to facilitate the gastric absorption of heparin.

Methods and Results
—

To investigate the effects of orally delivered heparin on neointimal hyperplasia after varying forms of arterial injury, 57 New Zealand White rabbits underwent iliac artery balloon dilatation. In half of the rabbits, endovascular stents were implanted and heparin was delivered through a variety of methods. Arteries were harvested at 14 days. Neointimal area was assessed with computer-aided morphometry. After balloon injury, both intravenous (0.3 mg/kg per hour) and oral heparin (90 mg/kg BID) effectively inhibited neointimal hyperplasia (0.11±0.02 and 0.09±0.07 mm
2
, respectively, versus 0.16±0.06 mm
2
in control;
P
<0.05). After stent implantation, intravenous administration of heparin (0.3 mg/kg per hour) effectively inhibited neointimal growth (0.35±0.05 mm
2
versus 0.51±0.09 mm
2
in control;
P
<0.05), but oral heparin at 90 mg/kg BID and 180 mg/kg BID (0.48±0.04 and 0.49±0.08 mm
2
, respectively;
P
=NS versus control) did not. A dose of 120 mg/kg TID, however, was effective (0.40±0.10 mm
2
;
P
<0.05 versus control).

Conclusions
—

These data suggest that oral heparin may be an effective therapy against restenosis after percutaneous intervention. Stented arteries required higher and more frequent dosing for efficacy. These data suggest that differences in the type of vascular injury must be considered in the design of drug delivery.
Conceptus Radiation Dose and Risk From Cardiac Catheter Ablation Procedures
Authors: Damilakis John , Theocharopoulos Nicholas , Perisinakis Kostas , Manios Emmanouel , Dimitriou Panayiotis , Vardas Panos , Gourtsoyiannis Nicholas
Published: September 2007

Background

—

The aim of the current study was to estimate the conceptus radiation dose and risk associated with fluoroscopic imaging during a catheter ablation procedure for supraventricular tachycardia performed on the expectant mother.

Methods and Results

—

Exposure parameters and fluoroscopy times for each projection of the cardiac ablation procedure performed in 20 female patients of childbearing age were recorded. Radiation doses for a potential conceptus were estimated by using dose data obtained in anthropomorphic phantoms simulating pregnancy at the first, second, and third trimesters. Dose measurements were carried out using thermoluminescent dosimeters. For a typical examination, the average radiation dose to the conceptus was <1 mGy in all periods of gestation. Average excess fatal cancer was 14.5/10
6
unborn children irradiated during the first postconception weeks. Corresponding values for the second and third trimesters were 30 and 55.7/10
6
, respectively. The risk for hereditary effects in future generations was 1.5/10
6
cases for conceptus irradiation during the first postconception weeks. Corresponding values for the second and third trimesters were 3.0 and 5.6/10
6
, respectively. Formulas and dose data are presented for estimating the conceptus risk from any technique and x-ray system used for catheter ablation procedures.

Conclusions

—

A typical catheter ablation procedure results in a very small increase in risk of harmful effects to the conceptus. However, estimation of conceptus dose from catheter ablation procedures is always needed to assess the risk to the individual developing in utero.
Cerebral Vasoconstriction in Vasovagal Syncope: Any Link With Symptoms?
Authors: Lagi Alfonso , Cencetti Simone , Corsoni Vanni , Georgiadis Dimitrios , Bacalli Stefano
Published: September 2007

Background

Cerebral vasoconstriction has been described previously in vasovagal syncope (VVS). This phenomenon appears paradoxical in view of the well-known decrease of systemic vascular resistances taking places during VVS. We aimed to assess (1) whether cerebral vasoconstriction in VVS is an independent paradoxical phenomenon and (2) whether cerebral vasoconstriction has any link with symptoms and/or VVS onsets.

Methods and Results

Seven young patients with recurrent VVS participated in the study. Each patient underwent monitoring of heart rate, blood pressure, cerebral blood flow velocity (by means of transcranial Doppler), end-tidal P
co
2
, peripheral oximetry, respiratory rate, and tidal volumes both at rest and during head-up tilt. All the subjects experienced tilt-induced VVS. A significant increase of respiratory tidal volumes was observed in each subject ≥160 seconds before VVS. This deep breathing induced a P
co
2
decrease and, consequently, also a decrease in cerebral blood flow velocity and increase in cerebrovascular resistance (expressed by the increase of the pulsatility index). Within 40 seconds, 5 subjects started complaining of discomfort, in the absence of any significant blood pressure drop.

Conclusions

Cerebral vasoconstriction is not a paradoxical phenomenon when it occurs before tilt-induced VVS but rather is only the physiological consequence of the hyperventilation-induced hypocapnia that occurs in habitual fainters. The large lag between the onset of syncope and cerebral vasoconstriction excludes the hypothesis that VVS is dependent on abnormal behavior of cerebral hemodynamics.
Induction of JAB/SOCS-1/SSI-1 and CIS3/SOCS-3/SSI-3 Is Involved in gp130 Resistance in Cardiovascular System in Rat Treated With Cardiotrophin-1 In Vivo
Authors: Hamanaka Ichiro , Saito Yoshihiko , Yasukawa Hideo , Kishimoto Ichiro , Kuwahara Koichiro , Miyamoto Yoshihiro , Harada Masaki , Ogawa Emiko , Kajiyama Noboru , Takahashi Nobuki , Izumi Takehiko , Kawakami Rika , Masuda Izuru , Yoshimura Akihiko , Nakao Kazuwa
Published: September 2007

Abstract
—CIS (cytokine-inducible SH2 protein), SOCS (suppressor of cytokine signaling), or SSI (signal transducers and activators of transcription [STAT]-induced STAT inhibitor) proteins are a family of cytokine-inducible negative regulators of cytokine signaling via Janus kinase (JAK)-STAT pathways. Given the evidence that the JAK-STAT pathway plays a critical role in the cardiovascular system, the primary objective of this study was to assess the effects of the CIS family on JAK-STAT signaling in the cardiovascular system in rats treated with cardiotrophin-1 (CT-1), an interleukin-6 family of cytokines. Intravenous injection of 20 μg/kg body weight of CT-1 induced a transient, marked increase in STAT3 activation in various tissues, including heart and lung, and subsequent upregulation of 2 members of the CIS family, JAK-binding protein (JAB)/SOCS-1/SSI-1 and CIS3/SOCS-3/SSI-3, in the same tissues. It was also observed that CIS3 was directly associated with JAK2 in vivo. Pretreatment with the same dose of CT-1 60 minutes before significantly attenuated the STAT3 activation induced by a second injection of CT-1. We previously reported that intravenous injection of CT-1 results in the nitric oxide (NO)-dependent hypotension accompanied by the induction of inducible NO synthase mRNA. In rats pretreated with CT-1, the induction of inducible NO synthase mRNA or hypotension by subsequent CT-1 injection was not observed. Forced expression of JAB or CIS3, but not other CISs, directly blocked CT-1–induced STAT3 activation in 293 cells. These results suggest that JAB and CIS3 serve as endogenous inhibitors of CT-1–mediated JAK-STAT signaling in the cardiovascular system in vivo.
Thrombomodulin Prolongs Thrombin-Induced Extracellular Signal–Regulated Kinase Phosphorylation and Nuclear Retention in Endothelial Cells
Authors: Olivot Jean-Marc , Estebanell Eva , Lafay Monique , Brohard Brigitte , Aiach Martine , Rendu Francine
Published: September 2007

Abstract
—On endothelial cells, thrombin binds to thrombomodulin (TM), an integral membrane-bound glycoprotein, and to protease-activated receptors (PARs). Thrombin binding to TM modulates endothelial cell and smooth muscle cell proliferation mediated through PAR1. We studied the phosphorylation and nuclear translocation of extracellular signal–regulated kinases (ERKs) 1 and 2 in human umbilical vein endothelial cells activated by thrombin. Thrombin and thrombin receptor–activating peptide (TRAP)-induced DNA synthesis were significantly inhibited by PD98059, an inhibitor of ERK phosphorylation. Immunoblots of phosphorylated ERKs (pERKs) and immunocytochemical studies of pERK localization revealed differences in the signal generated by thrombin and TRAP. After a short activation (15 minutes), the phosphorylation and the intracellular localization of pERKs were the same with the 2 agonists. After 4 hours, however, pERKs were visualized in the nuclei of thrombin-activated cells but barely detectable in TRAP-activated cells. Moreover, after 4 hours, the pERKs were visualized in the nuclei of cells stimulated by TRAP in the presence of a thrombin mutant that bound to TM, whereas they were around the nuclei in cells stimulated by thrombin in the presence of a monoclonal antibody preventing thrombin binding to TM. The results demonstrate that ERKs are involved in human umbilical vein endothelial cell DNA synthesis mediated by PAR agonists, that the duration of pERK nuclear retention is in inverse ratio to the mitogenic response, and that in addition to its role in the regulation of blood coagulation, TM acts as a thrombin receptor that modulates the duration of pERK nuclear retention and cell proliferation in response to thrombin.