bluuebunny/crossref_metadata_2025 huggingface dataset:
Early Increase of von Willebrand Factor Predicts Adverse Outcome in Unstable Coronary Artery Disease
Authors: Montalescot Gilles , Philippe François , Ankri Annick , Vicaut Eric , Bearez Etienne , Poulard Jean Ernest , Carrie Didier , Flammang Daniel , Dutoit Albert , Carayon Alain , Jardel Claude , Chevrot Monique , Bastard Jean Philippe , Bigonzi Fredérique , Thomas Daniel
Published: June 2012

Background
—The pathogenesis of unstable angina and non–Q-wave myocardial infarction is still poorly understood, and early evaluation of prognosis remains difficult. We therefore studied the predictive value of 5 biological indicators of inflammation, thrombogenesis, vasoconstriction, and myocardial necrosis, and we examined the effects of enoxaparin and unfractionated heparin on these markers after 48 hours of treatment.

Methods and Results
—Sixty-eight patients with unstable angina or non–Q-wave myocardial infarction randomized in the international ESSENCE trial participated in this French substudy. C-reactive protein, fibrinogen, von Willebrand factor antigen, endothelin-1 and troponin I were measured on admission and 48 hours later. The composite end point of death, myocardial infarction, recurrent angina, or revascularization was significantly lower at 14 and 30 days of follow-up in patients allocated to enoxaparin compared with unfractionated heparin. All acute-phase reactant proteins were elevated on admission and increased further at 48 hours. Multivariate analysis demonstrated that the rise of von Willebrand factor over 48 hours was a significant and independent predictor of the composite end point at both 14 days and 30 days. Moreover the early increase of von Willebrand factor was more frequent and more severe with unfractionated heparin than with enoxaparin (mean change was +8.7±8.8% with enoxaparin versus +93.9±11.7% with unfractionated heparin,
P
<0.0001). The other clinical and biological variables did not predict outcome.

Conclusions
—In patients with unstable angina or non–Q-wave myocardial infarction, the acute-phase proteins increase over the first 2 days despite medical treatment. The early rise of von Willebrand factor is an independent predictor of adverse clinical outcome at 14 days and at 30 days. Enoxaparin provides protection as evidenced by the reduced release of von Willebrand factor, which represents a favorable prognostic finding.
Limb Blood Flow During Exercise Is Dependent on Nitric Oxide
Authors: Maxwell Andrew J. , Schauble Eric , Bernstein Daniel , Cooke John P.
Published: June 2012

Background
—We have recently reported that hypercholesterolemia reduces aerobic exercise capacity in mice and that this is associated with a reduced endothelium-dependent vasodilator function, endothelium-derived nitric oxide (EDNO) production, and urinary nitrate excretion. These findings led us to test the hypothesis that EDNO production contributes significantly to limb blood flow during exercise and to determine whether loss of EDNO production is responsible for the decline in exercise capacity observed in hypercholesterolemia.

Methods and Results
—Twelve-week-old wild-type (E
+
; n=9) and apoE-deficient (E
−
; n=9) C57BL/6J mice were treadmill-tested to measure indices defining exercise capacity on a metabolic chamber–enclosed treadmill capable of measuring oxygen uptake and carbon dioxide excretion. Urine was collected before and after treadmill exercise for determination of vascular NO production assessed by urinary nitrate excretion. The wild-type mice were then given nitro-
l-
arginine (E
+
LNA) in the drinking water (6 mg/dL) for 4 days before undergoing a second treadmill testing and urinary nitrate measurement. An additional set of 12-week-old wild-type mice was divided into 2 groups: 1 receiving regular water (E
+
; n=8) and 1 administered LNA for 4 days (E
+
LNA; n=8). These mice, along with an additional set of E
−
mice (n=8), underwent treadmill testing to determine maximal oxygen uptake (V̇
o
2
max). The mice were then cannulated such that the tip of the tubing was positioned in the ascending aorta. Fluorescent microspheres (20 000) were infused into the carotid cannula while the mice were sedentary and again while approaching V̇
o
2
max. When the mice were euthanized, the running muscles were collected and fluorescence intensity was measured to determine the peak-exercise redistribution of blood flow to the running muscles (expressed as percentage of total cardiac output, %COrm) during both states. Both E
+
LNA and E
−
mice demonstrated a markedly reduced postexercise urinary nitrate excretion, aerobic capacity, and %COrm at V̇
o
2
max compared with E
+
.

Conclusions
—EDNO contributes significantly to limb blood flow during exercise. Conditions that reduce EDNO production disturb the hyperemic response to exercise, resulting in a reduced exercise capacity.
Patients With Familial Hypertrophic Cardiomyopathy Caused by a Phe110Ile Missense Mutation in the Cardiac Troponin T Gene Have Variable Cardiac Morphologies and a Favorable Prognosis
Authors: Anan Ryuichiro , Shono Hirohisa , Kisanuki Akira , Arima Shinichi , Nakao Shoichiro , Tanaka Hiromitsu
Published: June 2012

Background
—Mutations that cause familial hypertrophic cardiomyopathy have been identified in several genes that encode contractile proteins. Patients with mutations in the cardiac troponin T (cTnT) gene have particularly poor prognosis but only mild hypertrophy. To date, no benign mutation in the cTnT gene has been reported. The clinical characteristics and prognosis of patients with the Phe110Ile mutation in the cTnT gene is unclear because few affected individuals have been identified.

Methods and Results
—Forty-six probands with familial hypertrophic cardiomyopathy were screened for mutations in the cTnT gene. The Phe110Ile missense mutation was found in 6 probands. Individuals in the 6 families were analyzed genetically and clinically. Haplotype analysis was performed with markers encompassing the cTnT gene. Left ventricular hypertrophy was classified as type I, II, III, or IV according to the criteria of Maron et al. The Phe110Ile mutation in the cTnT gene was identified in 16 individuals. Two of the 6 families shared the same flanking haplotype, and 4 were different from each other. Affected individuals exhibited different cardiac morphologies: 4 had type II, 6 had type III, and 3 had type IV hypertrophy with apical involvement. Three individuals with the disease-causing mutation did not fulfill clinical criteria for the disease. The product-limit survival curve analysis demonstrated a favorable prognosis.

Conclusions
—Multiple independent mutations of residue 340 in the cTnT gene have been described, suggesting that this may be a “hot spot” for such events. The Phe110Ile substitution causes hypertrophic cardiomyopathy with variable cardiac morphologies and a favorable prognosis.
Confirmed Previous Infection With
Chlamydia pneumoniae
(TWAR) and Its Presence in Early Coronary Atherosclerosis
Authors: Davidson Michael , Kuo Cho-Chou , Middaugh John P. , Campbell Lee Ann , Wang San-Pin , Newman William P. , Finley John C. , Grayston J. Thomas
Published: June 2012

Background
—
Chlamydia pneumoniae
has been identified in coronary atheroma, but concomitant serum antibody titers have been inconsistently positive and unavailable before the detection of early or advanced atherosclerotic lesions.

Methods and Results
—This retrospective investigation was performed on premortem serum specimens and autopsy tissue from 60 indigenous Alaska Natives at low risk for coronary heart disease, selected by the potential availability of their stored specimens. Serum specimens were drawn a mean of 8.8 years (range, 0.7 to 26.2 years) before death, which occurred at a mean age of 34.1 years (range, 15 to 57 years), primarily from noncardiovascular causes (97%). Coronary artery tissues were independently examined histologically and, for
C pneumoniae
organism and DNA, by immunocytochemistry (ICC) and polymerase chain reaction (PCR) with species-specific monoclonal antibody and primers. Microimmunofluorescence detected species-specific IgG, IgA, and IgM antibody in stored serum.
C pneumoniae
, frequently within macrophage foam cells, was identified in coronary fibrolipid atheroma (raised lesions, Stary types II through V) in 15 subjects (25%) and early flat lesions in 7 (11%) either by PCR (14, 23%) or ICC (20, 33%). The OR for
C pneumoniae
in raised atheroma after a level of IgG antibody ≥1:256 >8 years earlier was 6.1 (95% CI, 1.1 to 36.6) and for all coronary tissues after adjustment for multiple potential confounding variables, including tobacco exposure, was 9.4 (95% CI, 2.6 to 33.8).

Conclusions
—Serological evidence for
C pneumoniae
infection frequently precedes both the earliest and more advanced lesions of coronary atherosclerosis that harbor this intracellular pathogen, suggesting a chronic infection and developmental role in coronary heart disease.
Adverse Events With Transvenous Implantable Cardioverter-Defibrillators
Authors: Rosenqvist Mårten , Beyer Thorsten , Block Michael , den Dulk Karel , Minten Jaak , Lindemans Fred
Published: June 2012

Background
—A newly developed classification system relates adverse events to the surgical procedure or the function of the implantable defibrillator.

Methods and Results
—Adverse events were monitored during prospective clinical evaluation of the Medtronic model 7219 Jewel ICD and were classified according to the definitions of the ISO 14155 standard for device clinical trials into 3 groups: severe and mild device-related and severe non–device-related adverse events. In addition, events were related to the surgical procedure, treatment with the device, or cardiac function. Seven hundred seventy-eight patients were followed up for an average of 4.0 months after ICD implantation. In total, 356 adverse events were observed in 259 patients. At 1, 3, and 12 months after ICD implantation, 99%, 98%, and 97% of the patients, respectively, survived; 95%, 93%, and 92%, respectively, were free of surgical reintervention; and 79%, 68%, and 51%, respectively, were free of any adverse event. Twenty patients died: 6 deaths were related to the surgical procedure, 12 deaths were considered unrelated to ICD treatment, and 2 patients died of an unknown cause. Of 111 nonlethal severe adverse device effects, 47 required surgical intervention, 19 times for correction of a dislodged lead. Inappropriate delivery of therapy was observed 128 times in 111 patients, and the events were typically resolved by reprogramming or drug adjustment. Nine of these required rehospitalization.

Conclusions
—Approximately 50% of patients experience an adverse event within the first year after ICD implantation. The observed adverse event rate depends on the definitions and the prospective monitoring. The incidence of inappropriate therapy emphasizes the need for improved detection algorithms and for quality-of-life evaluations, especially when considering ICD treatment in high-risk but arrhythmia-free patients.
Helicobacter pylori
Seropositivity and Coronary Heart Disease Incidence
Authors: Folsom Aaron R. , Nieto F. Javier , Sorlie Paul , Chambless Lloyd E. , Graham David Y.
Published: June 2012

Background
—Several epidemiological and clinical reports have suggested seropositivity for
Helicobacter pylori
may be a risk factor for coronary heart disease. However, there has been no prospective study of this association involving an ethnically diverse sample of middle-aged men and women.

Methods and Results
—Using a prospective, case-cohort design, we determined
H pylori
seropositivity in relation to coronary heart disease incidence over a median follow-up period of 3.3 years among middle-aged men and women. There were 217 incident coronary heart disease cases and a cohort sample of 498. We determined
H pylori
antibody status by measuring IgG antibody to the high-molecular-weight cell-associated proteins of
H pylori
using a sensitive and specific ELISA. The prevalence of
H pylori
seropositivity was higher in blacks than whites, in those with less than high school education, in those with lower plasma pyridoxal 5′-phosphate and higher homocyst(e)ine concentrations, in those who did not use vitamin supplements, in those with higher fibrinogen levels, and in those seropositive for cytomegalovirus and herpes simplex type I (all
P
<0.05). The age-, sex-, race-, and field center–adjusted hazard ratio of coronary heart disease for
H pylori
seropositivity was 1.03 (95% CI=0.68 to 1.57). After adjustment for other risk factors, including fibrinogen, cytomegalovirus seropositivity, and herpes simplex type I seropositivity, the hazard ratio was 0.85 (95% CI=0.43 to 1.69).
H pylori
seropositivity also was not associated with increased mean intima-media thickness of the carotid artery, a measure of subclinical atherosclerosis.

Conclusions
—
H pylori
infection is probably not an important contributor to clinical coronary heart disease events.
Treatment With Growth Hormone Enhances Contractile Reserve and Intracellular Calcium Transients in Myocytes From Rats With Postinfarction Heart Failure
Authors: Tajima Minori , Weinberg Ellen O. , Bartunek Jozef , Jin Hongkui , Yang Renhui , Paoni Nicholas F. , Lorell Beverly H.
Published: June 2012

Background
—Recombinant human growth hormone (GH) improves in vivo cardiac function in rats with postinfarction heart failure (MI). We examined the effects of growth hormone (14 days of 3.5 mg · kg
−1
· d
−1
begun 4 weeks after MI) on contractile reserve in left ventricular myocytes from rats with chronic postinfarction heart failure.

Methods and Results
—Cell shortening and [Ca
2+
]
i
were measured with the indicator fluo 3 in myocytes from MI, MI+GH, control, and normal animals treated with GH (C+GH) under stimulation at 0.5 Hz at 37°C. Cell length was similar in MI and MI+GH rats (150±5 and 157±5 μm) and was greater in these groups than in the control and C+GH groups (140±4 and 139±4 μm,
P
<0.05). At baseline perfusate calcium of 1.2 mmol/L, myocyte fractional shortening and [Ca
2+
]
i
transients were similar among the 4 groups. We then assessed contractile reserve by measuring the increase in myocyte fractional shortening in the presence of high-perfusate calcium of 3.5 mmol/L. In the control and C+GH groups, myocyte fractional shortening and peak systolic [Ca
2+
]
i
were similarly increased in the presence of high-perfusate calcium. In the presence of high-perfusate calcium, both myocyte fractional shortening and peak systolic [Ca
2+
]
i
were depressed in the MI compared with the control groups. In contrast, myocyte fractional shortening (14.1±.9% versus 11.1±.9%,
P
<0.05) and peak systolic [Ca
2+
]
i
(647±43 versus 509±37 nmol/L,
P
<0.05) were significantly higher in MI+GH than in MI rats and were comparable to controls. Left ventricular myocyte expression of sarcoplasmic reticulum Ca
2+
ATPase 2 (SERCA-2) and left ventricular SERCA-2 protein levels were increased in MI+GH compared with MI rats.

Conclusions
—Calcium-dependent contractile reserve is depressed in myocytes from rats with postinfarction heart failure. Long-term growth hormone therapy increases contractile reserve by restoring normal augmentation of systolic [Ca
2+
]
i
in myocytes from rats with postinfarction heart failure.
Sustained Improvement in Flow-Mediated Vasodilation After Short-Term Administration of Dobutamine in Patients With Severe Congestive Heart Failure
Authors: Patel Mrugesh B. , Kaplan Ilya V. , Patni Rajiv N. , Levy Daniel , Strom Joel A. , Shirani Jamshid , LeJemtel Thierry H.
Published: June 2012

Background
—In patients with severe congestive heart failure (CHF), short-term administration of dobutamine exerts sustained clinical benefits that are partially mediated by a training-like effect on skeletal muscle. Recently, physical training has been shown to enhance endothelial function in the skeletal muscle vasculature by improving endothelial function. Whether the dobutamine-induced training effect is also associated with an improvement in endothelial function in the skeletal muscle vasculature is currently unknown.

Methods and Results
—Flow-mediated vasodilation in response to peak reactive hyperemia was evaluated in the forearms of 9 patients with severe CHF who were treated with dobutamine for 72 hours. Resting and peak hyperemic brachial artery blood flow and diameter (BABF [mL/min] and BAD [mm], respectively) were measured by 2-dimensional and Doppler ultrasonography at baseline, at 3 and 72 hours during dobutamine infusion, and at 2 and 4 weeks after discontinuation of dobutamine therapy. In addition, the brachial artery response to sublingual (SL) administration of nitroglycerin (NTG) was evaluated at baseline and at 2 and 4 weeks after discontinuation of dobutamine therapy. Ten patients with severe CHF who did not receive dobutamine served as control subjects. Resting BABF was significantly increased at 3 and 72 hours (391.2±31.8 and 366.8±31.0 mL/min, respectively, compared with 289.8±18.6 mL/min at baseline;
P
<0.05). Peak hyperemic BABF was not altered by dobutamine infusion compared with baseline values. The increase in BAD during peak hyperemic response was greater after infusion of dobutamine for 72 hours (15.2±2.7% versus 9.1±1.8%,
P
<0.05) and remained significantly greater for ≥2 weeks after discontinuation of dobutamine (12.3±2.2% versus 9.1±1.8%,
P
<0.05). In contrast to the peak hyperemic response, the increase in BAD (%) induced by SL NTG was unchanged by administration of dobutamine for 72 hours. Two and 4 weeks after discontinuation of dobutamine, NTG-induced increases in BAD were similar to the BAD noted at baseline.

Conclusions
—In patients with severe CHF, short-term administration of dobutamine for 72 hours selectively improves vascular endothelial function for ≥2 weeks.
Is ε-Aminocaproic Acid as Effective as Aprotinin in Reducing Bleeding With Cardiac Surgery?
Authors: Munoz John J. , Birkmeyer Nancy J. O. , Birkmeyer John D. , O’Connor Gerald T. , Dacey Lawrence J.
Published: June 2012

Background
—Although aprotinin is known to be effective in reducing postoperative hemorrhage after cardiac surgery, ε-aminocaproic acid, an alternative antifibrinolytic, is considerably less expensive. Because the results of 3 small randomized clinical trials comparing these 2 agents directly were inconclusive, we performed a meta-analysis to compare the relative effectiveness and adverse-effect profile of these 2 agents against placebo.

Methods and Results
—Data from 52 randomized clinical trials published between 1985 and 1998 involving the use of ε-aminocaproic acid (n=9) or aprotinin (n=46) in patients undergoing cardiac surgery were abstracted. Our primary outcomes were total blood loss, red blood cell transfusion rates and amounts, reexploration, stroke, myocardial infarction, and mortality. The meta-analysis revealed substantial reductions in total blood loss with ε-aminocaproic acid and low-dose aprotinin (each with a 35% reduction versus placebo,
P
<0.001) and high-dose aprotinin (53% reduction,
P
<0.001). There were identical reductions in total postoperative transfusions with ε-aminocaproic acid (61% reduction versus placebo,
P
<0.010) and high-dose aprotinin (62% reduction,
P
<0.001). The proportion of patients transfused was similarly reduced with ε-aminocaproic acid (OR, 0.32; 95% CI, 0.15 to 0.69) and high-dose aprotinin (OR, 0.28; 0.22 to 0.37). Although both drugs reduced rates of reexploration to similar degrees, this effect was statistically significant only with high-dose aprotinin (OR, 0.39; 0.24 to 0.61). ε-Aminocaproic acid and aprotinin had no effect on risks of postoperative myocardial infarction or overall mortality.

Conclusions
—Because the 2 antifibrinolytic agents appear to have similar efficacies, the considerably less-expensive ε-aminocaproic acid may be preferred over aprotinin for reducing hemorrhage with cardiac surgery.
LocaLisa
Authors: Wittkampf Fred H. M. , Wever Eric F. D. , Derksen Richard , Wilde Arthur A. M. , Ramanna Hemanth , Hauer Richard N. W. , Robles de Medina Etienne O.
Published: June 2012

Background
—Estimation of the 3-dimensional (3D) position of ablation electrodes from fluoroscopic images is inadequate if a systematic lesion pattern is required in the treatment of complex arrhythmogenic substrates.

Methods and Results
—We developed a new technique for online 3D localization of intracardiac electrodes. Regular catheter electrodes are used as sensors for a high-frequency transthoracic electrical field, which is applied via standard skin electrodes. We investigated localization accuracy within the right atrium, right ventricle, and left ventricle by comparing measured and true interelectrode distances of a decapolar catheter. Long-term stability was analyzed by localization of the most proximal His bundle before and after slow pathway ablation. Electrogram recordings were unaffected by the applied electrical field. Localization data from 3 catheter positions, widely distributed within the right atrium, right ventricle, or left ventricle, were analyzed in 10 patients per group. The relationship between measured and true electrode positions was highly linear, with an average correlation coefficient of 0.996, 0.997, and 0.999 for the right atrium, right ventricle, and left ventricle, respectively. Localization accuracy was better than 2 mm, with an additional scaling error of 8% to 14%. After 2 hours, localization of the proximal His bundle was reproducible within 1.4±1.1 mm.

Conclusions
—This new technique enables accurate and reproducible real-time localization of electrode positions in cardiac mapping and ablation procedures. Its application does not distort the quality of electrograms and can be applied to any electrode catheter.
Homozygous Deletion in
KVLQT1
Associated With Jervell and Lange-Nielsen Syndrome
Authors: Chen Qiuyun , Zhang Danmei , Gingell Robert L. , Moss Arthur J. , Napolitano Carlo , Priori Silvia G. , Schwartz Peter J. , Kehoe Eileen , Robinson Jennifer L. , Schulze-Bahr Eric , Wang Qing , Towbin Jeffrey A.
Published: June 2012

Background
—Long-QT (LQT) syndrome is a cardiac disorder that causes syncope, seizures, and sudden death from ventricular arrhythmias, specifically torsade de pointes. Both autosomal dominant LQT (Romano-Ward syndrome) and autosomal recessive LQT (Jervell and Lange-Nielsen syndrome, JLNS) have been reported. Heterozygous mutations in 3 potassium channel genes,
KVLQT1,
KCNE1
(
minK
), and
HERG
, and the cardiac sodium channel gene
SCN5A
cause autosomal dominant LQT. Autosomal recessive LQT, which is associated with deafness, has been found to occur with homozygous mutations in
KVLQT1
and
KCNE1
in JLNS families in which QTc prolongation was inherited as a dominant trait.

Methods and Results
—An Amish family with clinical evidence of JLNS was analyzed for mutations by use of single-strand conformation polymorphism and DNA sequencing analyses for mutations in all known LQT genes. A novel homozygous 2-bp deletion in the S2 transmembrane segment of
KVLQT1
was identified in affected members of this Amish family in which both QTc prolongation and deafness were inherited as recessive traits. This deletion represents a new JLNS-associated mutation in
KVLQT1
and has deleterious effects on the
KVLQT1
potassium channel, causing a frameshift and the truncation of the
KVLQT1
protein. In contrast to previous reports in which LQT was inherited as a clear dominant trait, 2 parents in the JLNS family described here have normal QTc intervals (0.43 and 0.44 seconds, respectively).

Conclusions
—A novel homozygous
KVLQT1
mutation causes JLNS in an Amish family with deafness that is inherited as an autosomal recessive trait.
Mechanisms of Death in the CABG Patch Trial
Authors: Bigger J. Thomas , Whang William , Rottman Jeffrey N. , Kleiger Robert E. , Gottlieb Charles D. , Namerow Pearila B. , Steinman Richard C. , Estes N. A. Mark
Published: June 2012

Background
—The CABG Patch trial compared prophylactic implantable cardiac-defibrillator (ICD) implantation with no antiarrhythmic therapy in coronary bypass surgery patients who had a left ventricular ejection fraction <0.36 and an abnormal signal-averaged ECG. There were 102 deaths among the 446 ICD group patients and 96 deaths among the 454 control group patients, a hazard ratio of 1.07 (
P
=0.63). The mechanisms of death were classified, and hypotheses were tested about the effects of ICD therapy on arrhythmic and nonarrhythmic cardiac deaths in the CABG Patch Trial and the Multicenter Automatic Defibrillator Implantation Trial (MADIT).

Methods and Results
—The 198 deaths in the trial were reviewed by an independent Events Committee and classified by the method of Hinkle and Thaler. Only 54 deaths (27%) occurred out of hospital; 145 deaths (73%) were witnessed. Seventy-nine (82%) of the 96 deaths in the control group and 76 (75%) of the 102 deaths in the ICD group were due to cardiac causes. Cumulative arrhythmic mortality at 42 months was 6.9% in the control group and 4.0% in the ICD group (
P
=0.057). Cumulative nonarrhythmic cardiac mortality at 42 months was 12.4% in the control group and 13.0% in the ICD group (
P
=0.275). Death due to pump failure was significantly associated with death >1 hour from the onset of symptoms, dyspnea within 7 days of death, and overt heart failure within 7 days of death.

Conclusions
—In the CABG Patch Trial, ICD therapy reduced arrhythmic death 45% without significant effect on nonarrhythmic deaths. Because 71% of the deaths were nonarrhythmic, total mortality was not significantly reduced.
Effect of Right Atrial Isthmus Ablation on the Occurrence of Atrial Fibrillation
Authors: Nabar Ashish , Rodriguez Luz-Maria , Timmermans Carl , van den Dool Adri , Smeets Joep L. R. M. , Wellens Hein J. J.
Published: June 2012

Background
—The goal of this study was to test the hypothesis that the occurrence of atrial fibrillation (AF), in at least some patients with coexisting type I atrial flutter (AFL), is based on macro-reentry around the tricuspid valve orifice, including the right atrial (RA) isthmus, by evaluation of AF recurrences after successful ablation of AFL.

Methods and Results
—Eighty-two consecutive patients with type I AFL, with or without concomitant AF, underwent radiofrequency ablation (RFA) of the RA isthmus by an anatomical approach. The results were analyzed in 4 groups of patients: group 1 (only AFL; 29 patients), group 2 (AFL >AF; 22 patients), group 3 (AF >AFL; 15 patients), and group 4 (developing AFL while receiving class IC antiarrhythmic drug therapy for AF, the “class IC atrial flutter”; 16 patients). In all groups, RFA of type I AFL was performed with a high (≥93%) procedural success rate. In group 1, only 2 patients (8%) had AF after (18±14 months) AFL ablation. These figures were 38% (20±14 months) and 86% (13±8 months) in groups 2 and 3, respectively. Group 4 patients (4±2 months) had a 73% freedom of AF recurrences with continuation of the class IC agent.

Conclusions
—The low incidence of new AF during long-term follow-up after RFA of type I AFL makes it unlikely that radiofrequency lesions promote the development of AF. The impact of isthmus ablation on AF recurrences differs according to the clinically predominant atrial arrhythmia and suggests a possible role of the RA isthmus in the occurrence of AF in some patients. Ablation of class IC atrial flutter in patients with therapy-resistant AF is a novel approach to management of this patient subset. Careful classification of AF patients plays a role in the selection of the site of ablation therapy.
Effect of Etilefrine in Preventing Syncopal Recurrence in Patients With Vasovagal Syncope
Authors: Raviele Antonio , Brignole Michele , Sutton Richard , Alboni Paolo , Giani Paolo , Menozzi Carlo , Moya Angel
Published: June 2012

Background
—Etilefrine is an α-agonist agent with a potent vasoconstrictor effect, which is potentially useful in preventing vasovagal syncope by reducing venous pooling and/or by counteracting reflex arteriolar vasodilatation. The present multicenter, randomized, placebo-controlled study was designed to evaluate the efficacy of this drug for the long-term management of patients with recurrent vasovagal syncope.

Methods and Results
—In the 20 participating centers, 126 patients with recurrent vasovagal syncope (at least 3 episodes in the last 2 years) and a positive baseline head-up tilt response were randomly assigned to placebo (63 patients) or etilefrine at a dosage of 75 mg/d (63 patients) and were followed up for 1 year or until syncope recurred. The primary end-point of the study was the first recurrence of syncope. There were no differences between the 2 study groups in the patients’ baseline characteristics. During follow-up, the group treated with etilefrine had a similar incidence of first syncopal recurrence to that of placebo group both in the intention-to-treat analysis (24% versus 24%) and in on- treatment analysis (26% versus 24%). Moreover, the median time to the first syncopal recurrence did not significantly differ between the 2 study groups (106 days in the etilefrine arm and 112 days in the placebo arm).

Conclusions
—Oral etilefrine is not superior to placebo in preventing spontaneous episodes of vasovagal syncope. Randomized controlled studies are essential to assess the real usefulness of any proposed therapy for patients with vasovagal syncope.
QT Dispersion as an Attribute of T-Loop Morphology
Authors: Kors Jan A. , van Herpen Gerard , van Bemmel Jan H.
Published: June 2012

Background
—The suggestion that increased QT dispersion (QTD) is due to increased differences in local action potential durations within the myocardium is wanting. An alternative explanation was sought by relating QTD to vectorcardiographic T-loop morphology.

Methods and Results
—The T loop is characterized by its amplitude and width (defined as the spatial angle between the mean vectors of the first and second halves of the loop). We reasoned that small, wide (“pathological”) T loops produce larger QTD than large, narrow (“normal”) loops. To quantify the relationship between QTD and T-loop morphology, we used a program for automated analysis of ECGs and a database of 1220 standard simultaneous 12-lead ECGs. For each ECG, QT durations, QTD, and T-loop parameters were computed. T-loop amplitude and width were dichotomized, with 250 μV (small versus large amplitudes) and 30° (narrow versus wide loops) taken as thresholds. Over all 1220 ECGs, QTDs were smallest for large, narrow T loops (54.2±27.1 ms) and largest for small, wide loops (69.5±33.5 ms;
P
<0.001).

Conclusions
—QTD is an attribute of T-loop morphology, as expressed by T-loop amplitude and width.
Conduction Disturbances and Increased Atrial Vulnerability in Connexin40-Deficient Mice Analyzed by Transesophageal Stimulation
Authors: Hagendorff Andreas , Schumacher Burghard , Kirchhoff Susanne , Lüderitz Berndt , Willecke Klaus
Published: June 2012

Background
—Recently, it has been reported that connexin40 (Cx40) deficiency in targeted mouse mutants is associated with a prolongation of P-wave and QRS complex duration on surface electrograms. The specific effects of Cx40 deficiency on sinus node function, sinoatrial, and atrioventricular conduction properties as well as on atrial vulnerability have not yet been investigated systematically by electrophysiological analysis.

Methods and Results
—Fifty-two mice (18 Cx40
+/+
, 15 Cx40
+/−
, and 19 Cx40
−/−
mice) were subjected to rapid atrial transesophageal stimulation after anesthesia with avertin. A significant prolongation of sinus node recovery time was noticed in Cx40
−/−
mice compared with Cx40
+/−
and Cx40
+/+
mice (287.8±109.0 vs 211.1±61.8 vs 204.4±60.9 ms;
P
<0.05). In addition, Wenckebach periodicity occurred at significantly longer atrial pacing cycle lengths in Cx40
−/−
mice than in Cx40
+/−
or Cx40
+/+
mice (93.3±11.8 vs 83.9±9.7 vs 82.8±8.0 ms,
P
<0.05). Analysis of 27 Cx40
−/−
mice showed a significant increase in intra-atrial conduction time and atrioventricular conduction time compared with 52 Cx40
+/−
and 31 wild-type (Cx40
+/+
) mice. Furthermore, in Cx40
−/−
mice, atrial tachyarrhythmias could be induced frequently by atrial burst pacing, whereas no atrial arrhythmias were inducible in heterozygous or wild-type mice.

Conclusions
—This study demonstrates that Cx40 deficiency is associated with sinoatrial, intra-atrial, and atrioventricular conduction disturbances. In atrial myocardium of the mouse, Cx40 deficiency results in increased atrial vulnerability and might contribute to arrhythmogenesis.
Slow Intramural Heating With Diffused Laser Light
Authors: Ware David L. , Boor Paul , Yang Chunjie , Gowda Ashok , Grady James J. , Motamedi Massoud
Published: June 2012

Background
—Catheter ablation of postinfarction ventricular tachycardia (VT) may be limited by insufficient myocardial coagulation or excessive endocardial or epicardial damage. We propose that volumetric heating restricted to intramural sites may improve the outcome and safety of this procedure, especially if delivered at rates that enhance heat conduction and forestall adverse tissue changes.

Methods and Results
—A novel optical fiber with a diffusing tip for direct intramural, volumetric laser heating was tested via thoracotomy and percutaneously in normal dogs. Low-power (2.0- to 4.5-W) diode laser light (805 nm) diffused within tissue induced large lesions but no visible surface damage, mural thrombi, or transmural perforation. Mean lesion depth approximated tip length (10 mm). Mean lesion widths in the thoracotomy and percutaneous groups were 5.8±0.5 to 9.1±0.84 mm and 5.2±0.85 to 7.9±1.1 mm, respectively, depending on the light dose. Mean volumes in the percutaneous group were 1006±245 to 2471±934 mm. ST-segment depression, appearing in unfiltered bipolar electrograms recorded from the guiding catheter, was specific for lesion induction. All dogs survived the protocol, which included a 1-hour observation period. In cross section, lesions were elliptical to spherical and characterized by extensive contraction-band necrosis abruptly bordering viable tissue. No platelets or fibrin adhered to the endocardium.

Conclusions
—Slow, volumetric, and direct intramyocardial heating induces large, deep lesions without hazardous tissue damage. Such heating might cure postinfarction VT more successfully and safely than present techniques. Further testing and development of this method seem warranted.
Effects of Human Cytomegalovirus Immediate-Early Proteins on p53-mediated Apoptosis in Coronary Artery Smooth Muscle Cells
Authors: Tanaka Koichi , Zou Jian-Ping , Takeda Kazuyo , Ferrans Victor J. , Sandford Gordon R. , Johnson Thomas M. , Finkel Toren , Epstein Stephen E.
Published: June 2012

Background
—Restenotic and atherosclerotic lesions often contain smooth muscle cells (SMCs), which display high rates of proliferation and apoptosis. Human cytomegalovirus (HCMV) may increase the incidence of restenosis and predispose to atherosclerosis. Although the mechanisms contributing to these processes are unclear, studies demonstrate that one of the immediate-early (IE) gene products of HCMV, IE2-84, binds to and inhibits p53 transcriptional activity. Given the role of p53 in mediating apoptosis, we studied the ability of IE2-84 to inhibit p53-dependent apoptosis in human coronary artery SMCs.

Methods and Results
—Apoptosis of SMCs was induced either by use of an adenovirus vector encoding human wild-type p53 protein or by treatment with doxorubicin. HCMV IE1-72 and IE2-84, the major IE proteins of HCMV, were overexpressed separately with adenovirus vectors encoding each protein, and the effects on p53-induced apoptosis were examined by both nick end-labeling (TUNEL) assay and flow cytometry. Expression of IE2-84, but not IE1-72, protected SMCs from p53-mediated apoptosis.

Conclusions
—These data indicate that an HCMV IE protein antagonizes p53-mediated apoptosis, suggesting a pathway by which HCMV infection predisposes to SMC accumulation and thereby contributes to restenosis and atherosclerosis.
Acute Anti-Ischemic Effect of Testosterone in Men With Coronary Artery Disease
Authors: Rosano Giuseppe M. C. , Leonardo Filippo , Pagnotta Paolo , Pelliccia Francesco , Panina Gaia , Cerquetani Elena , della Monica Paola Lilla , Bonfigli Bruno , Volpe Massimo , Chierchia Sergio L.
Published: June 2012

Background
—The role of testosterone on the development of coronary artery disease in men is controversial. The evidence that men have a greater incidence of coronary artery disease than women of a similar age suggests a possible causal role of testosterone. Conversely, recent studies have shown that the hormone improves endothelium-dependent relaxation of coronary arteries in men. Accordingly, the aim of the present study was to evaluate the effect of acute administration of testosterone on exercise-induced myocardial ischemia in men.

Methods and Results
—After withdrawal of antianginal therapy, 14 men (mean age, 58±4 years) with coronary artery disease underwent 3 exercise tests according to the modified Bruce protocol on 3 different days (baseline and either testosterone or placebo given in a random order). The exercise tests were performed 30 minutes after administration of testosterone (2.5 mg IV in 5 minutes) or placebo. All patients showed at least 1-mm ST-segment depression during the baseline exercise test and after placebo, whereas only 10 patients had a positive exercise test after testosterone. Chest pain during exercise was reported by 12 patients during baseline and placebo exercise tests and by 8 patients after testosterone. Compared with placebo, testosterone increased time to 1-mm ST-segment depression (579±204 versus 471±210 seconds;
P
<0.01) and total exercise time (631±180 versus 541±204 seconds;
P
<0.01). Testosterone significantly increased heart rate at the onset of 1-mm ST-segment depression (135±12 versus 123±14 bpm;
P
<0.01) and at peak exercise (140±12 versus 132±12 bpm;
P
<0.01) and the rate-pressure product at the onset of 1-mm ST-segment depression (24 213±3750 versus 21 619±3542 mm Hg×bpm;
P
<0.05) and at peak exercise (26 746±3109 versus 22 527±5443 mm Hg×bpm;
P
<0.05).

Conclusions
—Short-term administration of testosterone induces a beneficial effect on exercise-induced myocardial ischemia in men with coronary artery disease. This effect may be related to a direct coronary-relaxing effect.
Proatherogenic and Antiatherogenic Effects of Probucol and Phytosterols in Apolipoprotein E–Deficient Mice
Authors: Moghadasian Mohammed H. , McManus Bruce M. , Godin David V. , Rodrigues Brian , Frohlich Jiri J.
Published: June 2012

Background
—The effects of probucol and a phytosterol mixture (FCP-3PI) on atherosclerotic lesion formation, plasma lipoproteins, hepatic and lipoprotein lipase activities, antioxidant enzyme activities, and plasma fibrinogen were investigated in apolipoprotein E–knockout (apoE-KO) mice.

Methods and Results
—Three groups of 8 mice were fed a diet containing 9% (wt/wt) fat (controls) or the foregoing diet supplemented with either 1% (wt/wt) probucol (the probucol group) or 2% (wt/wt) FCP-3PI (the FCP-3PI group) for 20 weeks. Compared with controls, atherosclerotic lesion size was 3 times greater in the probucol group, whereas it was decreased by half in the FCP-3PI group. Probucol treatment resulted in high plasma probucol concentrations, which correlated (
r
=0.69) with the lesion area. HDL cholesterol was reduced (>75%) in the probucol group and slightly increased (14%) in the FCP-3PI–treated group. Postheparin lipoprotein lipase (LPL) activity was significantly reduced in both treatment groups, but only FCP-3PI significantly decreased hepatic lipase activity. Plasma fibrinogen was increased 42% by probucol and decreased 19% by FCP-3PI relative to controls. Probucol significantly increased plasma glutathione reductase, glutathione peroxidase, and superoxide dismutase activities (
P
<0.05). In contrast to findings in apoE-KO mice, there was no probucol-induced atherosclerosis in their wild-type counterparts fed the same dose for the same period of time.

Conclusions
—Antiatherogenic activity of FCP-3PI in apoE-KO mice is associated with an increase in HDL cholesterol concentration along with decreases in hepatic lipase activity and plasma fibrinogen concentrations. Proatherogenic effects of probucol may be related to increased plasma fibrinogen, decreased HDL cholesterol concentrations along with decreased LPL activity, or its direct “toxicity” due to very high plasma concentration. Our studies demonstrate that the antioxidant and cholesterol-lowering properties of probucol do not prevent atherogenesis in this particular animal model.
LDL Increases Inactive Tissue Factor on Vascular Smooth Muscle Cell Surfaces
Authors: Penn Marc S. , Patel Chandrashekhar V. , Cui Mei-Zhen , DiCorleto Paul E. , Chisolm Guy M.
Published: June 2012

Background
−Tissue factor, which is required for the initiation of the extrinsic coagulation cascade, is known to be upregulated in cells within atherosclerotic lesions, including smooth muscle cells. Tissue factor expression on the smooth muscle cell surface could be of pathological significance as a contributor to plaque growth, thrombus formation, and the acute coronary syndrome after plaque rupture.

Methods and Results
−In this study, we show that LDL increased tissue factor mRNA and cell surface protein in smooth muscle cells without a marked increase in surface tissue factor activity. Hydrogen peroxide activated tissue factor on the cell surface but did not increase tissue factor mRNA or cell surface protein. Sequentially added LDL and hydrogen peroxide increased mRNA, cell surface protein, and activity; surface activity was greater than that observed with hydrogen peroxide alone. The action of hydrogen peroxide did not involve a regulatory mechanism associated with the cytoplasmic tail of tissue factor because a truncated tissue factor lacking the cytoplasmic tail was activated by hydrogen peroxide.

Conclusions
−These results suggest a novel 2-step pathway for increased tissue factor activity on smooth muscle cell surfaces in which lipoproteins regulate synthesis of a latent tissue factor and oxidants activate the protein complex.
Proinflammatory Mediators Chronically Downregulate the Formation of the Endothelium-Derived Hyperpolarizing Factor in Arteries Via a Nitric Oxide/Cyclic GMP–Dependent Mechanism
Authors: Kessler Paul , Popp Rüdiger , Busse Rudi , Schini-Kerth Valérie B.
Published: June 2012

Background
—Endothelium-dependent dilator responses mediated by NO and endothelium-derived hyperpolarizing factor (EDHF) are altered in arteriosclerosis and sepsis. The possibility that proinflammatory mediators that stimulate the expression of inducible NO synthase (NOS II) affect the generation of EDHF was examined in isolated arteries.

Methods and Results
—Under combined blockade of NOS and cyclooxygenase, EDHF-mediated relaxation elicited by several agonists was significantly attenuated in rabbit carotid and porcine coronary arteries exposed to cytokines and lipopolysaccharide. The blunted relaxation was coincident with NOS II expression and was prevented by inhibition of NOS II as well as of global protein synthesis. The NO donor CAS 1609 and 8-bromo-cGMP mimicked the proinflammatory mediator effect. In contrast, long-term blockade of endothelial NO generation increased the relaxation in carotid but not in coronary arteries. Proinflammatory mediators reduced the synthesis of EDHF assessed as hyperpolarization of vascular smooth muscle cells elicited by the effluent from bradykinin-stimulated coronary arteries. Proinflammatory mediators induced NOS II expression in cultured endothelial cells and decreased the expression of cytochrome P450 enzymes, which are the most probable candidates for the synthesis of EDHF.

Conclusions
—Proinflammatory mediators inhibit the formation of EDHF in isolated arteries. This impairment is coincident with NOS II expression in the arterial wall and seems to be mediated through the induced generation of NO, which downregulates the putative EDHF-forming enzyme. Thus, a decreased formation of EDHF may contribute to the endothelial dysfunction in arteriosclerosis and sepsis.
Generation of Humanized Mice Susceptible to Peptide-Induced Inflammatory Heart Disease
Authors: Bachmaier Kurt , Neu Nikolaus , Yeung Rae S. M. , Mak Tak W. , Liu Peter , Penninger Josef M.
Published: June 2012

Background
−Dilated cardiomyopathy (DCM) is a major cause of sudden cardiac death. In certain mouse major histocompatibility complex (MHC) backgrounds, myocarditis and inflammatory cardiomyopathy can be triggered by immunization with heart muscle–specific proteins. Similarly, chronic heart disease in humans has been linked to certain HLA alleles, such as HLA-DQ6. However, there is no experimental evidence showing that human MHC class II molecules and peptides derived from human proteins are involved in the pathogenesis of myocarditis and DCM.

Methods and Results
—We generated double CD4- and CD8-deficient mice transgenic for human CD4 (hCD4) and human HLA-DQ6 to specifically reconstitute the human CD4/DQ6 arm of the immune system in mice. Transgenic hCD4 and HLA-DQ6 expression rendered genetically resistant C57BL/6 mice susceptible to the induction of autoimmune myocarditis induced by immunization with cardiac myosin. Moreover, we identified heart-specific peptides derived from both mouse and human α-myosin heavy chains capable of inducing inflammatory heart disease in hCD4 and HLA-DQ6 double transgenic mice but not in hCD4 single transgenic littermates. The autoimmune inflammatory heart disease induced by the human heart muscle–specific peptide in hCD4 and HLA-DQ6 double transgenic mice shared functional and phenotypic features with the disease occurring in disease-susceptible nontransgenic mice.

Conclusions
—Our data provide the first genetic and functional evidence that human MHC class II molecules and a human α-myosin heavy chain–derived peptide can cause inflammatory heart disease and suggest that human inflammatory cardiomyopathy can be caused by organ-specific autoimmunity. The humanized mice generated in this study will be an ideal animal model to further elucidate the pathogenesis of inflammatory heart disease and facilitate the development of rational treatment strategies.