bluuebunny/crossref_metadata_2025 huggingface dataset:
Transient Outward Current,
I
to1
, Is Altered in Cardiac Memory
Authors: Yu Hangang , McKinnon David , Dixon Jane E. , Gao Junyuan , Wymore Randy , Cohen Ira S. , Danilo Peter , Shvilkin Alexei , Anyukhovsky Evgeny P. , Sosunov Eugene A. , Hara Motoki , Rosen Michael R.
Published: June 2012

Background
—Cardiac memory refers to an altered T-wave morphology induced by ventricular pacing or arrhythmias that persist for variable intervals after resumption of sinus rhythm.

Methods and Results
—We induced long-term cardiac memory (LTM) in conscious dogs by pacing the ventricles at 120 bpm for 3 weeks. ECGs were recorded daily for 1 hour, during which time pacing was discontinued. At terminal study, the heart was removed and the electrophysiology of left ventricular epicardial myocytes was investigated. Control (C) and LTM ECG did not differ, except for T-wave amplitude, which decreased from 0.12±0.18 to −0.34±0.21 mV (±SEM,
P
<0.05), and T-wave vector, which shifted from −37±12° to −143±4° (
P
<0.05). Epicardial action potentials revealed loss of the notch and lengthening of duration at 20 days (both
P
<0.05). Calcium-insensitive transient outward current (
I
to
) was investigated by whole-cell patch clamp. No difference in capacitance was seen in C and LTM myocytes.
I
to
activated on membrane depolarization to −25±1 mV in C and −7±1 mV (
P
<0.05) in LTM myocytes, indicating a positive voltage shift of activation.
I
to
density was reduced in LTM myocytes, and a decreased mRNA level for
Kv4.3
was observed. Recovery of
I
to
from inactivation was significantly prolonged: it was 531±80 ms (n=10) in LTM and 27±6 ms (n=9) in C (
P
<0.05) at −65 mV.

Conclusions
—
I
to
changes are associated with and can provide at least a partial explanation for action-potential and T-wave changes occurring with LTM.
Frequency of Atrial Septal Aneurysms in Patients With Cerebral Ischemic Events
Authors: Agmon Yoram , Khandheria Bijoy K. , Meissner Irene , Gentile Federico , Whisnant Jack P. , Sicks JoRean D. , O’Fallon W. Michael , Covalt Jody L. , Wiebers David O. , Seward James B.
Published: June 2012

Background
—Atrial septal aneurysm (ASA) is a putative risk factor for cardioembolism. However, the frequency of ASA in the general population has not been adequately determined. Therefore, the frequency in patients with cerebral ischemic events, compared with the frequency in the general population, is poorly defined. We sought to determine the frequency of ASA in the general population and to compare the frequency of ASA in patients with cerebral ischemic events with the frequency in the general population.

Methods and Results
—The frequency of ASA in the population was determined in 363 subjects, a sample of the participants in the Stroke Prevention: Assessment of Risk in a Community study (control subjects), and was compared with the frequency in 355 age- and sex-matched patients undergoing transesophageal echocardiography in search of a cardiac source of embolism after a focal cerebral ischemic event. The proportion with ASA was 7.9% in patients versus 2.2% in control subjects (
P
=0.002; odds ratio of ASA, 3.65; 95% CI, 1.64 to 8.13, in patients versus control subjects). Patent foramen ovale (PFO) was detected with contrast injections in 56% of subjects with ASA. The presence of ASA predicted the presence of PFO (odds ratio of PFO, 4.57; 95% CI, 2.18 to 9.57, in subjects with versus those without ASA). In 86% of subjects with ASA and cerebral ischemia, transesophageal echocardiography did not detect an alternative source of cardioembolism other than an associated PFO.

Conclusions
—The prevalence of ASA based on this population-based study is 2.2%. The frequency of ASA is relatively higher in patients evaluated with transesophageal echocardiography after a cerebral ischemic event. ASA is frequently associated with PFO, suggesting paradoxical embolism as a mechanism of cardioembolism. In patients with cerebral ischemia and ASA, ASA (with or without PFO) commonly is the only potential cardioembolic source detected with transesophageal echocardiography.
Determinants and Prognostic Implications of Persistent ST-Segment Elevation After Primary Angioplasty for Acute Myocardial Infarction
Authors: Claeys Marc J. , Bosmans Johan , Veenstra Leonard , Jorens Philippe , Herbert De Raedt  , Vrints Chris J.
Published: June 2012

Background
—Despite early recanalization of an occluded infarct artery, reperfusion at the level of the microcirculation may remain impaired owing to a process of microvascular reperfusion injury.

Methods and Results
—Microvascular reperfusion injury was studied in 91 patients with acute myocardial infarction (AMI) by evaluation of the resolution of ST-segment elevation after successful PTCA. Impaired microvascular reperfusion, defined as the presence of persistent (≥50% of initial value) ST-segment elevation (ST ≥50%) at the end of coronary intervention, was observed in 33 patients (36%) and was independently correlated with low systolic pressure on admission and high age. Patients ≥55 years of age with systolic pressures ≤120 mm Hg were at high risk for development of impaired reperfusion compared with patients not meeting these criteria (72% versus 14%,
P
<0.001). Impaired microvascular reperfusion was associated with a more extensive infarction and worse clinical outcome at the 1-year follow-up: cardiac death rate, 15% versus 2% (ST ≥50% versus ST <50%,
P
=0.01); nonfatal MI rate, 9% versus 2% (
P
=0.1); and total major adverse cardiac event (MACE) rate, 45% versus 15% (
P
<0.005). ST ≥50% was the most important independent determinant of MACE with an adjusted risk ratio of 3.4.

Conclusions
—Impaired microvascular reperfusion, as evidenced by ST ≥50% after successful recanalization, occurs in more than one third of our AMI patients, especially in older patients with low systolic pressure. Its detrimental implications on clinical outcome reinforce the need to develop adjunctive agents that attenuate the process of reperfusion injury.
Kallidin- and Bradykinin-Degrading Pathways in Human Heart
Authors: Kokkonen Jorma O. , Kuoppala Antti , Saarinen Juhani , Lindstedt Ken A. , Kovanen Petri T.
Published: June 2012

Background
—Since kinins kallidin (KD) and bradykinin (BK) appear to have cardioprotective effects ranging from improved hemodynamics to antiproliferative effects, inhibition of kinin-degrading enzymes should potentiate such effects. Indeed, it is believed that this mechanism is partly responsible for the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors. In the heart, enzymes other than ACE may contribute to local degradation of kinins. The purpose of this study was to investigate which enzymes are responsible for the degradation of KD and BK in human heart tissue.

Methods and Results
—Cardiac membranes were prepared from the left ventricles of normal (n=5) and failing (n=10) hearts. The patients had end-stage congestive heart failure as the result of coronary heart disease or idiopathic dilated cardiomyopathy. Heart tissue was incubated with KD or BK in the presence or absence of enzyme inhibitors. We found no difference in the enzymes responsible for kinin metabolism or their activities between normal and failing hearts. Thus KD was mostly converted into BK by the aminopeptidase M–like activity. When BK was used as substrate, it was converted into an inactive metabolite BK-(1-7) mostly (80% to 90%) by the neutral endopeptidase (NEP) activity, with ACE unexpectedly playing only a minor role. The low enzymatic activity of ACE in the cardiac membranes, compared with that of NEP, was not due to chronic ACE inhibitor therapy, because the cardiac ACE activities of patients, whether receiving ACE inhibitors or not, and of normal subjects were all equal.

Conclusions
—The present in vitro study shows that in human cardiac membranes, the most critical step in kinin metabolism, that is, inactivation of BK, appears to be mediated mostly by NEP. This observation suggests a role for NEP in the local control of BK concentration in heart tissue. Thus inhibition of cardiac NEP activity could be cardioprotective by elevating the local concentration of BK in the heart.
Vascular Cell Apoptosis
Authors: Pollman Matthew J. , Naumovski Louie , Gibbons Gary H.
Published: June 2012

Background
—It is postulated that vascular lesion formation and remodeling involves a balance between vascular cell death and cell proliferation. Transforming growth factor-β
1
(TGF-β
1
) is a pleiotropic factor expressed within vascular cells that regulates cell growth in a tissue-specific manner. This study tested the hypothesis that the control of vascular cell apoptosis involves cell type–specific regulation by TGF-β
1
.

Methods and Results
—In response to serum withdrawal, cultured endothelial cells and vascular smooth muscle cells exhibited apoptosis as evidenced by DNA laddering and quantitated by analysis of nuclear chromatin morphology. Addition of TGF-β
1
to endothelial cells in serum-free media further potentiated the induction of apoptosis in a dose-dependent fashion. Moreover, TGF-β
1
promoted endothelial cell death despite the presence of 10% serum. However, endothelial cells plated on collagen I were resistant to TGF-β
1
–induced apoptosis. This antiapoptotic influence of the matrix was mimicked by integrin activation with anti-β
1
antibodies and associated with increased expression of the antiapoptotic factor
bcl
-2. In accord with the hypothesis that the modulation of antiapoptotic gene expression may mediate the effects of TGF-β
1
and β
1
integrins on cell fate, we observed that endothelial cells with constitutive upregulation of
bcl
-2 remained viable despite exposure to TGF-β
1
in serum-free conditions. In contrast to the proapoptotic effect of TGF-β
1
in endothelial cells, addition of TGF-β
1
to vascular smooth muscle cells in serum-free media inhibited apoptosis.

Conclusions
—These findings suggest that the effect of cytokines such as TGF-β
1
on cell fate is contextual and is modulated by cell-matrix interactions in a cell type–specific manner.
Hyperhomocysteinemia
Authors: van Beynum Ingrid M. , Smeitink Jan A. M. , den Heijer Martin , te Poele Pothoff Maria T. W. B. , Blom Henk J.
Published: June 2012

Background
—Moderate hyperhomocysteinemia is a risk factor for arterial vascular disease and venous thrombosis in adults. We performed a case-control study to assess a possible relation between moderate hyperhomocysteinemia and ischemic stroke in Dutch children (age range, 0 to 18 years).

Methods and Results
—We measured plasma total homocysteine levels (tHcy) in 45 patients with ischemic stroke and in 234 controls. Hyperhomocysteinemia was defined as a tHcy above the 95th percentile regression line for the respective age of the controls. Hyperhomocysteinemia was present in 8 (18%) of the 45 patients with ischemic stroke. The odds ratio was 4.4 (95% CI, 1.7 to 11.6).

Conclusions
—We conclude that moderate hyperhomocysteinemia is a risk factor for ischemic stroke in children.
Beneficial Impact of Preconditioning During PTCA on Creatine Kinase Release
Authors: Laskey Warren K.
Published: June 2012

Background
—Previous studies in humans have indicated that there is less ischemic dysfunction during PTCA when ischemic preconditioning is elicited. However, the clinical relevance of these observations remains unclear. The present study design tests the hypothesis that PTCA performed to elicit the preconditioning response would result in less myocardial necrosis as assessed by postprocedure creatine kinase (CK) levels

Methods and Results
—Patients (n=150) undergoing PTCA for unstable ischemic syndromes were randomly assigned to receive a previously validated approach to PTCA-mediated preconditioning (PC) or an unrestricted approach to balloon angioplasty (UC). CK levels were determined at 8, 12, and, if necessary, 24 hours. Clinical success rates were equivalent for the 2 groups. However, the frequency of any CK elevation was significantly higher in the UC group (25%) than in the PC group (7.1%) (
P
<0.005). Multivariable analysis confirmed a significant effect of preconditioning on CK release.

Conclusions
—A standardized protocol to elicit preconditioning during PTCA results in a significant reduction in the rate of CK elevation in a high-risk population. These observations support the clinical relevance of ischemic preconditioning in humans.
Ready-Made, Recalibrated, or Remodeled?
Authors: Ivanov Joan , Tu Jack V. , Naylor C. David
Published: June 2012

Background
—Risk indexes for operative mortality after cardiac surgery are used for comparative profiling of surgeons or centers. We examined whether clinicians and managers should use an existing index without modification, recalibrate it for their populations, or derive a new model altogether.

Methods and Results
—Drawing on 7491 consecutive patients who underwent isolated CABG at 2 Toronto teaching hospitals between 1993 and 1996, we compared 3 strategies: (1) using a ready-made model originally derived and validated in our jurisdiction; (2) recalibrating the ready-made model to better fit the population; and (3) deriving a new model with additional risk factors. We assessed statistical accuracy, ie, area under a receiver-operator characteristic curve (ROC); precision, ie, statistical goodness-of-fit; and actual impact on both risk-adjusted operative mortalities (RAOM) and performance rankings for 14 surgeons. The new model was slightly more accurate than the ready-made model (ROC, 0.78 versus 0.76;
P
<0.05), albeit not different from the recalibrated model (ROC, 0.77). The ready-made model showed poor fit between the predicted and observed results (
P
<0.001), leading to significant underestimation of RAOM (1.6±0.2%) compared with the other strategies (2.5±0.2%;
P
=0.048). Remodeling also changed the performance rankings among half the surgeons with higher RAOM.

Conclusions
—Poorly calibrated risk algorithms can bias the calculation of RAOM and alter the results of surgeon-specific profiles. Any existing index used for risk assessment in cardiac surgery should be episodically recalibrated or compared with new models derived from local subjects to ensure that its performance remains optimal.
Mechanisms Underlying Aortic Dilatation in Congenital Aortic Valve Malformation
Authors: Bonderman Diana , Gharehbaghi-Schnell Elisabeth , Wollenek Gregor , Maurer Gerald , Baumgartner Helmut , Lang Irene M.
Published: June 2012

Background
—The high incidence of aortic disease in subjects with congenital aortic valve malformations suggests a causative relationship between these 2 conditions. The histological observation in aortic dilatation/aneurysm/dissection is Erdheim cystic medial necrosis (CMN), a noninflammatory loss of smooth muscle cells (SMCs), fragmentation of elastic fibers, and mucoid degeneration.

Methods and Results
—To examine whether apoptosis is 1 of the mechanisms underlying CMN and aortic medial layer SMC loss, ascending aortic wall specimens from 32 patients were collected at cardiothoracic surgery and examined by histochemical staining and terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick end labeling. From echocardiography results, 4 groups of patients were identified: bicuspid valve carriers with (bi/dil) or without (bi/0) aortic dilatation and tricuspid valve carriers with (tri/dil) or without (tri/0) aortic dilatation. Massive focal apoptosis was observed in the medial layers of bi/dil (mean apoptotic index [mAI], 8.1±6.0) and tri/dil (mAI, 8.1±8.3) compared with tri/0 (mAI, 0.9±1.2;
P
=0.0079 and
P
=0.037). In bi/0 (mAI, 9.1±5.7) compared with tri/0 (mAI, 0.9±1.2), rates of medial SMC apoptosis were increased (
P
=0.0025). Bi/dil (mean age, 40.6±15.7 years) were significantly younger than tri/dil (mean age, 56.4±12.8 years) undergoing the same operation (
P
=0.0123).

Conclusions
—Premature medial layer SMC apoptosis could be part of a genetic program underlying aortic disease in patients with aortic valve malformations.
Granulocyte-Macrophage Colony–Stimulating Factor Prevents the Progression of Atherosclerosis via Changes in the Cellular and Extracellular Composition of Atherosclerotic Lesions in Watanabe Heritable Hyperlipidemic Rabbits
Authors: Shindo Joji , Ishibashi Toshiyuki , Yokoyama Keiko , Nakazato Kazuhiko , Ohwada Takayuki , Shiomi Masashi , Maruyama Yukio
Published: June 2012

Background
—A cytokine network is involved in atherogenesis. This study was conducted to investigate the effects of granulocyte-macrophage colony–stimulating factor (GM-CSF) on the development and composition of atherosclerotic lesions in Watanabe heritable hyperlipidemic (WHHL) rabbits.

Methods and Results
—GM-CSF (10 μg · kg
−1
· d
−1
) was administered to 4-month-old WHHL rabbits (n=9) 5 days a week for 7.5 months, whereas an equal dose of human serum albumin was administered to controls (n=9). The cholesterol levels were not changed significantly by the treatment. Age-matched 4-month-old rabbits (n=7) had atheromatous plaques over 30.7±5.7% of the inner surface area of the aortic arch. After treatment, the percentages of surface atheromatous plaques to total aortic arch area were 45.0±12.6% in the GM-CSF group and 74.3±11.0% in controls (
P
<0.0001). Histological examination demonstrated that GM-CSF reduced the ratio of intima to media (
P
<0.01) and cross-sectional areas of atherosclerotic lesions (
P
<0.0001). Quantitative analysis indicated a marked decrease in the areas of smooth muscle cells (
P
=0.0001), collagen (
P
=0.0001), and extracellular lipid deposits (
P
<0.05) of atheromatous plaques in GM-CSF–treated rabbits compared with controls. The terminal deoxynucleotidyltransferase–mediated dUTP-digoxigenin nick end-labeling (TUNEL) method and immunohistochemistry were performed to examine the relationship between decreased atherosclerotic lesions and apoptosis. The percentage of TUNEL-positive cells increased in the GM-CSF group (GM-CSF, 24.1±4.4% versus control, 11.6±3.2%;
P
<0.0001). GM-CSF enhanced the apoptosis of smooth muscle cells in the shoulder region and the fibrous cap (
P
<0.0001), suggesting one of the mechanisms for the antiatherogenic effect.

Conclusions
—GM-CSF altered the composition of atherosclerotic lesions and reduced the atherosclerosis in WHHL rabbits.
Amiodarone Interaction With β-Blockers
Authors: Boutitie Florent , Boissel Jean-Pierre , Connolly Stuart J. , Camm A. John , Cairns John A. , Julian Desmond G. , Gent Michael , Janse Michiel J. , Dorian Paul , Frangin Gerald
Published: June 2012

Background
—Investigations with in vitro and animal models suggest an interaction between amiodarone and β-blockers. The objective of this work was to explore if an interaction with β-blocker treatment plays a role in the decrease of cardiac arrhythmic deaths with amiodarone in patients recovered from an acute myocardial infarction.

Methods and Results
—A pooled database from 2 similar randomized clinical trials, the European Amiodarone Myocardial Infarction Trial (EMIAT) and the Canadian Amiodarone Myocardial Infarction Trial (CAMIAT), was used. Four groups of post–myocardial infarction patients were defined: β-blockers and amiodarone used, β-blockers used alone, amiodarone used alone, and neither used. All analyses were done on an intention-to-treat basis. Unadjusted and adjusted relative risks for all-cause mortality, cardiac death, arrhythmic cardiac death, nonarrhythmic cardiac death, arrhythmic death, or resuscitated cardiac arrest were lower for patients receiving β-blockers and amiodarone than for those without β-blockers, with or without amiodarone. The interaction was statistically significant for cardiac death and arrhythmic death or resuscitated cardiac arrest (
P
=0.05 and 0.03, respectively). Findings were consistent across subgroups.

Conclusions
—These findings are based on a post hoc analysis. However, they confirm prior results from in vitro and animal experiments suggesting an interaction between β-blockers and amiodarone. In practice, not only is the adjunct of amiodarone to β-blockers not hazardous, but β-blocker therapy should be continued if possible in patients in whom amiodarone is indicated.
Hyperhomocysteinemia but Not the C677T Mutation of Methylenetetrahydrofolate Reductase Is an Independent Risk Determinant of Carotid Wall Thickening
Authors: McQuillan Brendan M. , Beilby John P. , Nidorf Mark , Thompson Peter L. , Hung Joseph
Published: June 2012

Background
—Hyperhomocysteinemia has been identified as a potential risk factor for atherosclerosis. This study examined whether a modest elevation of plasma total homocysteine (tHcy) was an independent risk factor for increased carotid artery intimal-medial wall thickness (IMT) and focal plaque formation in a large, randomly selected community population. We also examined whether vitamin cofactors and the C677T genetic mutation of the methylenetetrahydrofolate reductase (
MTHFR
) enzyme were major contributors to elevated plasma tHcy and carotid vascular disease.

Methods and Results
—In 1111 subjects (558 men, 553 women) 52±13 years old (mean±SD; range, 27 to 77 years) recruited from a random electoral roll survey, we measured fasting tHcy and performed bilateral carotid B-mode ultrasound. For the total population, mean tHcy was 12.1±4.0 μmol/L. Plasma tHcy levels were correlated with IMT (Spearman rank
r
s
=0.31,
P
=0.0001). After adjustment for age, sex, and other conventional risk factors, subjects in the highest versus the lowest quartile of tHcy had an odds ratio of 2.60 (95% CI, 1.51 to 4.45) for increased IMT and 1.76 (95% CI, 1.10 to 2.82) for plaque. Serum and dietary folate levels and the C677T mutation in
MTHFR
were independent determinants of tHcy (all
P
=0.0001). The mutant homozygotes (10% of the population) had higher mean tHcy than heterozygotes or those without the mutation (14.2 versus 12.3 versus 11.6 μmol/L, respectively,
P
=0.0001). The inverse association of folate levels with tHcy was steeper in the mutant homozygotes. Despite this, the C677T
MTHFR
mutation was not independently predictive of increased carotid IMT or plaque formation.

Conclusions
—Mild hyperhomocysteinemia is an independent risk factor for increased carotid artery wall thickness and plaque formation in a general population. Lower levels of dietary folate intake and the C677T mutation in
MTHFR
are important causes of mild hyperhomocysteinemia and may therefore contribute to vascular disease in the community.
Effect of NO Donors on LV Diastolic Function in Patients With Severe Pressure-Overload Hypertrophy
Authors: Matter Christian M. , Mandinov Lazar , Kaufmann Philipp A. , Vassalli Giuseppe , Jiang Zihua , Hess Otto M.
Published: June 2012

Background
—Previous experimental studies have shown that nitric oxide (NO) modulates cardiac function by an abbreviation of systolic contraction and an enhancement of diastolic relaxation. However, the response to NO donors of patients with severe pressure-overload hypertrophy and diastolic dysfunction is unknown.

Methods and Results
—Intracoronary NO donors were given to 17 patients with severe aortic stenosis. A dose-response curve was obtained with nitroglycerin (30, 90, and 150 μg) in 11 patients and sodium nitroprusside (1, 2, and 4 μg/min) in 6. Left ventricular (LV) high-fidelity pressure measurements with simultaneous LV angiograms were performed at baseline and after the maximal dose of NO. The dose-response curve for intracoronary NO donors showed a marked fall in LV end-diastolic pressure, from 23 to 14 mm Hg (−39%;
P
<0.0001), whereas LV peak systolic pressure fell only slightly, from 206 to 196 mm Hg (−4%;
P
<0.01). End-diastolic chamber stiffness decreased from 0.12 to 0.07 mm Hg/mL (
P
<0.0001) and end-systolic stiffness from 1.6 to 1.3 mm Hg/mL (
P
<0.01). Heart rate, right atrial pressure, LV ejection fraction, the time constant of isovolumic pressure decay (τ), and LV filling rates remained unchanged.

Conclusions
—In patients with severe pressure-overload hypertrophy, intracoronary NO donors exert a marked decrease in LV end-diastolic pressure without affecting LV systolic pump function. Thus, the hypertrophied myocardium appears to be particularly susceptible to NO donors, with a marked improvement in diastolic function.
Beneficial Effects of Fibrates on Apolipoprotein A-I Metabolism Occur Independently of Any Peroxisome Proliferative Response
Authors: Hennuyer Nathalie , Poulain Philippe , Madsen Lise , Berge Rolf K. , Houdebine Louis-Marie , Branellec Didier , Fruchart Jean-Charles , Fiévet Catherine , Duverger Nicolas , Staels Bart
Published: June 2012

Background
—In humans, fibrates are frequently used normolipidemic drugs. Fibrates act by regulating genes involved in lipoprotein metabolism via activation of the peroxisome proliferator-activated receptor-α (PPARα) in liver. In rodents, however, fibrates induce a peroxisome proliferation, leading to hepatomegaly and possibly hepatocarcinogenesis. Although this peroxisome proliferative response appears not to occur in humans, it remains controversial whether the beneficial effects of fibrates on lipoprotein metabolism can occur dissociated from such undesirable peroxisomal response. Here, we assessed the influence of fenofibrate on lipoprotein metabolism and peroxisome proliferation in the rabbit, an animal that, contrary to rodents and similar to humans, is less sensitive to peroxisome proliferators.

Methods and Results
—First, we demonstrate that in normal rabbits, fenofibrate given at a high dose for 2 weeks does not influence serum concentrations or intestinal mRNA levels of the HDL apolipoprotein apoA-I. Therefore, the study was continued with human apoA-I transgenic rabbits that overexpress the human apoA-I gene under control of its homologous promoter, including its PPAR-response elements. In these animals, fenofibrate increases serum human apoA-I concentrations via an increased expression of the human apoA-I gene in liver. Interestingly, liver weight or mRNA levels and activity of fatty acyl-CoA oxidase, a rate-limiting and marker enzyme of peroxisomal β-oxidation, remain unchanged after fenofibrate.

Conclusions
—Expression of the human apoA-I transgene in rabbit liver suffices to confer fibrate-mediated induction of serum apoA-I. Furthermore, these data provide in vivo evidence that the beneficial effects of fibrates on lipoprotein metabolism occur mechanistically dissociated from any deleterious activity on peroxisome proliferation and possibly hepatocarcinogenesis.
β
2
-Adrenergic cAMP Signaling Is Uncoupled From Phosphorylation of Cytoplasmic Proteins in Canine Heart
Authors: Kuschel Meike , Zhou Ying-Ying , Spurgeon Harold A. , Bartel Sabine , Karczewski Peter , Zhang Sheng-Jun , Krause Ernst-Georg , Lakatta Edward G. , Xiao Rui-Ping
Published: June 2012

Background
—Recent studies of β-adrenergic receptor (β-AR) subtype signaling in in vitro preparations have raised doubts as to whether the cAMP/protein kinase A (PKA) signaling is activated in the same manner in response to β
2
-AR versus β
1
-AR stimulation.

Methods and Results
—The present study compared, in the intact dog, the magnitude and characteristics of chronotropic, inotropic, and lusitropic effects of cAMP accumulation, PKA activation, and PKA-dependent phosphorylation of key effector proteins in response to β-AR subtype stimulation. In addition, many of these parameters and L-type Ca
2+
current (
I
Ca
) were also measured in single canine ventricular myocytes. The results indicate that although the cAMP/PKA-dependent phosphorylation cascade activated by β
1
-AR stimulation could explain the resultant modulation of cardiac function, substantial β
2
-AR–mediated chronotropic, inotropic, and lusitropic responses occurred in the absence of PKA activation and phosphorylation of nonsarcolemmal proteins, including phospholamban, troponin I, C protein, and glycogen phosphorylase kinase. However, in single canine myocytes, we found that β
2
-AR–stimulated increases in both
I
Ca
and contraction were abolished by PKA inhibition. Thus, the β
2
-AR–directed cAMP/PKA signaling modulates sarcolemmal L-type Ca
2+
channels but does not regulate PKA-dependent phosphorylation of cytoplasmic proteins.

Conclusions
—These results indicate that the dissociation of β
2
-AR signaling from cAMP regulatory systems is only apparent and that β
2
-AR–stimulated cAMP/PKA signaling is uncoupled from phosphorylation of nonsarcolemmal regulatory proteins involved in excitation-contraction coupling.
Calcium Antagonists Ameliorate Ischemia-Induced Endothelial Cell Permeability by Inhibiting Protein Kinase C
Authors: Hempel Albrecht , Lindschau Carsten , Maasch Christian , Mahn Matthias , Bychkov Rostislav , Noll Thomas , Luft Friedrich C. , Haller Hermann
Published: June 2012

Background
—Dihydropyridines block calcium channels; however, they also influence endothelial cells, which do not express calcium channels. We tested the hypothesis that nifedipine can prevent ischemia-induced endothelial permeability increases by inhibiting protein kinase C (PKC) in cultured porcine endothelial cells.

Methods and Results
—Ischemia was induced by potassium cyanide/deoxyglucose, and permeability was measured by albumin flux. Ion channels were characterized by patch clamp. [Ca
2+
]
i
was measured by fura 2. PKC activity was measured by substrate phosphorylation after cell fractionation. PKC isoforms were assessed by Western blot and confocal microscopy. Nifedipine prevented the ischemia-induced increase in permeability in a dose-dependent manner. Ischemia increased [Ca
2+
]
i
, which was not affected by nifedipine. Instead, ischemia-induced PKC translocation was prevented by nifedipine. Phorbol ester also increased endothelial cell permeability, which was dose dependently inhibited by nifedipine. The effects of non–calcium-channel–binding dihydropyridine derivatives were similar. Analysis of the PKC isoforms showed that nifedipine prevented ischemia-induced translocation of PKC-α and PKC-ζ. Specific inhibition of PKC isoforms with antisense oligodeoxynucleotides demonstrated a major role for PKC-α.

Conclusions
—Nifedipine exerts a direct effect on endothelial cell permeability that is independent of calcium channels. The inhibition of ischemia-induced permeability by nifedipine seems to be mediated primarily by PKC-α inhibition. Anti-ischemic effects of dihydropyridine calcium antagonists could be due in part to their effects on endothelial cell permeability.
Increased Sympathetic Nerve Activity in Renovascular Hypertension
Authors: Johansson Mats , Elam Mikael , Rundqvist Bengt , Eisenhofer Graeme , Herlitz Hans , Lambert Gavin , Friberg Peter
Published: June 2012

Background
—Increased sympathetic nerve activity may contribute to the progression of renovascular hypertension. Because previous results have been inconclusive, we investigated whether renovascular hypertensives show increased total and regional sympathetic nerve activity.

Methods and Results
—Sixty-five patients underwent renal angiography and measurements of plasma renin activity and angiotensin II in conjunction with estimation of sympathetic nerve activity by means of radiotracer dilution and intraneural recordings of muscle sympathetic nerve activity (MSNA). Age-matched healthy subjects (n=15) were examined for comparison. Total body norepinephrine (NE) spillover, an index of overall sympathetic nerve activity, was increased by 100% and MSNA by 60% in the hypertensive patients compared with healthy subjects (
P
<0.01 for both). A subgroup of 24 patients with well-defined renovascular hypertension (cured or improved hypertension after renal angioplasty) showed similar increases in total body NE spillover compared with the group at large. Patients with arterial plasma renin activity and angiotensin II levels above median had higher values for total body NE spillover than patients below median (
P
<0.01).

Conclusions
—This study unequivocally demonstrates elevated sympathetic nerve activity in patients with renovascular hypertension. The adrenergic overactivity may contribute to the blood pressure elevation and perhaps also to the high cardiovascular mortality in renovascular hypertension.
Feasibility of a Noncontact Catheter for Endocardial Mapping of Human Ventricular Tachycardia
Authors: Schilling Richard J. , Peters Nicholas S. , Davies D. Wyn
Published: June 2012

Background
—Catheter ablation of ventricular tachycardia (VT) is limited by difficulty in identifying suitable sites for ablation. This study assesses use of a system capable of simultaneous endocardial mapping of the human left ventricle to map and guide radiofrequency (RF) catheter ablation of VT.

Methods and Results
—A catheter-mounted noncontact multielectrode array was used to reconstruct 3360 electrograms, superimposed onto a computer-simulated endocardial model. Of 24 patients studied, 20 had ischemic heart disease. Exit sites were demonstrated by the noncontact system in 80 (99%) of 81 VTs, with complete VT circuits traced in 17 (21%). In another 37 VTs, 36±30% (mean±SD) of the diastolic interval was identified. Thirty-eight VT morphologies were ablated with 154 RF energy applications. Successful ablation was achieved by 77% of RF applications to relevant diastolic activity identified by the system and was significantly more likely (
P
<0.0001) than by RF at the VT exit or remote from diastolic activation. Over a mean follow-up of 1.5 years, 14 patients (64%) have had no recurrence of VT, and only 2 target VTs (5.3%) have recurred. Five patients have had recurrence of other VTs.

Conclusions
—This noncontact mapping system identified diastolic portions of the circuit in most VTs studied and can safely map and guide ablation of human VT.
High-Density Mapping of Activation Through an Incomplete Isthmus Ablation Line
Authors: Shah Dipen , Haïssaguerre Michel , Jaïs Pierre , Takahashi Atsushi , Hocini Meleze , Clémenty Jacques
Published: June 2012

Background
—Activation mechanisms through gaps in ablation lines and resulting electrograms are poorly understood.

Methods and Results
—Eight patients (all men; age, 59±9 years) were studied during a recurrence of typical atrial flutter (cycle length, 233±19 ms) after a previous catheter ablation in the cavotricuspid isthmus. High-density 3-dimensional mapping of the isthmus was performed with the Cordis-Biosense EP Navigation system, and local conduction velocity (CV) was estimated. Maps created with 96±19 points revealed 0.8±0.3-cm gaps of recovered conduction in the ablation line. A broad wave front entered the lateral isthmus with a CV of 1.8±0.7 m/s, halted on the lesion line, and penetrated slowly through the gap with a CV of 0.3±0.1 m/s. Activation then curved and returned antidromically to activate the downstream flank of the line with a CV of 1.1±0.7 m/s. This front fused downstream of the line with slow transverse activation (CV, 0.4±0.3 m/s) parallel to it. The ablation line was demarcated by an incomplete line of convergent double potentials with isoelectric intervals (from 123±34 to 62±16 ms); each potential corresponded to local activation upstream and downstream of the lesions, while the intervening delay was produced by slow conduction through the gap combined with the progressively longer curved pathway of downstream antidromic activation as a function of distance from the gap.

Conclusions
—High-density isthmus mapping during recurrent flutter indicates slow conduction through gaps of recovered conduction of varying dimensions in the ablation line followed by a curved front of activation antidromically activating its downstream flank, this detour producing wide double potentials on the line.
Safety and Efficacy of Ticlopidine for Only 2 Weeks After Successful Intracoronary Stent Placement
Authors: Berger Peter B. , Bell Malcolm R. , Hasdai David , Grill Diane E. , Melby Steve , Holmes David R.
Published: June 2012

Background
—In patients receiving intracoronary stents, stent thrombosis is reduced when ticlopidine therapy is combined with aspirin after the procedure. However, ticlopidine causes neutropenia in 1% of patients when administered for >2 weeks, and little is known about the duration that ticlopidine needs be administered to prevent stent thrombosis.

Methods and Results
—We analyzed 827 patients undergoing successful stent placement in 1061 coronary segments at Mayo Clinic who were treated between May 1, 1996, and October 31, 1997. Chronic warfarin therapy, cardiogenic shock, and enrollment in research protocols requiring 4 weeks of ticlopidine were exclusion criteria; ticlopidine was discontinued after 14 days in all remaining patients. The mean age of the study population was 64±11 years; 49% had suffered a prior infarction, 20% had undergone coronary artery bypass surgery, and 65% had multivessel disease. The indication for stent placement was dissection or abrupt closure in 31% of patients and suboptimal results from balloon angioplasty in 18%. Placement was elective in 51% of patients, and 10.3% of patients were treated within 12 hours of an acute myocardial infarction. Mean nominal stent size was 3.3±0.5 mm. High-pressure inflations (≥12 atm) were performed in all patients (mean, 17±4 atm). Intravascular ultrasound was used to facilitate stent placement in 8.8% of patients. Abciximab was administered to 38% of patients; 11% of patients who were at increased risk of stent thrombosis were treated with enoxaparin for 10 to 14 days. Adverse cardiovascular events in the 14 days after stent placement occurred in 11 patients (1.3%). Two patients died of nonischemic causes (sepsis and renal failure) in the 15th through 30th days after ticlopidine was stopped. However, there were no cardiovascular deaths, myocardial infarctions, coronary artery bypass operations, or repeat angioplasty procedures between the 15th and 30th days; stent thrombosis did not occur in any patient after ticlopidine had been stopped. No patient developed neutropenia, although 1.8% of the first 489 patients who were closely monitored for side effects from ticlopidine developed side effects requiring its discontinuation, and milder side effects occurred in 4.7%.

Conclusions
—In patients receiving intracoronary stents, the discontinuation of ticlopidine therapy 14 days after stent placement is associated with a very low frequency of stent thrombosis and other adverse events.
Variant Estrogen and Progesterone Receptor Messages in Human Vascular Smooth Muscle
Authors: Hodges Yvonne K. , Richer Jennifer K. , Horwitz Kathryn B. , Horwitz Lawrence D.
Published: June 2012

Background
—Estrogens stimulate growth of breast or uterine cells but have the opposite effect on vascular smooth muscle cells, in which they protect against coronary artery disease with or without concomitant administration of progesterone. A possible cause of differences in hormone action is variable tissue-specific expression of hormone receptor. Therefore, we analyzed the structure of estrogen receptors (ERs) and progesterone receptors (PRs) in human vascular smooth muscle.

Methods and Results
—RNA was isolated from human vascular smooth muscle, and the functional domains of ER-α and PR were characterized by reverse transcriptase and polymerase chain reaction. Interestingly, in addition to wild-type ER-α and PR, 5 variant ER-α and 2 variant PR transcripts were found. These variants contained precise deletions of exons encoding regions of the hormone-binding domain. The PR transcripts lacked exon 4 (PRΔ4) and exon 6 (PRΔ6). The ER-α transcripts were missing exon 4 (ERΔ4), exon 5 (ERΔ5), exon 6 (ERΔ6), exon 7 (ERΔ7), and exons 6 and 7, (ERΔ6,7). ER-β variants were also detected. The PR variants were functionally characterized, and PRΔ6 was found to be a dominant-negative transcription inhibitor of wild-type receptors. Variant PR was present in premenopausal women but absent in postmenopausal women.

Conclusions
—Variant PR and ER transcripts are extensively expressed in human vascular smooth muscle. The complex tissue-specific effects of sex hormones may be mediated by the expression of heterogeneous forms of their cognate receptors. The presence of variant ERs and PRs may be of importance in altering the physiological effects of estrogens or progestins in vascular smooth muscle.
Relation Between Direct Detection of
Chlamydia pneumoniae
DNA in Human Coronary Arteries at Postmortem Examination and Histological Severity (Stary Grading) of Associated Atherosclerotic Plaque
Authors: Thomas M. , Wong Y. , Thomas D. , Ajaz M. , Tsang V. , Gallagher P. J. , Ward M. E.
Published: June 2012

Background
—Numerous studies have suggested a link between
Chlamydia pneumoniae
infection, atherosclerosis, and coronary artery disease. However, it is still unclear whether
C pneumoniae
plays a causal role in the pathogenesis of these conditions. Accordingly, we have performed a systematic dissection of the 3 coronary arteries on 33 postmortem subjects and studied the relationship in individual artery segments between the presence of
C pneumoniae
DNA and the severity of associated atherosclerosis.

Methods and Results
—The prevalence of
C pneumoniae
DNA in arterial segments was determined by polymerase chain reaction (PCR) after controlling for the presence of PCR inhibitors. Atherosclerosis in each arterial segment was graded histologically with the Stary classification.
C pneumoniae
was detected by PCR in 78.8% of subjects, but there was no association between the presence of this DNA and cause of death or grade of atherosclerosis. When paired mild and severe atherosclerotic lesions within subjects were compared, mild lesions were as likely to be positive for
C pneumoniae
as severe lesions.

Conclusions
—This study demonstrates that
C pneumoniae
can frequently be detected in atheromatous plaques in coronary arteries. However, its distribution did not correlate with severity or extent of disease.
Chaos and the Transition to Ventricular Fibrillation
Authors: Weiss James N. , Garfinkel Alan , Karagueuzian Hrayr S. , Qu Zhilin , Chen Peng-Sheng
Published: June 2012

Abstract
—Sudden cardiac death resulting from ventricular fibrillation can be separated into 2 components: initiation of tachycardia and degeneration of tachycardia to fibrillation. Clinical drug studies such as CAST and SWORD demonstrated that focusing exclusively on the first component is inadequate as a therapeutic modality. The hope for developing effective pharmacological therapy rests on a comprehensive understanding of the second component, the transition from tachycardia to fibrillation. We summarize evidence that the transition from tachycardia to fibrillation is a transition to spatiotemporal chaos, with similarities to the quasiperiodic transition to chaos seen in fluid turbulence. In this scenario, chaos results from the interaction of multiple causally independent oscillatory motions. Simulations in 2-dimensional cardiac tissue suggest that the destabilizing oscillatory motions during spiral-wave reentry arise from restitution properties of action potential duration and conduction velocity. The process of spiral-wave breakup in simulated cardiac tissue predicts remarkably well the sequence by which tachycardia degenerates to fibrillation in real cardiac tissue. Modifying action potential duration and conduction velocity restitution characteristics can prevent spiral-wave breakup in simulated cardiac tissue, suggesting that drugs with similar effects in real cardiac tissue may have antifibrillatory efficacy (the Restitution Hypothesis). If valid for the real heart, the Restitution Hypothesis will support a new paradigm for antiarrhythmic drug classification, incorporating an antifibrillatory profile based on effects on cardiac restitution and the traditional antitachycardia profile (classes 1 through 4).
T
−786
→C Mutation in the 5′-Flanking Region of the Endothelial Nitric Oxide Synthase Gene Is Associated With Coronary Spasm
Authors: Nakayama Masafumi , Yasue Hirofumi , Yoshimura Michihiro , Shimasaki Yukio , Kugiyama Kiyotaka , Ogawa Hisao , Motoyama Takeshi , Saito Yoshihiko , Ogawa Yoshihiro , Miyamoto Yoshihiro , Nakao Kazuwa
Published: June 2012

Background
—Coronary spasm plays an important role in the pathogenesis of ischemic heart diseases in general. However, the precise mechanism(s) responsible for coronary spasm remains to be elucidated, and we examined the molecular genetics of coronary spasm.

Methods and Results
—We searched for the possible mutations in the endothelial nitric oxide synthase (eNOS) gene in patients with coronary spasm. In this study, we demonstrate the existence of 3 linked mutations in the 5′-flanking region of the eNOS gene (T
−786
→C, A
−922
→G, and T
−1468
→A). The incidence of the mutations was significantly greater in patients with coronary spasm than in the control group (
P
<0.0001). Multiple logistic regression analysis with forward stepwise selection using the environmental risk factors and the eNOS gene variant revealed that the most predictive independent risk factor for coronary spasm was the mutant allele (
P
<0.0001). As assessed by luciferase reporter gene assays, the T
−786
→C mutation resulted in a significant reduction in eNOS gene promoter activity (
P
<0.05), whereas neither the A
−922
→G nor the T
−1468
→A mutation had any affect.

Conclusions
—Taken together, these findings strongly suggest that the T
−786
→C mutation in the eNOS gene reduces the endothelial NO synthesis and predisposes the patients with the mutation to coronary spasm.
Assessment of Permanent Dual-Chamber Pacing as a Treatment for Drug-Refractory Symptomatic Patients With Obstructive Hypertrophic Cardiomyopathy
Authors: Maron Barry J. , Nishimura Rick A. , McKenna William J. , Rakowski Harry , Josephson Mark E. , Kieval Robert S.
Published: June 2012

Background
—Dual-chamber pacing (DDD) has been proposed as a treatment alternative to surgery for severely symptomatic patients with obstructive hypertrophic cardiomyopathy (HCM), based largely on uncontrolled studies.

Methods and Results
—This prospective, multicenter trial assessed pacing in 48 symptomatic HCM patients with ≥50 mm Hg basal gradient, refractory to drug therapy. Patients were randomized to 3 months each of DDD pacing and pacing backup (AAI-30) in a double-blind, crossover study design, followed by an uncontrolled and unblinded 6-month pacing trial. With randomization, no significant differences were evident between pacing and no pacing for subjective or objective measures of symptoms or exercise capacity, including NYHA functional class, quality of life score, treadmill exercise time or peak oxygen consumption. After 6 additional months of unblinded pacing, functional class and quality of life score were improved compared with baseline (
P
<0.01), but peak oxygen consumption was unchanged. Outflow gradient decreased 40%, 82±32 mm Hg to 48±32 mm Hg (
P
<0.001), and was reduced in 57% of patients but showed no change or an increase in 43%. At 12 months, 6 individual patients (12%) showed improved functional capacity; each was 65 to 75 years of age. Left ventricular wall thicknesses in the overall study group showed no remodeling between baseline (22±5 mm) and 12 months (21±5 mm;
P=
NS).

Conclusions
—(1) Pacing cannot be regarded as a primary treatment for obstructive HCM; (2) with randomization, perceived symptomatic improvement was most consistent with a substantial placebo effect; (3) longer, uncontrolled pacing periods were associated with some subjective benefit but unaccompanied by objective improvement in cardiovascular performance and should be interpreted cautiously; (4) modest reduction in outflow gradient was achieved in most patients; and (5) a small subset (12%) ≥ 65 years of age showed a clinical response, suggesting that DDD pacing could be a therapeutic option for some elderly patients.