bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of the Na
+
/H
+
Exchanger in Short-Term Atrial Electrophysiological Remodeling
Authors: Jayachandran J. Vijay , Zipes Douglas P. , Weksler Juan , Olgin Jeffrey E.
Published: June 2012

Background
—The pathophysiology underlying electrophysiological remodeling (ER) from rapid atrial rates is unknown. We tested the hypothesis that activation of the Na
+
/H
+
exchanger (NHE) by ischemia contributes to ER.

Methods and Results
—Twenty-eight dogs were studied under autonomic blockade. In 15 closed-chest dogs, atrial fibrillation was simulated by right atrial pacing at 600 bpm over 5 hours. Of these, 9 (pace/NHEI) received HOE642, a selective inhibitor of the NHE, and 6 (pace/control) received saline. In pace/controls, atrial effective refractory period (AERP) at a drive cycle length (DCL) of 400 ms shortened from 143±7 to 118±5 ms (1 hour) and to 122±17 ms (5 hours). Shortening of AERP was prevented in the pace/NHEI group (
P
=0.02 compared with pace/controls). At baseline in all 15 dogs, pacing at shorter DCL resulted in shortening of AERP (physiological rate adaptation), which was lost at 5 hours in pace/controls. In pace/NHEI animals, rate adaptation was maintained despite 5 hours of pacing (
P
=0.02). In 13 other open-chest dogs, right atrial ERP was determined before and after occlusion of the right coronary artery. Five received HOE642 (ischemia/NHEI), 5 saline (ischemia/control), and 3 intravenous glibenclamide. In ischemia/controls, AERP
400
decreased (156±30 to 130±32 ms). Shortening of AERP was not prevented by glibenclamide (180±20 to 153±33 ms) but was prevented in ischemia/NHEI dogs (169±12 to 184±19 ms,
P
=0.001 compared with ischemia/controls and ischemia/glibenclamide). Rate adaptation was lost in ischemia/controls and preserved in ischemia/NHEI dogs (
P
=0.02).

Conclusions
—Activation of the NHE is one mechanism underlying short-term ER.
Intracoronary β-Radiation Therapy Inhibits Recurrence of In-Stent Restenosis
Authors: Waksman Ron , Bhargava Balram , White Larry , Chan Rosanna C. , Mehran Roxana , Lansky Alexandra J. , Mintz Gary S. , Satler Lowell F. , Pichard Augusto D. , Leon Martin B. , Kent Kenneth K.
Published: June 2012

Background
—Intracoronary γ-radiation therapy reduces recurrent in-stent restenosis (ISR). This study, BETA WRIST (Washington Radiation for In-Stent restenosis Trial) was designed to examine the efficacy and safety of the β-emitter 90-yttrium for the prevention of recurrent ISR.

Methods and Results
—A total of 50 consecutive patients with ISR in native coronaries underwent percutaneous transluminal coronary angioplasty, laser angioplasty, rotational atherectomy, and/or stent implantation. Afterward, a segmented balloon catheter was positioned and automatically loaded with a 90-yttrium, 0.014-inch source wire that was 29 mm in length to deliver a dose of 20.6 Gy at 1.0 mm from the balloon surface. In 17 patients, manual stepping of the radiation catheter was necessary for lesions >25 mm in length. The radiation was delivered successfully to all patients, with a mean dwell time of 3.0±0.4 minutes. Fractionation of the dose due to ischemia was required in 11 patients. At 6 months, the binary angiographic restenosis rate was 22%, the target lesion revascularization rate was 26%, and the target vessel revascularization rate was 34%; all rates were significantly lower than those of the placebo group of γ-WRIST.

Conclusions
—β-Radiation with a 90-yttrium source used as adjunct therapy for patients with ISR results in a lower-than-expected rate of angiographic and clinical restenosis.
Beneficial Effects of Intracoronary Adenosine as an Adjunct to Primary Angioplasty in Acute Myocardial Infarction
Authors: Marzilli Mario , Orsini Enrico , Marraccini Paolo , Testa Roberto
Published: June 2012

Background
—The benefits of vessel recanalization in acute myocardial infarction (AMI) are limited by reperfusion damage. In animal models, adenosine limits reperfusion injury, reducing infarct size and improving ventricular function. The aim of this study was to evaluate the safety and feasibility of adenosine adjunct to primary PTCA in AMI.

Methods and Results
—Fifty-four AMI patients undergoing primary PTCA were randomized to intracoronary adenosine or saline. The 2 groups were similar for age, sex, and infarct location. Adenosine administration was feasible and well tolerated. PTCA was successful in all patients and resulted in TIMI 3 flow in all patients given adenosine and in 19 given saline (
P
<0.05). The no-reflow phenomenon occurred in 1 adenosine patient and in 7 saline patients (
P
=0.02). Creatine kinase was lower in the adenosine group, and a Q-wave MI developed in 16 adenosine patients and in 23 saline patients (
P
=0.04). Sixty-four percent of dyssynergic segments improved in the adenosine group and 36% in the saline group (
P
=0.001). Function worsened in 2% of dyssynergic segments in the adenosine group and in 20% in the saline group (
P
=0.0001). Adverse cardiac events occurred in 5 patients in the adenosine group and in 13 patients in the saline group (
P
=0.03).

Conclusions
—Intracoronary adenosine administration is feasible and well tolerated in AMI. Adenosine adjunct to primary PTCA ameliorates flow, prevents the no-reflow phenomenon, improves ventricular function, and is associated with a more favorable clinical course.
Clenbuterol-Supported Dynamic Training of Skeletal Muscle Ventricles Against Systemic Load
Authors: Guldner Norbert W. , Klapproth Peter , Großherr Martin , Stephan Matthias , Rumpel Elisabeth , Noel Ralf , Sievers Hans-H.
Published: June 2012

Background
—The profound loss of power that occurs in skeletal muscle after electrical conditioning has been the major limiting factor in its clinical application. This study investigates a 3-fold approach for chronic conditioning of skeletal muscle ventricles (SMVs) combining electrical transformation, dynamic training against systemic load, and pharmacological support with clenbuterol.

Methods and Results
—In 10 adult male goats, SMVs were constructed from latissimus dorsi muscle wrapped around an intrathoracic training device with windkessel characteristics. SMVs were stimulated electrically and trained dynamically by shifting volume against systemic load. Group 1 goats were controls (n=5), and group 2 goats (n=5) were supported with clenbuterol (150 μg 3 times a week). SMV dynamics were recorded weekly over 5 to 8 months: peak pressure (P
max
), stroke volume (SV), volume displacement per minute (VD), stroke work per day (SW/d), and maximum rates of pressure generation, +dP/dt
max
, and decay, −dP/dt
max
. In group 1, after 149.5±2.7 days (n=4), data were P
max
=70.8±4.7 mm Hg, SV=3.2±1.2 mL, VD=62.3±21.1 mL/min, SW/d=0.8±0.4 kJ, +dP/dt
max
=64±13 mm Hg/s, and −dP/dt
max
=156±32 mm Hg/s. These parameters were significantly improved (
P
<0.007) in the clenbuterol-treated group 2 after 151±2.7 days: P
max
=176.2±43.8 mm Hg, SV=23.3±6.1 mL, VD=568.2±186.1 mL/min, SW/d=9.1±2.2 kJ, +dP/dt
max
=1134±267 mm Hg/s, and −dP/dt
max
=1028±92 mm Hg/s. In 2 SMVs of group 2, VD increased to 1090 and 1235 mL/min after 202 and 246 days of training, respectively. At termination, myosin heavy chains were totally transformed into myosin heavy chain-1 in all SMVs.

Conclusions
—This clenbuterol-supported dynamic training provides powerful SMVs that may have important clinical implications for the treatment of end-stage heart failure by muscular blood pumps.
Dopamine as a Novel Antioxidative Agent for Rat Vascular Smooth Muscle Cells Through Dopamine D
1
-Like Receptors
Authors: Yasunari Kenichi , Kohno Masakazu , Kano Hiroaki , Minami Mieko , Yoshikawa Junichi
Published: June 2012

Background
—To elucidate the roles of vascular D
1
-like receptors in atherosclerosis, the effects of the specific D
1
-like agonists on platelet-derived growth factor (PDGF)-BB–mediated oxidative stress in vascular smooth muscle cells (VSMCs) were studied.

Methods and Results
—Immunohistochemical studies demonstrated the coexistence of D
1A
and D
1B
dopamine receptors in VSMCs. Western blotting revealed a band of ≈70 kDa for D
1A
and D
1B
dopamine receptors. VSMCs stimulated by PDGF-BB exhibited increased oxidative stress directly measured by flow cytometry. These effects were prevented by dopamine, SKF 38393, or YM 435, and this prevention was reversed by Sch 23390. These effects were blocked by a specific protein kinase A (PKA) inhibitor,
N
-(2-[
p
-bromocinnamylamino]ethyl)-5-isoquinolinesulfonamide (H 89). The PDGF-BB–mediated increase in oxidative stress of VSMCs was significantly suppressed by the indirect phospholipase D (PLD) inhibitor suramin or the specific protein kinase C (PKC) inhibitor calphostin C. Both antisense but neither sense nor scrambled oligonucleotides to D
1A
and D
1B
receptors inhibited dopamine-induced suppression of increase in oxidative stress of VSMCs induced by PDGF-BB.

Conclusions
—These findings suggest that vascular D
1
-like receptors (D
1A
and D
1B
receptors) inhibit any increase in oxidative stress of VSMCs, possibly through activation of PKA and suppression of PLD and PKC.
A Common Mutation in Lipoprotein Lipase Confers a 2-Fold Increase in Risk of Ischemic Cerebrovascular Disease in Women but Not in Men
Authors: Wittrup Hans H. , Nordestgaard Børge G. , Sillesen Henrik , Schnohr Peter , Tybjærg-Hansen Anne
Published: June 2012

Background
—We previously showed that the common Asn291Ser substitution in lipoprotein lipase is associated with elevated plasma triglyceride levels and a 2-fold increase in the risk of ischemic heart disease in women but not men. In this study, we tested the hypothesis that this substitution is also associated with an increased risk of ischemic cerebrovascular disease (ICVD).

Methods and Results
—We compared 260 patients who had nonfatal ICVD and carotid stenosis ≥50% with 1560 age-matched controls and also compared 205 Copenhagen City Heart Study cases who had nonfatal ICVD with 1210 age-matched controls. All subjects were white and from Denmark. Overall, no significant difference was observed between carrier frequencies among those with and without ICVD; however, sex interacted with genotype in predicting ICVD in the ICVD and carotid stenosis cases (
P
=0.02). In Copenhagen City Heart Study cases, sex was not significant (
P
=0.18). Odds ratios for ICVD in female mutation carriers were 2.9 (95% confidence interval [CI], 1.3 to 6.4) and 1.9 (95% CI, 0.8 to 4.6) in ICVD plus carotid stenosis cases and Copenhagen City Heart Study cases, respectively. Equivalent values in male mutation carriers were 0.8 (95% CI, 0.3 to 1.8) and 0.8 (95% CI, 0.3 to 2.0), respectively. These results were similar in analyses that also allowed for other conventional cardiovascular risk factors.

Conclusions
—These results suggest that the Asn291Ser substitution in lipoprotein lipase is not associated with nonfatal ICVD in men but that it possibly confers a 2-fold risk in women.
Soluble Tumor Necrosis Factor Receptor Abrogates Myocardial Inflammation but Not Hypertrophy in Cytokine-Induced Cardiomyopathy
Authors: Kubota Toru , Bounoutas George S. , Miyagishima Masayuki , Kadokami Toshiaki , Sanders Virginia J. , Bruton Christina , Robbins Paul D. , McTiernan Charles F. , Feldman Arthur M.
Published: June 2012

Background
—Transgenic mice with cardiac-specific overexpression of tumor necrosis factor (TNF)-α develop dilated cardiomyopathy. The present study was designed to evaluate therapeutic effects of adenovirus-mediated neutralization of TNF-α on this model.

Methods and Results
—An adenovirus encoding the 55-kDa TNF receptor–IgG fusion protein (AdTNFRI) was injected intravenously into 6-week-old transgenic mice, which resulted in high levels of TNFRI in both plasma and myocardium. AdTNFRI did not reverse cardiomegaly but abrogated myocardial inflammation. Furthermore, AdTNFRI blocked the myocardial expression of intercellular adhesion molecule-1 and downstream cytokines, including interleukin-1β and monocyte chemotactic protein-1. Downregulation of α-myosin heavy chain was restored by the treatment, whereas upregulation of β-myosin heavy chain was not reversed. In contrast, the downregulation of sarcoplasmic reticulum Ca
2+
-ATPase and phospholamban was normalized by AdTNFRI. Echocardiographic measurements showed that left ventricular end-systolic diameter was significantly larger in transgenic mice than in control mice, and this increase was reversed by the AdTNFRI treatment. However, left ventricular wall thickening was not reversed.

Conclusions
—These results suggest that anti-TNF therapy may hold promise in the treatment of end-stage heart failure.
Rapid Electrical Stimulation of Contraction Reduces the Density of β-Adrenergic Receptors and Responsiveness of Cultured Neonatal Rat Cardiomyocytes
Authors: Yonemochi Hidetoshi , Yasunaga Seikoh , Teshima Yasushi , Takahashi Naohiko , Nakagawa Mikiko , Ito Morio , Saikawa Tetsunori
Published: June 2012

Background
—Although tachycardia is commonly present in patients with congestive heart failure, its role in the development of congestive heart failure remains unclear. We studied the effect of rapid electrical stimulation of contraction on β-adrenergic receptor (β-AR) signal pathway in cultured cardiomyocytes of neonatal rats.

Methods and Results
—Contraction of cardiomyocytes was induced by electrical stimulation at 50 V with twice the threshold pulse width. β-ARs were identified by [
3
H]CGP-12177 and [
3
H]dihydroalprenolol. Electrical stimulation reduced cell-surface but not total β-AR density; the effect was dependent on pacing frequency (a reduction of 11%, 28%, and 18% in cells paced at 2.5, 3.0, and 3.3 Hz, respectively). This reduction was apparent at 3 hours, in contrast to reduced β-AR density after exposure to isoproterenol (ISP) for 1 hour. The fraction and inhibition constant of β-AR binding agonist with high affinity were not affected by rapid electrical stimulation. In cardiomyocytes paced at 3.0 Hz for 24 hours, the response to ISP decreased compared with unpaced cells, 142% versus 204% of baseline with 1 μmol/L ISP, whereas the responses to forskolin or acetylcholine were not different. Treatment of cardiomyocytes with 2,3-butanedione monoxime (10 mmol/L) or taxol (10 μmol/L) inhibited the rapid pacing–induced reduction in β-AR density.

Conclusions
—Our results suggest that contractile activity is involved in regulation of cardiac function by modulating the β-AR system independently of hemodynamic and neurohormonal factors. This may help to elucidate the role of mechanical stress in the development of heart failure.
Calcium-Activated Cl
−
Current Contributes to Delayed Afterdepolarizations in Single Purkinje and Ventricular Myocytes
Authors: Verkerk Arie O. , Veldkamp Marieke W. , Bouman Lennart N. , van Ginneken Antoni C. G.
Published: June 2012

Background
—The ionic mechanism underlying the transient inward current (
I
ti
), the current responsible for delayed afterdepolarizations (DADs), appears to be different in ventricular myocytes and Purkinje fibers. In ventricular myocytes,
I
ti
was ascribed to a Na
+
-Ca
2+
exchange current, whereas in Purkinje fibers, it was additionally ascribed to a Cl
−
current and a nonselective cation current. If Cl
−
current contributes to
I
ti
and thus to DADs, Cl
−
current blockade may be potentially antiarrhythmogenic. In this study, we investigated the ionic nature of
I
ti
in single sheep Purkinje and ventricular myocytes and the effects of Cl
−
current blockade on DADs.

Methods and Results
—In whole-cell patch-clamp experiments,
I
ti
was induced by repetitive depolarizations from −93 to +37 mV in the presence of 1 μmol/L norepinephrine. In both Purkinje and ventricular myocytes,
I
ti
was inward at negative potentials and outward at positive potentials. The anion blocker 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid (DIDS) blocked outward
I
ti
completely but inward
I
ti
only slightly. The DIDS-sensitive component of
I
ti
was outwardly rectifying, with a reversal close to the reversal potential of Cl
−
currents. Blockade of Na
+
-Ca
2+
exchange by substitution of extracellular Na
+
by equimolar Li
+
abolished the DIDS-insensitive component of
I
ti
. DIDS reduced both DAD amplitude and triggered activity based on DADs.

Conclusions
—In both Purkinje and ventricular myocytes,
I
ti
consists of 2 ionic mechanisms: a Cl
−
current and a Na
+
-Ca
2+
exchange current. Blockade of the Cl
−
current may be potentially antiarrhythmogenic by lowering DAD amplitude and triggered activity based on DADs.
Magnetic Resonance–Based Assessment of Global Coronary Flow and Flow Reserve and Its Relation to Left Ventricular Functional Parameters
Authors: Schwitter J. , DeMarco T. , Kneifel S. , von Schulthess G. K. , Jörg M. Ciopor , Arheden Hakan , Rühm S. , Stumpe K. , Buck A. , Parmley W. W. , Lüscher T. F. , Higgins C. B.
Published: June 2012

Background
—Measurement of coronary sinus blood flow (CSF) by phase-contrast magnetic resonance (PC-MR) imaging at rest and during hyperemia may allow noninvasive assessment of global coronary hemodynamics.

Methods and Results
—Sixteen healthy volunteers (age, 22 to 32 years) were examined with MR and PET in random order within 1 to 2 days. At rest and during hyperemia (dipyridamole 0.56 mg/kg), CSF was measured by a cine PC-MR technique (temporal resolution, 40 ms; spatial resolution, 1.25×0.8 mm
2
), and myocardial blood flow (MBF) was measured by [
13
N]NH
3
PET. PET and MR agreed closely for coronary flow reserve (CFR; mean difference, 2.2±14.7%; Bland-Altman method). CSF divided by either total left ventricular mass or an estimate of drained myocardium (LVM
drain
) correlated highly with PET flow data (
r
=0.93 and 0.95, respectively) and with measures of oxygen demand, ie, heart rate, afterload-corrected fiber shortening, and peak systolic stress determined by MR (overall correlation coefficients, 0.81 and 0.87, respectively, multivariate analysis). CSF/LVM
drain
did not differ significantly from PET-derived MBF (difference, 3.6±16.6%). In orthotopic heart transplant recipients (n=9), CFR was reduced and blood supply-demand relationships at rest were shifted toward higher flows (
P
<0.0001).

Conclusions
—This integrated MR approach allows comprehensive assessment of autoregulated and hyperemic coronary flow and is suitable for serial measurements in patients. In transplanted hearts, elevated resting flow is the major cause of reduced CFR.
Association of a T29→C Polymorphism of the Transforming Growth Factor-β1 Gene With Genetic Susceptibility to Myocardial Infarction in Japanese
Authors: Yokota Mitsuhiro , Ichihara Sahoko , Lin Tong-Lang , Nakashima Nobuo , Yamada Yoshiji
Published: June 2012

Background
—Transforming growth factor-β (TGF-β) is an important regulator of vascular remodeling and is involved in the pathogenesis of atherosclerosis. A T→C transition at nucleotide 29 of the
TGF-β1
gene results in a Leu→Pro substitution at amino acid 10 of the signal peptide. We have now examined a possible association of
TGF-β1
genotype with myocardial infarction (MI) in a Japanese population.

Methods and Results
—
TGF-β1
genotype was determined in 315 Japanese patients (234 men and 81 women) with MI and 591 control subjects (289 men and 302 women). We found that age, body mass index, and incidence of habitual smoking, hypertension, diabetes mellitus, and hypercholesterolemia did not differ between the 2 groups for either men or women. Multivariable logistic regression analysis, however, demonstrated the frequency of the
T
allele to be significantly higher in male subjects with MI than in controls (
TT
+
TC
versus
CC
;
P
<0.0001, odds ratio 3.5, 95% CI 2.0 to 6.3). In contrast, the
T
allele was not associated with the prevalence of MI in women. In both male MI patients and controls, the serum concentration of TGF-β1 was significantly higher in individuals with the
CC
genotype than in subjects with the
TT
or
TC
genotype.

Conclusions
—Findings suggest that the
T
allele at nucleotide 29 in the
TGF-β1
gene is a risk factor for genetic susceptibility to MI, at least in middle-aged Japanese men.
QTL Influencing Blood Pressure Maps to the Region of
PPH1
on Chromosome 2q31-34 in Old Order Amish
Authors: Hsueh Wen-Chi , Mitchell Braxton D. , Schneider Jennifer L. , Wagner Michael J. , Bell Callum J. , Nanthakumar Elizabeth , Shuldiner Alan R.
Published: June 2012

Background
—Hypertension is a major risk factor for coronary heart disease, stroke, congestive heart failure, renal insufficiency, and peripheral vascular disease. Although the genetic contribution to variation in blood pressure is well recognized, the specific genes involved are mostly unknown. We carried out a genome-wide scan to identify loci influencing blood pressure in the Old Order Amish population of Lancaster County, Pennsylvania.

Methods and Results
—Blood pressures were measured in 694 adult participants from families recruited without regard to blood pressure. We performed a quantitative linkage analysis by using 357 microsatellite markers. In multipoint analysis, strong evidence for linkage was observed with both diastolic (lod=3.36;
P
=0.00004) and to a lesser extent systolic (lod=1.64;
P
=0.003) blood pressure in the region of chromosome 2q31-34. Peak evidence for linkage occurred at map positions 217 and 221 cM from pter for diastolic and systolic blood pressure, respectively.

Conclusions
—A gene linked to familial primary pulmonary hypertension has recently been mapped to this same region, suggesting the intriguing hypothesis that other (attenuated) mutations in this same gene may influence variation in systolic and diastolic blood pressure in this population.
Cardiovascular Responses to the Isoprostanes iPF
2α
-III and iPE
2
-III Are Mediated via the Thromboxane A
2
Receptor In Vivo
Authors: Audoly Laurent P. , Rocca Bianca , Fabre Jean-Etienne , Koller Beverly H. , Thomas Dennis , Loeb Alex L. , Coffman Thomas M. , FitzGerald Garret A.
Published: June 2012

Background
—Isoprostanes (iPs) are free radical–catalyzed products of arachidonic acid that reflect lipid peroxidation in vivo. Several iPs exert biological effects in vitro and may contribute to the functional consequences of oxidant stress. For example, iPF
2α
-III (8-
iso
PGF
2α
) and iPE
2
-III modulate platelet function and vascular tone. Although these effects are blocked by antagonists of the receptor (TP) for the cyclooxygenase product thromboxane A
2
, it has been speculated that the iPs may activate a receptor related to, but distinct from, the TP.

Methods and Results
—Transgenic mice (TPOEs) were generated in which the TP-β isoform was under the control of the preproendothelin promoter. They overexpressed TP-β in the vasculature but not in platelets and exhibited an exaggerated pressor response to infused iPF
2α
-III compared with wild-type mice. This was blocked by TP antagonism. The platelet response to the iP was unaltered in TPOEs compared with wild-type mice. By contrast, both the pressor response to iPF
2α
-III and its effects on platelet function were abolished in mice lacking the TP gene. This was also true of the effects of infused iPE
2
-III on mean arterial pressure and platelet aggregation.

Conclusions
—Both iPF
2α
-III and iPE
2
-III exert their effects on platelet function and vascular tone in vivo by acting as incidental ligands at membrane TPs rather than via a distinct iP receptor. Activation of TPs by iPs may be of importance in syndromes in which cyclooxygenase activation and oxidant stress coincide, such as in atherosclerosis and reperfusion after tissue ischemia.
Resuscitation After Prolonged Ventricular Fibrillation With Use of Monophasic and Biphasic Waveform Pulses for External Defibrillation
Authors: Leng Charles T. , Paradis Norman A. , Calkins Hugh , Berger Ronald D. , Lardo Albert C. , Rent Kenneth C. , Halperin Henry R.
Published: June 2012

Background
—Survival after prolonged ventricular fibrillation (VF) appears severely limited by 2 major factors: (1) low defibrillation success rates and (2) persistent post-countershock myocardial dysfunction. Biphasic (BP) waveforms may prove capable of favorably modifying these limitations. However, they have not been rigorously tested against monophasic (MP) waveforms in clinical models of external defibrillation, particularly where rescue from prolonged VF is the general rule.

Methods and Results
—We randomized 26 dogs to external countershocks with either MP or BP waveforms. Hemodynamics were assessed after shocks applied during sinus rhythm, after brief VF (>10 seconds), and after resuscitation from prolonged VF (>10 minutes). Short-term differences in percent change in left ventricular +dP/dt
max
(MP −16±28%, BP +9.1±24%;
P
=0.03) and left ventricular −dP/dt
max
(MP −37±26%, BP −18±20%;
P
=0.05) were present after rescue from brief VF, with BP animals exhibiting less countershock-induced dysfunction. After prolonged VF, the BP group had lower mean defibrillation thresholds (107±57 versus 172±88 J for MP,
P
=0.04) and significantly shorter resuscitation times (397±73.7 versus 488±74.3 seconds for MP,
P
=0.03).

Conclusions
—External defibrillation is more efficacious with BP countershocks than with MP countershocks. The lower defibrillation thresholds and shorter resuscitation times associated with BP waveform defibrillation may improve survival after prolonged VF arrest.
Accumulation of Apolipoprotein C-I–Rich and Cholesterol-Rich VLDL Remnants During Exaggerated Postprandial Triglyceridemia in Normolipidemic Patients With Coronary Artery Disease
Authors: Björkegren Johan , Boquist Susanna , Samnegård Ann , Lundman Pia , Tornvall Per , Ericsson Carl-Göran , Hamsten Anders
Published: June 2012

Background
—Exaggerated postprandial triglyceridemia is common in normolipidemic patients with coronary artery disease (CAD). Alterations in the composition of triglyceride-rich lipoproteins (TRLs) are likely to underlie this metabolic disturbance. However, the composition of very-low-density lipoproteins (VLDLs), which are the most abundant postprandial TRLs, has never been defined in CAD patients.

Methods and Results
—We examined postprandial changes in the number and composition of VLDLs in middle-aged, normolipidemic CAD patients and control subjects. TRLs from 14 patients and 14 control subjects aged 45 to 55 years were subfractionated by density gradient ultracentrifugation into Svedberg flotation rate (Sf) fractions >400, 60 to 400, and 20 to 60. The VLDLs were separated from chylomicron remnants by immunoaffinity chromatography. In CAD patients, the postprandial concentrations of triglycerides and large (Sf 60 to 400) VLDL particles were elevated. In addition, their postprandial large VLDLs were enriched in apolipoprotein (apo) C-I and their postprandial small (Sf 20 to 60) VLDL remnants were enriched with apo C-I and cholesterol.

Conclusions
—Perturbed handling of postprandial triglycerides in normolipidemic CAD patients involves the accumulation of apo C-I–rich large VLDL particles and the generation of small, apo C-I– and cholesterol-rich VLDL remnants.
Association of Blood Pressure With Fibrinolytic Potential in the Framingham Offspring Population
Authors: Poli Kim A. , Tofler Geoffrey H. , Larson Martin G. , Evans Jane C. , Sutherland Patrice A. , Lipinska Izabella , Mittleman Murray A. , Muller James E. , D’Agostino Ralph B. , Wilson Peter W. F. , Levy Daniel
Published: June 2012

Background
—Hypertension is an established risk factor for acute coronary events. Because fibrinolytic and hemostatic factors are also associated with cardiovascular disease, we examined the relations of systolic and diastolic blood pressures (SBP and DBP) to levels of plasminogen activator inhibitor antigen, tissue plasminogen activator antigen, fibrinogen, factor VII, von Willebrand factor, fibrinogen, and plasma viscosity in subjects of the Framingham Offspring Study.

Methods and Results
—We studied 1193 men and 1459 women after the exclusion of subjects with known cardiovascular disease and those receiving anticoagulant or antihypertensive therapy. Linear regression models were used to evaluate SBP and DBP as predictors of fibrinolytic and hemostatic factor levels in separate sex models, with adjustment for age, body mass index, smoking, diabetes, total cholesterol, HDL, triglycerides, alcohol intake, and estrogen use (in women). In both sexes, levels of plasminogen activator inhibitor and tissue plasminogen activator antigen were positively related to SBP and DBP (
P
<0.001). Plasma viscosity was positively related to SBP (
P
=0.008) and DBP (
P
=0.001) in women only. There was no association between SBP or DBP and fibrinogen, factor VII, or von Willebrand factor in either sex.

Conclusions
—These data suggest that impaired fibrinolysis may play an important role in the pathogenesis of cardiovascular disease in hypertensive patients.
Atypical Atrial Flutter Originating in the Right Atrial Free Wall
Authors: Kall John G. , Rubenstein Donald S. , Kopp Douglas E. , Burke Martin C. , Verdino Ralph J. , Lin Albert C. , Johnson C. Timothy , Cooke Philip A. , Wang Zhong G. , Fumo Michael , Wilber David J.
Published: June 2012

Background
—Data from experimental models of atrial flutter indicate that macro-reentrant circuits may be confined by anatomic and functional barriers remote from the tricuspid annulus–eustachian ridge atrial isthmus. Data characterizing the various forms of atypical atrial flutter in humans are limited.

Methods and Results
—In 6 of 160 consecutive patients referred for ablation of counterclockwise and/or clockwise typical atrial flutter, an additional atypical atrial flutter was mapped to the right atrial free wall. Five patients had no prior cardiac surgery. Incisional atrial tachycardia was excluded in the remaining patient. High-density electroanatomic maps of the reentrant circuit were obtained in 3 patients. Radiofrequency energy application from a discrete midlateral right atrial central line of conduction block to the inferior vena cava terminated and prevented the reinduction of atypical atrial flutter in each patient. Atrial flutter has not recurred in any patient (follow-up, 18±17 months; range, 3 to 40 months).

Conclusions
—Atrial flutter can arise in the right atrial free wall. This form of atypical atrial flutter could account for spontaneous or inducible atrial flutter observed in patients referred for ablation and is eliminated with linear ablation directed at the inferolateral right atrium.
α-Adrenergic Coronary Vasoconstriction and Myocardial Ischemia in Humans
Authors: Heusch Gerd , Baumgart Dietrich , Camici Paolo , Chilian William , Gregorini Luisa , Hess Otto , Indolfi Ciro , Rimoldi Ornella
Published: June 2012

Abstract
—The use of quantitative coronary angiography, combined with Doppler and PET, has recently been directed at the study of α-adrenergic coronary vasomotion in humans. Confirming prior animal experiments, there is no evidence of α-adrenergic coronary constrictor tone at rest. Again confirming prior experiments, responses to α-adrenoceptor activation are augmented in the presence of coronary endothelial dysfunction and atherosclerosis, involving both α
1
- and α
2
-adrenoceptors in epicardial conduit arteries and microvessels. Such augmented α-adrenergic coronary constriction is observed during exercise and coronary interventions, and it is powerful enough to induce myocardial ischemia and limit myocardial function. Recent studies indicate a genetic determination of α
2
-adrenergic coronary constriction.
Effect of Mibefradil, a T-Type Calcium Channel Blocker, on Morbidity and Mortality in Moderate to Severe Congestive Heart Failure
Authors: Levine T. Barry , Bernink Peter J. L. M. , Caspi Abraham , Elkayam Uri , Geltman Edward M. , Greenberg Barry , McKenna William J. , Ghali Jalal K. , Giles Thomas D. , Marmor Alon , Reisin Leonardo H. , Ammon Susan , Lindberg Elisabet
Published: June 2012

Background
—Calcium antagonists have proved disappointing in long-term congestive heart failure (CHF) studies. Mibefradil, a new calcium antagonist that selectively blocks T-type calcium channels, has been shown to be an effective antihypertensive, antianginal, and anti-ischemic agent, and because of its different mechanism of action, it may be beneficial as adjunct therapy in CHF patients.

Methods and Results
—This multicenter, randomized, double-blind study compared mibefradil with placebo as adjunct to usual therapy in 2590 CHF patients (NYHA class II to IV; left ventricular fraction <35%). The initial 50-mg daily dose of mibefradil was uptitrated to 100 mg after 1 month and continued up to 3 years. Patients were monitored at 1 week; 1, 2, and 3 months; and every 3 months thereafter. All-cause mortality, cardiovascular mortality, and cardiovascular morbidity/mortality were analyzed by use of the log-rank test (α=0.05). Substudies included exercise tolerance, plasma hormone and cytokines, echocardiography, and quality of life. Total mortality was similar between mibefradil- and placebo-treated patients (
P
=0.151). The 14% increased risk of mortality with mibefradil in the first 3 months was not statistically significant (
P
=0.093). Treatment groups had similar cardiovascular mortality (
P
=0.246), cardiovascular morbidity/mortality (
P
=0.783), and reasons for death or hospitalization. Patients comedicated with mibefradil and antiarrhythmics (class I or III), including amiodarone, had a significantly increased risk of death. Substudies demonstrated no significant differences between treatments.

Conclusions
—When used as adjunct therapy, mibefradil did not affect the usual outcome of CHF. The potential interaction with antiarrhythmic drugs, especially amiodarone, and drugs associated with torsade de pointes may have contributed to poor outcomes early in the study.
Identification of Patients at Increased Risk of First Unheralded Acute Myocardial Infarction by Electron-Beam Computed Tomography
Authors: Raggi Paolo , Callister Tracy Q. , Cooil Bruce , He Zuo-Xiang , Lippolis Nicholas J. , Russo Donald J. , Zelinger Alan , Mahmarian John J.
Published: June 2012

Background
—There is a clear relationship between absolute calcium scores (CS) and severity of coronary artery disease. However, hard coronary events have been shown to occur across all ranges of CS.

Methods and Results
—We conducted 2 analyses: in group A, 172 patients underwent electron-beam CT (EBCT) imaging within 60 days of suffering an unheralded myocardial infarction. In group B, 632 patients screened by EBCT were followed up for a mean of 32±7 months for the development of acute myocardial infarction or cardiac death. The mean patient age and prevalence of coronary calcification were similar in the 2 groups (53±8 versus 52±9 years and 96% each). In group B, the annualized event rate was 0.11% for subjects with CS of 0, 2.1% for CS 1 to 99, 4.1% for CS 100 to 400, and 4.8% for CS >400, and only 7% of the patients had CS >400. However, mild, moderate, and extensive absolute CSs were distributed similarly between patients with events in both groups (34%, 35%, and 27%, respectively, in group A and 44%, 30%, and 22% in group B). In contrast, the majority of events in both groups occurred in patients with CS >75th percentile (70% in each group).

Conclusions
—Coronary calcium is present in most patients who suffer acute coronary events. Although the event rate is greater for patients with high absolute CSs, few patients have this degree of calcification on a screening EBCT. Conversely, the majority of events occur in individuals with high CS percentiles. Hence, CS percentiles constitute a more effective screening method to stratify individuals at risk.
Platelet GP IIIa Pl
A
Polymorphisms Display Different Sensitivities to Agonists
Authors: Michelson Alan D. , Furman Mark I. , Goldschmidt-Clermont Pascal , Mascelli Mary Ann , Hendrix Craig , Coleman Lindsay , Hamlington Jeanette , Barnard Marc R. , Kickler Thomas , Christie Douglas J. , Kundu Sourav , Bray Paul F.
Published: June 2012

Background
—Both inherited predisposition and platelet hyperreactivity have been associated with ischemic coronary events, but mechanisms that support genetic differences among platelets from different subjects are generally lacking. Associations between the platelet Pl
A2
polymorphism of GP IIIa and coronary syndromes raise the question as to whether this inherited variation may contribute to platelet hyperreactivity.

Methods and Results
—In this study, we characterized functional parameters in platelets from healthy donors with the Pl
A
(HPA-1) polymorphism, a Leu (Pl
A1
) to Pro (Pl
A2
) substitution at position 33 of the GP IIIa subunit of the platelet GP IIb/IIIa receptor (integrin α
IIb
β
3
). We studied 56 normal donors (20 Pl
A1,A1
, 20 Pl
A1,A2
, and 16 Pl
A2,A2
). Compared with Pl
A1,A1
platelets, Pl
A2
-positive platelets showed a gene dosage effect for significantly greater surface-expressed P-selectin, GP IIb/IIIa–bound fibrinogen, and activated GP IIb/IIIa in response to low-dose ADP. Surface expression of GP IIb/IIIa was similar in resting platelets of all 3 genotypes but was significantly greater on Pl
A2,A2
platelets after ADP stimulation (
P
=0.003 versus Pl
A1,A1
;
P
=0.03 versus Pl
A1,A2
). Pl
A1,A2
platelets were more sensitive to inhibition of aggregation by pharmacologically relevant concentrations of aspirin and abciximab.

Conclusions
—Pl
A2
-positive platelets displayed a lower threshold for activation, and platelets heterozygous for Pl
A
alleles showed increased sensitivity to 2 antiplatelet drugs. These in vitro platelet studies may have relevance for in vivo thrombotic conditions.
Prediction of Restenosis After Coronary Angioplasty by Use of a New Index
Authors: Stankovic Goran , Manginas Athanassios , Voudris Vassilis , Pavlides Gregory , Athanassopoulos George , Ostojic Miodrag , Cokkinos Dennis V.
Published: June 2012

Background
—It has been shown recently that postangioplasty coronary flow reserve and the degree of residual stenosis have a modest predictive value for short- and long-term clinical outcomes after coronary angioplasty. Corrected TIMI frame count (CTFC) is a simple quantitative index of coronary blood flow. Its relationship with Doppler coronary flow velocity and clinical outcome after coronary angioplasty has not been fully clarified. The aim of this study was to identify clinical, angiographic, and functional predictors of clinical and angiographic restenosis after conventional coronary angioplasty.

Methods and Results
—We studied 70 consecutive patients in whom intracoronary Doppler flow-velocity measurements were performed before and after angioplasty. Patients were evaluated for restenosis by clinical follow-up, exercise stress test/
201
Tl scintigraphy, and follow-up angiography, which was performed at 10.5±10.3 months in 63 patients. According to the results of univariate analysis, a new index, postangioplasty CTFC/minimal luminal diameter (MLD) ratio, was created. Multivariate analysis revealed that CTFC/MLD ratio was the only independent predictor of angiographic (OR 2.02; 95% CI 1.37 to 2.97;
P
<0.0004) and clinical (OR 1.60; 95% CI 1.15 to 2.21;
P
<0.005) restenosis. The receiver operating characteristic curve area of this index was 79% for angiographic and 73% for clinical restenosis. The optimal CTFC/MLD ratio cutoff values were 7.88 for angiographic and 7.94 for clinical restenosis, respectively.

Conclusions
—Our data indicate that postangioplasty CTFC/MLD ratio, which incorporates both the angiographic and functional features of coronary lesions, is a reliable, objective, and inexpensive index for prediction of angiographic and clinical restenosis after conventional coronary angioplasty.
Identification of the Substrate of Atrial Vulnerability in Patients With Idiopathic Atrial Fibrillation
Authors: Ramanna Hemanth , Hauer Richard N. W. , Wittkampf Fred H. M. , de Bakker Jacques M. T. , Wever Eric F. D. , Elvan Arif , Robles de Medina Etienne O.
Published: June 2012

Background
—Experimental studies have shown that atrial fibrillation (AF) causes remodeling, which facilitates AF perpetuation. AF may also, however, occur in patients without remodeling and underlying structural cardiac disease. The substrate for enhanced vulnerability in these patients is unknown.

Methods and Results
—We studied 43 patients without structural heart disease: 18 patients with documented sporadic paroxysmal AF and 25 control patients without AF. In each patient, a decapolar catheter was positioned against the right atrial free wall, and a quadripolar catheter was positioned in the right atrial appendage. Unipolar electrograms were recorded. Atrial vulnerability was assessed according to an increasingly aggressive stimulation protocol. Mean local fibrillatory interval (FI) was used as an index of local refractoriness. Spatial dispersion of refractoriness was assessed through the calculation of the coefficient of dispersion (CD), which was defined as the SD of mean local FI expressed as a percentage of the mean FI. In the AF group, AF was induced with a single extrastimulus in 16 of 18 patients; the CD was 5.4±2.6, and the mean FI was 164±29 ms. In the control group, AF could be induced only with more aggressive pacing in 23 of the 25 patients; the CD was 1.4±0.7 (
P
<0.0001), and the mean FI was 175±26 ms (NS).

Conclusions
—Patients with idiopathic AF showed increased dispersion of refractoriness, which may be the substrate for the observed enhanced inducibility and spontaneous occurrence of AF.
Contrasting Efficacy of Dofetilide in Differing Experimental Models of Atrial Fibrillation
Authors: Li Danshi , Bénardeau Agnes , Nattel Stanley
Published: June 2012

Background
—Rapid atrial pacing (RAP) and congestive heart failure (CHF) produce different experimental substrates for atrial fibrillation (AF). We tested the hypothesis that AF maintained by different substrates responds differently to antiarrhythmic-drug therapy.

Methods and Results
—The class III antiarrhythmic agent dofetilide was given intravenously at doses of 10 (D10) and 80 (D80) μg/kg to dogs with AF induced either (1) after 7 days of RAP at 400 bpm or (2) in the presence of CHF induced by rapid ventricular pacing. Dofetilide terminated AF in all CHF dogs, but D10 failed to terminate AF in any RAP dog, and D80 terminated AF in only 1 of 5 RAP dogs (20%) (
P
<0.01 for efficacy in CHF versus RAP dogs). Dofetilide was highly effective in preventing AF induction by atrial burst pacing in dogs with CHF but was totally ineffective in dogs with RAP. Dofetilide increased atrial effective refractory period and AF cycle length to a greater extent in CHF dogs. Epicardial mapping with 248 bipolar electrodes showed that CHF-related AF was often due to macroreentry, with dofetilide terminating AF by causing block in reentry circuits. RAP-related AF was due to multiple–wave front reentry, with dofetilide slowing reentry and decreasing the number of simultaneous waves, but not sufficiently to stop AF.

Conclusions
—The mechanism underlying AF importantly influences dofetilide efficacy. The dependence of drug efficacy in AF on the underlying mechanism has potentially significant implications for antiarrhythmic drug use and development and may explain the well-known therapeutic resistance of longer-duration AF.
Pronounced Benefit of Coronary Stenting and Adjunctive Platelet Glycoprotein IIb/IIIa Inhibition in Complex Atherosclerotic Lesions
Authors: Cura Fernando A. , Bhatt Deepak L. , Lincoff A. Michael , Kapadia Samir R. , L’Allier Philippe L. , Ziada Khaled M. , Wolski Katherine E. , Moliterno David J. , Brener Sorin J. , Ellis Stephen G. , Topol Eric J.
Published: June 2012

Background
—Previous trials testing stents compared with balloon angioplasty excluded patients with complex lesions and did not assess the effect of adjunctive platelet IIb/IIIa inhibition. This analysis sought to assess the effect of stenting and abciximab specifically for patients with complex lesions.

Methods and Results
—Patients with complex lesions (long, tandem, severely calcified, restenotic, thrombotic, or ostial; total occlusions; bifurcations; saphenous vein grafts; and multivessel interventions) from the Evaluation of PTCA to Improve Long-Term Outcome by c7E3 GP IIb/IIIa Receptor Blockade (EPILOG) and the Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT) trials were included in the analysis. The 1-year combined death or myocardial infarction rates in the 4 treatment groups were as follows: balloon angioplasty/placebo, 14.2%; stent/placebo, 15.8%; balloon angioplasty/abciximab, 7.6%; and stent/abciximab, 8.0% (
P
<0.001). Death rates were 3.2%, 3.1%, 2.1%, and 0.5%, respectively (
P
=0.03). The incidence of target vessel revascularization at 1 year was 30.5%, 18.0%, 24.4%, and 19.7% in the 4 groups, respectively (
P
<0.001). After adjustment for baseline differences, multivariate analysis demonstrated that the rate of death or myocardial infarction was independently reduced by balloon angioplasty/abciximab (hazard ratio, 0.51;
P
<0.001) and stent/abciximab (hazard ratio, 0.60;
P
=0.02) but was not affected by the use of stents alone. Conversely, target vessel revascularization was reduced by stent/placebo (hazard ratio, 0.53;
P
<0.001), stent/abciximab (hazard ratio, 0.58;
P
<0.001), and balloon angioplasty/abciximab (hazard ratio, 0.74;
P
=0.006) compared with balloon angioplasty/placebo, respectively.

Conclusions
—The combination of stenting and abciximab during percutaneous coronary interventions for patients with angiographically complex lesions confers additive long-term benefit with respect to death, myocardial infarction, and target vessel revascularization.
Nicotine Is a Potent Blocker of the Cardiac A-Type K
+
Channels
Authors: Wang Huizhen , Shi Hong , Zhang Liming , Pourrier Marc , Yang Baofeng , Nattel Stanley , Wang Zhiguo
Published: June 2012

Background
—Nicotine is a main constituent of cigarette smoke and smokeless tobacco, known to increase the risk of sudden cardiac death. This study aimed at establishing ionic mechanisms underlying potential electrophysiological effects of nicotine.

Methods and Results
—Effects of nicotine on Kv4.3 and Kv4.2 channels expressed in
Xenopus
oocytes were studied at the whole-cell and single-channel levels. The effects of nicotine on the transient outward K
+
current (
I
to
) were studied by use of whole-cell patch-clamp techniques in canine ventricular myocytes. Nicotine potently inhibited Kv4 current. The concentration for half-maximal inhibition (IC
50
) was 40±4 nmol/L, and the current was abolished by 100 μmol/L nicotine. The IC
50
for block of native
I
to
was 270±43 nmol/L. The steady-state activation properties of Kv4.3 and
I
to
were unaltered by nicotine, whereas positive shifts of the inactivation curves were observed. Of the total inhibition of Kv4.3 and
I
to
by nicotine, 40% was due to tonic block and 60% was attributable to use-dependent block. Activation, inactivation, and reactivation kinetics were not significantly changed by nicotine. Nicotine reduced single-channel conductance, open probability, and open time but increased the closed time of Kv4.3. The effects of nicotine were not altered by antagonists to various neurotransmitter receptors, indicating direct effects on
I
to
channels.

Conclusions
—Nicotine is a potent inhibitor of cardiac A-type K
+
channels, with blockade probably due to block of closed and open channels. This action may contribute to the ability of nicotine to affect cardiac electrophysiology and induce arrhythmias.