bluuebunny/crossref_metadata_2025 huggingface dataset:
Preservation of Myocyte Contractile Function After Hypothermic Cardioplegic Arrest by Activation of ATP-Sensitive Potassium Channels
Authors: Dorman B. Hugh , Hebbar Latha , Hinton Robert B. , Roy Raymond C. , Spinale Francis G.
Published: June 2012

Background
Left ventricular (LV) dysfunction can occur after hyperkalemic cardioplegic arrest and subsequent reperfusion and rewarming. Activation of adenosine triphosphate (ATP)-sensitive potassium (K
atp
) channels within the myocyte sarcolemma has been shown to be cardioprotective for myocardial reperfusion injury and ischemia and may play a contributory role in preconditioning for cardioplegic arrest. Accordingly, the present study tested the hypothesis that cardioplegic arrest and activation of K
atp
channels by a potassium channel opener (PCO) would attenuate alterations in ionic homeostasis and improve myocyte contractile function.

Methods and Results
Porcine LV myocytes were isolated and randomly assigned to the following treatment groups: normothermic control, incubation in cell culture media for 2 hours at 37°C (n=60); hyperkalemic cardioplegia, incubation for 2 hours in hypothermic hyperkalemic cardioplegic solution (n=60); or PCO/cardioplegia, incubation in cardioplegic solution containing 100 μmol/L of the PCO aprikalim (n=60). Hyperkalemic cardioplegia and rewarming caused a significant reduction in myocyte velocity of shortening compared with normothermic control values (33±2 versus 66±2 μm/s,
P
<.05). Cardioplegic arrest with PCO supplementation significantly improved indices of myocyte contractile function when compared with hyperkalemic cardioplegia (58±4 μm/s,
P
<.05). Myocyte intracellular calcium increased during hyperkalemic cardioplegic arrest compared with baseline values (147±2 versus 85±2 nmol/L,
P
<.05). The increase in intracellular calcium was significantly reduced in myocytes exposed to the PCO-supplemented cardioplegic solution (109±4 nmol/L,
P
<.05).

Conclusions
Cardioplegic arrest with simultaneous activation of K
atp
channels preserves myocyte contractile processes and attenuates the accumulation of intracellular calcium. These findings suggest that changes in intracellular calcium play a role in myocyte contractile dysfunction associated with cardioplegic arrest. Moreover, alternative strategies may exist for preservation of myocyte contractile function during cardioplegic arrest.
Endothelial Dysfunction and Cardiorenal Injury in Experimental Salt-Sensitive Hypertension
Authors: Hayakawa Hiroshi , Coffee Karen , Raij Leopoldo
Published: June 2012

Background
Pharmacological control of hypertension has contributed to a significant decrease in cardiovascular morbidity and mortality, although the beneficial effect on cardiac and renal diseases has been far more modest than the reduction in stroke. The endothelium plays a crucial homeostatic role in the regulation of vascular tone thrombogenesis and vascular remodeling. We studied the relationship between endothelial dysfunction and cardiorenal injury in hypertensive rats and evaluated the effects of two classes of antihypertensive agents commonly used in the clinical setting, a diuretic (DIU) and an ACE inhibitor (CEI).

Methods and Results
Dahl salt-sensitive rats (DS) given high dietary salt (4% NaCl) developed hypertension (systolic blood pressure [SBP], 218±9 versus 147±3 mm Hg in DS given 0.5% NaCl;
P
<.001), which was associated with impaired endothelium-dependent relaxations (EDRs) in aortic rings (ED
50
, 5.44±.18 versus 7.51±.10;
P
<.05) and mesenteric vessels (area under the curve, 299±11 versus 217±11 arbitrary units;
P
<.05). Hypertensive DS also demonstrated depressed nitric oxide synthase activity in the aorta (0.76±.15 versus 2.83±.17 nmol · min
−1
· g protein
−1
;
P
<.05), left ventricular hypertrophy (0.43±.02 versus 0.29±.02 g ventricular weight/100 g body weight;
P
<.05), glomerular injury (histological injury score: 151±8 versus 11±2;
P
<.05), and increased urinary protein excretion (95±21 versus 25±5 mg/24 hours;
P
<.05). Treatment of DS rats with the CEI perindopril (4.56 mg · kg
−1
· d
−1
) did not affect SBP (225±6 mm Hg) but modestly improved EDR (ED
50
: 6.07±.37;
P
<.05 versus hypertensive DS) as well as proteinuria and glomerular histology. Addition of the DIU indapamide (1.44 mg · kg
−1
· d
−1
) normalized SBP (151±2 mm Hg;
P
<.05), EDR (ED
50
, 7.33±.08;
P
<.05), left ventricular hypertrophy (0.27±.01 g/100 g body weight;
P
<.05), and proteinuria (31±4 mg/24 hours;
P
<.05) and prevented glomerular injury (injury score: 30±2;
P
<.05). Monotherapy with DIU reduced SBP (175±3 mm Hg;
P
<.05) and normalized EDR and left ventricular hypertrophy but did not provide effective renal protection. In hypertensive DS, impaired EDR and left ventricular hypertrophy were positively correlated with SBP. In addition, we found a significant correlation between cardiac hypertrophy and endothelial dysfunction. Indeed, a hierarchical regression analysis revealed that impaired aortic EDR, and therefore decreased aortic compliance, positively contributed to left ventricular hypertrophy in addition to but independently of SBP [F
(2, 37)
=6.29;
P
=.004].

Conclusions
These studies suggest a dissociation of the endothelial, cardiac, and renal effects of antihypertensive therapy in hypertension and may explain the variable success of antihypertensive regimens in treating hypertension while preventing cardiac and renal damage.
Transcutaneous Multielectrode Basket Catheter for Endocardial Mapping and Ablation of Ventricular Tachycardia in the Pig
Authors: Eldar Michael , Ohad Dan G. , Goldberger Jeffrey J. , Rotstein Zeev , Hsu Steve , Swanson David K. , Greenspon Arnold J.
Published: June 2012

Background
Endocardial mapping using standard electrode catheters is often technically limited in ventricular tachycardia and constitutes a major obstacle to successful ablation. We wished to examine the utility of a basket-shaped multielectrode mapping catheter (MMC) in the mapping and ablation of ventricular tachycardia.

Methods and Results
This study of sustained monomorphic ventricular tachycardia (SMVT) was conducted in two phases in the postinfarction pig model. In the first phase, the utility of the MMC in providing adequate localization of potential ablation site(s) of SMVT by different techniques (presystolic potentials, pace mapping, and concealed entrainment) was assessed in 21 pigs. In the second phase, ablation of induced SMVT was attempted in 10 pigs. Mapping of SMVT was performed after percutaneous introduction of the MMC to the LV. Comprehensive mapping was performed in 90 episodes of SMVT and required 2.0 to 25 seconds. Diastolic potentials were recorded during 86 episodes; good or identical pace maps (≥9 of 12 paced surface ECG leads identical to ventricular tachycardia surface ECG leads) were obtained in 25 of 31 maps, and entrainment was achieved during 28 of 42 SMVTs. In 10 pigs, 10 SMVTs were recorded at least twice and were considered for radiofrequency ablation. An 8-mm tip ablation catheter was advanced to potential ablation sites with a specially designed “homing” device, requiring a median time of 120 seconds. In these 10 pigs, either identical pace map (≥11 of 12, 6 SMVTs) or concealed entrainment (4 SMVTs) guided the ablation procedure. After ablation, 8 of 10 SMVTs were rendered noninducible, while 2 pigs died during energy application of degeneration of SMVT to ventricular fibrillation.

Conclusions
The MMC allows rapid, comprehensive, and reliable endocardial mapping during SMVTs, which facilitates successful ablation in the porcine post–myocardial infarction model.
Collagen Scar Formation After Acute Myocardial Infarction
Authors: Uusimaa Paavo , Risteli Juha , Niemelä Matti , Lumme Jarmo , Ikäheimo Markku , Jounela Antti , Peuhkurinen Keijo
Published: June 2012

Background
Left ventricular function after acute myocardial infarction (AMI) is determined by the expansion of the infarct zone and remodeling of the noninfarcted myocardium. An occluded infarct-related artery (IRA) is an independent risk factor for remodeling.

Methods and Results
Changes in myocardial collagen metabolism were evaluated in 36 patients with suspected AMI. The plasma creatine kinase MB fraction and myoglobin release curves were analyzed for assessment of early reperfusion and infarct size. Collagen scar formation was evaluated by measurement of serum concentrations of the aminoterminal propeptide of type III procollagen (PIIINP), the aminoterminal propeptide of type I procollagen (intact PINP), and the carboxyterminal propeptide of type I procollagen (PICP). Plasma renin activity and urine excretion of cortisol and aldosterone were also measured. Coronary angiography and left ventricular cineangiography were performed during early hospitalization. The serum concentration of PIIINP increased from 3.50±0.20 to a maximum of 5.08±0.36 μg/L (n=32) in the patients with AMI, whereas the concentrations of intact PINP and PICP tended to decrease. The area under the curve (AUC) of PIIINP during the first 10 postinfarction days was larger in patients with severe heart failure or ejection fractions ≤40% than in those with no heart failure or with an ejection fraction >40% (
P
<.05 and
P
<.01, respectively), and it was also larger in the patients with TIMI grade 0 to 2 flows than in those with TIMI 3 flows (
P
<.05), despite similar enzymatically determined infarct sizes. No significant correlations between PIIINP and neurohumoral parameters were observed. The AUC of PIIINP and the change in PIIINP during the first 4 days were significantly correlated with indices of cardiac function.

Conclusions
Collagen scar formation after AMI can be quantified by measurement of serum PIIINP concentrations. Scar formation is more prominent in large infarctions causing left ventricular dysfunction and in patients with occluded IRAs.
Significance of Morphological Abnormalities Detected by MRI in Patients Undergoing Successful Ablation of Right Ventricular Outflow Tract Tachycardia
Authors: Globits Sebastian , Kreiner Gerhard , Frank Herbert , Heinz Gottfried , Klaar Ursula , Frey Bernhard , Gössinger Heinz
Published: June 2012

Background
MRI can demonstrate subtle morphological changes of the right ventricle in patients with idiopathic right ventricular outflow tract tachycardia (RVOT). The present study examines the incidence and significance of right ventricular (RV) abnormalities detected by MRI with respect to the site of successful radiofrequency catheter ablation of the clinical tachycardia.

Methods and Results
The study population comprised 20 patients (mean age, 40±12 years) undergoing elimination of recurrent RVOT by radiofrequency catheter ablation. MRI studies were performed before ablation to assess RV volumes and function, as well as structural abnormalities of the RV myocardium. Ten healthy age- and sex-matched subjects served as control subjects. The successful ablation sites, as documented by radiographs of the catheter position, were compared with MRI findings. Patients with RVOT showed no difference in respect to RV volumes and ejection fractions compared with control subjects. Whereas RV abnormalities were limited to prominent fatty deposits of the right atrioventricular groove extending into the inlet portion of the RV wall in 2 of 10 control subjects, MRI studies demonstrated morphological changes of the RV free wall in 13 (65%) of 20 patients with RVOT, including presence of fatty tissue (n=5), wall thinning (n=9), and dyskinetic wall segments (n=4). Eight of these patients had additional fat deposits, thinning, or a saccular aneurysm in the RV outflow tract, corresponding with the ablation site in 6 patients.

Conclusions
In RVOT, structural abnormalities of the right ventricle can be detected in a substantial number of patients despite normal RV volumes and global function. MRI abnormalities within the RV outflow tract are significantly associated with the origin of tachycardia.
KVLQT1
C-Terminal Missense Mutation Causes a Forme Fruste Long-QT Syndrome
Authors: Donger Claire , Denjoy Isabelle , Berthet Myriam , Neyroud Nathalie , Cruaud Corinne , Bennaceur Mohammed , Chivoret Guy , Schwartz Ketty , Coumel Philippe , Guicheney Pascale
Published: June 2012

Background
KVLQT1
, the gene encoding the α-subunit of a cardiac potassium channel, is the most common cause of the dominant form of long-QT syndrome (LQT1-type), the Romano-Ward syndrome (RWS). The overall phenotype of RWS is characterized by a prolonged QT interval on the ECG and cardiac ventricular arrhythmias leading to recurrent syncopes and sudden death. However, there is considerable variability in the clinical presentation, and potential severity is often difficult to evaluate. To analyze the relationship between phenotypes and underlying defects in
KVLQT1
, we investigated mutations in this gene in 20 RWS families originating from France.

Methods and Results
By PCR-SSCP analysis, 16 missense mutations were identified in
KVLQT1
, 11 of them being novel. Fifteen mutations, localized in the transmembrane domains S2-S3, S4-S5, P, and S6, were associated with a high percentage of symptomatic carriers (55 of 95, or 58%) and sudden deaths (23 of 95, or 24%). In contrast, a missense mutation, Arg
555
Cys, identified in the C-terminal domain in 3 families, was associated with a significantly less pronounced QT prolongation (459±33 ms, n=41, versus 480±32 ms, n=70,
P
=.0012), and significantly lower percentages of symptomatic carriers (7 of 44, or 16%,
P
<.001) and sudden deaths (2 of 44, or 5%,
P
<.01). Most of the cardiac events occurring in these 3 families were triggered by drugs known to affect ventricular repolarization.

Conclusions
Our data show a wide KVLQT1 allelic heterogeneity among 20 families in which KVLQT1 causes RWS. We describe the first missense mutation in the C-terminal domain of KVLQT1, which is clearly associated with a fruste phenotype, which could be a favoring factor of acquired LQT syndrome.
Application of Models of Defibrillation to Human Defibrillation Data
Authors: Swerdlow Charles D. , Brewer James E. , Kass Robert M. , Kroll Mark W.
Published: June 2012

Background
Theoretical models predict that optimal capacitance for implantable cardioverter-defibrillators (ICDs) is proportional to the time-dependent parameter of the strength-duration relationship. The hyperbolic model gives this relationship for average current in terms of the chronaxie (t
c
). The exponential model gives the relationship for leading-edge current in terms of the membrane time constant (τ
m
). We hypothesized that these models predict results of clinical studies of ICD capacitance if human time constants are used.

Methods and Results
We studied 12 patients with epicardial ICDs and 15 patients with transvenous ICDs. Defibrillation threshold (DFT) was determined for 120-μF monophasic capacitive-discharge pulses at pulse widths of 1.5, 3.0, 7.5, and 15 ms. To compare the predictions of the average-current versus leading-edge-current methods, we derived a new exponential average-current model. We then calculated individual patient time parameters for each model. Model predictions were validated by retrospective comparison with clinical crossover studies of small-capacitor and standard-capacitor waveforms. All three models provided a good fit to the data (
r
2
=.88 to .97,
P
<.001). Time constants were lower for transvenous pathways (53±7 Ω) than epicardial pathways (36±6 Ω) (t
c
,
P
<.001; average-current τ
m
,
P
=.002; leading-edge-current τ
m
,
P
<.06). For epicardial pathways, optimal capacitance was greater for either average-current model than for the leading-edge-current model (
P
<.001). For transvenous pathways, optimal capacitance differed for all three models (
P
<.001). All models provided a good correlation with the effect of capacitance on DFT in previous clinical studies:
r
2
=.75 to .84,
P
<.003. For 90-μF, 120-μF, and 150-μF capacitors, predicted stored-energy DFTs were 3% to 8%, 8% to 16%, and 14% to 26% above that for the optimal capacitance.

Conclusions
Model predictions based on measured human cardiac-muscle time parameter have a good correlation with clinical studies of ICD capacitance. Most of the predicted reduction in DFT can be achieved with ≈90-μF capacitors.
Dependence of Augmentation of Arterial Endothelial Cell Expression of Plasminogen Activator Inhibitor Type 1 by Insulin on Soluble Factors Released From Vascular Smooth Muscle Cells
Authors: Schneider David J. , Absher P. Marlene , Ricci Michael A.
Published: June 2012

Background
Insulin-resistant states are characterized by accelerated atherosclerosis and are associated with increased plasma concentrations of insulin and plasminogen activator inhibitor type 1 (PAI-1). To determine whether arterial expression of PAI-1 in response to insulin contributes to the increased PAI-1 observed, human and porcine arteries in culture were exposed to insulin, and results were compared with responses of specific arterial cellular constituents maintained in culture and coculture.

Methods and Results
Human and porcine arterial segments and cells obtained from arteries were maintained in culture. Insulin increased accumulation of PAI-1 in conditioned medium from arterial segments (ng PAI-1 [1 nmol/L insulin minus control]: human arteries 47±17, porcine arteries 3.1±1.2,
P
<.05 for each) and from endothelial cells (ECs) cocultured with smooth muscle cells (SMCs, ng PAI-1 [1 nmol/L insulin minus control]: human cells 43±8, porcine cells 0.5±0.1,
P
<.05 for each). Insulin had no effect on EC expression of PAI-1 when not cocultured with SMCs. Increased accumulation of PAI-1 was seen when ECs, in coculture chambers without SMCs, were cultured with medium previously conditioned by SMCs in the presence of insulin. The increased accumulation of PAI-1 in conditioned medium was secondary to both an increased transport of PAI-1 from the basal to the apical surface of ECs as well as an increased production of PAI-1 by ECs.

Conclusions
Insulin augments arterial expression of PAI-1 by stimulating release of a soluble factor(s) from SMCs. Accordingly, increased arterial elaboration of PAI-1 in response to insulin is likely to account, in part, for the elevated PAI-1 observed in the blood of subjects with insulin-resistant states.
Empirical Versus Tested Antitachycardia Pacing in Implantable Cardioverter Defibrillators
Authors: Schaumann Anselm , Mühlen Friederike von zur , Herse Bernhard , Gonska Bernd-Dieter , Kreuzer Heinrich
Published: June 2012

Background
—Implantable cardioverter-defibrillators (ICDs) reduce the risk of sudden cardiac death. The objective of this study was to evaluate whether testing of antitachycardia pacing (ATP) for induced ventricular tachycardias (VTs) at predischarge examination can predict ATP success during follow-up.

Methods and Results
—The study covers 200 consecutive patients who received ICD implants from June 1991 through December 1995. All underwent electrophysiological testing. In 54 patients (ATP tested, group T), ATP terminated induced VTs successfully. In 146 patients (empirically programmed ATP, group E), only ventricular fibrillation could be induced, including 18 with unsuccessful ATP attempts for induced VTs. Disregarding the results of ATP testing, the same ATP scheme was programmed in all patients: three attempts of autodecremental ramp with 81% of the VT cycle length, with 8 to 10 pulses. During a follow-up of 20.4±10 months, 95% of 3819 spontaneous VTs were successfully terminated with ATP in 42 patients of group T. In group E, 90% of 1346 spontaneous VTs in 81 patients were terminated with ATP. Acceleration after ATP occurred in 2% in group T versus 5% in group E. The success for all episodes in individual patients was ≥90% in >60% of the ATP tested and empirically programmed patients.

Conclusions
—The results of this 200-patient prospective study comparing tested versus empirical ATP show high success (95% versus 90%) for VT termination, with low rates of acceleration. ATP is safe and very effective and should be programmed “on” in all patients regardless of the predischarge EP inducibility.
Contribution of Tonic Chemoreflex Activation to Sympathetic Activity and Blood Pressure in Patients With Obstructive Sleep Apnea
Authors: Narkiewicz Krzysztof , van de Borne Philippe J. H. , Montano Nicola , Dyken Mark E. , Phillips Bradley G. , Somers Virend K.
Published: June 2012

Background
—Muscle sympathetic nerve activity (MSNA) is increased in patients with obstructive sleep apnea (OSA). We tested the hypothesis that tonic activation of excitatory chemoreceptor afferents contributes to the elevated sympathetic activity in OSA.

Methods and Results
—Using a double-blind, randomized, vehicle-controlled design, we examined the effects of chemoreflex deactivation (by comparing effects of breathing 100% oxygen for 15 minutes with effects of breathing room air for 15 minutes) on MSNA, heart rate, blood pressure, and minute ventilation in 14 untreated patients with OSA and in 12 normal subjects matched for age and body mass index. All control subjects underwent overnight polysomnography to exclude the existence of occult OSA. Baseline MSNA was markedly elevated in the patients with OSA compared with the control subjects (44±4 versus 30±3 bursts per minute;
P
=.01). In both control subjects and patients with OSA, heart rate decreased during administration of 100% oxygen but did not change during administration of room air. By contrast, both MSNA (
P
=.008) and mean arterial pressure (
P
=.02) were significantly reduced during chemoreflex deactivation by 100% oxygen only in patients with OSA but not in control subjects.

Conclusions
—Tonic activation of excitatory chemoreflex afferents may contribute to increased efferent sympathetic activity to muscle circulation in patients with OSA.
Effect of Postmenopausal Hormone Therapy on Lipoprotein(a) Concentration
Authors: Espeland Mark A. , Marcovina Santica M. , Miller Valery , Wood Peter D. , Wasilauskas Carol , Sherwin Roger , Schrott Helmut , Bush Trudy L.
Published: June 2012

Background
—Postmenopausal hormone therapy has been reported to decrease levels of lipoprotein (Lp)(a) in cross-sectional studies and small or short-term longitudinal studies. We report findings from a large, prospective, placebo-controlled clinical trial that allows a broad characterization of these effects for four regimens of hormone therapy.

Methods and Results
—The Postmenopausal Estrogen/Progestin Interventions study was a 3-year, placebo-controlled, randomized clinical trial to assess the effect of hormone regimens on cardiovascular disease risk factors in postmenopausal women 45 to 65 years of age. The active regimens were conjugated equine estrogens therapy at 0.625 mg daily, alone or in combination with each of three regimens of progestational agents: medroxyprogesterone acetate (MPA) at 2.5 mg daily (ie, continuous MPA), MPA at 10 mg days 1 to 12 (ie, cyclical MPA), and micronized progesterone at 200 mg days 1 to 12. Plasma levels of Lp(a) were measured at baseline (n=366), 12 months (n=354), and 36 months (n=342). Assignment to hormone therapy resulted in a 17% to 23% average drop in Lp(a) concentrations relative to placebo (
P
<.0001), which was maintained across 3 years of follow-up. No significant differences were observed among the four active arms. Changes in Lp(a) associated with hormone therapy were positively correlated with changes in LDL cholesterol, total cholesterol, apolipoprotein B, and fibrinogen levels and were similar across subgroups defined by age, weight, ethnicity, and prior hormone use.

Conclusions
—Postmenopausal estrogen therapy, with or without concomitant progestin regimens, produces consistent and sustained reductions in plasma Lp(a) concentrations.
Prospective Temporal Analysis of the Onset of Preinfarction Angina Versus Outcome
Authors: Kloner Robert A. , Shook Thomas , Antman Elliott M. , Cannon Christopher P. , Przyklenk Karin , Yoo Kissok , McCabe Carolyn H. , Braunwald Eugene
Published: June 2012

Background
—The timing of onset of angina before myocardial infarction in relation to outcome is unknown.

Methods and Results
—We prospectively determined the importance of the time of onset of preinfarction angina in relation to 30-day outcomes in the TIMI-9B study from standardized forms. Of the 3002 patients entered into the study, 425 reported angina before their myocardial infarction. Patients with angina onset within 24 hours of infarction had a lower 30-day cardiac event rate (mortality, recurrent myocardial infarction, heart failure, or shock) at 4% than those with onset of angina >24 hours (17%;
P
=.030). A history of any angina alone was not associated with reduced event rate. Peak creatine kinase levels tended to be lower in the group with angina within 24 hours. These benefits were not due to higher rates of use of antianginal medicines or aspirin and were not a consequence of differences in baseline characteristics or disease states (hypertension, hypercholesterolemia) among subgroups.

Conclusions
—These temporal observations are consistent with the concept of preconditioning by preinfarction angina but do not rule out other mechanisms.
Electrical Stimulation Versus Coronary Artery Bypass Surgery in Severe Angina Pectoris
Authors: Mannheimer Clas , Eliasson Tore , Augustinsson Lars-Erik , Blomstrand Christian , Emanuelsson Håkan , Larsson Sture , Norrsell Henrik , Hjalmarsson Åke
Published: June 2012

Background
—Spinal cord stimulation (SCS) has been shown to have antianginal and anti-ischemic effects in severe angina pectoris. The present study was performed to investigate whether SCS can be used as an alternative to coronary artery bypass grafting (CABG) in selected patient groups, ie, patients with no proven prognostic benefit from CABG and with an increased surgical risk.

Methods and Results
—One hundred four patients were randomized (SCS, 53; CABG, 51). The patients were assessed with respect to symptoms, exercise capacity, ischemic ECG changes during exercise, rate-pressure product, mortality, and cardiovascular morbidity before and 6 months after the operation. Both groups had adequate symptom relief (
P
<.0001), and there was no difference between SCS and CABG. The CABG group had an increase in exercise capacity (
P
=.02), less ST-segment depression on maximum (
P
=.005) and comparable (
P
=.0009) workloads, and an increase in the rate-pressure product both at maximum (
P
=.0003) and comparable (
P
=.03) workloads compared with the SCS group. Eight deaths occurred during the follow-up period, 7 in the CABG group and 1 in the SCS group. On an intention-to-treat basis, the mortality rate was lower in the SCS group (
P
=.02). Cerebrovascular morbidity was also lower in the SCS group (
P
=.03).

Conclusions
—CABG and SCS appear to be equivalent methods in terms of symptom relief in this group of patients. Effects on ischemia, morbidity, and mortality should be considered in the choice of treatment method. Taking all factors into account, it seems reasonable to conclude that SCS may be a therapeutic alternative for patients with an increased risk of surgical complications.
Linear Atrial Ablations in a Canine Model of Chronic Atrial Fibrillation
Authors: Mitchell Mark A. , McRury Ian D. , Haines David E.
Published: June 2012

Background
—To test the hypothesis that susceptibility to sustained atrial fibrillation may be decreased by creation of linear atrial ablations, we established a canine model of chronic atrial fibrillation and used a novel catheter design to create atrial ablations.

Methods and Results
—Chronic atrial fibrillation was induced in 16 dogs by creation of mitral regurgitation and rapid pacing of the atria. Temperature-controlled radiofrequency ablations were attempted along empirically derived, preselected atrial target sites in 11 dogs (ablation group), and a sham procedure was performed in 5 dogs (control group). Follow-up electrophysiology study and pathological examination were conducted 13±5 days after the initial procedure. Immediately after ablation, sustained atrial fibrillation could be initiated in 1 of 9 surviving ablation dogs and 5 of 5 controls (
P
=.004). Four dogs died within 24 hours of the procedure. Permanent pacing was required in 4 dogs. At follow-up, 0 of 7 ablation dogs and 5 of 5 controls had atrial fibrillation (
P
=.001). Furthermore, 2 of 7 ablation dogs had sustained atrial tachycardias, one of which was successfully ablated. Pathological examination demonstrated frequent incomplete lesion sets and discontinuous lesions.

Conclusions
—In this model, a reduction in the susceptibility to sustained atrial fibrillation can be achieved by long linear atrial ablations created with specially designed coil electrode catheters. Complete lesion continuity was not required to achieve a therapeutic effect.
Left Ventricular Structure and Function in Children Infected With Human Immunodeficiency Virus
Authors: Lipshultz Steven E. , Easley Kirk A. , Orav E. John , Kaplan Samuel , Starc Thomas J. , Bricker J. Timothy , Lai Wyman W. , Moodie Douglas S. , McIntosh Kenneth , Schluchter Mark D. , Colan Steven D.
Published: June 2012

Background
—The frequency of, course of, and factors associated with cardiovascular abnormalities in pediatric HIV are incompletely understood.

Methods and Results
—A baseline echocardiogram (median age, 2.1 years) and 2 years of follow-up every 4 months were obtained as part of a prospective study on 196 vertically HIV-infected children. Age- or body surface area–adjusted
z
scores were calculated by use of data from normal control subjects. Although 88% had symptomatic HIV infection, only 2 had CHF at enrollment, with a 2-year cumulative incidence of 4.7% (95% CI, 1.5% to 7.9%). All mean cardiac measurements were abnormal at baseline (decreased left ventricular fractional shortening [LV FS] and contractility and increased heart rate and LV dimension, mass, and wall stresses). Most of the abnormal baseline cardiac measurements correlated with depressed CD4 cell count
z
scores and the presence of HIV encephalopathy. Heart rate and LV mass showed significantly progressive abnormalities, whereas FS and contractility tended to decline. No association was seen between longitudinal changes in FS and CD4 cell count
z
score. Children who developed encephalopathy during follow-up had depressed initial FS, and FS continued to decline during follow-up.

Conclusions
—Subclinical cardiac abnormalities in HIV-infected children are common, persistent, and often progressive. Dilated cardiomyopathy (depressed contractility and dilatation) and inappropriate LV hypertrophy (elevated LV mass in the setting of decreased height and weight) were noted. Depressed LV function correlated with immune dysfunction at baseline but not longitudinally, suggesting that the CD4 cell count may not be a useful surrogate marker of HIV-associated LV dysfunction. However, the development of encephalopathy may signal a decline in FS.
Ischemic Preconditioning in the Intact Rat Heart Is Mediated by δ
1
- But Not μ- or κ-Opioid Receptors
Authors: Schultz Jo El J. , Hsu Anna K. , Gross Garrett J.
Published: June 2012

Background
—Our laboratory has previously shown that δ-opioid receptors are involved in the cardioprotective effect of ischemic preconditioning in the rat heart. However, this class of receptors consists of two subtypes, δ
1
and δ
2
, and μ- or κ-opioid receptors may also exist in the heart. Therefore, the purpose of the present study was to test the hypothesis that ischemic preconditioning is mediated through stimulation of one or both δ-opioid receptor subtypes.

Methods and Results
—Anesthetized, open chest, male Wistar rats were assigned to 1 of 14 groups. All animals were subjected to 30 minutes of occlusion and 2 hours of reperfusion. Ischemic preconditioning was elicited by three 5-minute occlusion periods interspersed with 5 minutes of reperfusion. Two doses of 7-benzylidenenaltrexone (BNTX; 1 and 3 mg/kg IV), a selective δ
1
-opioid receptor antagonist, or naltriben (NTB; 1 and 3 mg/kg IV), a selective δ
2
-opioid receptor antagonist, were given before ischemic preconditioning. To test for a role of μ-opioid receptors, rats were pretreated with β-funaltrexamine (β-FNA; 15 mg/kg SC), an irreversible μ-opioid receptor antagonist, 24 hours before ischemic preconditioning or given the μ-opioid receptor agonist D-Ala,
2
N-Me-Phe,
4
glycerol
5
-enkephalin (DAMGO) as three 5-minute infusions (1, 10, and 100 μg/kg per infusion IV, respectively) interspersed with 5-minute drug-free periods before the prolonged ischemic and reperfusion periods (lowDAMGO, medDAMGO, and hiDAMGO, respectively). The involvement of κ-opioid receptors was tested by administering one of two doses of
nor
-binaltorphimine (
nor
-BNI; 1 and 5 mg/kg IV) before ischemic preconditioning. Infarct size (IS) as a percent of the area at risk (AAR) was measured by triphenyltetrazolium stain. Ischemic preconditioning markedly reduced IS/AAR (14±4%,
P
<.05) compared with control (55±4%). NTB, β-FNA, and
nor
-BNI were unable to block the cardioprotective effect of ischemic preconditioning. In addition, DAMGO had no effect on IS/AAR. However, the high dose of BNTX (3 mg/kg IV) significantly attenuated the cardioprotective effect of ischemic preconditioning (39±5%;
P
<.05 versus control and ischemic preconditioning).

Conclusions
—These results indicate that δ
1
-opioid receptors play an important role in the cardioprotective effect of ischemic preconditioning in the rat heart.
Elevated Levels of 8-iso-Prostaglandin F
2α
in Pericardial Fluid of Patients With Heart Failure
Authors: Mallat Ziad , Philip Ivan , Lebret Maryline , Chatel Didier , Maclouf Jacques , Tedgui Alain
Published: June 2012

Background
—It has been suggested that oxidant stress may play a role in the pathophysiology of heart failure. However, no definitive information is available because most previous approaches used to measure oxidant stress are nonspecific, inaccurate, and unreliable.

Methods and Results
—To evaluate oxidant stress in the heart, we measured pericardial fluid levels of 8-iso-prostaglandin F
2α
(8-iso-PGF
2α
), a specific and quantitative marker of oxidant stress in vivo, in a series of 51 consecutive patients with ischemic and/or valvular heart disease referred for cardiac surgery. Pericardial levels of 8-iso-PGF
2α
were correlated with the functional severity of heart failure (NYHA classification) and with echocardiographic indices of ventricular dilatation measured by independent physicians. Pericardial levels of 8-iso-PGF
2α
were significantly increased in patients with symptomatic heart failure compared with asymptomatic patients and gradually increased with the functional severity of heart failure (
P
=.0003). In addition, pericardial levels of 8-iso-PGF
2α
were significantly correlated with left ventricular end-diastolic and end-systolic diameters (
P
=.008 and .026, respectively).

Conclusions
—Pericardial levels of 8-iso-PGF
2α
increase with the functional severity of heart failure and are associated with ventricular dilatation. These data suggest an important role for in vivo oxidant stress on ventricular remodeling and the progression to heart failure.
Prognostic Value of Vasodilator Myocardial Perfusion Imaging in Patients With Left Bundle-Branch Block
Authors: Wagdy Hisham M. , Hodge David , Christian Timothy F. , Miller Todd D. , Gibbons Raymond J.
Published: June 2012

Background
—The prognostic value of tomographic myocardial perfusion imaging with dipyridamole or adenosine in patients with left bundle-branch block has not been established.

Methods and Results
—The study group consisted of 245 patients with left bundle-branch block who underwent tomographic (single photon emission tomography) myocardial perfusion imaging with thallium-201 (n=173) or technetium-99m sestamibi (n=72) and either dipyridamole (n=153) or adenosine (n=92) stress. Patients were prospectively classified into two groups. Patients were classified as “high risk” if they had (1) a large severe fixed defect (n=28), (2) a large reversible defect (n=36), or (3) cardiac enlargement and either increased pulmonary uptake (thallium) or a decreased resting ejection fraction (sestamibi) (n=20). The remaining 161 patients (66% of the study group) were at “low risk.” Follow-up was 99% complete at 3±1.4 years. Three-year overall survival was 57% in the high-risk group compared with 87% in the low-risk group (
P
<.0001). Survival free of cardiac death/nonfatal myocardial infarction/cardiac transplantation was 55% in the high-risk group and 93% in the low-risk group (
P
<.0001). The presence of a high-risk scan had significant incremental prognostic value after adjustment for age, sex, diabetes, and previous myocardial infarction (
P
<.0001). Patients with a low-risk scan had an overall survival that was not significantly different from that of a US age-matched population (
P
=.86).

Conclusions
—Tomographic myocardial perfusion imaging with adenosine or dipyridamole stress provides important prognostic information in patients with left bundle-branch block, which is incremental to clinical assessment.
Acceleration of Typical Atrial Flutter Due to Double-Wave Reentry Induced by Programmed Electrical Stimulation
Authors: Cheng Jie , Scheinman Melvin M.
Published: June 2012

Background
—Acceleration of reentrant tachycardia induced by programmed electrical stimulation is a well-documented phenomenon, but the mechanisms remain poorly understood.

Methods and Results
—Twelve patients with typical atrial flutter were studied. Activation sequence of the underlying reentrant circuit was recorded by multiple multipolar electrodes placed in the right atrium. In five patients, 27 episodes of atrial flutter acceleration were induced by single extrastimuli delivered in the isthmus between the tricuspid annulus and eustachian ridge (TA-ER isthmus) and one by rapid overdrive atrial pacing. Analyses of the activation sequences, intracardiac electrograms, and 12-lead surface ECG P-wave morphology indicated that the acceleration was caused by two successive activation wave fronts circulating in the same direction along the same reentrant circuit (double-wave reentry, DWR). DWR was induced only within a narrow range of coupling interval, from 2 to 45 ms beyond the effective refractory period, and was associated with unidirectional antidromic block of the paced impulse. Patients with DWR had a shorter effective refractory period (138.8±13.4 versus 163.8±12.2 ms,
P
<.015) and larger excitable gap (124.0±22.6 versus 83.2±13.2 ms,
P
<.009) compared with patients without inducible DWR. All of the DWR episodes were transient. Most (78.6%) terminated after one of the double wave fronts was blocked in the TA-ER isthmus.

Conclusions
—DWR is one of the mechanisms responsible for programmed electrical stimulation–induced atrial flutter acceleration in human subjects. Its induction requires a sufficient excitable gap and antidromic unidirectional block of the paced impulse in the TA-ER isthmus. In addition, the TA-ER isthmus is the usual site of DWR termination.
Effects of Atrial Defibrillation Shocks on the Ventricles in Isolated Sheep Hearts
Authors: Gray Richard A. , Jalife José
Published: June 2012

Background
—The effects of cardioversion of atrial fibrillation on the activation sequence of the ventricles have not been previously studied. In this study we examined the events in the ventricle that follow the application of atrial defibrillatory shocks.

Methods and Results
—We used video imaging technology to study the sequence of activation on the surface of the ventricles in the Langendorff-perfused sheep heart. We recorded transmembrane potentials simultaneously from over 20 000 sites on the epicardium before and after biphasic shocks applied by a programmable atrial defibrillator. The first epicardial activation after the shock depended on both the voltage and timing of the shock. During ventricular diastole shocks as low as 10 V produced ventricular excitation, although the time between the shock and the first epicardial activation (latency) was ≈30 ms. As the shock voltage was increased to 120 V, latency decreased to zero and the entire epicardium was depolarized within 30 ms. For 120-V shocks delivered late in systole, the depolarization sequence produced by the shock was similar to the previous repolarization sequence. Shocks of 120 V applied 150 to 300 ms after the previous ventricular excitation induced ventricular fibrillation. Ventricular fibrillation was induced by multiple focal beats after the shock, which produced waves that propagated but broke down into reentry within regions of high repolarization gradients.

Conclusions
—These results demonstrate that atrial defibrillation shocks excite the ventricles even at low shock voltages. In addition, ventricular fibrillation can be induced by shocks given in the vulnerable period by producing focal patterns that break down into reentrant waves.
Contrast Media–Enhanced Magnetic Resonance Imaging Visualizes Myocardial Changes in the Course of Viral Myocarditis
Authors: Friedrich Matthias G. , Strohm Oliver , Schulz-Menger Jeanette , Marciniak Heinz , Luft Friedrich C. , Dietz Rainer
Published: June 2012

Background
—The course of tissue changes in acute myocarditis in humans is not well understood. Diagnostic tools currently available are unsatisfactory. We tested the hypothesis that inflammation is reflected by signal changes in contrast-enhanced magnetic resonance imaging (MRI).

Methods and Results
—We assessed 44 consecutive patients with symptoms of acute myocarditis. Nineteen patients met the inclusion criteria revealing ECG changes, reduced myocardial function, elevated creatine kinase, positive troponin T, serological evidence for acute viral infection, exclusion of coronary heart disease, and positive antimyosin scintigraphy. We studied these patients on days 2, 7, 14, 28, and 84 after the onset of symptoms. We obtained ECG-triggered, T1-weighted images before and after application of 0.1 mmol/kg gadolinium. We measured the global relative signal enhancement of the left ventricular myocardium related to skeletal muscle and compared it with measurements in 18 volunteers. The global relative enhancement was higher in patients on days 2 (4.8±0.3 [mean±SE] versus 2.5±0.2;
P
<.0001); 7 (4.7±0.5,
P
<.0001); 14 (4.6±0.5,
P
<.0002); and 28 (3.9±0.4,
P
=.009) but not on day 84 (3.1±0.3;
P
=NS). On day 2, the enhancement was focal, whereas at later time points, the enhancement was diffuse. In patients with evidence of ongoing disease, the values remained elevated.

Conclusions
—Acute myocarditis evolves from a focal to a disseminated process during the first 2 weeks after onset of symptoms. Contrast media–enhanced MRI visualizes the localization, activity, and extent of inflammation and may serve as a powerful noninvasive diagnostic tool in acute myocarditis.
Diabetes Mellitus, Glycoprotein IIb/IIIa Blockade, and Heparin
Authors: Kleiman Neal S. , Lincoff A. Michael , Kereiakes Dean J. , Miller Dave P. , Aguirre Frank V. , Anderson Keaven M. , Weisman Harlan F. , Califf Robert M. , Topol Eric J.
Published: June 2012

Background
—After angioplasty, major complications and ischemic events occur more frequently in diabetic than nondiabetic patients. To determine whether treatment with abciximab is effective in reducing these events in diabetics, we analyzed characteristics and outcomes of diabetic patients enrolled in a large multicenter study (EPILOG).

Methods and Results
—Of 2792 patients enrolled, 638 (23%) were diabetic. Diabetic patients were older, shorter, and heavier; more likely to be female and have three-vessel disease, prior coronary artery bypass graft surgery, a history of hypertension, or a recent myocardial infarction; and less likely to be current smokers than their nondiabetic counterparts. During hospitalization, death, myocardial infarction, or urgent revascularization occurred in 7.1% of diabetics and 7.5% of nondiabetics. By 6 months, the composite of death and myocardial infarction had occurred in 8.8% of diabetic patients and 7.4% of nondiabetics, whereas death, myocardial infarction, or revascularization had occurred in 27.2% and 22.6%, respectively. Abciximab treatment reduced death or myocardial infarction among diabetic and nondiabetic patients (hazard ratios, 0.28 [95% confidence interval (CI), 0.13 to 0.57] and 0.47 [95% CI, 0.33 to 0.70] at 30 days for diabetics and nondiabetics, respectively, and 0.36 [95% CI, 0.21 to 0.61] and 0.60 [95% CI, 0.44 to 0.82] at 6 months for diabetics and nondiabetics, respectively). Abciximab reduced target vessel revascularization among nondiabetic patients (hazard ratio, 0.78 [95% CI, 0.63 to 0.96]) but not among diabetics (hazard ratio, 1.4 [95% CI, 0.94 to 2.08]). When standard- and low-dose heparin adjuncts were compared, diabetics receiving abciximab with standard-dose heparin had marginally greater reductions in the composite of death and myocardial infarction and in target vessel revascularization than diabetics assigned to abciximab with low-dose heparin.

Conclusions
—Abciximab treatment in diabetic patients led to a reduction in the composite of death and myocardial infarction, which was at least as great as that seen in nondiabetic patients. However, target vessel revascularization was reduced in nondiabetic but not diabetic patients. This effect may be associated in part with lower doses of heparin. These differences may be related to differences in the platelet and coagulation systems between diabetics and nondiabetics, the greater extent of coronary artery disease in diabetics, or patient selection and management factors.
PDGF-Receptor Tyrosine Kinase Blocker AG1295 Selectively Attenuates Smooth Muscle Cell Growth In Vitro and Reduces Neointimal Formation After Balloon Angioplasty in Swine
Authors: Banai Shmuel , Wolf Yehuda , Golomb Gershon , Pearle Andrew , Waltenberger Johannes , Fishbein Ilia , Schneider Aviva , Gazit Aviv , Perez Louise , Huber Rita , Lazarovichi Galila , Rabinovich Laura , Levitzki Alexander , Gertz S. David
Published: June 2012

Background
—Signaling through protein tyrosine kinases (PTKs) is a major contributor to the transmission of mitogenic stimuli to the interior of the cell and nucleus. The present study was designed to determine the effect of the tyrphostin AG1295, a selective blocker of PDGF-receptor PTK, on the growth of porcine and human smooth muscle cells (SMCs) in culture, on the outgrowth kinetics of SMCs from porcine and human arterial explants, and on neointimal formation after balloon injury in pigs.

Methods and Results
—SMCs for culture were obtained from porcine abdominal aortas, human internal mammary arteries, and endarterectomy tissue from a single human carotid artery. Addition of AG1295 to SMCs before PDGF stimulation completely inhibited PDGF-β-receptor tyrosine phosphorylation without affecting the level of PDGF-β-receptor. AG1295 resulted in a selective, reversible inhibition of SMC proliferation in culture (76%) with only mild (13.5%) inhibition of endothelial cell proliferation. The number of SMCs accumulating around explants of porcine carotid arteries and human endarterectomy specimens 12, 15, 19, 22, and 24 days after plating was reduced by 82% to 92% in AG1295-treated compared with nontreated specimens, and initiation of SMC outgrowth was markedly delayed. The numbers of cells accumulated 10 days after initiation of outgrowth were significantly lower in treated versus control explants. Local intravascular delivery of AG1295-impregnated polylactic acid–based nanoparticles (130±25 nm) to the site of balloon injury to porcine femoral arteries resulted in significant reductions in intima/media area ratio and luminal cross-sectional area narrowing by neointima compared with contralateral control arteries to which empty nanoparticles were applied (0.15±0.07 versus 0.09±0.03,
P
=.046 and 20±4% versus 10±4%,
P
=.0009, n=6 for both).

Conclusions
—The tyrphostin AG1295, a selective blocker of PDGF-receptor kinase, exerts a marked inhibitory effect on the activation, migration, and proliferation of porcine and human SMCs in vitro and an ≈50% inhibitory effect on neointimal formation after balloon injury in porcine femoral arteries when delivered via biodegradable nanoparticles. Further studies appear to be warranted to evaluate the applicability of this novel approach to the interventional setting.