bluuebunny/crossref_metadata_2025 huggingface dataset:
Double-Blind, Placebo-Controlled Study of the Effects of Carvedilol in Patients With Moderate to Severe Heart Failure
Authors: Packer Milton , Colucci Wilson S. , Sackner-Bernstein Jonathan D. , Liang Chang-seng , Goldscher David A. , Freeman Israel , Kukin Marrick L. , Kinhal Vithal , Udelson James E. , Klapholz Marc , Gottlieb Stephen S. , Pearle David , Cody Robert J. , Gregory John J. , Kantrowitz Nikki E. , LeJemtel Thierry H. , Young Sarah T. , Lukas Mary Ann , Shusterman Neil H.
Published: June 2012

Background
Carvedilol has improved the symptomatic status of patients with moderate to severe heart failure in single-center studies, but its clinical effects have not been evaluated in large, multicenter trials.

Methods and Results
We enrolled 278 patients with moderate to severe heart failure (6-minute walk distance, 150 to 450 m) and a left ventricular ejection fraction ≤0.35 at 31 centers. After an open-label, run-in period, each patient was randomly assigned (double-blind) to either placebo (n=145) or carvedilol (n=133; target dose, 25 to 50 mg BID) for 6 months, while background therapy with digoxin, diuretics, and an ACE inhibitor remained constant. Compared with placebo, patients in the carvedilol group had a greater frequency of symptomatic improvement and lower risk of clinical deterioration, as evaluated by changes in the NYHA functional class (
P
=.014) or by a global assessment of progress judged either by the patient (
P
=.002) or by the physician (
P
<.001). In addition, treatment with carvedilol was associated with a significant increase in ejection fraction (
P
<.001) and a significant decrease in the combined risk of morbidity and mortality (
P
=.029). In contrast, carvedilol therapy had little effect on indirect measures of patient benefit, including changes in exercise tolerance or quality-of-life scores. The effects of the drug were similar in patients with ischemic heart disease or idiopathic dilated cardiomyopathy as the cause of heart failure.

Conclusions
These findings indicate that, in addition to its favorable effects on survival, carvedilol produces important clinical benefits in patients with moderate to severe heart failure treated with digoxin, diuretics, and an ACE inhibitor. (Circulation. 1996;94:2793-2799.)
Effect of Coupling Interval and Pacing Cycle Length on Morphology of Paced Ventricular Complexes
Authors: Goyal Rajiva , Harvey Mark , Daoud Emile G. , Brinkman Karin , Knight Bradley P. , Bahu Marwan , Weiss Raul , Bogun Frank , Man K. Ching , Strickberger S. Adam , Morady Fred
Published: June 2012

Background
Ventricular pace mapping is performed by comparing the QRS morphology of ventricular paced complexes to that of a template arrhythmia, either a premature ventricular depolarization or a QRS complex during ventricular tachycardia. The objective of this study was to evaluate the effect of coupling interval and pacing cycle length on QRS morphology.

Methods and Results
The study population consisted of 20 patients (mean age, 38±16 years) undergoing a clinically indicated electrophysiology procedure. In the first 10 patients, the effect of coupling interval on the morphology of single paced ventricular complexes was evaluated visually and by signal processing techniques. Visually apparent differences in QRS morphology occurred in a mean of 4/12 electrocardiographic leads with a change in coupling interval of ≥100 ms. In the next 10 patients, the QRS complex morphology during ventricular overdrive pacing at cycle lengths of 600 and 300 ms was found to differ significantly in a mean of 4/12 leads. The QRS morphology during overdrive pacing differed significantly from that of a single paced complex whenever the pacing cycle length differed from the coupling interval of the single paced complex by >80 ms.

Conclusions
The morphology of single paced QRS complexes may vary, depending on coupling interval, and the QRS morphology during overdrive pacing is affected by the pacing cycle length. During ventricular pace mapping, the coupling interval or cycle length of the template arrhythmia should be matched during pacing. If not, rate-dependent changes in QRS morphology that are independent of the pacing site may confound the results of pace mapping.
Secular Trends in Cardiac Transplant Recipient and Donor Management in the United States, 1990 to 1994
Authors: Rodeheffer Richard J. , Naftel David C. , Stevenson Lynne Warner , Porter Charles B. , Young James B. , Miller Leslie W. , Kenzora Joseph L. , Haas Garrie J. , Kirklin James K. , Bourge Robert C.
Published: June 2012

Background
The growth of the US cardiac transplant waiting list has outpaced the increase in donors, resulting in a widening gap between the number of waiting recipients and available donors. These trends have generated concern that longer waiting times may result in more patients deteriorating to urgent status and that transplanting only patients who are in an advanced state of decompensation will reduce posttransplant survival. Furthermore, the shortage of donors may result in extending the guidelines for donor acceptability to a degree that increases graft failure and posttransplant mortality. We measured these secular trends in the Cardiac Transplant Research Database to provide current data on time-dependent changes in US cardiac transplant practice and survival.

Methods and Results
At the time of this analysis, the Cardiac Transplant Research Database included all 2749 patients transplanted from January 1, 1990, to June 30, 1994, in the 25 participating transplant centers. During this 4.5-year period, the median waiting time for recipients who received a transplant increased from 2.7 to 3.5 months (
P
<.0001), and the proportion of recipients whose status was urgent at transplantation increased from 41% to 60% (
P
<.0001). Donor ischemic time increased from 150 to 166 minutes (
P
<.0001), and the proportion of donors requiring pressor support increased from 68% to 85% (
P
<.0001). Despite these changes in practice, the 1-year survival rate remained constant at 84% during this 4.5-year interval. There was no significant difference in 1-year survival rate between urgent status patients (83%) and nonurgent status patients (85%) (
P
=.08).

Conclusions
The widening gap between the number of waiting recipients and the number of donors has resulted in a continuing trend toward transplanting urgent status recipients and to a liberalization of donor acceptance criteria. Despite these changes, posttransplant survival has remained constant.
Cardiac Sympathetic Responses to Acute Vasodilation
Authors: Newton Gary E. , Parker John D.
Published: June 2012

Background
Although there is indirect evidence of impaired baroreflex control of sympathetic outflow directed at heart muscle, the regulation of cardiac sympathetic activity in the setting of heart failure is largely unexplored. We used the norepinephrine spillover method to address the hypothesis that baroreflex control of cardiac sympathetic activity is reduced in heart failure.

Methods and Results
Twenty-three patients were studied, 17 in a group with heart failure and 6 in a group with normal ventricular function. In both groups, cardiac norepinephrine spillover was assessed in response to nitroprusside infused to steady-state conditions. Nitroprusside resulted in significant reductions in mean systemic arterial pressure (normal group, −15±3% [mean±SEM]; heart failure group, −13±1%) and mean pulmonary artery pressure (normal group, −25±10%; heart failure group, −29±4%). In response to nitroprusside, there was a 98±16% increase in cardiac norepinephrine spillover in the normal group (from 81±10 to 159±25 pmol/min,
P
<.05). Despite similar hemodynamic responses to nitroprusside in the heart failure group, there was only a 28±14% increase in cardiac spillover (from 211±71 to 245±59 pmol/min,
P
=NS), a response that was significantly smaller than that seen in the normal group.

Conclusions
In patients with heart failure compared with subjects with normal ventricular function, there was a significantly smaller increase in cardiac sympathetic activity in response to a steady-state infusion of nitroprusside. This result provides evidence for reduced baroreflex control of cardiac sympathetic activity in heart failure.
Hemodynamic and Renal Excretory Effects of Human Brain Natriuretic Peptide Infusion in Patients With Congestive Heart Failure
Authors: Marcus Lee S. , Hart Douglas , Packer Milton , Yushak Madeline , Medina Norma , Danziger Robert S. , Heitjan Daniel F. , Katz Stuart D.
Published: June 2012

Background
The pharmacological effects of infusion of human brain natriuretic peptide (hBNP) in patients with severe congestive heart failure have not been characterized previously.

Methods and Results
Twenty patients with severe congestive heart failure were randomized in a double-blind, placebo-controlled, crossover trial to receive incremental 90-minute infusions of hBNP (0.003, 0.01, 0.03, and 0.1 μg/kg per minute) or placebo on 2 consecutive days. At the highest completed dose of the hBNP, mean pulmonary artery pressure decreased from 38.3±1.6 to 25.9±1.7 mm Hg; mean pulmonary capillary wedge pressure decreased from 25.1±1.1 to 13.2±1.3 mm Hg; mean right atrial pressure decreased from 10.9±1 to 4.8±1.0 mm Hg; mean arterial pressure decreased from 85.2±2.0 to 74.9±1.7 mm Hg; and cardiac index increased from 2.0±0.1 to 2.5±0.1 L/min per square meter (all
P
<.01 versus placebo). Urine volume and urine sodium excretion increased significantly during hBNP infusion when compared with placebo infusion (90±38 versus 67±27 mL/h and 2.6±2.4 versus 1.4±1.2 mEq/h, respectively, both
P
<.05 versus placebo), whereas creatinine clearance and urinary potassium excretion did not change.

Conclusions
Infusion of incremental doses of hBNP is associated with favorable hemodynamic and natriuretic effects in patients with severe congestive heart failure. (Circulation. 1996;94:3184-3189.)
Radiofrequency Catheter Ablation of Atrial Flutter
Authors: Poty Herve , Saoudi Nadir , Nair Mohan , Anselme Frederic , Letac Brice
Published: June 2012

Background
Radiofrequency ablation of type 1 atrial flutter (AFl) has recently evolved toward an anatomically guided procedure directed to isthmuses at the lower part of the right atrium (RA). However, different types of block at these isthmuses may be observed and potentially correlated with different late outcomes. In addition, because the ablation is anatomically guided, ablation should be possible during sinus rhythm.

Methods and Results
Forty-four patients underwent ablation of type 1 AFl performed during ongoing tachycardia (33 patients) or sinus rhythm (11 patients). Evidence of inferior vena cava–tricuspid annulus isthmus block was assessed by changes in RA impulse propagation while pacing from both sides of the ablation site. Apparent complete isthmus block was achieved in 43 of 44 patients with 9±7 pulses. However, incomplete block mimicking complete block because of intra-atrial conduction delay but leading to a different low RA activation pattern was individualized. At the end of the procedure, isthmus block was complete in 35 patients and incomplete in 8, but since AFl reinduction was no longer possible, patients were discharged. During a follow-up period of 12.1±5.5 months, 4 patients experienced AFl recurrence; all had shown incomplete or no block.

Conclusions
Detailed multiple-point low RA mapping is necessary to differentiate incomplete from complete isthmus block. Complete block is the best marker for long-term success of AFl ablation, although incomplete block may be sufficient to prevent recurrence in a significant number of cases. Isthmus block is achievable during sinus rhythm, and AFl induction is not mandatory.
Autoimmune Response in Chronic Ongoing Myocarditis Demonstrated by Heterotopic Cardiac Transplantation in Mice
Authors: Nakamura Hiroshi , Yamamura Taisei , Umemoto Seiji , Fukuta Shinji , Shioi Tetsuo , Matsumori Akira , Sasayama Shigetake , Matsuzaki Masunori
Published: June 2012

Background
Autoimmune mechanisms have been implicated in the pathogenesis of chronic ongoing myocarditis. To investigate this relation, we used an A/J mouse model inoculated with coxsackievirus B3 and determined whether myocarditis would be transferred to normal hearts that were heterotopically transplanted.

Methods and Results
Inbred 3-week-old A/J mice were inoculated intraperitoneally with coxsackievirus B3 (Nancy strain; 2×10
4
plaque-forming units) and housed for >60 days. The presence of the viral genome in the myocardium was determined by the polymerase chain reaction with primers specific for the 5′ end of the coxsackievirus B3 genome performed at 40, 50, or 60 days after inoculation. Normal A/J mouse hearts were transplanted into the same strain of mice without myocarditis (group A) and into mice with chronic ongoing myocarditis (group B). The hearts were evaluated histologically 2 weeks after transplantation. Conventional histological examination of infiltrated T cells and macrophages was performed, and the expression of intercellular adhesion molecule-1, major histocompatibility complex (MHC) class I antigen, and MHC class II antigen was evaluated by immunoenzymatic staining. The concentrations of interleukin-1α (IL-1α) and tumor necrosis factor (TNF-α) in the grafts were measured with an ELISA. The viral RNA genomes were not detected in the mice with chronic ongoing myocarditis, but their transplanted hearts did show myocarditis. In the hearts with induced myocarditis, infiltrated mononuclear cells consisted of CD4+ T cells, CD8+ T cells (CD4+ cell number >CD8+ cell number), and macrophages. Intercellular adhesion molecule-1, MHC class I antigen, and MHC class II antigen were expressed in the vascular endothelial cells and myocardial cells in and around the infiltrated lesions. The concentrations of IL-1α and TNF-α in group B were significantly higher than those in group A (group A versus group B: IL-1α, 125±35 versus 180±34 pg/mL; TNF-α, 45±15 versus 96±40 pg/mL;
P
<.05).

Conclusions
Results suggest that an autoimmune response may play a key role in the progression of chronic ongoing myocarditis.
Coronary Artery Spasm Does Not Depend on the Intracellular Calcium Store but Is Substantially Mediated by the Protein Kinase C–Mediated Pathway in a Swine Model With Interleukin-1β In Vivo
Authors: Kadokami Toshiaki , Shimokawa Hiroaki , Fukumoto Yoshihiro , Ito Akira , Takayanagi Tsuneo , Egashira Kensuke , Takeshita Akira
Published: June 2012

Background
The intracellular mechanism for coronary artery spasm is still unknown. Since the protein kinase C (PKC)–mediated pathway and Ca
2+
release from sarcoplasmic reticulum (SR) are important intracellular mechanisms of vascular smooth muscle contraction, we examined the possible role of these two mechanisms in the pathogenesis of coronary spasm in our swine model in vivo.

Methods and Results
In 25 pigs, interleukin-1β (IL-1β) was applied chronically to the coronary arteries from the adventitia to induce an inflammatory/proliferative lesion. Two weeks after the operation, either intracoronary serotonin or histamine repeatedly induced coronary spasm at the IL-1β–treated site. At those spastic sites, phorbol-12,13-dibutyrate, a PKC-activating phorbol ester, also induced coronary spasm, which was blocked by pretreatment with the PKC inhibitors staurosporine and sphingosine. Serotonin- and histamine-induced coronary spasm was also significantly inhibited by pretreatment with staurosporine, sphingosine, or nifedipine (an L-type Ca
2+
channel antagonist) but not by ryanodine (an inhibitor of Ca
2+
-induced Ca
2+
release from SR) or thapsigargin (an inhibitor of Ca
2+
-ATPase of SR). Bay K 8644 (an L-type Ca
2+
channel agonist) also induced coronary spasm at the IL-1β–treated site, which was significantly inhibited by pretreatment with staurosporine, sphingosine, and nifedipine. In contrast, coronary vasoconstriction induced by prostaglandin F
2α
was not affected by pretreatment with staurosporine or sphingosine but was significantly inhibited by pretreatment with ryanodine, thapsigargin, or nifedipine.

Conclusions
These results suggest that (1) PKC activation largely accounts for the serotonin- and histamine-induced coronary spasm; (2) at the spastic site, the calcium influx through L-type Ca
2+
channels may be augmented via the PKC-mediated pathway; and (3) the Ca
2+
release from the SR into the cytosol may not play a primary role in coronary spasm.
Low-Temperature Mapping Predicts Site of Successful Ablation While Minimizing Myocardial Damage
Authors: Cote Jean-Marc , Epstein Michael R. , Triedman John K. , Walsh Edward P. , Saul J. Philip
Published: June 2012

Background
Temperatures near 50°C can cause reversible loss of excitability in myocardial cells.

Methods and Results
Low-temperature, short-duration applications of radiofrequency energy were used to determine the adequacy of electrophysiological mapping of accessory pathway (AP) locations in 15 patients at 27 target sites using a closed-loop, temperature-controlled generator set to 50°C. Energy was delivered until evidence of conduction block, or for a maximum of 10 seconds. If AP block occurred, a full 70°C set point radiofrequency application was delivered to the same site. In the absence of AP block, tests with higher temperature settings (60°C and 70°C) were delivered to determine if inadequate temperature or catheter position led to failure of the initial 50°C test. At 15 successful target sites where permanent AP block was achieved, the 50°C test resulted in AP block in 14 (93%). Conduction returned in 13 of 14 APs after radiofrequency power was turned off. The time to block for the 70°C applications was significantly shorter than for the 50°C tests, and the peak temperature achieved was significantly higher. At unsuccessful sites where permanent AP block was not achieved, no block was induced with 11 of 12 tests at 50°C, 6 of 6 tests at 60°C, and 1 of 2 tests at 70°C, suggesting that failure was due to incorrect catheter position. The sensitivity and positive predictive values of a 50°C test identifying a successful site were >90%.

Conclusions
Low-temperature radiofrequency applications that cause transient AP block predict permanent success when a higher-temperature application is delivered at the same site. The time to achieve conduction block is a function of the temperature set point, and low-temperature tests produce reversible conduction block, suggesting minimal permanent injury.
Angiotensin-Converting Enzyme Inhibition With Quinapril Improves Endothelial Vasomotor Dysfunction in Patients With Coronary Artery Disease
Authors: Mancini G.B. John , Henry Gregory C. , Macaya Carlos , O'Neill Blair J. , Pucillo Anthony L. , Carere Ronald G. , Wargovich Thomas J. , Mudra Harald , Lu¨scher Thomas F. , Klibaner Michael I. , Haber Harry E. , Uprichard Andrew C.G. , Pepine Carl J. , Pitt Bertram
Published: June 2012

Background
Angiotensin-converting enzyme (ACE) inhibitors may exert some of their benefits in the therapy of hypertension, congestive heart failure, and acute myocardial infarction by their improvement of endothelial dysfunction. TREND (Trial on Reversing ENdothelial Dysfunction) investigated whether quinapril might improve endothelial dysfunction in normotensive patients with coronary artery disease and no heart failure, cardiomyopathy, or major lipid abnormalities so that confounding variables that affect endothelial dysfunction could be minimized.

Methods and Results
Using a double-blind, randomized, placebo-controlled design, we measured the effects of quinapril (40 mg daily) on coronary artery diameter responses to acetylcholine using quantitative coronary angiography. The primary response variable was the net change in the acetylcholine-provoked constriction of target segments between the baseline (prerandomization) and 6-month follow-up angiograms. The constrictive responses to acetylcholine were comparable in the placebo (n=54) and quinapril (n=51) groups at baseline. After 6 months, only the quinapril group showed significant net improvement in response to incremental concentrations of acetylcholine (4.5±3.0% [mean±SEM] versus −0.1±2.8% at 10
−
6
mol/L and 12.1±3.0% versus −0.8±2.9% at 10
−
4
mol/L, quinapril versus placebo, respectively; overall
P
=.002).

Conclusions
TREND shows that ACE inhibition with quinapril improved endothelial dysfunction in patients who were normotensive and who did not have severe hyperlipidemia or evidence of heart failure. These benefits of ACE inhibition are likely due to attenuation of the contractile effects and superoxide-generating effects of angiotensin II and to enhancement of endothelial cell release of nitric oxide secondary to diminished breakdown of bradykinin.
Comparison of Myocardial Perfusion Reserve Before and After Coronary Balloon Predilatation and After Stent Implantation in Patients With Postangioplasty Restenosis
Authors: Haude Michael , Caspari Guido , Baumgart Dietrich , Brennecke Ru¨diger , Meyer Ju¨rgen , Erbel Raimund
Published: June 2012

Background
Stents provide a scaffold for coronary arteries after angioplasty and inhibit elastic recoil.

Methods and Results
In 25 patients with postangioplasty restenosis of the left anterior descending artery, ECG-gated digital subtraction coronary angiograms were recorded at baseline and during hyperemia (12 mg papaverine IC) before and after balloon predilatation (PTCA), after implantation of a Palmaz-Schatz stent, and after 6 months. Densitometric evaluation revealed different time and density parameters to calculate two definitions of myocardial perfusion reserve (MPR1 and MPR2) and maximum flow ratio (MaxFR). Poststenotic MPR1 increased from 1.57±0.14 to 2.59±0.86 after PTCA and to 3.10±0.41 after stenting, with 2.90±0.65 at follow-up (ANOVA,
P
<.05), while reference MPR1 remained unchanged at 3.10±0.40. Poststenotic MPR2 increased from 1.36±0.28 to 2.50±1.20 and to 3.40±0.58, respectively, with 3.20±0.92 at follow-up (ANOVA,
P
<.05), while reference MPR2 remained unchanged at 3.40±0.60. MaxFR was 2.13±0.53 after PTCA, 2.83±0.35 after stenting, and 2.73±0.58 at follow-up (ANOVA,
P
<.05). A good correlation was found between minimal stenotic luminal diameter and MPR1 or MPR2 (
r
=.87 and
r
=.94) and between luminal gain and MaxFR (
r
=.75). A negative correlation was measured between recoil and MPR1, MPR2, and MaxFR (
r
=−.80,
r
=−.86, and
r
=−.83). At follow-up, a steeper correlation was found between MPR and minimal stenosis diameter (MPR1: slope, 0.52 versus 0.91; MPR2: slope, 1.48 versus 1.95) and between MaxFR and net lumen gain (slope, 0.78 versus 1.27).

Conclusions
Coronary stent implantation in patients with postangioplasty restenosis normalized poststenotic myocardial perfusion immediately as a result of a larger postprocedural lumen and a more pronounced inhibition of elastic recoil. After 6 months this benefit was sustained despite progressive lumen loss.
Diltiazem Improves Cardiac Function and Exercise Capacity in Patients With Idiopathic Dilated Cardiomyopathy
Authors: Figulla Hans R. , Gietzen Frank , Zeymer Uwe , Raiber Martin , Hegselmann Johannes , Soballa Reinhild , Hilgers Reinhard
Published: June 2012

Background
Evidence is arising that calcium antagonists in idiopathic dilated cardiomyopathy (IDC) may have beneficial effects on virus-induced cardiopathology, alcohol toxicity, microcirculatory disorders, and impaired calcium cycling, all possibly involved in the pathogenesis of the disease. Thus, the effect of adjunct diltiazem (60 to 90 mg TID) on standard treatment was investigated.

Methods and Results
The Diltiazem in Dilated Cardiomyopathy (DiDi) trial was a randomized, double-blind, placebo-controlled, multicenter trial of 186 patients (92 receiving diltiazem, 94 receiving placebo) with IDC diagnosed by coronary angiography, catheterization of the left side of the heart, and a left ventricular ejection fraction of <0.50 (mean, 0.34±0.11). The effect of adjunct diltiazem treatment on transplant listing–free survival, hemodynamics, exercise capacity, and subjective status was investigated. During the 24-month study period, 33 patients dropped out of the study; 153 patients finished the study protocol. Twenty-seven patients died or had a listing for heart transplantation: 16 in the placebo group and 11 in the diltiazem group. The transplant listing–free survival rate was 85% for diltiazem and 80% for placebo recipients (
P
=.444). After 24 months, only diltiazem significantly increased cardiac index at rest (
P
=.01) and under a workload (
P
=.02), systolic and diastolic pressures (
P
=.003 and
P
=.004), stroke volume index (
P
=.003), and stroke work index (
P
=.000) and decreased both pulmonary artery pressure under workload (
P
=.007) and heart rate (
P
=.001). Diltiazem also increased exercise capacity (
P
=.002) and subjective well-being (
P
=.01). Adverse reactions were minor and evenly distributed in both groups, except for an increase in the PQ interval in the diltiazem group.

Conclusions
In patients with IDC, the adjunct therapy of diltiazem improves cardiac function, exercise capacity, and subjective status without deleterious effects on transplant listing–free survival.
Continuum of Cardiovascular Performance Across a Broad Range of Fitness Levels in Healthy Older Men
Authors: Schulman Steven P. , Fleg Jerome L. , Goldberg Andrew P. , Busby-Whitehead Jan , Hagberg James M. , O'Connor Frances C. , Gerstenblith Gary , Becker Lewis C. , Katzel Leslie I. , Lakatta Loretta E. , Lakatta Edward G.
Published: June 2012

Background
Although it has become clear that habitual exercise in older individuals can partially offset age-associated cardiovascular declines, it is not known whether the beneficial effects of exercise training in older individuals depend on their prior fitness level.

Methods and Results
Ten sedentary men (S), age 60.0±1.6 years (mean±SEM), who were carefully screened to exclude cardiac disease underwent exercise training for 24 to 32 weeks, and eight age-matched endurance-trained men (ET) stopped their exercise training for 12 weeks. All underwent treadmill exercise and rest and maximal cycle exercise upright gated blood pool scans at baseline and after the lifestyle intervention. Before the intervention, the treadmill maximum rate of oxygen consumption (V̇
o
2max
) was 49.9±1.9 and 32.1±1.4 mL·kg
−1
·min
−1
in ET and S, respectively. During upright cycle exercise at exhaustion, although heart rate did not differ between groups, cardiac index, stroke volume index, ejection fraction, and left ventricular contractility index (systolic blood pressure/end-systolic volume index) all were significantly higher, and end-systolic volume index, diastolic blood pressure, and total systemic vascular resistance all were significantly lower in ET versus S. After the partial deconditioning of ET men, V̇
o
2max
fell to 42±2.2 mL·kg
−1
·min
−1
, and training of S increased V̇
o
2max
to 36.2±1.6 mL·kg
−1
·min
−1
. Training of S had effects on cardiovascular function that were similar in magnitude but directionally opposite those of detraining ET. All initial differences in cardiovascular performance at peak work rate between S and ET were abolished with the intervention. Across the broad range of fitness levels encountered before and after change in training status (V̇
o
2max
of 26 to 58 mL·kg
−1
·min
−1
), cardiac index, stroke volume index, end-systolic volume index, ejection fraction, and the left ventricular contractility index were all linearly correlated with V̇
o
2max
.

Conclusions
Exercise training or detraining of older men results in changes in left ventricular performance that are qualitatively and quantitatively similar, regardless of the initial level of fitness before the intervention.
Radiofrequency Current Catheter Ablation of Accessory Atrioventricular Pathways in Ebstein's Anomaly
Authors: Cappato Riccardo , Schlu¨ter Michael , Weiß Christian , Antz Matthias , Koschyk Dietmar H. , Hofmann Thomas , Kuck Karl-Heinz
Published: June 2012

Background
In patients with Ebstein's anomaly, localization of accessory pathways (APs) may be impeded by abnormal local electrograms recorded along the atrialized right ventricle and by the presence of multiple APs. The impact of these factors on radiofrequency (RF) current catheter ablation of APs has not been evaluated yet.

Methods and Results
Twenty-one patients with Ebstein's anomaly and reentrant atrioventricular tachycardias underwent electrophysiological evaluation and subsequent attempts at RF catheter ablation. Thirty-four right-sided APs were found, with 30 located along the atrialized ventricle. Local electrograms in this region were normal in 10 patients but fragmented in 11. Fragmented electrograms prevented the clear distinction between atrial and ventricular activation potentials as well as the identification of AP potentials. Right coronary artery mapping was performed in 7 patients. Abolition of all 26 APs was achieved in the 10 patients with normal local electrograms and in 6 of 11 patients with abnormal electrograms. Right coronary artery mapping allowed AP localization and ablation in 5 patients. In the 5 patients with abnormal electrograms and a total of 8 APs, 6 APs could not be ablated. Unsuccessfully treated patients received antiarrhythmic drugs. During 22±12 months of follow-up, 5 patients had clinical recurrences, including 4 who had undergone a successful RF procedure.

Conclusions
In patients with Ebstein's anomaly and reentrant atrioventricular tachycardias, factors likely to account for failure of RF catheter ablation include an AP located along the atrialized right ventricle and the abnormal morphology of endocardial activation potentials generated in this region.
Site-Dependent Intra-Atrial Conduction Delay
Authors: Papageorgiou Panos , Monahan Kevin , Boyle Noel G. , Seifert Mark J. , Beswick Philippa , Zebede Joseph , Epstein Laurence M. , Josephson Mark E.
Published: June 2012

Background
Atrial dysrhythmia patients have exaggerated intra-atrial conduction delays and prolonged relative refractoriness in response to atrial premature depolarizations (APDs). Furthermore, atrial fibrillation (AF) is more readily inducible by APDs from the high right atrium (HRA) than the coronary sinus (CS). In this study, we postulated that site-specific intra-atrial conduction delays can explain why AF is initiated more from the HRA than from the CS.

Methods and Results
We examined 17 patients (age, 49±22 years) without a history of atrial flutter, AF, or structural heart disease. Programmed stimulation was carried out from the HRA and distal CS, and bipolar recordings were made at the HRA, His bundle, posterior triangle of Koch, and CS. More prolongations in conduction and relative refractoriness in all intra-atrial sites were observed during HRA than CS APDs. AF was induced in 8 patients after HRA and not CS stimulation. During HRA stimulation, patients with AF inducibility exhibited significant prolongation of conduction to the posterior triangle of Koch and marked broadening of the posterior triangle of Koch electrogram compared with CS stimulation. In patients without AF inducibility, the posterior triangle of Koch electrogram width was the same during HRA and CS stimulation.

Conclusions
The existence of site-dependent intra-atrial conduction delays and site-dependent dispersion of refractoriness appears to be a common property of the atrial myocardium and does not necessarily forecast AF inducibility. However, the presence of nonuniform anisotropic characteristics of the posterior triangle of Koch may be critical for AF induction.
Role of the Tricuspid Annulus and the Eustachian Valve/Ridge on Atrial Flutter
Authors: Nakagawa Hiroshi , Lazzara Ralph , Khastgir Terrance , Beckman Karen J. , McClelland James H. , Imai Shinobu , Pitha Jan V. , Becker Anton E. , Arruda Mauricio , Gonzalez Mario D. , Widman Lawrence E. , Rome Michael , Neuhauser Jeffrey , Wang Xunzhang , Calame James D. , Goudeau Maurice D. , Jackman Warren M.
Published: June 2012

Background
Typical atrial flutter (AFL) results from right atrial reentry by propagation through an isthmus between the inferior vena cava (IVC) and tricuspid annulus (TA). We postulated that the eustachian valve and ridge (EVR) forms a line of conduction block between the IVC and coronary sinus (CS) ostium and forms a second isthmus (septal isthmus) between the TA and CS ostium.

Methods and Results
Endocardial mapping in 30 patients with AFL demonstrated atrial activation around the TA in the counterclockwise direction (left anterior oblique projection). Double atrial potentials were recorded along the EVR in all patients during AFL. Pacing either side of the EVR during sinus rhythm also produced double potentials, which indicated fixed anatomic block across EVR. Entrainment pacing at the septal isthmus and multiple sites around the TA produced a Δ return interval ≤8 ms in 14 of 15 patients tested. Catheter ablation eliminated AFL in all patients by ablation of the septal isthmus in 26 patients and the posterior isthmus in 4. AFL recurred in 2 of 12 patients (mean follow-up, 33.9±16.3 months) in whom ablation success was defined by the inability to reinduce AFL, compared with none of 18 patients (mean follow-up, 10.3±8.3 months) in whom success required formation of a complete line of conduction block between the TA and the EVR, identified by CS pacing that produced atrial activation around the TA only in the counterclockwise direction and by pacing the posterior TA with only clockwise atrial activation.

Conclusions
(
1) The EVR forms a line of fixed conduction block between the IVC and the CS; (2) the EVR and the TA provide boundaries for the AFL reentrant circuit; and (3) verification of a complete line of block between the TA and the EVR is a more reliable criterion for long-term ablation success.
Usefulness of Electron-Beam Computed Tomography in Arrhythmogenic Right Ventricular Dysplasia
Authors: Tada Hiroshi , Shimizu Wataru , Ohe Tohru , Hamada Seiki , Kurita Takashi , Aihara Naohiko , Kamakura Shir , Takamiya Makoto , Shimomura Katsuro
Published: June 2012

Background
Electron-beam computed tomography (CT) may be useful for detecting myocardial fat infiltration and diagnosing arrhythmogenic right ventricular dysplasia (ARVD). There are several characteristic electron-beam CT findings of ARVD. However, the incidence, their relation to electrophysiological abnormalities, and the usefulness of electron-beam CT for evaluating left ventricular involvement are unknown. This study aimed to clarify these issues.

Methods and Results
Electron-beam CT was performed in 14 patients with ARVD (ARVD group), 16 age- and sex-matched patients with right ventricular enlargement and/or dysfunction without ARVD (RV enlargement group), and 13 control subjects (control group). The incidences of abnormal electron-beam CT findings in the three groups were examined. Furthermore, we examined the endocardial fat–infiltrated areas detected by electron-beam CT (CT-A) and electrophysiologically abnormal areas detected in the mapping study (EPS-A) and compared the relationship between them in the ARVD group. (1) The frequencies of abundant epicardial adipose tissue, low-attenuation trabeculations, scalloping of the right ventricular free wall, and intramyocardial fat deposits were 86%, 71%, 79%, and 50%, respectively, in the ARVD group, whereas these findings were not observed in the RV enlargement and control groups. (2) Three ARVD patients (21%) had adipose tissue involvement of the left ventricle. (3) The relationship between CT-A and EPS-A was as follows: CT-A>EPS-A, 71%; CT-A=EPS-A, 14%; and EPS-A only, 14%.

Conclusions
Characteristic electron-beam CT findings are frequently observed only in patients with ARVD. Electron-beam CT is useful for evaluating for left ventricular involvement and can estimate EPS-A.
Accurate Measurement of Left Ventricular Ejection Fraction by Three-dimensional Echocardiography
Authors: Nosir Youssef F.M. , Fioretti Paolo M. , Vletter Wim B. , Boersma Eric , Salustri Alessandro , Postma Joyce Tjoa , Reijs Ambroos E.M. , Ten Cate Folkert J. , Roelandt Jos R.T.C.
Published: June 2012

Background
Three-dimensional echocardiography is a promising technique for calculation of left ventricular ejection fraction, because it allows its measurement without geometric assumptions. However, few data exist that study its reproducibility and accuracy in patients.

Methods and Results
Twenty-five patients underwent radionuclide angiography and three-dimensional echocardiography that used the rotational technique (2° interval and ECG and respiratory gating). Left ventricular volume and ejection fraction were calculated by use of Simpson's rule at a slice thickness of 3 mm. Analyses were performed to define the largest slice thickness required for accurate calculation of left ventricular volume and ejection fraction. Three-dimensional echocardiography showed excellent correlation with radionuclide angiography for calculation of left ventricular ejection fraction (mean±SD, 38.9±19.8 and 38.5±18.0, respectively;
r
=.99); their mean difference was not significant (0.03±0.17;
P
=.3), and they had a close limit of agreement (−0.385, 0.315). Intraobserver variability for radionuclide angiography and three-dimensional echocardiography was 4.2% and 2.6%, respectively, whereas interobserver variability was 6.2% and 5.3%, respectively. There was no significant difference between left ventricular volume and ejection fraction calculated at a slice thickness of 3 mm and that calculated at different slice thicknesses up to 24 mm. However, the standard deviation of the mean difference showed a stepwise increase, particularly at thicknesses >15 mm. At a slice thickness of 15 mm, the probability of three-dimensional echocardiography to detect ≥6% difference in ejection fraction was 80%.

Conclusions
Three-dimensional echocardiography has excellent correlation with radionuclide angiography for calculation of left ventricular ejection fraction in patients and has an observer variability similar to that of radionuclide angiography. We recommend the use of a 15-mm-thick slice for accurate and rapid measurement of left ventricular volume and ejection fraction.
Cardiac Troponin T Isoform Expression Correlates With Pathophysiological Descriptors in Patients Who Underwent Corrective Surgery for Congenital Heart Disease
Authors: Saba Ziad , Nassar Rashid , Ungerleider Ross M. , Oakeley Annette E. , Anderson Page A.W.
Published: June 2012

Background
This study examined cardiac troponin T (cTnT) isoform expression in patients who had undergone surgery at Duke University Medical Center (Durham, NC) between December 1, 1993, and January 31, 1995, to correct congenital heart defects. The human heart expresses four cTnT isoforms (cTnT
1
through cTnT
4
) whose sequence differences result from combinatorial alternative splicing of two exons. We have previously shown that cTnT
4
is expressed at higher levels in severely failing hearts from transplant patients. In this study, we tested the hypothesis that congenital heart defects that have a more negative effect on myocardial function increase cTnT
4
expression. We used the presence or absence of drug treatment for heart failure or congested circulation before surgery and the duration of inotropic support after corrective surgery as indicators of the pathophysiological state of the heart just before surgery.

Methods and Results
Right atrial appendage tissue was collected from 34 patients, 6 days to 35 years old (median age, 3.4 months). The amounts of the cTnT
1
through cTnT
4
isoforms, measured as a percentage of total cTnT, were determined from Western blots probed with MAb13-11, a cTnT-specific monoclonal antibody. We found that cTnT
4
expression correlated positively with the duration of inotropic support and was higher in patients who received drug treatment before surgery than in those who did not. Furthermore, we found that the percent of cTnT
4
was significantly higher in hearts with congenital defects that caused congestive failure than in hearts with tetralogy of Fallot.

Conclusions
These findings suggest that in patients with congenital cardiac defects, cTnT
4
expression is modulated by heart failure and is increased in hearts that are more hemodynamically stressed.
α
1
-Adrenergic Receptor Coupling With G
h
in the Failing Human Heart
Authors: Hwang Ki-Chul , Gray Caroline D. , Sweet Wendy E. , Moravec Christine S. , Im Mie-Jae
Published: June 2012

Background
We recently demonstrated that G
h
, which transfers the signal from the α
1
-adrenergic receptor to the 69-kD phospholipase C, is the previously identified tissue-type transglutaminase (TGase II). The α
1
-adrenergic receptor mediates actions of the sympathetic nervous system, including cardiac, arteriolar, and smooth muscle contractions. In human cardiac tissue, the expression of the α
1
-adrenergic receptor is increased under pathophysiological conditions, but changes in the physiological response are small. Therefore, it has been suggested that the other components involved in the α
1
-adrenergic receptor–mediated signaling pathway are probably altered.

Methods and Results
Immunological and biochemical studies with nonfailing and failing human heart tissues revealed that the GTP-binding and TGase activities of human heart TGase II (hhGα
h
) are downregulated in both ischemic and dilated cardiomyopathic human heart. In ischemic cardiomyopathy, the α
1
-adrenergic receptor number increased twofold (27.0 fmol/mg) compared with the nonfailing (12.8 fmol/mg) and the dilated cardiomyopathic (15.6 fmol/mg) heart tissues, but the coupling of hhGα
h
with the α
1
-adrenergic receptor did not increase. The intrinsic activity of hhGα
h
was greatly decreased in membrane fractions, whereas the cytosolic TGase activity was not changed. In the dilated cardiomyopathic human heart, these intrinsic enzyme activities of hhGα
h
were also downregulated in the membrane fraction, whereas the amount of hhGα
h
protein was greatly increased (2.8-fold) compared with the nonfailing heart.

Conclusions
The results of the present study clearly demonstrate that the α
1
-adrenergic receptor in human heart couples with G
h
(TGase II) and indicate that downregulation of hhGα
h
activity is associated with human cardiac failure but that the mechanism differs between ischemic and dilated cardiomyopathies.
Myocardial Adaptation During and After Sustained, Demand-Induced Ischemia
Authors: Berman Mark , Fischman Alan J. , Southern James , Carter Edward , Mirecki Francis , Strauss H. William , Nunn Adrian , Gewirtz Henry
Published: June 2012

Background
We tested the hypotheses that prolonged, demand-induced myocardial ischemia plateaus and that on relief of stress, myocardial function remains depressed, with proportionate reductions in blood flow and oxygen consumption indicative of hibernation.

Methods and Results
Closed-chest swine (n=20) were prepared with an 80% coronary stenosis. Hemodynamics, myocardial blood flow, oxygen, and lactate metabolism were measured in group 1 (n=9) (1) at baseline, (2) at 10 and 30 minutes of atrial pacing plus intravenous norepinephrine infusion, and (3) in 5 of 9 (group 1a) at ≈50 minutes after stress. Group 1a had ischemia assessed with
99m
Tc-labeled BMS 181321. In group 2 (n=11), myocardial function was determined with radionuclide ventriculography (n=8), and myocardial necrosis was looked for with trichlorotetrazolium chloride staining (n=7), histology (n=10), and myocardial creatine kinase concentration (n=4). Baseline stenotic-zone endocardial blood flow was reduced versus the normal zone (0.94±0.33 versus 1.38±0.27 mL·min
−1
·g
−1
, mean±SD;
P
<.05), whereas epicardial flows were comparable (1.15±0.36 versus 1.16±0.26 mL·min
−1
·g
−1
). Stenotic-zone endocardial flow was unchanged versus baseline at 10 and 30 minutes of stress, whereas epicardial flow increased (1.62±0.53 mL·min
−1
·g
−1
at 10 minutes and 1.44±0.51 mL·min
−1
·g
−1
at 30 minutes, both
P
<.05). Myocardial oxygen consumption increased versus baseline (10.8±2.9 mL·min
−1
·100 g
−1
) at 10 and 30 minutes of stress (14.9±5.2 and 13.9±4.5 mL·min
−1
·100 g
−1
, both
P
<.05). After stress, stenotic-zone blood flow and oxygen consumption were reduced ≈30% (
P
<.01) versus baseline. In group 2, stenotic-zone contraction with stress declined versus baseline and remained depressed throughout recovery. Histological and biochemical evidence of myocardial necrosis was absent in group 2.

Conclusions
Myocardial ischemia induced by a sustained increase in oxygen demand may not progress to necrosis but may instead plateau. After relief of stress, myocardial function remains depressed, with a proportionate reduction in blood flow and oxygen consumption consistent with myocardial hibernation.
Diagnosis of Sinus Venosus Atrial Septal Defect With Transesophageal Echocardiography
Authors: Pascoe Roess D. , Oh Jae K. , Warnes Carole A. , Danielson Gordon K. , Tajik A. Jamil , Seward James B.
Published: June 2012

Background
Sinus venosus atrial septal defect (SVD) is underdiagnosed with transthoracic echocardiography because of its posterior (far field) location. Transesophageal echocardiography (TEE) should be ideally suited to diagnose SVD, given the proximity of the transducer to the defect.

Methods and Results
A retrospective study was undertaken that used the medical history, echocardiographic findings, and surgical data of patients identified from computer records as having the diagnosis of SVD during the period in which TEE has been in use (1987 to 1995). Twenty-five patients (14 females and 11 males; median age, 45 years; range, 10 to 75 years) with SVD had TEE between 1987 and 1995. Prior transthoracic echocardiography clearly defined the SVD in 3 of these patients, and it was suspected in another 11 on the basis of color-flow imaging. Ten patients had unexplained dilatation of the right side of the heart, which prompted TEE examination. SVD was visualized with TEE in all 25 patients and ranged in size from 1 to 3 cm. Thirty-seven right-sided anomalous pulmonary venous connections were identified in 23 patients. No left-sided anomalous pulmonary venous connections were detected. Anatomic confirmation was obtained in all 23 surgical patients. No patient required preoperative cardiac catheterization for diagnosis.

Conclusions
TEE is accurate for the diagnosis of SVD and should be undertaken in any patient with unexplained dilatation of the right side of the heart. The associated pulmonary venous abnormalities can be identified with TEE. Cardiac catheterization for diagnostic purposes should not be required before surgical correction.
Prospective Analysis of HLA Immunogenicity of Cryopreserved Valved Allografts Used in Pediatric Heart Surgery
Authors: Shaddy Robert E. , Hunter Dixie D. , Osborn Karen A. , Lambert Linda M. , Minich L. LuAnn , Hawkins John A. , McGough Edwin C. , Fuller Thomas C.
Published: June 2012

Background
The HLA immunogenicity of cryopreserved valved allografts used in the surgical repair of congenital heart defects is unknown.

Methods and Results
To determine the immunogenicity of these allografts, we measured prospectively the frequency of panel-reactive HLA class I alloantibodies (PRA) before, 1 month after, and 3 months after allograft implantation in 9 children (age, 5.4±2.1 years) and after open-heart surgery without allograft implantation in 11 age-matched control children (age, 4.0±1.5 years). PRA was determined against an HLA-select frozen T-lymphocyte panel using the antiglobulin cytotoxicity technique. After allograft implantation, PRA increased from 3.2±2.7% before surgery to 63.3±12% at 25±2 days after surgery and 99.7±0.3% at 3.4±0.3 months after surgery. The use of dithiothreitol to remove IgM alloantibodies resulted in a modest decrease in PRA at 1 month (33.2±13%) but no change at 3 months (93.0±3.4%), suggesting the initial humoral response is an IgM alloantibody that switches almost exclusively to IgG by 3 months. Control patients showed no increase in PRA over time: 1.6±1% before surgery, 3.2±1% at 28±5 days after surgery, and 1.7±1% at 2.7±0.3 months after surgery.

Conclusions
Cryopreserved valved allografts in children induce a marked HLA alloantibody response that increases to broad panel reactivity within 3 months after surgery. This HLA sensitization has potential not only for causing deleterious effects on allograft function but also for limiting the future opportunity of heart transplantation in patients who receive cryopreserved valved allografts.