bluuebunny/crossref_metadata_2025 huggingface dataset:
Electrocardiographic Signs of Chronic Cor Pulmonale
Authors: Incalzi Raffaele Antonelli , Fuso Leonello , De Rosa Marino , Di Napoli Anteo , Basso Salvatore , Pagliari Gabriella , Pistelli Riccardo
Published: June 2012

Background
—Chronic cor pulmonale (CCP) is a strong predictor of death in chronic obstructive pulmonary disease (COPD). The aims of this study were to assess the prognostic role of individual ECG signs of CCP and of the interaction between these signs and abnormal arterial blood gases.

Methods and Results
—Two hundred sixty-three patients (217 men) with COPD, mean age 67±9 years, were grouped according to whether they had no ECG signs (group 1, n=100) or ≥1 ECG signs (group 2, n=163) of CCP and were followed up for 13 years after an exacerbation of respiratory failure. The median survival was significantly shorter in group 2 than in group 1 (2.58 versus 3.45 years, respectively; Mantel-Cox test, 9.58;
P
=0.002). The Cox regression analysis identified S
1
S
2
S
3
pattern, right atrial overload (RAO), and alveolar-arterial oxygen gradient (P
ao
2
−Pa
o
2
) >48 mm Hg during oxygen therapy as the strongest predictors of death, with hazard rate (HR)=1.81 (95% CI, 1.22 to 2.69), HR=1.58 (95% CI, 1.15 to 2.18), and HR=1.96 (95% CI, 1.19 to 3.25), respectively. The median survivals of patients having both S
1
S
2
S
3
pattern and RAO (n=14) and of patients having either S
1
S
2
S
3
pattern or RAO (n=77) were 1.33 and 2.70 years, respectively (
P
=0.022). Group 2 patients had a 3-year survival of 18% or 53%, depending on whether their P
ao
2
−Pa
o
2
during oxygen therapy was or was not >48 mm Hg.

Conclusions
—Some ECG signs of CCP and P
ao
2
−Pa
o
2
>48 mm Hg during oxygen therapy qualified as a simple and inexpensive tool for targeting subsets of COPD patients with severe or very severe short-term prognosis.
Diagnostic Marker Cooperative Study for the Diagnosis of Myocardial Infarction
Authors: Zimmerman Janice , Fromm Robert , Meyer Denise , Boudreaux Ann , Wun Chuan-Chuan C. , Smalling Richard , Davis Barry , Habib Gabriel , Roberts Robert
Published: June 2012

Background
—Millions of patients present annually with chest pain, but only 10% to 15% have myocardial infarction. Lack of diagnostic sensitivity and specificity of clinical and conventional markers prevents or delays treatment and leads to unnecessary costly admissions. Comparative data are lacking on the new markers, yet using all of them is inappropriate and expensive.

Methods and Results
—The Diagnostic Marker Cooperative Study was a prospective, multicenter, double-blind study with consecutive enrollment of patients with chest pain presenting to the emergency department. Diagnostic sensitivity and specificity and frequency of increase in patients with unstable angina were determined for creatine kinase-MB (CK-MB) subforms, myoglobin, total CK-MB (activity and mass), and troponin T and I on the basis of frequent serial sampling for ≤24 hours. Of 955 patients with chest pain, 119 (12.5%) had infarction identified by use of CK-MB mass, and 203 (21%) had unstable angina. CK-MB subforms were most sensitive and specific (91% and 89%) within 6 hours of onset, followed by myoglobin (78% and 89%). For late diagnosis, total CK-MB activity (derived from subforms) was the most sensitive and specific (96% and 98%) at 10 hours from onset, followed by troponin I (96% and 93%), but not until 18 hours, and troponin T (87% and 93% at 10 hours). In unstable angina, CK-MB subforms were increased in 29.5%, myoglobin in 23.7%, troponin I in 19.7%, and troponin T in 14.8%. All markers were increased in 99 patients. With each marker as the diagnostic standard, CK-MB subforms and myoglobin remained the most sensitive for early diagnosis.

Conclusions
—The CK-MB subform assay alone or in combination with a troponin reliably triages patients with chest pain and should lead to improved therapy and reduced cost.
Inhibition of p38 Mitogen-Activated Protein Kinase Decreases Cardiomyocyte Apoptosis and Improves Cardiac Function After Myocardial Ischemia and Reperfusion
Authors: Ma Xin L. , Kumar Sanjay , Gao Feng , Louden Calvert S. , Lopez Bernard L. , Christopher Theodore A. , Wang Chuanlin , Lee John C. , Feuerstein Giora Z. , Yue Tian-Li
Published: June 2012

Background
—Activation of p38 mitogen-activated protein kinase (MAPK) plays an important role in apoptotic cell death. The role of p38 MAPK in myocardial injury caused by ischemia/reperfusion, an extreme stress to the heart, is unknown.

Methods and Results
—Studies were performed with isolated, Langendorff-perfused rabbit hearts. Ischemia alone caused a moderate but transient increase in p38 MAPK activity (3.5-fold increase,
P
<0.05 versus basal). Ischemia followed by reperfusion further activated p38 MAPK, and the maximal level of activation (6.3-fold,
P
<0.01) was reached 10 minutes after reperfusion. Administration of SB 203580, a p38 MAPK inhibitor, decreased myocardial apoptosis (14.7±3.2% versus 30.6±3.5% in vehicle,
P
<0.01) and improved postischemic cardiac function. The cardioprotective effects of SB 203580 were closely related to its inhibition of p38 MAPK. Administering SB 203580 before ischemia and during reperfusion completely inhibited p38 MAPK activation and exerted the most cardioprotective effects. In contrast, administering SB 203580 10 minutes after reperfusion (a time point when maximal MAPK activation had already been achieved) failed to convey significant cardioprotection. Moreover, inhibition of p38 MAPK attenuated myocardial necrosis after a prolonged reperfusion.

Conclusions
—These results demonstrate that p38 MAPK plays a pivotal role in the signal transduction pathway mediating postischemic myocardial apoptosis and that inhibiting p38 MAPK may attenuate reperfusion injury.
Right Atrial Flutter Due to Lower Loop Reentry
Authors: Cheng Jie , Cabeen William R. , Scheinman Melvin M.
Published: June 2012

Background
—The mechanisms of an atrial flutter (AFL) that is more rapid and at times more irregular than typical AFL are unknown.

Methods and Results
—Twenty-nine patients with AFL were studied. Atrial electrograms were recorded from a 20-pole catheter placed against the tricuspid annulus (TA), with its distal electrodes lateral to the isthmus between the TA and the eustachian ridge (ER), and from the His bundle and coronary sinus catheters. Atrial extrastimuli were delivered in the TA-ER isthmus during typical AFL. Episodes of a right atrial flutter rhythm that was different from typical AFL were induced in 3 patients and occurred spontaneously in 3 patients. This sustained AFL, designated as lower-loop reentry (LLR), involved the lower right atrium (RA), as manifested by early breakthrough in the lower RA, wave-front collision in the high lateral RA or septum, and conduction through the TA-ER isthmus. Linear ablation resulting in bidirectional conduction block in the TA-ER isthmus terminated spontaneous LLR in 3 patients and rendered LLR noninducible in all patients. The cycle length of LLR was shorter than that of typical AFL (217±32 versus 272±40 ms,
P
<0.01). Alternating LLR and typical AFL in 1 patient resulted in cycle length oscillation.

Conclusions
—LLR is a subtype of right atrial flutter and depends on conduction through the TA-ER isthmus.
Augmented Sympathetic Activation During Short-Term Hypoxia and High-Altitude Exposure in Subjects Susceptible to High-Altitude Pulmonary Edema
Authors: Duplain Hervé , Vollenweider Laurent , Delabays Alain , Nicod Pascal , Bärtsch Peter , Scherrer Urs
Published: June 2012

Background
—Pulmonary hypertension is a hallmark of high-altitude pulmonary edema and may contribute to its pathogenesis. Cardiovascular adjustments to hypoxia are mediated, at least in part, by the sympathetic nervous system, and sympathetic activation promotes pulmonary vasoconstriction and alveolar fluid flooding in experimental animals.

Methods and Results
—We measured sympathetic nerve activity (using intraneural microelectrodes) in 8 mountaineers susceptible to high-altitude pulmonary edema and 7 mountaineers resistant to this condition during short-term hypoxic breathing at low altitude and at rest at a high-altitude laboratory (4559 m). We also measured systolic pulmonary artery pressure to examine the relationship between sympathetic activation and pulmonary vasoconstriction. In subjects prone to pulmonary edema, short-term hypoxic breathing at low altitude evoked comparable hypoxemia but a 2- to 3-times-larger increase in the rate of the sympathetic nerve discharge than in subjects resistant to edema (
P
<0.001). At high altitude, in subjects prone to edema, the increase in the mean±SE sympathetic firing rate was >2 times larger than in those resistant to edema (36±7 versus 15±4 bursts per minute,
P
<0.001) and preceded the development of lung edema. We observed a direct relationship between sympathetic nerve activity and pulmonary artery pressure measured at low and high altitude in the 2 groups (
r
=0.83,
P
<0.0001).

Conclusions
—With the use of direct measurements of postganglionic sympathetic nerve discharge, these data provide the first evidence for an exaggerated sympathetic activation in subjects prone to high-altitude pulmonary edema both during short-term hypoxic breathing at low altitude and during actual high-altitude exposure. Sympathetic overactivation may contribute to high-altitude pulmonary edema.
Investigating Feed-Forward Neural Regulation of Circulation From Analysis of Spontaneous Arterial Pressure and Heart Rate Fluctuations
Authors: Legramante Jacopo M. , Raimondi Gianfranco , Massaro Michele , Cassarino Salvatore , Peruzzi Giuseppe , Iellamo Ferdinando
Published: June 2012

Background
—Analysis of spontaneous fluctuations in systolic arterial pressure (SAP) and pulse interval (PI) reveals the occurrence of sequences of consecutive beats characterized by SAP and PI changing in the same (+PI/+SAP and −PI/−SAP) or opposite (−PI/+SAP and +PI/−SAP) direction. Although the former reflects baroreflex regulatory mechanisms, the physiological meaning of −PI/+SAP and +PI/−SAP is unclear. We tested the hypothesis that −PI/+SAP and +PI/−SAP “nonbaroreflex” sequences represent a phenomenon modulated by the autonomic nervous system reflecting a feed-forward mechanism of cardiovascular regulation.

Methods and Results
—We studied anesthetized rabbits before and after (1) complete autonomic blockade (guanethidine+propranolol+atropine, n=13; CAB), (2) sympathetic blockade (guanethidine+propranolol, n=15; SB), (3) parasympathetic blockade (atropine, n=16), (4) sinoaortic denervation (n=10; SAD), and (5) controlled respiration (n=10; CR). Nonbaroreflex sequences were defined as ≥3 beats in which SAP and PI of the following beat changed in the opposite direction. CAB reduced the number of nonbaroreflex sequences (19.1±12.3 versus 88.7±36.6,
P
<0.05), as did SB (25.3±11.7 versus 84.6±23.9,
P
<0.001) and atropine (11.2±6.8 versus 94.1±32.4,
P
<0.05). SB concomitantly increased baroreflex sensitivity (1.18±0.11 versus 0.47±0.09 ms/mm Hg,
P
<0.01). SAD and CR did not significantly affect their occurrence.

Conclusions
—These results suggest that nonbaroreflex sequences represent the expression of an integrated, neurally mediated, feed-forward type of short-term cardiovascular regulation able to interact dynamically with the feedback mechanisms of baroreflex origin in the control of heart period.
Effect of Atrial Natriuretic Peptide on Muscle Sympathetic Activity and Its Reflex Control in Human Heart Failure
Authors: Abramson Beth L. , Ando Shin-ichi , Notarius Catherine F. , Rongen Gerard A. , Floras John S.
Published: June 2012

Background
—The purpose of this study was to determine if atrial natriuretic peptide (ANP) exerts a relative inhibitory effect on muscle sympathetic nerve activity (MSNA) at rest and during nonhypotensive lower body negative pressure (LBNP) in heart failure, as in healthy subjects.

Methods and Results
—Fifteen men (age 39±2 years [mean±SE]) with dilated cardiomyopathy (ejection fraction 18±3%) received intravenous ANP (50 μg bolus, then 50 ng · kg
−1
· min
−1
) and nitroglycerin (NTG, 8 mg/min) as a hemodynamic control. During each infusion MSNA, blood pressure (BP), central venous pressure (CVP), and heart rate (HR) were recorded before and during LBNP at −6 and −12 mm Hg. NTG and ANP caused similar and significant reductions in CVP and diastolic BP, but resting MSNA did not increase with either infusion. LBNP at −6 mm Hg lowered CVP (
P
<0.05), whereas LBNP at −12 mm Hg caused significant reductions in CVP, systolic BP, and diastolic BP. These effects of nonhypotensive and hypotensive LBNP on CVP and BP were similar during ANP and NTG infusions, yet MSNA was lower both before and with LBNP during ANP (
P
<0.02). Nonhypotensive LBNP increased MSNA during NTG (+133±68 Units;
P
<0.001) but not during ANP infusion (+24±23 Units;
P
=NS).

Conclusions
—These observations are consistent with the concept that ANP exerts a sympathoinhibitory action in heart failure. This is most evident in response to reductions in atrial pressures that do not affect systemic BP.
Gender Differences in Survival in Advanced Heart Failure
Authors: Adams Kirkwood F. , Sueta Carla A. , Gheorghiade Mihai , O’Connor Christopher M. , Schwartz Todd A. , Koch Gary G. , Uretsky Barry , Swedberg Karl , McKenna William , Soler-Soler Jordi , Califf Robert M.
Published: June 2012

Background
—Previous natural history studies in broad populations of heart failure patients have associated female gender with improved survival, particularly in patients with a nonischemic etiology of ventricular dysfunction. This study investigates whether a similar survival advantage for women would be evident among patients with advanced heart failure.

Methods and Results
—The study analysis is based on the Flolan International Randomized Survival Trial (FIRST) study which enrolled 471 patients (359 men and 112 women) who had evidence of end-stage heart failure with marked symptoms (60% NYHA class IV) and severe left ventricular dysfunction (left ventricular ejection fraction 18±4.9%). A Cox proportional-hazards model, adjusted for age, gender, 6-minute walk, dobutamine use at randomization, mean pulmonary artery blood pressure, and treatment assignment, showed a significant association between female gender and better survival (relative risk of death for men versus women was 2.18, 95% CI 1.39 to 3.41;
P
<0.001). Although formal interaction testing was negative (
P
=0.275), among patients with a nonischemic etiology of heart failure, the relative risk of death for men versus women was 3.08 (95% CI 1.56 to 6.09,
P
=0.001), whereas among those with ischemic heart disease, the relative risk of death for men versus women was 1.64 (95% CI 0.87 to 3.09,
P
=0.127).

Conclusions
—Women with advanced heart failure appear to have better survival than men. Subgroup analysis suggests this finding is strongest among patients with a nonischemic etiology of heart failure.
Impaired Force-Frequency Relations in Patients With Hypertensive Left Ventricular Hypertrophy
Authors: Inagaki Masafumi , Yokota Mitsuhiro , Izawa Hideo , Ishiki Ryoji , Nagata Kohzo , Iwase Mitsunori , Yamada Yoshiji , Koide Masafumi , Sobue Toshikazu
Published: June 2012

Background
—The extent to which force-frequency and relaxation-frequency relations (FFR and RFR, respectively) and exercise-induced adrenergic stimulation affect myocardial inotropic and lusitropic reserves has not been established in patients with left ventricular (LV) hypertrophy (LVH).

Methods and Results
—We calculated the maximum first derivative of LV pressure (LV dP/dt
max
) and the LV pressure half-time (T
1/2
) during pacing, exercise, and isoproterenol infusion in 17 patients with hypertensive LVH and 9 control subjects to investigate the influence of increases in heart rate (HR) and adrenergic stimulation on inotropic and lusitropic reserves. Group A consisted of 10 LVH patients who showed a progressive increase in the HR-LV dP/dt
max
relation. Group B consisted of 7 LVH patients in whom the HR-dP/dt
max
relation at physiological pacing rates was biphasic. The LV mass index was larger and the LV ejection fraction was smaller in group B than in group A (244±72 g/m
2
versus 172±22 g/m
2
and 55±18% versus 72±6%, respectively; both
P
<0.05). The increase in LV dP/dt
max
was greater during exercise than pacing alone for similar increases in HR in all groups (
P
<0.05) (group A, 111±22% versus 25±14%; group B, 105±35% versus 14±10%; control, 111±24% versus 25±12%). T
1/2
was shorter (
P
<0.05) during exercise than with pacing alone in all groups (group A, 41±6% versus 11±3%; group B, 38±9% versus 14±4%; control, 44±6% versus 12±5%). Isoproterenol infusion caused similar increases in LV dP/dt
max
and similar decreases in T
1/2
in all groups.

Conclusions
—The FFR was biphasic in patients with severe LVH irrespective of LV function but was preserved in patients with less severe LVH and control subjects. Importantly, the RFR and adrenergic control of both inotropic and lusitropic reserves were well preserved in all LVH patients. A biphasic FFR at physiological pacing rates may be one of the earliest markers of the transition from physiological adaptation to the pathological process in LVH patients.
Effect of Butorphanol Tartrate on Shock-Related Discomfort During Internal Atrial Defibrillation
Authors: Timmermans Carl , Rodriguez Luz-Maria , Ayers Gregory M. , Lambert Hendrik , Smeets Joep L. R. M. , Vlaeyen Johan W. S. , Albert Adelin , Wellens Hein J. J.
Published: June 2012

Background
—In patients with atrial fibrillation, intracardiac atrial defibrillation causes discomfort. An easily applicable, short-acting analgesic and anxiolytic drug would increase acceptability of this new treatment mode.

Methods and Results
—In a double-blind, placebo-controlled manner, the effect of intranasal butorphanol, an opioid, was evaluated in 47 patients with the use of a step-up internal atrial defibrillation protocol (stage I). On request, additional butorphanol was administered and the step-up protocol continued (stage II). Thereafter, if necessary, patients were intravenously sedated (stage III). After each shock, the McGill Pain Questionnaire was used to obtain a sensory (S), affective (A), evaluative (E), and total (T) pain rating index (PRI) and a visual analogue scale analyzing pain (VAS-P) and fear (VAS-F). For every patient, the slope of each pain or fear parameter against the shock number was calculated and individual slopes were averaged for the placebo and butorphanol group. All patients were cardioverted at a mean threshold of 4.4±3.3 J. Comparing both patient groups for stage II, the mean slopes for PRI-T (
P
=0.0099), PRI-S (
P
=0.019), and PRI-E (
P
=0.015) became significantly lower in the butorphanol group than in the placebo group. Comparing patients who received the same shock intensity ending stage I and going to stage II, in those patients randomized to placebo the mean VAS-P (
P
=0.023), PRI-T (
P
=0.029), PRI-S (
P
=0.030), and PRI-E (
P
=0.023) became significantly lower after butorphanol administration.

Conclusions
—During a step-up internal atrial defibrillation protocol, intranasal butorphanol decreased or stabilized the value of several pain variables and did not affect fear. Of the 3 qualitative components of pain, only the affective component was not influenced by butorphanol. The PRI evaluated pain more accurately than the VAS.
Serial Assessment of Sympathetic Reinnervation After Orthotopic Heart Transplantation
Authors: Bengel Frank M. , Ueberfuhr Peter , Ziegler Sibylle I. , Nekolla Stephan , Reichart Bruno , Schwaiger Markus
Published: June 2012

Background
—Little is known about the progressiveness of sympathetic reinnervation late after cardiac transplantation (HTX). The aim of the present study was to describe individual growth of sympathetic terminals after HTX by a longitudinal quantitative assessment.

Methods and Results
—In 20 patients after HTX, dynamic PET with C-11 hydroxyephedrine (HED) was performed twice within 3.0±0.5 years. According to the time interval between HTX and first PET, subgroups of patients early (group A, <1.5 years; n=7), intermediate (group B, 1.5 to 7 years; n=7) and late (group C, >7 years; n=6) after HTX were defined. At the time of first HED PET, 10 patients were completely denervated (7 in group A, 2 in group B, and 1 in group C). Only 3 remained denervated at second PET. A significant increase of reinnervated myocardium between first and second PET was found in all 3 groups (0% to 9±9% of left ventricle for group A,
P
<0.05; 13±12% to 23±17% for group B,
P
<0.05; 21±21% to 37±23% for group C,
P
<0.05). The magnitude of increase was similar between groups. Reinnervation was first surveyed in the basal anterior region, then toward apex, septal, and lateral wall. Inferior wall remained denervated. The largest reinnervated area surveyed in an individuum was 66% of the left ventricle.

Conclusions
—The present data confirm the low likelihood of sympathetic reinnervation within 18 months after HTX. Once the reinnervation process is initiated, a continuous growth is observed even late after HTX, suggesting a progressive nature of reinnervation. Reinnervation, however, remained regionally heterogeneous, and a complete restoration was not found until 15 years after HTX.
Electrocardiographic Abnormalities in a Murine Model Injected With IgG From Mothers of Children With Congenital Heart Block
Authors: Mazel Jay A. , El-Sherif Nabil , Buyon Jill , Boutjdir Mohamed
Published: June 2012

Background
—It is a widely held view that congenital heart block (CHB) is caused by the transplacental transfer of maternal autoantibodies (anti-SSA/Ro and/or anti-SSB/La) into the fetal circulation. To test this hypothesis and to reproduce human CHB, an experimental mouse model (
BALB/c)
was developed by passive transfer of human autoantibodies into pregnant mice.

Methods and Results
—Timed pregnant mice (n=54) were injected with a single intravenous bolus of purified IgG containing human anti-SSA/Ro and anti-SSB/La antibodies from mothers of children with CHB. To parallel the “window period” of susceptibility to CHB in humans, 3 groups of mice were used: 8, 11, and 16 days of gestation. Within each group, we tested 10, 25, 50, and 100 μg of IgG. At delivery, ECGs were recorded and analyzed for conduction abnormalities. Bradycardia and PR interval were significantly increased in 8-, 11-, and 16-day gestational groups when compared with controls (
P
<0.05). QRS duration was not significantly different between all groups. Antibody levels measured by ELISA in both mothers and their offspring confirmed the transplacental transfer of the human antibodies to the pups.

Conclusions
—The passive transfer model demonstrated bradycardia, first-degree but not complete atrioventricular block in pups. The greater percentage and degree of bradycardia and PR prolongation in the 11-day mouse group correlates with the “window period” of susceptibility observed in humans. The high incidence of bradycardia suggests possible sinoatrial node involvement. All together, these data provide relevant insights into the pathogenesis of CHB.
Relationship Between TIMI Frame Count and Clinical Outcomes After Thrombolytic Administration
Authors: Gibson C. Michael , Murphy Sabina A. , Rizzo Michael J. , Ryan Kathryn A. , Marble Susan J. , McCabe Carolyn H. , Cannon Christopher P. , Van de Werf Frans , Braunwald Eugene
Published: June 2012

Background
—The corrected TIMI frame count (CTFC) is the number of cine frames required for dye to first reach standardized distal coronary landmarks, and it is an objective and quantitative index of coronary blood flow.

Methods and Results
—The CTFC was measured in 1248 patients in the TIMI 4, 10A, and 10B trials, and its relationship to clinical outcomes was examined. Patients who died in the hospital had a higher CTFC (ie, slower flow) than survivors (69.6±35.4 [n=53] versus 49.5±32.3 [n=1195];
P
=0.0003). Likewise, patients who died by 30 to 42 days had higher CTFCs than survivors (66.2±36.4 [n=57] versus 49.9±32.1 [n=1059];
P
=0.006). In a multivariate model that excluded TIMI flow grades, the 90-minute CTFC was an independent predictor of in-hospital mortality (OR=1.21 per 10-frame rise [95% CI, 1.1 to 1.3], an ≈0.7% increase in absolute mortality for every 10-frame rise;
P
<0.001) even when other significant correlates of mortality (age, heart rate, anterior myocardial infarction, and female sex) were adjusted for in the model. The CTFC identified a subgroup of patients with TIMI grade 3 flow who were at a particularly low risk of adverse outcomes. The risk of in-hospital mortality increased in a stepwise fashion from 0.0% (n=41) in patients with a 90-minute CTFC that was faster than the 95% CI for normal flow (0 to 13 frames, hyperemia, TIMI grade 4 flow), to 2.7% (n=18 of 658 patients) in patients with a CTFC of 14 to 40 (a CTFC of 40 has previously been identified as the cutpoint for distinguishing TIMI grade 3 flow), to 6.4% (35/549) in patients with a CTFC >40 (
P
=0.003). Although the risk of death, recurrent myocardial infarction, shock, congestive heart failure, or left ventricular ejection fraction ≤40% was 13.0% among patients with TIMI grade 3 flow (CTFC ≤40), the CTFC tended to segregate patients into lower-risk (CTFC ≤20, risk of adverse outcome of 7.9%) and higher-risk subgroups (CTFC >20 to ≤40, risk of adverse outcome of 15.5%;
P
=0.17).

Conclusions
—Faster (lower) 90-minute CTFCs are related to improved in-hospital and 1-month clinical outcomes after thrombolytic administration in both univariate and multivariate models. Even among those patients classified as having normal flow (TIMI grade 3 flow, CTFC ≤40), there may be lower- and higher-risk subgroups.
Relationship Between Left Ventricular Mass and Endothelium-Dependent Vasodilation in Never-Treated Hypertensive Patients
Authors: Perticone Francesco , Maio Raffaele , Ceravolo Roberto , Cosco Carmela , Cloro Cosima , Mattioli Pier Luigi
Published: June 2012

Background
—Hypertensive patients are characterized by development of both left ventricular hypertrophy (LVH) and endothelial dysfunction

Methods and Results
—We enrolled 65 never-treated hypertensive patients (36 men and 29 women aged 45.6±6.0 years) to assess the possible relationship between echocardiographic left ventricular mass (LVM) and endothelium-dependent vasodilation. Left ventricular measurements were performed at end diastole and end systole according to the recommendations of the American Society of Echocardiography and the Penn Convention. LVM was calculated with the Devereux formula and indexed by body surface area and height raised to the 2.7th power. The endothelial function was tested as responses of forearm vasculature to acetylcholine (ACh), an endothelium-dependent vasodilator (7.5, 15, and 30 μg · mL
−1
· min
−1
, each for 5 minutes), and sodium nitroprusside (SNP), an endothelium-independent vasodilator (0.8, 1.6, and 3.2 μg · mL
−1
· min
−1
, each for 5 minutes). Drugs were infused into the brachial artery, and forearm blood flow (FBF) was measured by strain-gauge plethysmography. A negative significant relationship between indexed LVM and peak of increase in FBF was found during ACh infusions (
r
=−0.554;
P
<0.0001). In addition, hypertrophic patients had a significantly lower responsive to ACh than patients without LVH (the peak increase in FBF was 9.9±3.7 versus 16.1±8.1 mL per 100 mL of tissue per minute;
P
<0.0001). No significant correlation was observed between LVM and FBF during SNP infusion.

Conclusions
—Our data provide the first evidence that echocardiographic LVM in hypertensive patients is inversely related to FBF responses to the endothelium-dependent vasodilating agent ACh, but it is likely that both endothelium and LVM are damaged by hypertension.
Expression of Cell Adhesion Molecules in Dilated Cardiomyopathy
Authors: Noutsias Michel , Seeberg Bettina , Schultheiss Heinz-Peter , Kühl Uwe
Published: June 2012

Background
—Dilated cardiomyopathy (DCM) is pathogenically linked to inflammatory cardiomyopathy (InfCM), which is characterized by intramyocardial infiltration. The transendothelial migration of immunocompetent cells is mediated by cell adhesion molecules (CAMs).

Methods and Results
—We investigated the expression pattern of CAMs (immunoglobulin superfamily, 32 selectins, and β
1
- and β
2
-integrins) in endomyocardial biopsies from DCM patients (n=152; left ventricular ejection fraction <40%) using immunohistochemistry. Whereas few specimens obtained at autopsy (controls; n=14) presented enhanced expression regarding single endothelial CAMs (human leukocyte antigen [HLA] class I, 7%; HLA-DR, 14%; CD29, 14%), none demonstrated concurrent abundance of >3 CAMs (inflammatory endothelial activation), nor did any control tissue prove positive for InfCM (>7.0 CD3+ lymphocytes per 1 mm
2
). In comparison, 64% (n=97) of the DCM biopsies were evaluated positive for InfCM and 67% (n=101) for inflammatory endothelial activation, respectively. Whereas expression of HLA class I, HLA-DR, intercellular cell adhesion molecule-1, and CD29 was distributed homogeneously within a patient’s serial sections, immunoreactivity of vascular cell adhesion molecule-1, lymphocyte function antigen-3, and the selectins was accentuated on single vascular endothelia. Sixty-six percent of the DCM biopsies presented CD29 abundance also within the extracellular matrix and the sarcolemma. CD62P and CD62E were present in 16% and 40% of the DCM patients, respectively. Endothelial CAM representatives correlated with one another (
P
<0.05), except for CD62P with HLA. Endothelial CAM expression correlated with intramyocardial infiltrates phenotyped by the corresponding counterreceptors.

Conclusions
—Inflammatory endothelial activation is present in 67% of DCM patients. Because CAM expression correlates with the immunohistological diagnosis of InfCM and counterreceptor-bearing intramyocardial infiltrates, evaluation of endothelial CAMs might be of diagnostic significance in InfCM.
Plasma Homocysteine Distribution and Its Association With Parental History of Coronary Artery Disease in Black and White Children
Authors: Greenlund Kurt J. , Srinivasan Sathanur R. , Xu Ji-Hua , Dalferes Edward , Myers Leann , Pickoff Arthur , Berenson Gerald S.
Published: June 2012

Background
—Elevated homocysteine is associated with increased risk for coronary artery disease (CAD) in adults, but its distribution in children is not well documented. We examined the distribution of homocysteine in children and its relation to parental history of CAD.

Methods and Results
—A subsample of 1137 children (53% white, 47% black) aged 5 to 17 years in 1992 to 1994 examined in the Bogalusa Heart Study (n=3135), including all with a positive parental history of CAD (n=154), had plasma homocysteine levels measured. Homocysteine correlated positively with age (
r
=0.16,
P
=0.001). No race or sex differences in homocysteine levels were observed; geometric mean (GM) levels were 5.8 μmol/L (95% CI, 5.6 to 6.1) among white males, 5.8 μmol/L (95% CI, 5.5 to 6.0) among white females, 5.6 μmol/L (95% CI, 5.4 to 5.8) among black males, and 5.6 μmol/L (95% CI, 5.4 to 5.9) among black females. Children with a positive parental history of CAD had a significantly greater age-adjusted GM homocysteine level (GM, 6.7 μmol/L; 95% CI, 6.4 to 7.1) than those without a positive history (GM, 5.6 μmol/L; 95% CI, 5.4 to 5.7); this relation was observed in each race-sex group.

Conclusions
—Higher homocysteine levels were observed among children with a positive family history of CAD. Additional studies should elucidate the contribution of genetic, dietary, and other factors to homocysteine levels in children.
Hemodynamic Effects of Direct Biventricular Compression Studied in Isovolumic and Ejecting Isolated Canine Hearts
Authors: Artrip John H. , Wang Jie , Leventhal Andrew R. , Tsitlik Joshua E. , Levin Howard R. , Burkhoff Daniel
Published: June 2012

Background
—Biventricular direct cardiac compression (DCC) can potentially support the failing heart without the complications associated with a blood/device interface. The effect of uniform DCC on left and right ventricular performance was evaluated in 7 isolated canine heart preparations.

Methods and Results
—A computer-controlled afterload system either constrained the isolated heart to contract isovolumically or simulated hemodynamic properties of physiological ejection. Biventricular DCC was provided by a chamber surrounding the heart that allowed adjustment of the compression pressure, onset time, and duration. Through a series of ventricular preloads, the effect of DCC on the end-systolic pressure-volume relationship (ESPVR) was evaluated under isovolumic and ejecting conditions. Under both conditions, DCC shifted the ESPVR of the left and right ventricles upward by an amount approximately equal to the compression pressure. The augmentation of end-systolic pressure for each initial preload tested, however, was less under ejecting conditions, because reductions in end-systolic and end-diastolic volumes occurred with ejection. Nevertheless, the net effect was to increase stroke volume. Measurement of MV̇
o
2
demonstrated that at a given ventricular volume, MV̇
o
2
did not change with DCC; however, peak ventricular pressure increased substantially, so that the effective pressure-volume area increased.

Conclusions
—Biventricular DCC can augment end-systolic pressure with no added costs of MV̇
o
2
. Under ejecting conditions, this augmentation of ventricular contracting ability manifests as increases in stroke volume. Thus, DCC represents a feasible alternative form of ventricular assist, and devices that support the heart in this manner should be further explored.
Effect of Diabetes Mellitus on Formation of Coronary Collateral Vessels
Authors: Abacı Adnan , Oğuzhan Abdurrahman , Kahraman Sinan , Eryol Namık Kemal , Ünal Şükrü , Arınç Hüseyin , Ergin Ali
Published: June 2012

Background
—Although myocardial ischemia is known to be significantly related to the development of coronary collateral vessels (CCVs), there is considerable variation between patients with ischemic heart disease in the presence of collateral development. The nature of this variability is not well known. Likewise, it remains unclear whether diabetes mellitus (DM) has any effect on CCVs. The aim of this study was to evaluate the effect of DM on CCVs.

Methods and Results
—Of the patients who underwent coronary angiography during the interval between March 1, 1993, and June 20, 1998, in our institution, 306 were diabetic. Those patients in whom coronary angiography is normal or severity of coronary artery stenosis is thought not to be sufficient for the development of CCVs (<75%) were excluded from the study. A total of 205 patients (mean age, 59±8 years) met the criteria for the DM group. For case-control matching, 205 consecutive nondiabetic patients (mean age, 58±9 years) who had ≥1 diseased vessel with >75% stenosis were included in the control group. The CCVs were graded according to the Rentrop scoring system, and the collateral score was calculated by summing the Rentrop numbers of every patient. There was no statistical difference between patients with and without DM in clinical baseline characteristics. The mean number of diseased vessels in the DM group (1.58±0.68) was higher than that in the nondiabetic group (1.42±0.65,
P
=0.005). The mean collateral score was 2.41±2.20 in the DM group and 2.60±2.39 in the control group. After confounding variables were controlled for, the collateral score in the diabetic group was significantly different from that in the nondiabetic group (
P
=0.034).

Conclusions
—Our findings suggest that CCV development is poorer in patients with than in patients without DM. Thus, we can speculate that DM is an important factor affecting CCV development.
Angiographically Documented Late Reocclusion After Successful Coronary Angioplasty of an Infarct-Related Lesion Is a Powerful Predictor of Long-Term Mortality
Authors: Bauters Christophe , Delomez Maxence , Van Belle Eric , McFadden Eugène , Lablanche Jean-Marc , Bertrand Michel E.
Published: June 2012

Background
—Late reocclusion of an infarct-related artery (IRA) that was patent in the early days after acute myocardial infarction (MI) is a frequent event; the reocclusion rate may be as high as 30%. Few studies have been designed to analyze the impact of late reocclusion of the IRA on late survival.

Methods and Results
—We studied 528 patients who all had a patent IRA after a successful PTCA procedure 10±6 days after MI and who underwent systematic 6-month angiographic follow-up to assess late patency of the IRA. We compared long-term survival of patients with and without late reocclusion. Based on the results of 6-month follow-up angiography, 2 groups of patients were defined: (1) 90 patients (17%) with reocclusion (Thrombolysis In Myocardial Infarction [TIMI] flow 0 or 1) and (2) 438 patients (83%) without reocclusion. Long-term clinical follow-up was obtained for all 528 patients at a median of 5.7 years after follow-up angiography (6.4 years after PTCA). The overall actuarial 8-year total mortality rate was 13%. At the end of follow-up, there were 35 deaths (8%) among the 438 patients without reocclusion and 18 deaths (20%) among the 90 patients with reocclusion (
P
=0.002). The actuarial 8-year total mortality rate was 10% in patients without reocclusion and 28% in patients with reocclusion (
P
=0.0003). The actuarial cardiovascular mortality rate was 7% in patients without reocclusion and 25% in patients with reocclusion (
P
<0.0001). The impact of reocclusion on long-term mortality was greater in patients with anterior MI.

Conclusions
—Late IRA patency is strongly associated with long-term survival after MI. These observations should encourage prospective studies to evaluate the impact of strategies designed to prevent late reocclusion in postinfarction patients.
Diastolic Dysfunction in Hypertensive Heart Disease Is Associated With Altered Myocardial Metabolism
Authors: Lamb Hildo J. , Beyerbacht Hugo P. , van der Laarse Arnoud , Stoel Berend C. , Doornbos Joost , van der Wall Ernst E. , de Roos Albert
Published: June 2012

Background
—Hypertension is an important clinical problem and is often accompanied by left ventricular (LV) hypertrophy and dysfunction. Whether the myocardial high-energy phosphate (HEP) metabolism is altered in human hypertensive heart disease and whether this is associated with LV dysfunction is not known.

Methods and Results
—Eleven patients with hypertension and 13 age-matched healthy subjects were studied with magnetic resonance imaging at rest and with phosphorus-31 magnetic resonance spectroscopy at rest and during high-dose atropine-dobutamine stress. Hypertensive patients showed higher LV mass (98±28 g/m
2
) than healthy control subjects (73±13 g/m
2
,
P
<0.01). LV filling was impaired in patients, reflected by a decreased peak rate of wall thinning (PRWThn), E/A ratio, early peak filling rate, and early deceleration peak (all
P
<0.05), whereas systolic function was still normal. The myocardial phosphocreatine (PCr)/ATP ratio determined in patients at rest (1.20±0.18) and during stress (0.95±0.25) was lower than corresponding values obtained from healthy control subjects at rest (1.39±0.17,
P
<0.05) and during stress (1.16±0.18,
P
<0.05). The PCr/ATP ratio correlated significantly with PRWThn (
r
=−0.55,
P
<0.01), early deceleration peak (
r
=−0.56,
P
<0.01), and with the rate-pressure product (
r
=−0.53,
P
<0.001).

Conclusions
—Myocardial HEP metabolism is altered in patients with hypertensive heart disease. In addition, there is an association between impaired LV diastolic function and altered myocardial HEP metabolism in humans. The level of myocardial PCr/ATP is most likely determined by the level of cardiac work load.
Effectiveness of Clopidogrel and Aspirin Versus Ticlopidine and Aspirin in Preventing Stent Thrombosis After Coronary Stent Implantation
Authors: Moussa Issam , Oetgen Mathew , Roubin Gary , Colombo Antonio , Wang Xangdong , Iyer Sriram , Maida Roberta , Collins Michael , Kreps Edward , Moses Jeffrey W.
Published: June 2012

Background
—Ticlopidine has been shown to reduce the incidence of stent thrombosis compared with warfarin, but it may cause serious hematological side effects. Clopidogrel, a new thienopyridine derivative, may be a safe alternative to ticlopidine. The aim of this study was to compare the safety and efficacy of clopidogrel and aspirin with those of ticlopidine and aspirin in patients undergoing coronary stent implantation.

Methods and Results
—The population of this study consisted of 2 groups: patients who underwent coronary stenting and were treated with ticlopidine and aspirin (TA group, n=1406), and patients who underwent coronary stenting followed by treatment with clopidogrel and aspirin (CA group, n=283). At 1-month follow-up, there was no difference in stent thrombosis (1.5% versus 1.4%,
P
=1.0) or major adverse cardiac events (3.1% versus 2.4%,
P
=0.85) between the TA and CA groups, respectively. The probability of any side effect (neutropenia, diarrhea, rash) was significantly higher in the TA group (10.6% versus 5.3%,
P
=0.006; relative risk, 0.53; CI, 0.32 to 0.86).

Conclusions
—These data suggest that clopidogrel may be an effective pharmacological regimen after coronary stent implantation. Furthermore, the simpler dosing regimen, the absence of neutropenia, and the lower frequency of other side effects make it a safe alternative to ticlopidine.
Stroke in Patients With Acute Coronary Syndromes
Authors: Mahaffey Kenneth W. , Harrington Robert A. , Simoons Maarten L. , Granger Christopher B. , Graffagnino Carmelo , Alberts Mark J. , Laskowitz Daniel T. , Miller Julie M. , Sloan Michael A. , Berdan Lisa G. , MacAulay Cynthia M. , Lincoff A. Michael , Deckers Jaap , Topol Eric J. , Califf Robert M.
Published: June 2012

Background
—The incidence of stroke in patients with acute coronary syndromes has not been clearly defined because few trials in this patient population have been large enough to provide stable estimates of stroke rates.

Methods and Results
—We studied the 10 948 patients with acute coronary syndromes without persistent ST-segment elevation who were randomly assigned to placebo or the platelet glycoprotein IIb/IIIa receptor inhibitor eptifibatide in the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial to determine stroke rates, stroke types, clinical outcomes in patients with stroke, and independent baseline clinical predictors for nonhemorrhagic stroke. Stroke occurred in 79 (0.7%) patients, with 66 (0.6%) nonhemorrhagic, 6 intracranial hemorrhages, 3 cerebral infarctions with hemorrhagic conversion, and 4 of uncertain cause. There were no differences in stroke rates between patients who received placebo and those assigned high-dose eptifibatide (odds ratios and 95% confidence intervals 0.82 [0.59, 1.14] and 0.70 [0.49, 0.99], respectively). Of the 79 patients with stroke, 17 (22%) died within 30 days, and another 26 (32%) were disabled by hospital discharge or 30 days, whichever came first. Higher heart rate was the most important baseline clinical predictor of nonhemorrhagic stroke, followed by older age, prior anterior myocardial infarction, prior stroke or transient ischemic attack, and diabetes mellitus. These factors were used to develop a simple scoring nomogram that can predict the risk of nonhemorrhagic stroke.

Conclusions
—Stroke was an uncommon event in patients with acute coronary syndromes in the PURSUIT trial. These strokes are, however, associated with substantial morbidity and mortality rates. The majority of strokes were of nonhemorrhagic causes. Eptifibatide was not associated with an increase in intracranial hemorrhage, and no significant effect on nonhemorrhagic stroke was observed. We developed a useful nomogram for assigning baseline nonhemorrhagic stroke risk in this patient population.
Role of Plasminogen System Components in Focal Cerebral Ischemic Infarction
Authors: Nagai N. , De Mol M. , Lijnen H. R. , Carmeliet P. , Collen D.
Published: June 2012

Background
—The role of plasminogen system components in focal cerebral ischemic infarction (FCI) was studied in mice deficient in plasminogen (Plg
−/−
), in tissue or urokinase plasminogen activator (tPA
−/−
or uPA
−/−
), or in plasminogen activator inhibitor-1 or α
2
-antiplasmin (PAI-1
−/−
or α
2
-AP
−/−
).

Methods and Results
—FCI was produced by ligation of the left middle cerebral artery and measured after 24 hours by planimetry of stained brain slices. In control (wild-type) mice, infarct size was 7.6±1.1 mm
3
(mean±SEM), uPA
−/−
mice had similar infarcts (7.8±1.0 mm
3
,
P
=NS), tPA
−/−
mice smaller (2.6±0.80 mm
3
,
P
<0.0001), PAI-1
−/−
mice larger (16±0.52 mm
3
,
P
<0.0001), and Plg
−/−
mice larger (12±1.2 mm
3
,
P
=0.037) infarcts. α
2
-AP
−/−
mice had smaller infarcts (2.2±1.1 mm
3
,
P
<0.0001 versus wild-type), which increased to 13±2.5 mm
3
(
P
<0.005 versus α
2
-AP
−/−
) after intravenous injection of human α
2
-AP. Injection into α
2
-AP
−/−
mice of Fab fragments of affinospecific rabbit IgG against human α
2
-AP, after injection of 200 μg human α
2
-AP, reduced FCI from 11±1.5 to 5.1±1.1 mm
3
(
P
=0.004).

Conclusions
—Plg system components affect FCI at 2 different levels: (1) reduction of tPA activity (
tPA
gene inactivation) reduces whereas its augmentation (
PAI-1
gene inactivation) increases infarct size, and (2) reduction of Plg activity (
Plg
gene inactivation or α
2
-AP injection) increases whereas its augmentation (α
2
-
AP
gene inactivation or α
2
-AP neutralization) reduces infarct size. Inhibition of α
2
-AP may constitute a potential avenue to treatment of FCI.
Myocardial Dysfunction in Donor Hearts
Authors: Owen Virginia J. , Burton Paul B. J. , Michel Martin C. , Zolk Oliver , Böhm Michael , Pepper John R. , Barton Paul J. R. , Yacoub Magdi H. , Harding Sian E.
Published: June 2012

Background
—Potential cardiac donors show various degrees of myocardial dysfunction, and the most severely affected hearts are unsuitable for transplantation. The cause of this acute heart failure is poorly understood. We investigated whether alterations in calcium-handling proteins, β-adrenoceptor density, or the inhibitory G protein G
iα
could account for this phenomenon in unused donor hearts (n=4 to 8). We compared these with end-stage failing hearts (n=14 to 16) and nonfailing hearts (n=3 to 12).

Methods and Results
—Myocardial samples were obtained from unused donor hearts displaying ejection fractions <30%. Both trabeculae and isolated myocytes responded as poorly as those from the group of failing hearts to increasing stimulation frequency with regard to inotropic function in vitro. Immunodetectable abundance of sarcoplasmic reticulum calcium-ATPase and sodium calcium exchanger were greater (177%;
P
<0.01) and smaller (29%;
P
<0.01), respectively, in the unused donor hearts relative to the failing group, which suggests that alterations of these proteins are not a common cause of contractile dysfunction in the 2 groups. Myocytes from the unused donor group were desensitized to isoprenaline to a similar degree as those from the failing heart group. However, β-adrenoceptor density was reduced in the failing (
P
<0.001) but not in the unused donor heart group (
P
=0.37) relative to the nonfailing heart group (n=5). G
iα
activity was increased in samples from unused donor and failing hearts relative to nonfailing hearts (
P
<0.05).

Conclusions
—Increased activity of the inhibitory G protein G
iα
is a significant contributory factor for impaired contractility in these acutely failing donor hearts.