bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recombinant hirudin for unstable angina pectoris. A multicenter, randomized angiographic trial.
Authors: Topol E J , Fuster V , Harrington R A , Califf R M , Kleiman N S , Kereiakes D J , Cohen M , Chapekis A , Gold H K , Tannenbaum M A 
Published: June 2012

BACKGROUND
Coronary artery thrombosis plays an important pathophysiological role in unstable angina and non-Q-wave myocardial infarction. To date, heparin and thrombolytic therapy has not provided complete or consistent benefit. We hypothesized that recombinant hirudin, a direct thrombin inhibitor, would prevent accumulation of coronary artery thrombus in a manner superior to heparin.

METHODS AND RESULTS
Patients with rest ischemic pain, abnormal ECG, and baseline angiogram indicating a > or = 60% stenosis of a culprit coronary artery or saphenous vein graft with visual appearance of thrombus were randomized to one of two different doses of heparin (either a target activated partial thromboplastin time [aPTT] of 65 to 90 or 90 to 110 seconds) or one of four doses of hirudin (0.05, 0.10, 0.20, or 0.30 mg.kg-1.h-1 infusion) in a dose-escalating protocol. After 72 to 120 hours of study drug, a repeat coronary angiogram was obtained, and the paired studies underwent quantitative analysis. The primary end point was change in the average cross-sectional area of the culprit lesion. Other efficacy end points also involved changes in culprit lesion dimensions and TIMI flow grade. Recombinant hirudin led to a dose-dependent elevation of aPTT that appeared to plateau at the 0.2-mg/kg dose. A higher proportion of hirudin-treated patients had their aPTT within a 40-second range (16% heparin versus 71% hirudin, P < .001). Overall, the 116 patients treated with hirudin tended to show more improvement than the 50 patients receiving heparin relative to the primary efficacy variable--the average cross-sectional area (P = .08)--as well as minimal cross-sectional area (P = .028), minimal luminal diameter (P = .029), and percent diameter stenosis (P = .07).

CONCLUSIONS
Recombinant hirudin appears to be a promising antithrombotic intervention compared with heparin for inhibition of coronary artery thrombus. Large-scale comparative trials are warranted.
Plasma endothelin determination as a prognostic indicator of 1-year mortality after acute myocardial infarction.
Authors: Omland T , Lie R T , Aakvaag A , Aarsland T , Dickstein K 
Published: June 2012

BACKGROUND
Plasma endothelin concentrations are increased in the acute phase of myocardial infarction and in chronic heart failure. Since endothelin may contribute to hemodynamic deterioration by potent vasoconstrictory and cardiotoxic actions, increased plasma levels may be associated with an unfavorable prognosis after myocardial infarction.

METHODS AND RESULTS
We tested the hypothesis that plasma endothelin determination in the subacute phase of myocardial infarction is related to subsequent survival and assessed whether plasma endothelin measurements provide additional prognostic information to that obtained from clinical and biochemical variables previously known to be associated with high mortality. Plasma endothelin determination was obtained from 142 patients (average age +/- SD, 67.8 +/- 10.1 years) on day 3 after documented myocardial infarction and was related to 1-year mortality. Sixteen patients died during the follow-up period. In a univariate Cox proportional-hazards model, day 3 plasma endothelin concentrations were significantly related to mortality (P < .0001). Patient age, previous treatment for systemic hypertension, presence of clinical heart failure, and plasma atrial natriuretic factor levels were all related to mortality in univariate analysis but provided no additional prognostic information to that obtained from endothelin determination in a multivariate model.

CONCLUSIONS
Plasma endothelin concentrations are strongly related to outcome after myocardial infarction and provide prognostic information independent of clinical and biochemical variables previously associated with a poor prognosis.
Assessment of effects of autonomic stimulation and blockade on the signal-averaged electrocardiogram.
Authors: Goldberger J J , Ahmed M W , Parker M A , Kadish A H 
Published: June 2012

BACKGROUND
Signal-averaged ECG is a noninvasive test designed to detect "late potentials." The effects of alterations in autonomic tone on the signal-averaged ECG have not been evaluated systematically.

METHODS AND RESULTS
The effects of autonomic stimulation and blockade on the signal-averaged ECG were evaluated in 14 healthy subjects (8 men and 6 women; age, 28.5 +/- 4.8 years) on 2 separate days. The signal-averaged ECG was recorded at baseline and after physiological and pharmacologic beta-adrenergic stimulation (tilt, exercise, and epinephrine and isoproterenol infusions), sequential and combined beta-adrenergic and parasympathetic blockade, and alpha-adrenergic stimulation before and after parasympathetic blockade. Analysis was performed with a bidirectional filter (40-Hz high-pass). Significant changes in the signal-averaged QRS duration from baseline (105.1 +/- 12.0 milliseconds) were noted with tilt (96.8 +/- 8.8 milliseconds), tilt after double blockade (97.5 +/- 9.0 milliseconds), epinephrine (110.5 +/- 11.8 milliseconds), and isoproterenol (99.6 +/- 12.6 milliseconds). Changes in the root-mean-square voltage of the terminal 40 milliseconds and the low-amplitude (< 40 microV) signal duration paralleled the changes in the QRS duration.

CONCLUSIONS
The signal-averaged ECG does not measure only "fixed" parameters but rather is altered under a variety of physiological and pharmacologic conditions. Upright tilt leads to shortening of the QRS duration before and after autonomic blockade; thus, the decrease in QRS duration with tilt may be related to factors other than changes in autonomic tone. These findings have implications for interpretation of the results of signal-averaged ECG.
High-density mapping of electrically induced atrial fibrillation in humans.
Authors: Konings K T , Kirchhof C J , Smeets J R , Wellens H J , Penn O C , Allessie M A 
Published: June 2012

BACKGROUND
Mapping studies in animals have suggested that atrial fibrillation (AF) is based on multiple reentering wavelets. Little information is available about the patterns of activation during AF in humans. The objective of the present study was to reconstruct and classify the patterns of human right atrial (RA) activation during electrically induced AF.

METHODS AND RESULTS
AF was induced by rapid atrial pacing in 25 patients with Wolff-Parkinson-White syndrome undergoing surgery for interruption of their accessory pathway(s). The free wall of the RA was mapped using a spoon-shaped electrode containing 244 unipolar electrodes. The activation of the RA during AF showed large interindividual differences. Based on the complexity of atrial activation, three types of AF were defined. In type I (40% of patients), single broad wave fronts propagated uniformly across the RA. Type II (32%) was characterized by one or two nonuniformly conducting wavelets, whereas in type III (28%), activation of the RA was highly fragmented and showed three or more different wavelets that frequently changed their direction of propagation as a result of numerous arcs of functional conduction block. There were significant differences (P < .05) among the three types of AF in median intervals (174 +/- 28, 150 +/- 14, and 136 +/- 16 milliseconds), variation in AF intervals (P5-95) (54 +/- 25, 94 +/- 21, and 104 +/- 22 milliseconds), incidence of electrical inactivity (42 +/- 11%, 21 +/- 4%, and 8 +/- 4%) and reentry (3 +/- 7%, 36 +/- 28%, and 99 +/- 36%), and average conduction velocity during AF (61 +/- 6, 54 +/- 4, and 38 +/- 10 cm/s).

CONCLUSIONS
During pacing-induced AF in humans, the RA is activated by one or multiple wavelets propagating in different directions. Three types of RA activation during AF were identified. From type I to type III, the frequency and irregularity of AF increased, and the incidence of continuous electrical activity and reentry became higher. These various types of AF in humans appear to be characterized by different numbers and dimensions of the intra-atrial reentrant circuits.
Innervation of the human cardiac conduction system. A quantitative immunohistochemical and histochemical study.
Authors: Crick S J , Wharton J , Sheppard M N , Royston D , Yacoub M H , Anderson R H , Polak J M 
Published: June 2012

BACKGROUND
Cardiac conduction is influenced by peptidergic mechanisms as well as classic neurotransmitters. The distribution of peptide-containing nerves has not been well defined.

METHODS AND RESULTS
Immunofluorescence and histochemical techniques were used to visualize the innervation of the human conduction system and to distinguish nerve subpopulations according to their peptide and enzyme content. Nerve fibers and fascicles displaying immunoreactivity for protein gene product 9.5 (PGP 9.5) were more numerous in the sinus and atrioventricular nodes than in the penetrating bundle, bundle branches, and adjacent myocardium. The relative density of innervation was greater in the central region of the sinus node than in the peripheral regions. Nerve densities were also higher in the transitional region of the atrioventricular node compared with its compact region. Acetylcholinesterase (AChE)-positive nerves were the main subtype identified in the sinus and atrioventricular nodes, representing half to two thirds of the stained area occupied by PGP 9.5-immunoreactive nerves. Neuropeptide Y-immunoreactive nerves represented the main peptide-containing subpopulation and occurred throughout the conduction system, displaying a similar pattern of distribution and relative density to those demonstrating tyrosine hydroxylase immunoreactivity. Nerve fibers showing immunoreactivity for vasoactive intestinal polypeptide, somatostatin, substance P, or calcitonin gene-related peptide exhibited distinct patterns of distribution and comprised a relatively minor component of the innervation, the percentage of stained area being 10- to 40-fold lower than that occupied by neuropeptide Y- and PGP 9.5-immunoreactive nerves, respectively.

CONCLUSIONS
The innervation of human conduction tissues exhibits significant regional variation and comprises putative parasympathetic nerves and intrinsic neurons (AChE positive), sympathetic efferent nerves (neuropeptide Y- and tyrosine hydroxylase-immunoreactive nerves), and other peptide-containing nerves, some of which (substance P and calcitonin gene-related peptide containing) are considered to represent afferent nerves. Locally released peptides may be involved in the neural modulation of the human conduction system.
Independent predictors of long-term results after balloon pulmonary valvuloplasty. Valvuloplasty and Angioplasty of Congenital Anomalies (VACA) Registry Investigators.
Authors: McCrindle B W 
Published: June 2012

BACKGROUND
This study was performed to determine independent predictors of long-term outcome after percutaneous balloon dilation of congenital pulmonary valve stenosis. Smaller follow-up series of patients after balloon pulmonary valvuloplasty have shown inconsistent results regarding the independent relation between prognostic factors and long-term outcome, as many patient selection and technical factors are correlated.

METHODS AND RESULTS
Follow-up data were obtained for 533 patients from 22 institutions at up to 8.7 years after an initial balloon pulmonary valvuloplasty. Patients were grouped based on defined long-term outcomes, and the independent effects of patient selection and technical factors were sought in multivariate statistical analyses. At follow-up, 23% of patients were noted to have an outcome judged to be suboptimal because of either a residual right ventricle to pulmonary artery peak systolic gradient of > or = 36 mm Hg or further treatment of pulmonary stenosis requiring repeat balloon pulmonary valvuloplasty or surgical therapy. Significant independent predictors of a suboptimal long-term outcome included an earlier study year of the initial valvuloplasty (adjusted odds ratio, 0.71 per consecutive year), a small valve hinge point diameter (0.81 per 1-mm increase), and a higher immediate residual gradient (1.32 per 10 mm Hg increase). A smaller ratio of balloon to valve hinge point diameter significantly predicted suboptimal outcomes for patients with valve morphologies classified as typical (0.52 per 0.1 increase in ratio) and complex (primarily postsurgical valvotomy, 0.43) but not for patients with dysplastic (0.95) or combined morphologies (dysplasia with commissural fusion, 1.01). Patient age, the presence of Noonan's syndrome or associated cardiac lesions, pre-balloon valvuloplasty hemodynamic parameters, and the use of a simultaneous double-balloon technique did not independently predict follow-up outcomes.

CONCLUSIONS
Accurate prognostication after balloon pulmonary valvuloplasty depends on the careful determination of valvar anatomy. The use of an appropriate ratio of balloon to valve hinge point diameter in the setting of typical valve morphology will optimize the chance of long-term success.
Combination of platelet fibrinogen receptor antagonist and direct thrombin inhibitor at low doses markedly improves thrombolysis.
Authors: Nicolini F A , Lee P , Rios G , Kottke-Marchant K , Topol E J 
Published: June 2012

BACKGROUND
We evaluated the effects of a novel platelet fibrinogen receptor antagonist, Integrelin, and a direct thrombin inhibitor, recombinant hirudin, given together with recombinant tissue plasminogen activator (rTPA) in a canine experimental model of intracoronary thrombosis. We tested the hypothesis that combination of both agents at low doses would have an additive antithrombotic effect, resulting in a significant improvement in the efficacy of rTPA.

METHODS AND RESULTS
Thirty-two dogs with an electrically induced coronary thrombus were treated with rTPA (1 mg/kg over 20 minutes) together with one of the following adjunctive treatments in a random fashion. Eight dogs received saline for 90 minutes; Integrelin (5 micrograms.kg-1.min-1 for 90 minutes) was given to 8 dogs; 8 dogs received recombinant hirudin (20 micrograms.kg-1.min-1 for 90 minutes); and 8 dogs were treated with a low-dose combination of Integrelin (2.5 micrograms.kg-1.min-1) plus recombinant hirudin (10 micrograms.kg-1.min-1) for 90 minutes. Integrelin or recombinant hirudin, when given as single adjunct to rTPA, enhanced the lysis of the occlusive thrombus, causing full restoration of coronary blood flow (100% of its baseline value) for 29 +/- 16 and 26 +/- 5 minutes, respectively, whereas coronary blood flow was fully restored for only 5 +/- 1 minutes in dogs receiving rTPA plus saline (both P < .05). However, either Integrelin or recombinant hirudin failed to modify the reocclusion rate (57% and 63%, respectively) compared with saline (83%; all P = NS). Conversely, the low-dose combination therapy led to complete restoration of coronary blood flow for 92 +/- 19 minutes (P < .01 versus all treatments) and significantly reduced the reocclusion rate (25%; P < .05 versus saline).

CONCLUSIONS
These data show that inhibition of specific pathways of platelet and thrombin activity improves the extent and duration of rTPA-induced thrombolysis in the electrolytic canine model. Furthermore, our findings suggest that low doses of platelet IIb/IIIa and direct thrombin antagonists in combination may be used successfully during thrombolysis.
Functional improvement precedes structural regression of atherosclerosis.
Authors: Benzuly K H , Padgett R C , Kaul S , Piegors D J , Armstrong M L , Heistad D D 
Published: June 2012

BACKGROUND
Vasoconstrictor responses to serotonin are augmented in monkeys with diet-induced atherosclerosis and improve after 18 months of normal diet. We tested the hypothesis that functional improvement may occur early during regression, before evidence of structural improvement.

METHODS AND RESULTS
Responses of the iliac artery to serotonin were measured by quantitative angiography and a Doppler flow probe in several groups of monkeys: (1) normal monkeys, (2) monkeys fed an atherogenic diet for 2 years (atherosclerotic), and (3) monkeys fed an atherogenic diet for 2 years (preregression) followed by a normal diet for 4, 8, or 12 months (regression). In normal monkeys, serotonin produced minimal constriction of the iliac artery, and blood flow to the legs increased. In atherosclerotic monkeys, there was pronounced constriction of the iliac artery, and blood flow to the legs decreased markedly. After 4 months of regression diet, four of eight monkeys demonstrated marked reduction in hyperresponsiveness to serotonin angiographically, and by 8 months, six of eight monkeys had significant improvement. After regression, serotonin produced minimal changes in flow. There was no reduction in intimal area (ie, atherosclerotic lesion) in iliac arteries from regression monkeys compared with atherosclerotic monkeys, but there was a marked reduction in cholesteryl ester in arteries from regression monkeys.

CONCLUSIONS
Abnormal vasoconstrictor responses to serotonin usually return to or toward normal within a few months during regression of atherosclerosis. Functional improvement occurs in conjunction with early resorption of lipid from the arterial wall and occurs before detectable changes in mass of the atherosclerotic lesion.
High [Ca2+]o-induced electrical heterogeneity and extrasystolic activity in isolated canine ventricular epicardium. Phase 2 reentry.
Authors: Di Diego J M , Antzelevitch C 
Published: June 2012

BACKGROUND
Elevated intracellular calcium activity is thought to play an important role in arrhythmia induction, particularly during ischemia and reperfusion. Delayed after-depolarization-induced triggered activity and intracellular communication problems are thought to be responsible.

METHODS AND RESULTS
Increased extracellular calcium levels and rapid pacing are interventions known to elevate intracellular calcium activity. The present study, conducted using standard microelectrode techniques, was designed to compare the effects of increased [Ca2+]o (1.8 to 5.4 mmol/L) in isolated canine ventricular epicardial and endocardial tissues and to test the hypothesis that elevated intracellular calcium activity contributes to arrhythmogenesis in working ventricular myocardial tissues by promoting electrical heterogeneity. High [Ca2+]o caused a slight abbreviation of action potential duration (APD90) in endocardium but more dramatic rate-dependent and dynamic changes in epicardium. Under steady-state conditions, epicardium displayed a marked abbreviation of APD90 at fast rates but no significant changes at slow rates. A significant augmentation of phase 1 was evident at the faster stimulation rates. Vmax and conduction velocity were only slightly reduced. The marked abbreviation of the epicardial response at the factor rates was due to loss of the action potential dome. Recovery of the dome after deceleration was not synchronous throughout the preparation. As a consequence, a sudden slowing of rate caused marked dispersion of repolarization among neighboring epicardial sites, giving rise to ectopic activity via a phase 2 reentry mechanism. These effects of high [Ca2+]o were mimicked by exposure of the preparations to low [Na+]o. Electrical homogeneity was restored and arrhythmias were abolished after addition of the Ito blocker 4-aminopyridine 1 mmol/L. 4-Aminopyridine also eliminated the differential response of epicardium and endocardium to high [Ca2+]o.

CONCLUSIONS
Our data demonstrate the induction of marked electrical heterogeneity and reentrant activity by high [Ca2+]o and rapid stimulation, conditions known to elevate [Ca2+]i. The results suggest that increased intracellular calcium activity, as occurs during ischemia and reperfusion, may contribute to the development of electrical inhomogeneity in the ventricle and thus to the genesis of ventricular arrhythmias through a mechanism other than triggered activity, namely, phase 2 reentry. Our data point to an increase in net outward current as the underlying mechanism for the calcium-induced changes. Our results also suggest that the presence of a prominent transient outward current (Ito) in epicardium sensitizes that tissue to the effects of high calcium. Finally, the results suggest that Ito blockers can reverse high calcium-induced electrical heterogeneity and thus can exert antiarrhythmic actions.
Is 'silent' myocardial ischemia really as severe as symptomatic ischemia? The analytical effect of patient selection biases.
Authors: Klein J , Chao S Y , Berman D S , Rozanski A 
Published: June 2012

BACKGROUND
The clinical significance of exercise-induced chest pain remains controversial, as reflected by sharply discordant clinical results within the medical literature. Thus, we developed a prospective study to compare the functional significance of silent versus symptomatic ischemia and to evaluate whether patient selection biases influence this analysis.

METHODS AND RESULTS
We evaluated 117 patients (mean age, 63 +/- 9 years) with ischemic ST-segment depression during treadmill testing. Each patient underwent Tl-201 myocardial perfusion single-photon emission computed tomography (SPECT) after exercise followed by 24-ambulatory ECG monitoring. Patients were divided into silent versus symptomatic cohorts and were compared for the degree of hemodynamic, exercise and ambulatory ECG, and thallium abnormalities during stress testing. Analyses were repeated as the patient population became increasingly restricted. Compared with the silent patients, patients with chest pain during exercise had a shorter exercise duration (P < .009), lower peak heart rate (P = .009) and double product (P = .005), lower heart rate threshold for ST depression (P < .05), more episodes of ambulatory ST-segment depression (P < .05), a higher frequency of ischemia abnormalities during Tl-201 SPECT (P = .02), and higher summed Tl reversibility scores (P = .002). As the population became increasingly restricted, the relative magnitude of differences in silent versus symptomatic cohorts diminished, whereas the absolute magnitude of ischemic abnormalities progressively increased in both cohorts. For example, within the restricted group having ischemia on both exercise and ambulatory ECG, 50% of the silent cohort had severe ischemia on Tl SPECT (five or more reversible defects) and more than one third demonstrated the ominous finding of transient left ventricular dilation after exercise.

CONCLUSIONS
The induction of chest pain is associated with substantially more functional abnormalities when it is analyzed in a relatively "broad-spectrum" coronary artery disease population; by contrast, chest pain tends to lose its apparent value as a clinical test parameter when its analysis is restricted to coronary artery disease populations with a greater a priori likelihood of manifesting inducible ischemia. These findings may help resolve some of the previous discordant literature reports.