bluuebunny/crossref_metadata_2025 huggingface dataset:
Evidence That Angiotensin II Is Present in Human Monocytes
Authors: Kitazono Takanari , Padgett Richard C. , Armstrong Mark L. , Tompkins Pamela K. , Heistad Donald D.
Published: June 2012

Background
The purpose of the present study was to determine whether human monocytes and polymorphonuclear leukocytes contain angiotensins I and II.

Methods and Results
Human mononuclear and polymorphonuclear leukocytes were isolated from blood. To identify angiotensins in human leukocytes, we performed immunocytochemistry using both alkaline phosphatase and fluorescence methods. With light microscopy immunocytochemistry with akaline phosphatase, prominent staining of angiotensin II was observed in mononuclear leukocytes. Angiotensin I was also demonstrated in mononuclear leukocytes, but the signal was less pronounced than for angiotensin II. Polymorphonuclear leukocytes showed very little staining for angiotensin II. Fluorescence immunocytochemistry also demonstrated angiotensin II in mononuclear leukocytes. Angiotensins I and II in homogenate of leukocytes were quantified by radioimmunoassay. The concentration of angiotensins I and II in mononuclear leukocytes was 355±216 (mean±SEM) and 2331±106 fmol/mg protein, respectively, and the concentration in polymorphonuclear leukocytes was 36±10 and 336±120 fmol/mg protein.

Conclusions
These findings suggest that human mononuclear leukocytes contain large amounts of angiotensin II and lesser amounts of angiotensin I. Human polymorphonuclear leukocytes contain small amounts of angiotensin I and II.
Thrombolysis and Reocclusion in Experimental Jugular Vein and Coronary Artery Thrombosis
Authors: Biemond B. J. , Levi M. , Coronel R. , Janse M. J. , Cate J. W. ten , Pannekoek H.
Published: June 2012

Background
Thrombolytic therapy for acute myocardial infarction is often complicated by reocclusion of the initially reperfused artery. Platelets have been shown to play an important role in this process. We determined the contribution of plasminogen activator inhibitor type 1 (PAI-1), stored in the α-granules of platelets, to thrombolysis resistance and to reocclusion.

Methods and Results
In a rabbit jugular vein thrombosis model, the effect of a PAI-1–neutralizing monoclonal antibody (CLB-2C8) on thrombolysis and thrombus growth was assessed. The effect on reperfusion, reocclusion, and duration of vessel patency was studied in a canine model of coronary artery thrombosis superimposed on a high-grade stenosis and endothelial damage. In the rabbit jugular vein model, the intravenous administration of 1 mg/kg anti–PAI-1 antibody significantly enhanced the endogenous thrombolysis from 5.5±1.3% in the animals treated with a nonspecific monoclonal antibody (control) to 13.7±2.6% in the animals treated with the anti–PAI-1 antibody. Thrombus growth was reduced significantly, from 41.3±2.6% in the control animals to 22.8±2.8% in the animals treated with the anti–PAI-1 antibody. In combination with a single bolus injection of recombinant tissue-type plasminogen activator (rTPA; 0.25 mg/kg), the anti–PAI-1 antibody reduced thrombus growth significantly, from 21.5±2.7% in the animals treated with rTPA alone to 12.2±2.6% in the animals treated with rTPA and the antibody. No additional effect of the anti–PAI-1 antibody was observed on rTPA-induced thrombolysis. In the canine coronary artery thrombosis model, the administration of a suboptimal dose of rTPA (0.45 mg/kg) induced reperfusion in 7 of the 8 dogs after 19.5±8.2 minutes. Reperfusion was followed by reocclusion in all animals after 3.3±2.6 minutes. Administration of the anti–PAI-1 antibody in combination with rTPA significantly reduced time to reperfusion (8.1±5.2 minutes) and delayed the occurrence of reocclusion to 11.6±12.5 minutes.

Conclusions
Administration of the anti–PAI-1 antibody (CLB-2C8) results in increased endogenous thrombolysis and inhibition of thrombus growth in a venous thrombosis model in rabbits and facilitated reperfusion and reduction of reocclusion in a canine model of coronary artery thrombosis.
Comparison of Valvular Resistance, Stroke Work Loss, and Gorlin Valve Area for Quantification of Aortic Stenosis
Authors: Voelker Wolfram , Reul Helmut , Ing Georg Nienhaus , Ing Thomas Stelzer , Ing Bernhard Schmitz , Ing Anselm Steegers , Karsch Karl R.
Published: June 2012

Background
Valvular resistance and stroke work loss have been proposed as alternative measures of stenotic valvular lesions that may be less flow dependent and, thus, superior over valve area calculations for the quantification of aortic stenosis. The present in vitro study was designed to compare the impacts of valvular resistance, stroke work loss, and Gorlin valve area as hemodynamic indexes of aortic stenosis.

Methods and Results
In a pulsatile aortic flow model, rigid stenotic orifices in varying sizes (0.5, 1.0, 1.5, and 2.0 cm
2
) and geometry were studied under different hemodynamic conditions. Ventricular and aortic pressures were measured to determine the mean systolic ventricular pressure (LVSP
m
) and the transstenotic pressure gradient (ΔP
m
). Transvalvular flow (F
m
) was assessed with an electromagnetic flowmeter. Valvular resistance [VR=1333 · (ΔP
m
/F
m
)] and stroke work loss [SWL=100 · (ΔP
m
/LVSP
m
)] were calculated and compared with aortic valve area [AVA=F
m
/(50√ΔP
m
)]. The measurements were performed for a large range of transvalvular flows. At low-flow states, flow augmentation (100→200 mL/s) increased calculated valvular resistance between 21% (2.0-cm
2
orifice) and 66% (0.5-cm
2
orifice). Stroke work loss demonstrated an increase from 43% (2.0 cm
2
) to 100% (1.0 cm
2
). In contrast, Gorlin valve area revealed only a moderate change from 29% (2.0 cm
2
) to 5% (0.5 cm
2
). At physiological flow rates, increase in transvalvular flow (200→300 mL/s) did not alter calculated Gorlin valve area, whereas valvular resistance and stroke work loss demonstrated a continuing increase. Our experimental results were adopted to interpret the results of three clinical studies in aortic stenosis. The flow-dependent increase of Gorlin valve area, which was found in the cited clinical studies, can be elucidated as true further opening of the stenotic valve but not as a calculation error due to the Gorlin formula.

Conclusions
Within the physiological range of flow, calculated aortic valve area was less dependent on hemodynamic conditions than were valvular resistance and stroke work loss, which varied as a function of flow. Thus, for the assessment of the severity of aortic stenosis, the Gorlin valve area is superior over valvular resistance and stroke work loss, which must be indexed for flow to adequately quantify the hemodynamic severity of the obstruction.
Rapid Angiographic Progression of Coronary Artery Disease in Patients With Elevated Lipoprotein(a)
Authors: Terres Wolfram , Tatsis Efstratios , Pfalzer Benjamin , Beil F. Ulrich , Beisiegel Ulrike , Hamm Christian W.
Published: June 2012

Background
The mechanisms underlying rapid angiographic progression of coronary artery disease are still unknown. Intravascular thrombosis with or without plaque rupture may be involved.

Methods and Results
In a prospective study in 79 patients with coronary artery disease and at least one coronary diameter stenosis ≥50%, possible risk factors for rapid progression were investigated. Quantitative coronary angiography was performed twice at a mean time interval of 66±25 days. Rapid progression of coronary disease defined as (1) an increase >10% in stenosis severity in at least one stenosis ≥50%, (2) occurrence of a new stenosis ≥50%, or (3) occlusion of a formerly patent vessel was found in 21 patients (27%). Between patients with rapid progression and those without, there were no significant differences in sex distribution, age, smoking history, frequency of hypertension or diabetes mellitus, and serum LDL cholesterol, HDL cholesterol, and apolipoprotein B concentrations. In contrast, serum lipoprotein(a) [Lp(a)] concentrations ≥25 mg/dL were found in 14 of 21 patients (67%) with rapid progression of coronary artery disease but in only 19 of 58 (33%) in the group without progression (
P
=.007). The respective median Lp(a) concentrations were 66 mg/dL (range, 2 to 139) and 13 mg/dL (range, 2 to 211;
P
=.01).

Conclusions
Lp(a) appears to be a risk factor for the rapid angiographic progression of coronary artery disease. The pathophysiological link between Lp(a) and rapid progression may be an interference with thrombolysis through the partial structural homology of Lp(a) with plasminogen.
Intravenous Cocaine Induces Platelet Activation in the Conscious Dog
Authors: Kugelmass Aaron D. , Shannon Richard P. , Yeo Erik L. , Ware J. Anthony
Published: June 2012

Background
Cocaine consumption has been associated with thrombosis of coronary and peripheral arteries. Since cocaine has been found to induce platelet activation in vitro, we sought to establish whether cocaine induced platelet activation in vivo.

Methods and Results
Chronically instrumented, conscious dogs were infused with cocaine (1 mg/kg), norepinephrine (0.2 to 0.4 mg/kg), or saline intravenously over 1 minute. Activated canine platelets were identified in whole blood collected from an indwelling aortic catheter by flow cytometric detection of the binding of a monoclonal antibody directed against the activation-dependent antigen P-selectin. Infusion of cocaine resulted in an elevation of mean arterial pressure (91±3 to 128±7 mm Hg [
P
<.001]) and heart rate (87±9 to 125±11 beats per minute [
P
<.01]). A similar change (
P
=NS) in mean arterial pressure followed norepinephrine infusion (100±5 to 137±13 mm Hg [
P
<.04]), whereas saline infusion had no effect. Cocaine resulted in a substantial but delayed increase in platelet P-selectin expression (14±7% [
P
<.08], 31±12% [
P
<.04], and 55±22% [
P
<.04] at 17, 22, and 27 minutes after drug infusion, respectively). The magnitude of this increase was similar to that found in blood treated ex vivo with the agonists ADP or PAF (23±7% and 53±15%, respectively). No significant increase in P-selectin expression was detected in the blood of animals that received norepinephrine or saline. Serum cocaine concentrations were highest immediately after infusion (538±55 ng/mL at 2 minutes) but declined rapidly (185±22 and 110±25 ng/mL at 17 and 32 minutes after infusion); in contrast, the increase in benzoylecgonine concentrations was delayed (from <25 ng/mL in all but one animal [34 ng/mL] at 2 minutes to 46±4 and 71±11 ng/mL at 17 and 32 minutes, respectively, after infusion).

Conclusions
Intravenous cocaine induces activation of individual circulating platelets; this effect is not reproduced by infusion of norepinephrine at doses sufficient to exert similar hemodynamic effects. The delay in detection of activated platelets after treatment with cocaine may result from the adhesion and subsequent detachment of activated platelets; alternatively, cocaine metabolites, rather than the drug itself, may induce platelet activation.
Coronary Calcium, as Determined by Electron Beam Computed Tomography, and Coronary Disease on Arteriogram
Authors: Rumberger John A. , Sheedy Patrick F. , Breen Jerome F. , Schwartz Robert S.
Published: June 2012

Background
Coronary artery calcium identified by electron beam computed tomography (EBCT) has potential for noninvasive localization of coronary atherosclerotic disease. However, the effect of a patient’s sex on its diagnostic capability has not been examined in a clinical population.

Methods and Results
Fifty women and 89 men had EBCT scans done an average of 1 day after coronary arteriography. Maximum arteriographic percent luminal diameter stenosis of any artery was paired with the total EBCT coronary calcium score for each subject. The women (age, 56±11 years [mean±SD]) were older than the men (age, 47±7 years), but the subjects were matched for indications for arteriography and extent of disease as assessed by arteriography. Sensitivity, specificity, and positive and negative predictive values for coronary calcium were nearly identical for men and women, regardless of the degree of arteriographic disease. EBCT was highly sensitive to the presence of arteriographic disease (range, 94% to 100%), but had only moderate specificity (57% to 66%) for significant disease (≥50% stenosis) and low specificity (35% to 38%) for any arteriographic disease (>0% stenosis). Negative predictive values in men and women ranged from 79% to 91% for any arteriographic disease and from 95% to 100% for significant disease, respectively. Numerical calcium scores were significantly different between subjects with normal arteriograms and those with significant disease; however, calcium score had limited power to separate trivial, moderate, and significant disease. Receiver operating characteristic curve areas, determined as an extension of the analyses of sensitivity and specificity, were high for EBCT-defined calcium scores for both any arteriographic disease and significant arteriographic disease, and were not different between the sexes.

Conclusions
In a middle-aged population, noninvasive definition of coronary calcium by EBCT has similar predictive value for arteriographic coronary artery disease in men and women.
Non–Insulin-Dependent Diabetes Mellitus and Fasting Glucose and Insulin Concentrations Are Associated With Arterial Stiffness Indexes
Authors: Salomaa Veikko , Riley Ward , Kark Jeremy D. , Nardo Christopher , Folsom Aaron R.
Published: June 2012

Background
Cardiovascular diseases are the most common cause of disability and death among subjects with non–insulin-dependent diabetes mellitus (NIDDM). The atherosclerotic process begins during the prediabetic phase characterized by impaired glucose tolerance, hyperinsulinemia, and insulin resistance. In vitro studies have suggested that glucose and insulin can substantially alter the structure and function of the arterial wall and affect the development of atherosclerosis.

Methods and Results
We performed a cross-sectional study of the relation of arterial stiffness indexes with glucose tolerance and serum insulin concentrations. Several indexes of common carotid artery stiffness were assessed with noninvasive ultrasound methods in a biracial sample of 4701 men and women 45 to 64 years of age in the Atherosclerosis Risk in Communities (ARIC) Study. Arterial compliance (AC), stiffness index (SI), pressure-strain elastic modulus (Ep), and Young’s elastic modulus (YEM) were calculated. YEM includes wall (intima-media) thickness and thus gives an estimate of arterial stiffness controlling for wall thickness. All indexes of arterial stiffness were higher with increasing concentrations of fasting glucose. This finding was consistent in both black and white examinees and in both sexes. A 25% increase in fasting glucose (approximately 1 SD) was associated in nondiabetic white men with a 5.8% (95% CI, −9.6% to −1.9%;
P
=.004) decrease in AC and increases of 5.8% (95% CI, 2.0% to 9.7%;
P
=.002) in SI, 11.3% (95% CI, 6.9% to 15.9%;
P
<.001) in Ep, and 11.2% (95% CI, 6.2% to 16.6%;
P
<.001) in YEM. In nondiabetic white women, the corresponding predicted changes were a decrease of 15.0% (95% CI, −18.2% to −11.7%;
P
<.001) in AC and increases of 16.6% (95% CI, 12.5% to 20.8%;
P
<.001) in SI, 23.2% (95% CI, 18.4% to 28.2%;
P
<.001) in Ep, and 19.2% (95% CI, 14.0% to 24.7%;
P
<.001) in YEM. Glucose and insulin contributed synergistically to the increase in stiffness indexes. Insulin and triglycerides also had a synergistic association with stiffness indexes.

Conclusions
Our findings are compatible with the view that persons with NIDDM or borderline glucose intolerance have stiffer arteries than their counterparts with normal glucose tolerance and that the decreased elasticity is independent of artery wall thickness. The joint effect of elevated glucose, insulin, and triglycerides can have a considerable impact on arterial stiffness and play an important role in the early pathophysiology of macrovascular disease in NIDDM.
Paradoxical Arterial Wall Shrinkage May Contribute to Luminal Narrowing of Human Atherosclerotic Femoral Arteries
Authors: Pasterkamp Gerard , Wensing Peter J. W. , Post Mark J. , Hillen Berend , Mali Willem P. T. M. , Borst Cornelius
Published: June 2012

Background
This study was done to assess how local changes in vessel size, together with plaque load, determine luminal narrowing in atherosclerotic arteries. Fifty-one human femoral arteries were analyzed: 32 postmortem and 19 in vivo by 30-MHz intravascular ultrasound.

Methods and Results
Histological and intravascular ultrasound cross sections were examined every 0.5 cm over an arterial segment 10 to 15 cm long. In each cross section we measured the lumen area and the area circumscribed by the internal elastic lamina (the IEL area). In each arterial segment, the cross section that contained the least amount of plaque was the reference site. For each cross section, the lumen area stenosis was expressed as percent of the lumen area in the reference site. Similarly, the IEL area was expressed as percent of the IEL area in the reference site (the relative IEL area). There was a significant negative correlation between the relative IEL area and the lumen area stenosis percentage (
r
=−.62,
P
<.001 for histology and
r
=−.66,
P
<.001 for intravascular ultrasound). When lumen area stenosis was less than about 25%, mainly compensatory enlargement was observed. When lumen area stenosis exceeded about 25%, however, mainly a decrease of the IEL area was observed, which is consistent with arterial wall shrinkage. Furthermore, the increase in plaque area does not account for the total loss of luminal area. There was a moderate correlation between an increase in plaque area and reduction of the corresponding lumen area (
r
=.49 and
r
=.56 for histology and intravascular ultrasound, respectively).

Conclusions
The decrease in luminal area cannot be attributed to plaque increase alone. Arterial wall shrinkage is a paradoxical mechanism that may contribute to severe luminal narrowing of the atherosclerotic human femoral artery.
Effect of Diagnostic Criteria on the Prevalence of Peripheral Arterial Disease
Authors: Hiatt William R. , Hoag Sharon , Hamman Richard F.
Published: June 2012

Background
The ankle/brachial systolic blood pressure index (ABI), a noninvasive measure of peripheral arterial disease (PAD), is widely used in epidemiological studies. However, the normal ranges of the ABI in healthy populations and ABI criteria for the diagnosis of PAD in large population studies have not been critically evaluated.

Methods and Results
The San Luis Valley Diabetes Study (SLVDS) was designed to evaluate the prevalence and complications of non–insulin-dependent diabetes mellitus (NIDDM) in a biethnic population. The present study was conducted as part of the SLVDS to assess the prevalence of vascular disease in 1280 nondiabetic control subjects and 430 patients with NIDDM. The ABI criteria for PAD were developed in 403 healthy individuals with a low risk for cardiovascular disease. In these low-risk subjects, the average resting ABI value was 0.07 lower in women than in men. In both sexes, the dorsalis pedis ABI was 0.04 lower than in the posterior tibial artery, and the left leg ABI was 0.02 lower than the right leg ABI (all differences,
P
<.05). In the low-risk subjects, ABI values were lower after exercise than at rest and had similar differences by sex and leg as observed at rest. Using specific abnormal cutoff points for the ABI, we evaluated three criteria for PAD in the overall population: two abnormal vessels in the same leg at rest (both dorsalis pedis and posterior tibial arteries), one abnormal vessel per leg at rest, and an ABI abnormality only after exercise. Subjects classified with PAD by the two-vessel criterion had a higher frequency of claudication and the physical finding of an absent pulse compared with subjects without PAD or patients with PAD defined by the one-vessel or exercise criterion. Use of the two-vessel criterion identified an increased risk of PAD with increasing age, NIDDM, smoking, hypertension, and elevated cholesterol levels. In contrast, the one-vessel PAD criterion was associated only with increasing age and smoking, and exercise-diagnosed PAD was not associated with any cardiovascular risk factor except for male sex.

Conclusions
In low-risk subjects, the normal distribution and lower abnormal cutoff point values of the ABI differed by type of test, sex, ankle vessel, and leg. When these specific abnormal cutoff points were applied to the SLVDS population, the two-vessel abnormal criterion described patients with typical clinical characteristics of PAD and the expected associations of PAD with cardiovascular risk factors. These clinical characteristics and cardiovascular risk factor associations were less evident with PAD diagnosed by the one-vessel or exercise criterion. Therefore, an abnormal dorsalis pedis and posterior tibial ABI in the same leg at rest should be used for the diagnosis of PAD in epidemiological studies.
Three Distinct Patterns of Ventricular Activation in Infarcted Human Hearts
Authors: Hatala Robert , Savard Pierre , Tremblay Gaétan , Pagé Pierre , Cardinal René , Molin Franck , Kus Teresa , Nadeau Réginald
Published: June 2012

Background
Comprehensive data based on single-beat analysis of the ventricular activation sequence during sinus rhythm in infarcted hearts are currently not available. It was the aim of our study (1) to measure and analyze these activation sequences on the epicardial surface of the right and left ventricles and on the left ventricular endocardial surface, and (2) to correlate specific activation patterns with the surface ECG.

Methods and Results
Isochronal maps were computed from 127 endocardial and epicardial unipolar electrograms recorded simultaneously during sinus rhythm in 45 post–myocardial infarction patients operated on for recurrent ventricular tachycardia (age, 57±10 years [mean±SD], left ventricular ejection fraction, 29±9%). Patients with bundle-branch block, but not with intraventricular conduction defects, were excluded. Data such as the timing of initial and terminal activation, the number of breakthroughs, the total activation time, and the number of ventricular segments without activation were measured and analyzed according to location of the myocardial infarction. The global epicardial activation was characterized in all patients by a widespread initial breakthrough on the anterior right ventricle (16±8 milliseconds after QRS onset), which was followed by one or two other breakthroughs in 65% of patients. Subsequently, three characteristic epicardial patterns of the activation spread were found: (1) radial, from the right to the left ventricle, found in all patients with inferoposterior myocardial infarction; (2) counterclockwise rotation, in which posteroseptal crossing preceded the anteroseptal crossing, found in 38% of patients with anterior myocardial infarction; and (3) pincerlike encirclement, in which both septal crossings and/or breakthroughs occurred nearly simultaneously and merged at the left ventricular free wall (typical for apical involvement in anterior and combined myocardial infarction). The simultaneous presence of multiple major activation wave fronts typically found in patients with the pincerlike activation pattern was reflected on the surface ECG by multiphasic, notched QRS complexes. Activation delay was observed in 89% of patients, and terminal activation was topographically related to myocardial infarction in 94% of patients. Delayed activation exceeding the surface QRS was observed in 11% and 31% of cases on the endocardium and epicardium, respectively.

Conclusions
These results offer a solid basis for a more precise interpretation of a wide range of electrophysiological data and provide a framework for future investigations of surface ECG reflections of endocardial and epicardial activation patterns recorded in patients with chronic myocardial infarction.
Catecholaminergic Polymorphic Ventricular Tachycardia in Children
Authors: Leenhardt Antoine , Lucet Vincent , Denjoy Isabelle , Grau Francis , Ngoc Dien Do , Coumel Philippe
Published: June 2012

Background
Primary ventricular tachyarrhythmias are rarely seen in children. Among them, catecholaminergic polymorphic ventricular tachycardia has a poor spontaneous outcome. Its diagnosis is often delayed after the first symptoms, which is unacceptable because treatment with the appropriate β-blocker prevents sudden death.

Methods and Results
We observed 21 children (mean±SD age, 9.9±4 years) at the time of the diagnosis who had no structural heart disease and a normal QT interval on routine ECG. They were referred for stress- or emotion-induced syncope related to ventricular polymorphic tachyarrhythmias. The arrhythmia, consisting of isolated polymorphic ventricular extrasystoles followed by salvoes of bidirectional and polymorphic tachycardia susceptible to degeneration into ventricular fibrillation, was reproducibly induced by any form of increasing adrenergic stimulation. There was a familial history of syncope or sudden death in 30% of our patients. On receiving therapy with the appropriate β-blocker, the patients’ symptoms and polymorphic tachyarrhythmias disappeared. During a mean follow-up period of 7 years, three syncopal events and two sudden deaths occurred, probably due to treatment interruption.

Conclusions
The entity of adrenergic-dependent, potentially lethal tachyarrhythmia with no structural heart disease deserves to be individualized. It may form a variant of the congenital long QT syndrome in which the ECG marker is lacking; this primary ventricular arrhythmia must be looked for in a pediatric patient with stress- or emotion-induced syncope because only β-blocking therapy can prevent sudden death and therefore must be given for the patient’s lifetime.
Evaluation of Myocardial Cell Damage by In-111-Monoclonal Antimyosin Antibodies in Patients Under Chronic Tricyclic Antidepressant Drug Treatment
Authors: Martí Vicens , Ballester Manel , Udina Claudi , Carrió Ignasi , Alvarez Enric , Obrador Damià , Pons-Lladó Guillem
Published: June 2012

Background
The capability of chronic tricyclic antidepressant drug (TAD) treatment to elicit myocardial damage has been a subject of debate. Lack of an adequate noninvasive method to detect such damage has prevented an in-depth study.

Methods and Results
A prospective study with In-111-monoclonal antimyosin antibodies was undertaken in a series of 21 young patients with major depression on TADs and a control group of 19 healthy subjects. A heart-to-lung ratio (HLR) of antimyosin uptake was used to discriminate normal from abnormal scans. HLR in healthy subjects was 1.39±0.08. Patients on imipramine (HLR, 1.41±0.09) or clomipramine (HLR, 1.44±0.06) showed normal studies. Those under amitriptyline had a higher HLR (1.58±0.12) compared with nonamitriptyline or normal groups (
P
<.05). None of the 15 patients on imipramine or clomipramine showed abnormal HLR, while 3 of 6 on amitriptyline did (
P
<.01). In these 3 patients, uptake decreased or disappeared after drug withdrawal. Ejection fraction was normal in every patient.

Conclusions
Monoclonal antimyosin antibody studies are normal in imipramine- and clomipramine-treated patients. Antibody uptake in those under amitriptyline treatment, which disappears after drug withdrawal, would suggest early evidence of myocardial toxicity.
Complex Coronary Artery Lesion Morphology Influences Results of Stress Echocardiography
Authors: Lu Chunzeng , Picano Eugenio , Pingitore Alessandro , Sicari Rosa , Tongiani Rossana , Baratto Marco , Palmieri Cataldo , Marzilli Mario , L’Abbate Antonio
Published: June 2012

Background
The likelihood of a positive response with dipyridamole stress echocardiography (DSE) is directly related to the extent and severity of angiographically assessed coronary artery disease. Whether coronary lesion morphology—a known predictor of adverse cardiac events—may also modulate stress echo results remains unknown. The objective of our study was to assess the relation between stenosis lesion morphology and stress echocardiographic results.

Methods and Results
High-dose (up to 0.84 mg/kg over 10 minutes) DSE and coronary angiographic data of 68 in-hospital patients (39 with stable angina, 29 with angina at rest) with nonoccluding, single-vessel disease at angiography and no previous myocardial infarction were analyzed. DSE was performed in all patients within 3 days of coronary angiography. An angiographic lesion was considered complex when irregular borders and/or intraluminal lucencies suggestive of ulcer and/or thrombus were present. According to angiographic lesion morphology, two groups were identified: group 1, with simple coronary lesions, and group 2, with complex coronary lesions. The two groups were matched for number of patients (n=34 in each group), age (group 1, 59±9 versus group 2, 59±10 years,
P
=NS), and coronary artery stenosis severity by quantitative coronary angiography (group 1, 60±7% versus group 2, 58±6% diameter reduction,
P
=NS). The sensitivity of DSE was lower in patients of group 1 when compared with group 2 (53% versus 85%,
P
<.001). Among positive DSE, the low-dose (0.56 mg/kg over 4 minutes) positivity was less frequent in group 1 than in group 2 patients (17% versus 62%,
P
<.01). Exercise ECG was completed in 66 patients, and it was positive (>.1 mV ST-segment shift from baseline) in 20 out of 33 group 1 and in 22 out of 33 group 2 patients (61% versus 67%,
P
=NS). The peak rate-pressure product tended to be higher in group 1 than in group 2 patients (257±52 versus 240±64 mm Hg×beats per minute×10
2
,
P
=NS).

Conclusions
In patients with single-vessel disease without coronary occlusion or previous myocardial infarction, coronary lesion morphology of the complex type is associated with a higher DSE sensitivity and with a greater prevalence of low-dose, positive responses. Presence of irregular plaque contours, not only plaque geometry, is important in modulating stress responses in the presence of angiographically assessed coronary artery disease.
Dehydroepiandrosterone Sulfate Does Not Predict Cardiovascular Death in Postmenopausal Women
Authors: Barrett-Connor Elizabeth , Goodman-Gruen Deborah
Published: June 2012

Background
High levels of dehydroepiandrosterone sulfate (DHEAS) appear to be associated with a reduced risk of fatal cardiovascular disease (CVD) in men. We examined the association between baseline DHEAS levels and the 19-year CVD and ischemic heart disease (IHD) mortality rates in 942 postmenopausal women free of known heart disease at baseline.

Methods and Results
The 199 CVD deaths and 102 IHD deaths were not related to baseline DHEAS levels. DHEAS was not related to body mass index, fasting plasma glucose, or family history of coronary heart disease, but significantly higher DHEAS levels were found in women who had elevated total or HDL cholesterol or blood pressure, were current smokers, or were nonusers of estrogen replacement therapy. After we adjusted for age, cholesterol, blood pressure, smoking, estrogen replacement therapy, obesity, fasting plasma glucose, and family history of heart disease, the relative risk of fatal CVD and IHD was 1.11 (95% confidence interval, 0.81 to 1.23) and 0.92 (95% confidence interval, 0.85 to 1.17), respectively, for a 50-μg/dL decrease in DHEAS.

Conclusions
Although higher DHEAS levels were associated with several major CVD risk factors, they were unrelated to the risk of fatal CVD in women.
Endogenous Adenosine Is an Antiarrhythmic Agent
Authors: Conti Jamie Beth , Belardinelli Luiz , Utterback David B. , Curtis Anne B.
Published: June 2012

Background
Adenosine administered intravenously terminates supraventricular tachycardias (SVT) involving the AV node as part of the reentrant circuit. Dipyridamole increases interstitial myocardial levels of this nucleoside. This study was designed to determine whether intravenous dipyridamole increases coronary sinus plasma adenosine concentrations ([Ado]cs) in humans to levels sufficient to alter electrophysiological parameters and terminate SVT.

Methods and Results
A custom-designed catheter and syringe for sampling blood for measurement of [Ado]cs was placed in the coronary sinuses of 7 patients. [Ado]cs and refractory periods and conduction characteristics of the atrium and AV node were determined after autonomic blockade and dipyridamole infusion (5 μg · kg
−1
· min
−1
after a loading dose of 0.56 mg/kg). The atrial effective and functional refractory periods remained unchanged after dipyridamole infusion. In contrast, the AV nodal functional refractory period increased from 350±32 to 381±41 milliseconds (
P
=.03); the Wenckebach cycle length also increased from 309±47 to 350±57 milliseconds (
P
<.0001). Coincident with these changes, [ADO]cs increased from 0.18±0.11 to 0.31±0.12 μmol/L (
P
=.02). In another 10 patients with AV or AV nodal reentrant tachycardia, SVT was induced, and coronary sinus blood samples were drawn. Dipyridamole was infused, and coronary sinus blood samples were obtained after 15 minutes or coincident with termination of SVT. Mean [ADO]cs increased from 0.17±0.06 μmol/L during SVT to 0.38±0.21 μmol/L after dipyridamole (
P
=.02). Mean tachycardia cycle length increased from 334±132 to 375±139 milliseconds (
P
=.02); this effect was confined to the AV node, as demonstrated by an increase in AH interval from 171±144 to 214±140 milliseconds (
P
=.003). SVT terminated with the infusion of dipyridamole in 4 of the 10 patients.

Conclusions
Administration of dipyridamole is associated with elevation of [ADO]cs, with coincident prolongation of the mean Wenckebach cycle length and AV nodal functional refractory period. During SVT, dipyridamole leads to prolongation of the AH interval and tachycardia cycle length and to an increase in [ADO]cs, with termination of SVT in four patients. These results support the hypothesis that adenosine may function as an endogenous antiarrhythmic metabolite.
Right Ventricular Diastolic Function 15 to 35 Years After Repair of Tetralogy of Fallot
Authors: Gatzoulis Michael A. , Clark Andrew L. , Cullen Seamus , Newman Claus G. H. , Redington Andrew N.
Published: June 2012

Background
We have shown previously that transient right ventricular restriction after tetralogy of Fallot repair prolongs postoperative course. This is a prospective study of right ventricular diastolic performance in late follow-up patients.

Methods and Results
We studied biventricular function, using Doppler echocardiographic examination. Pulmonary arterial, tricuspid, and mitral valves and superior vena cava Doppler spectrals were obtained in 41 patients (mean age, 28.8 years), 15 to 35 years (mean, 23.6) after complete repair of tetralogy of Fallot. Patients were considered to have evidence of right ventricular restriction if antegrade diastolic flow was detected in the main pulmonary artery, coinciding with atrial systole (A wave), throughout the respiratory cycle. Exercise function was measured by graded treadmill testing with respiratory mass spectrometry. Three patients were excluded because of pulmonary outflow obstruction (Doppler gradient >40 mm Hg) or residual intracardiac shunts. Of the 38 patients, 37 were in sinus rhythm. Twenty (52.6%) had definite evidence of restriction with an A wave in the pulmonary artery, augmented during inspiration. In all 20 cases, there was superior vena caval flow reversal with atrial systole. Both inspiratory and expiratory transtricuspid E-wave deceleration time was significantly shorter in the restrictive group (
P
<.003 and
P
<.03, respectively). All patients had Doppler evidence of pulmonary regurgitation, but its duration was shorter in the restrictive group (
P
<.01) during inspiration. Cardiothoracic ratio was significantly lower in the restrictive group (
P
<.01), suggesting less severe pulmonary regurgitation. Both restrictive and nonrestrictive groups had reduced exercise MV̇
o
2
compared with healthy age- and sex-matched control subjects, but those with restrictive physiology had significantly better maximum oxygen uptake than the nonrestrictive group (
P
<.001).

Conclusions
Isolated right ventricular restriction late after tetralogy of Fallot repair is common. Although it reflects abnormal hemodynamics, the A wave contributes to forward pulmonary arterial flow and shortens the duration of pulmonary regurgitation. Consequently, there is less cardiomegaly and improved exercise performance in those patients.
Capillary Distribution in the Ventricles of Hearts With Pulmonary Atresia and Intact Ventricular Septum
Authors: Oosthoek Petra W. , Moorman Antoon F.M. , Sauer Ursula , Gittenberger-de Groot Adriana C.
Published: June 2012

Background
Pulmonary atresia and intact ventricular septum (PA-IVS) can be complicated by the presence of a severely hypoplastic thick-walled right ventricle with or without ventriculo–coronary arterial communications. A variable amount of myocardial pathology has been described in these hearts, probably the result of ischemic conditions and a high pressure in the right ventricle. We studied whether the capillary network is still intact, allowing a sufficient perfusion of the myocardium, which will be important for the success of palliative surgery.

Methods and Results
We studied the distribution of capillaries in the myocardium of hearts with PA-IVS and compared the results with normal hearts. The capillaries were detected by immunohistochemistry using a monoclonal antibody (408) against endothelium. Remarkable abnormalities in capillary distribution were found in the right ventricle of hearts with PA-IVS and reflect the arrangement of the myocytes. Thus, disorganization of capillaries, which is found to be the most common pattern, always paralleled the myocardial disarray. A low density of capillaries is always found in areas with a low density of myocytes, ie, with hypertrophied myocytes, compact fibrotic tissue, or diffuse fibrosis. Disarray and other disturbances in orientation of capillaries and myocytes are present in hearts with PA-IVS, a hypoplastic right ventricle, and ventriculo–coronary arterial communications. These disturbances are more extensive when interruptions of the coronary arteries are also present. In hearts with PA-IVS and a hypoplastic right ventricle only, extensive regions with low capillary densities and severe myocyte pathology are observed. On the contrary, hearts with PA-IVS and a normal-size right ventricle show minor abnormalities in capillary and myocyte organization.

Conclusions
In hearts with PA-IVS, various abnormal capillary distribution patterns are found. Our findings correlate well with clinical data that reported the best surgical results in hearts in which the major part of the myocardium showed a normal capillary distribution and myocyte morphology. This suggests that the capillary distribution may be an important parameter for the function of the heart. Because the distribution of the capillaries is found to be a good reflection of the arrangement of the myocytes, antibody 408 is also a useful tool in detecting abnormalities of the myocardium in a fast and easy way.
Sex Differences in Mortality After Myocardial Infarction
Authors: Vaccarino Viola , Krumholz Harlan M. , Berkman Lisa F. , Horwitz Ralph I.
Published: June 2012

Background
A number of studies have indicated that women who have a myocardial infarction have higher mortality rates than men. The purpose of the present study was to review the literature on sex differences in mortality after myocardial infarction to determine whether female sex is independently associated with lower survival.

Methods and Results
Reports were identified mainly through a MEDLINE search of the English-language literature from January 1966 through June 1994. Studies included were those comparing mortality after myocardial infarction between men and women, controlling at least for age and with more than 30 outcome events. After duplicate patient series were eliminated, 27 reports were included in our review. Crude rates were higher in women than in men during the early phase (in-hospital or first month), but control for age alone or in combination with other factors reduced sex differences in almost all studies. Unadjusted mortality rates among the survivors of the early phase were similar for men and women in most studies, and control for age and other factors resulted in an increased survival rate in women compared with men in several investigations, particularly those with a follow-up of >1 year.

Conclusions
Much of the increased early mortality after myocardial infarction in women is explained by the older age and more unfavorable risk characteristics of the women. In the long run, when differences in age and other risk factors are controlled for, women tend to have an improved survival compared with men.
Link Between the Angiographic Substudy and Mortality Outcomes in a Large Randomized Trial of Myocardial Reperfusion
Authors: Simes R.J. , Topol Eric J. , Holmes David R. , White Harvey D. , Rutsch Wolfgang R. , Vahanian Alec , Simoons Maarten L. , Morris Douglas , Betriu Amadeo , Califf Robert M. , Ross Allan M.
Published: June 2012

Background
The Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries (GUSTO-I) trial was designed to test whether thrombolytic strategies achieving more complete, early, sustained coronary artery patency would lead to further reductions in mortality in patients with acute myocardial infarction. An angiographic substudy within GUSTO-I provided a unique opportunity to examine the relation between mortality and degrees of patency among the regimens.

Methods and Results
Four thrombolytic strategies were compared in 41 021 patients in GUSTO-I: streptokinase with subcutaneous or intravenous heparin, accelerated tissue plasminogen activator (TPA) with intravenous heparin, and combination streptokinase plus TPA with intravenous heparin. Accelerated TPA was associated with lower 30-day mortality (6.3%) than the other strategies (7.2%, 7.4%, and 7.0%, respectively). Among the 1210 patients in the angiographic substudy randomized to angiography 90 minutes after starting treatment, there was improved patency, particularly Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow, with accelerated TPA over the other regimens (
P
<.0001). Coronary artery perfusion (TIMI grade 3) at 90 minutes was also a significant predictor of 30-day survival (
P
<.01). To determine whether differences in mortality among the four strategies matched differences in 90-minute patency, a model was developed for predicting mortality differences in the main trial from the angiographic substudy. The model assumed that any differences in treatment effects on 30-day mortality were mediated through differences in 90-minute patency for the four treatments. The predicted rates were then compared with observed mortality rates of the remaining patients in the main trial for each treatment group. The predicted and observed 30-day mortality rates of the four treatments were streptokinase with subcutaneous heparin, 7.46% versus 7.28%; streptokinase with intravenous heparin, 7.26% versus 7.39%; accelerated TPA, 6.31% versus 6.37%; and streptokinase plus TPA, 6.98% versus 6.96%. The correlation between predicted and observed results was .97, and the proportion of squared error explained (
R
2
) was .92.

Conclusions
The close relation between the predicted and observed 30-day mortality rates supports the concept that an important mechanism for improved survival with thrombolytic therapy is achievement of early, complete perfusion. The close match provides a strong biological explanation for the mortality differences seen in GUSTO-I and a sound rationale for the additional survival advantage of the accelerated TPA regimen. Irrespective of which treatment is used, early and complete restoration of infarct artery perfusion represents an essential goal of myocardial reperfusion therapy.
Rebound Increase in Thrombin Generation and Activity After Cessation of Intravenous Heparin in Patients With Acute Coronary Syndromes
Authors: Granger Christopher B. , Miller Julie M. , Bovill Edwin G. , Gruber Andras , Tracy Russell P. , Krucoff Mitchell W. , Green Cindy , Berrios Eric , Harrington Robert A. , Ohman E. Magnus , Califf Robert M.
Published: June 2012

Background
The abrupt cessation of heparin and other thrombin inhibitors when used to treat acute coronary syndromes has been accompanied by a clustering of thrombotic events. It is unknown whether these events are the result of inadequate antithrombin therapy or whether they represent a rebound increase in thrombin activity. This study was designed to determine whether there is a true rebound, as defined by an increase followed by a subsequent decrease, in thrombin activity after discontinuation of intravenous heparin therapy.

Methods and Results
Thirty-five patients with recent acute myocardial infarction or unstable angina who had received at least 48 hours of intravenous heparin were studied. Patients underwent ST-segment monitoring, and blood samples for determination of thrombin generation and activity were drawn at 0, 3, 6, 10, and 24 hours after heparin discontinuation. Median aPTT was 65 seconds before heparin discontinuation. Median fibrinopeptide A increased from 9.5 to 16.9 ng/mL at 3 hours (
P
<.0004) and returned to 10.5 by 24 hours. Prothrombin fragment 1.2 likewise transiently increased, from 0.34 to 0.51 nmol/L at 6 hours (
P
<.0002). Modified antithrombin III decreased over time (
P
<.002), and activated protein C increased from 2.3 to 4.5 ng/mL at 3 hours (
P
<.001). Although there were no clinical thrombotic events in the first 24 hours, 4 patients had evidence of ischemia by ST-segment monitoring at a median of 12 hours after heparin discontinuation. The degree of increase in fibrinopeptide A and prothrombin fragment 1.2 was not found to be associated with baseline diagnosis, duration of heparin therapy, baseline level of antithrombin III, or activated protein C.

Conclusions
This study demonstrates a transient rebound increase in thrombin activity as well as in activated protein C upon abrupt discontinuation of intravenous heparin. Clinicians should be vigilant for associated thrombotic events. Further investigation of the significance, mechanism, and possible prevention of this rebound phenomenon is needed.