bluuebunny/crossref_metadata_2025 huggingface dataset:
Dose-Dependent Effects of the Renin Inhibitor Zankiren HCl After a Single Oral Dose in Mildly Sodium-Depleted Normotensive Subjects
Authors: Ménard Joël , Boger Robert S. , Moyse Denise M. , Guyene Tam T. , Glassman Harriet N. , Kleinert Hollis D.
Published: June 2012

Background
Zankiren HCl (A-72517) is a potent renin inhibitor shown to have substantial bioavailability in several animal species and to produce dose-related reductions in blood pressure, plasma renin activity, and angiotensin II (Ang II) in salt-depleted dogs. The present study was designed to evaluate the hemodynamic effects of oral zankiren HCl administration in healthy volunteers and to characterize the response of the renin-angiotensin system (RAS) to specific blockade by this new renin inhibitor.

Methods and Results
Twenty-four male volunteers participated in a double-blind randomized, placebo-controlled in-hospital study to evaluate the effects of zankiren HCl (10 to 250 mg). All subjects were pretreated with 40 mg furosemide 12 hours before study drug administration. Blood pressure and heart rate were monitored by an automated oscillometric device, and blood samples were obtained for active renin, total renin, plasma renin activity, angiotensin I (Ang I), Ang II, aldosterone, and plasma zankiren concentration. Satisfactory absorption of zankiren HCl was demonstrated by the results of plasma drug concentration determinations, and renin inhibitory activity was confirmed by dose-related suppression of plasma renin activity, Ang I, Ang II, and aldosterone and increases in plasma active renin concentration. Furthermore, hypotensive activity was readily observed in these normotensive subjects, as evidenced by statistically significant dose-related blood pressure reductions (
P
<.01).

Conclusions
Results from this study demonstrate for the first time that oral administration of a renin inhibitor can dose-dependently decrease blood pressure and circulating components of the RAS in normotensive volunteers as a result of documented absorption.
The Growing Flood of Technetium-99m Myocardial Perfusion Agents
Authors: Miller D. Douglas
Published: June 2012

“Ol’ man river, dat ol’ man river,

He must know sumpin’, but don’t say nothin’,

He just keeps rollin’, he keeps on rollin’ along.”

Ol’ Man River

—Oscar Hammerstein II

© 1927 T.B. Harms Co. Copyright renewed.
Time- and Frequency-Domain Analyses of the Signal-Averaged ECG in Patients With Arrhythmogenic Right Ventricular Dysplasia
Authors: Kinoshita Osamu , Fontaine Guy , Rosas Fernando , Elias Jorge , Iwa Toru , Tonet Joelci , Lascault Gilles , Frank Robert
Published: June 2012

Background
Arrhythmogenic right ventricular dysplasia (ARVD) is characterized by recurrent ventricular tachycardia of right ventricular origin and a cardiomyopathy with hypokinetic areas involving the free wall of the right ventricle. Subjects have a risk of sudden cardiac death, particularly during sports and strenuous exercise. Routine clinical examinations may be normal, but fragmented or delayed electrograms are usually recorded in the right ventricle of these patients. However, the frequency with which late potentials are detected by conventional time-domain analysis of the signal-averaged ECG (SAECG) is not high. This study evaluated the usefulness of the frequency-domain analysis of the SAECG in addition to the conventional time-domain analysis for a screening test to detect patients with ARVD.

Methods and Results
SAECG was recorded by using a bipolar X, Y, and Z lead system in 28 patients with ARVD (mean age, 38±13 years) and 35 age-matched normal subjects (mean age, 35±11 years). The conventional time-domain analysis of the SAECG was performed at two different high-pass filter settings, 25 and 40 Hz, and the low-pass cutoff frequency was fixed at 250 Hz. The fast-Fourier transform analysis of SAECG was performed using a Blackman-Harris window. Area ratio 1 (area of 20 to 50 Hz)/(area of 0 to 20 Hz) and area ratio 2 (area of 40 to 100 Hz)/(area of 0 to 40 Hz) were calculated. In the conventional time-domain analysis, 20 (71%) and 18 (64%) patients had positive criteria at filter settings of 25 and 40 Hz, respectively. In the frequency-domain analysis, 18 (64%) and 20 (71%) patients had abnormal values in area ratios 1 and 2, respectively. Combining the time- and frequency-domain analyses, all patients were judged positive, with a sensitivity of 100% and a specificity of 94%.

Conclusions
Each result of the time- and frequency-domain analyses revealed that both methods had equivalent value. Combining the two domain analyses improved the sensitivity without reducing the specificity. These findings suggest that combining the time- and frequency-domain analyses of the SAECG may be useful as a screening test to detect patients with ARVD.
Cost of Initial Therapy in the Electrophysiological Study Versus ECG Monitoring Trial (ESVEM)
Authors: Omoigui Nowamagbe A. , Marcus Frank I. , Mason Jay W. , Hahn Elizabeth A. , Hartz Vernon L. , Hlatky Mark A.
Published: June 2012

Background
Patients randomized to either serial electrophysiological testing (EPS) or serial Holter monitoring (HM) to guide antiarrhythmic therapy for life-threatening ventricular arrhythmias had equivalent rates of mortality and arrhythmia recurrence in the ESVEM study. This report analyzes the effects of EPS, HM, and clinical factors on the charges for initial evaluation and management of patients with life-threatening ventricular arrhythmias.

Methods and Results
Ten of 14 clinical centers participating in ESVEM provided bills from the initial hospitalization for randomized patients. Predictors of charges (1991 dollars) were analyzed by linear regression after logarithmic transformation. Initial hospital charge data were obtained for 286 patients randomized in ESVEM (88% of patients eligible for this substudy, 59% of all ESVEM patients). Patients with charge data were somewhat more likely to be older, to be female, and to have failed previous antiarrhythmic drug therapy at study entry and were less likely to have a drug predicted effective after randomization. Mean overall hospital charges were $35 986 (SD, $32 628) with a median of $24 532 (interquartile range, $16 126 to $43 593). Prerandomization patient characteristics generally had insignificant effects on charges, with the exception of presentation with resuscitated sudden death (28% increase in charges,
P
=.01) and heart failure (26% increase in charges,
P
=.02). Patients randomized to EPS had higher mean charges for evaluation ($42 002 versus $29 970,
P
=.0015) as well as more drug trials (3.0 versus 2.1,
P
=.0001) and a longer hospital stay (19.6 versus 13.9 days,
P
=.0007). In a multivariate regression model, failure to find an effective drug (
P
=.0001), the number of drug trials (
P
=.0001), and resuscitated sudden death as the presenting arrhythmia (
P
=.0001) were the only independent predictors of higher initial charges.

Conclusions
(1) Initial hospital charges are significantly higher for EPS-guided than HM-guided therapy. (2) The higher charges for EPS-guided therapy were due to a greater number of drug trials and a lower probability of finding an effective drug. (3) Failure to find an effective drug, a larger number of drug trials, and a history of resuscitated sudden death independently predict higher charges.
Disparate Effects of Early Pressure Overload Hypertrophy on Velocity-Dependent and Force-Dependent Indices of Ventricular Performance in the Conscious Baboon
Authors: Hoit Brian D. , Shao Yanfu , Gabel Marjorie , Walsh Richard A.
Published: June 2012

Background
The effects of early pressure overload on left ventricular (LV) chamber mechanics in the primate heart are poorly understood.

Methods and Results
To test the hypothesis that early LV pressure overload hypertrophy is associated with depression of velocity-dependent indices of LV systolic (LV dP/dt) and diastolic function (time constant of relaxation, tau) but unchanged systolic elastance (E
es
), we studied six conscious baboons instrumented with LV micromanometers and LV dimension and wall thickness sonomicrometers. Loading conditions were altered by pharmacological angiotensin II generation both before and 12 weeks after producing renovascular hypertension (2 kidney, 1 clip). The LV systolic pressure (149±11 [SD] versus 114±5 mm Hg) and LV mass (125±25 versus 91±20 g) were greater 12 weeks after than before (both
P
<.05). Both E
es
and E
es
normalized for LV mass were similar before versus 12 weeks after (23.0±9.6 versus 22.3±9.8 mm Hg/mL and 26.5±14.5 versus 19.8±12.5 mm Hg/mL, respectively; both
P
=NS). At matched LV systolic and diastolic pressures, LV fractional shortening was similar (18.6±6.8% versus 21.6±4.9%), but the time constant of LV isovolumic relaxation was significantly longer (42.3±5.3 versus 31.4±7.0 ms,
P
<.05) and LV dP/dt and V
cf
were significantly less (1891±352 versus 2342±284 mm Hg/s and 0.9±0.4 versus 1.1±0.3 circ/s, respectively; both
P
<.05) 12 weeks after than before.

Conclusions
In conscious baboons with systemic arterial hypertension and early LV hypertrophy, there is depression of velocity-dependent indices of LV contraction and relaxation but unaltered force-dependent measures of contractility.
Comparison of Upper Limit of Vulnerability and Defibrillation Probability of Success Curves Using a Nonthoracotomy Lead System
Authors: Souza Joseph J. , Malkin Robert A. , Ideker Raymond E.
Published: June 2012

Background
An upper limit to the strength of shocks that induce fibrillation during the vulnerable period, the upper limit of vulnerability (ULV), has been shown to exist in both humans and animals. The purpose of this study was to compare ULV and defibrillation (DF) probability of success curves for a clinically useful nonthoracotomy lead system.

Methods and Results
Sixteen pentobarbital-anesthetized pigs were studied. Single-capacitor biphasic waveforms with both phases 5.5 ms in duration were used for ULV and DF testing. A right ventricular catheter electrode served as first-phase cathode and a superior vena cava catheter electrode coupled with a cutaneous R2 patch electrode served as common first-phase anodes. A pacing catheter was placed in the right ventricle to deliver a train of 15 S
1
stimuli at a pacing interval of 250 to 300 ms. A ULV shock was delivered on the peak of the T wave as measured from the surface ECG; if ventricular fibrillation was induced, a DF shock was delivered after 10 seconds of fibrillation. Shock voltages were determined by an up-down protocol. Ventricular fibrillation was induced an average of 53 times in each animal. The composite data indicate that below V97, that is, the voltage that leaves the animal in normal sinus rhythm 97% of the time when delivered on the peak of the T wave or the voltage that defibrillates 97% of the time, ULV is lower than DF. ULV and DF became significantly correlated at V80 and maximally correlated at V97. Even at V97, however, ULV and DF differed by more than 100 V in 2 of the 16 animals.

Conclusions
ULV approximately equaled DF at V97. This is fortunate because it is clinically important to set the device voltage at the uppermost portion of the probability of success curve. Estimating DF V97 from ULV V97 would reduce the number of fibrillation inductions needed to establish defibrillation shock strength requirements. However, the large difference between ULV V97 and DF in a few animals indicates that further improvement and testing of algorithms for determining ULV V97 must be developed before the technique is used clinically.
Nitric Oxide Is Responsible for Flow-Dependent Dilatation of Human Peripheral Conduit Arteries In Vivo
Authors: Joannides Robinson , Haefeli Walter E. , Linder Lilly , Richard Vincent , Bakkali El Hassan , Thuillez Christian , Lüscher Thomas F.
Published: June 2012

Background
Experimental evidence suggests that flow-dependent dilatation of conduit arteries is mediated by nitric oxide (NO) and/or prostacyclin. The present study was designed to assess whether NO or prostacyclin also contributes to flow-dependent dilatation of conduit arteries in humans.

Methods and Results
Radial artery internal diameter (ID) was measured continuously in 16 healthy volunteers (age, 24±1 years) with a transcutaneous A-mode echo-tracking system coupled to a Doppler device for the measurement of radial blood flow. In 8 subjects, a catheter was inserted into the brachial artery for measurement of arterial pressure and infusion of the NO synthase inhibitor
N
G
-monomethyl-
l
-arginine (L-NMMA; 8 μmol/min for 7 minutes; infusion rate, 0.8 mL/min). Flow-dependent dilatation was evaluated before and after L-NMMA or aspirin as the response of the radial artery to an acute increase in flow (reactive hyperemia after a 3-minute cuff wrist occlusion). Under control conditions, release of the occlusion induced a marked increase in radial blood flow (from 24±3 to 73±11 mL/min;
P
<.01) followed by a delayed increase in radial diameter (flow-mediated dilatation; from 2.67±0.10 to 2.77±0.12 mm;
P
<.01) without any change in heart rate or arterial pressure. L-NMMA decreased basal forearm blood flow (from 24±3 to 13±3 mL/min;
P
<.05) without affecting basal radial artery diameter, heart rate, or arterial pressure, whereas aspirin (1 g PO) was without any hemodynamic effect. In the presence of L-NMMA, the peak flow response during hyperemia was not affected (76±12 mL/min), but the duration of the hyperemic response was markedly reduced, and the flow-dependent dilatation of the radial artery was abolished and converted to a vasoconstriction (from 2.62±0.11 to 2.55±0.11 mm;
P
<.01). In contrast, aspirin did not affect the hyperemic response nor the flow-dependent dilatation of the radial artery.

Conclusions
The present investigation demonstrates that NO, but not prostacyclin, is essential for flow-mediated dilatation of large human arteries. Hence, this response can be used as a test for the
l
-arginine/NO pathway in clinical studies.
Antithrombotic Effects of Thrombolytic Agents in a Platelet-Rich Femoral Vein Thrombosis Model in the Hamster
Authors: Stassen Jean Marie , Nyström Åke , Hoylaerts Marc , Collen Désiré
Published: June 2012

Background
The extent and mechanism of the antithrombotic properties of fibrin-selective and non–fibrin-selective thrombolytic agents have not yet been established.

Methods and Results
The antithrombotic, thrombolytic, fibrinogenolytic, and pharmacokinetic properties of the following substances were determined in hamsters in the absence of conjunctive anticoagulant or antiplatelet therapy: recombinant tissue-type plasminogen activator (rTPA), recombinant single-chain urokinase-type plasminogen activator (rscu-PA), two-chain urokinase-type plasminogen activator (UK), with a rTPA deletion mutant lacking amino acids 6 to 173 and a mutation N184E (K
2
Pt), a rTPA/rscu-PA chimeric plasminogen activator consisting of amino acids 1 to 3 and 87 to 274 of rTPA and amino acids 138 to 411 of rscu-PA (K
1
K
2
Pu), streptokinase (SK), and recombinant staphylokinase (STAR). The antithrombotic effect, defined as the intravenous dose required to reduce mural thrombus formation to 50% in a platelet-mediated femoral vein thrombosis model in the hamster, was 6±1, 5±2, 1±0.05, 2.5±0.2, 0.02±0.002, 1±0.09, and 2±0.3 mg/kg (mean±SEM), respectively. The amounts, given as intravenous infusion over 60 minutes that induced 50% clot lysis in a hamster pulmonary embolism model, were 0.18±0.03, 1.1±0.05, 0.9±0.13, 0.34±0.03, 0.04±0.003, 0.05±0.005, and 0.04±0.001 mg/kg, respectively, indicating that for most thrombolytic agents the antithrombotic dose is much higher than their thrombolytic dose. The fibrinogen levels, measured 40 minutes after bolus injection, were reduced to 50% of baseline with 3.1±0.2, 2.5±0.3, 1.2±0.08, 2.0±0.14, 1.7±0.65, 0.54±0.03, and 1.2±0.11 mg/kg, respectively. Mean residence times following intravenous bolus injection were: 18±1, 14±1, 100±10, 80±2, 20±3, and 34±5 minutes for rTPA, rscu-PA, K
2
Pt, K
1
K
2
Pu, SK, and STAR, respectively. Regression analysis revealed a significant correlation of the antithrombotic effect with the fibrinogen breakdown (
P
=.006) but not with the thrombolytic potency or with the mean residence time.

Conclusions
These observations support the hypothesis that thrombolytic therapy with fibrinogen-sparing agents requires the conjunctive use of anticoagulant and/or antiplatelet agents.
Increased Prevalence of Coronary Ectasia in Heterozygous Familial Hypercholesterolemia
Authors: Sudhir Krishnankutty , Ports Thomas A. , Amidon Thomas M. , Goldberger Jeffrey J. , Bhushan Vikas , Kane John P. , Yock Paul , Malloy Mary J.
Published: June 2012

Background
Although coronary atherosclerosis most commonly produces clinical effects as a result of stenosis, aneurysmal disease also occurs. We have found an increased prevalence of ectasia and aneurysmal disease in familial hypercholesterolemia (FH) suggesting a link between plasma lipoproteins and coronary aneurysms.

Methods and Results
In 197 asymptomatic subjects with FH, we examined the prevalence of ectasia and its association with coronary risk factors. An ectatic segment was defined as one with a luminal diameter >1.5 times that of the adjacent normal segment, excluding poststenotic dilation. Among subjects with FH, 15% had ectasia compared with 2.5% of an age- and sex-matched control group of 198 subjects without FH pre- senting for coronary angiography (
P
<.001). These control patients had significantly more severe coronary atherosclerosis than patients with FH. Ectasia was 3 times more common in men than women (
P
<.025). Neither age nor hypertension was predictive. Although in part reflecting the striking sex differential, ectasia was strongly associated with a lower HDL cholesterol level (
P
=.003), a higher LDL/HDL ratio (
P
=.003), and to a lesser extent, a higher LDL cholesterol level (
P
=.07). No association was found with plasma triglycerides or very low-density lipoprotein cholesterol levels. Among FH patients, ectasia was strongly associated with an overall index of occlusive atherosclerotic disease, based on quantitative angiography (
P
=.004). Intracoronary ultrasound interrogation of aneurysmal segments revealed circumferential intimal thickening.

Conclusions
Coronary ectasia is more prevalent in patients with FH than in other patients with coronary atherosclerosis and shows a strong inverse association with HDL cholesterol levels. This suggests that disordered lipoprotein metabolism in FH may predispose patients to aneurysmal coronary artery disease.
Comparison of the Bleeding Potential of Vampire Bat Salivary Plasminogen Activator Versus Tissue Plasminogen Activator in an Experimental Rabbit Model
Authors: Montoney Michelle , Gardell Stephen J. , Marder Victor J.
Published: June 2012

Background
Vampire bat salivary plasminogen activator (Bat-PA) has significantly greater fibrin specificity than any of the fibrinolytic agents currently in clinical use. This study tests the hypothesis that avoiding fibrinogen depletion may protect against the hemorrhage induced by plasminogen activator treatment.

Methods and Results
Bat-PA was compared with tissue-type plasminogen activator (TPA) in a randomized, prospective, and blinded study using a rabbit ear puncture model of fibrinolytic bleeding. The two agents were used at equimolar dosages (42 nmol/kg) that yielded similar thrombolytic efficacies in a rabbit femoral artery thrombosis model. Both Bat-PA and TPA prolong primary bleeding to double the baseline values, from between 2.1 and 2.3 minutes to between 4.8 and 5.2 minutes. Rebleeding from hemostatically stable sites during the 3-hour observation period occurred equally often with Bat-PA and TPA, 31% from preinjection sites and 23% to 25% from postinjection sites. The lag time between the time of plasminogen activator injection and the onset of rebleeding was likewise the same for both agents, most occurring at 41 to 57 minutes. However, a greater number of prolonged primary or rebleeding occurrences continued for longer than 10 minutes (63% versus 36%) or longer than 30 minutes (30% versus 10%) after Bat-PA than TPA injection. Animals treated with TPA showed a dramatic decrease in plasma fibrinogen and factor VIII concentrations, but those in the Bat-PA treatment group showed only a slight decrease from control values.

Conclusions
The results indicate that fibrinolytic bleeding after plasminogen activator infusion into rabbits did not correlate with the intensity of the plasma proteolytic state. If anything, Bat-PA usage was associated with a higher proportion of more protracted fibrinolytic bleeding episodes, despite the relatively mild lytic state in comparison with that induced by TPA.
Ventricular Arrhythmias Detected After Transvenous Defibrillator Implantation in Patients With a Clinical History of Only Ventricular Fibrillation
Authors: Raitt Merritt H. , Dolack G. Lee , Kudenchuk Peter J. , Poole Jeanne E. , Bardy Gust H.
Published: June 2012

Background
Patients with a history of ventricular fibrillation (VF) have been shown to have a clinical profile, response to electrophysiological testing (EPS), and response to antiarrhythmic therapy that distinguishes them from patients with a history of sustained monomorphic ventricular tachycardia (MVT). Despite these differences, it is not clear whether VF in these patients is triggered by MVT or occurs de novo. The incidence of MVT and VF in such patients after their index VF event has important implications for therapeutic decisions regarding implantable defibrillator selection and programming.

Methods and Results
The records of 111 consecutive patients who had undergone transvenous cardioverter/defibrillator (ICD) implantation for malignant ventricular arrhythmias were reviewed retrospectively. For each patient, all device tachyarrhythmia detections were examined and classified as VF, MVT, rapid polymorphic VT, or other. The number of events, time to first arrhythmia detection, and cycle length of MVTs were recorded. There were 55 patients with a history of only VF and 56 with a history that included an episode of MVT. Over 14 months of follow-up, with all patients initially off of antiarrhythmic medications, MVT was detected by only 18% of patients with a history of only VF compared with 54% of those with a history that included MVT (
P
=.002). Among patients who did detect MVT, those with a history of only VF had fewer episodes (7±7 versus 20±31,
P
=.001) and a shorter mean MVT cycle length (279 versus 314 ms,
P
=.03) than those with a clinical history of MVT. Abrupt onset of VF not preceded by MVT was detected in 11% of patients with VF only. In addition to a history of MVT, male sex, age <60 years, and MVT inducible on EPS were all significantly associated with an increased likelihood of MVT detection. On multivariate analysis, the inducibility of MVT was the primary independent predictor of MVT detection but was of minimal incremental predictive value in the subgroup of patients with a history of only VF. When EPS results were not considered, arrhythmia history was the primary independent predictor of MVT detection.

Conclusions
Patients with a history of only VF infrequently have MVT detected by their defibrillators. When these patients do detect MVT, it is faster than that detected in patients with a clinical history of MVT before ICD surgery. A significant percentage of VF survivors detected the abrupt onset of VF not preceded by MVT, suggesting that the deterioration of rapid MVT to VF is not the only clinically important mechanism of VF induction. These findings may have important implications for the understanding of the mechanism of VF induction and for use of an implantable defibrillator.
Effects of Aspirin on Platelet-Neutrophil Interactions
Authors: López-Farré A. , Caramelo C. , Esteban A. , Alberola M. L. , Millás I. , Montón M. , Casado S.
Published: June 2012

Background
In recent studies, the hypothesis has been raised that the mechanisms by which aspirin acts as a protective anti-ischemic agent exceed the inhibition of platelet thromboxane A
2
synthesis. Recently, new data have been obtained disclosing a platelet-antiaggregating effect by neutrophils, which occurs through a nitric oxide (NO)/cGMP-dependent pathway.

Methods and Results
The present study, using platelets and neutrophils from normal subjects, was undertaken to assess the putative effect of aspirin on the neutrophil-mediated, platelet-inactivating effect. Aspirin facilitated the inhibitory effect of neutrophils on platelet activation by thrombin, ADP, or epinephrine. This effect was equally evident in vitro and in blood samples of normal individuals taking aspirin. A significant stimulation of NO-mediated mechanisms in the presence of aspirin was disclosed by different methods, as follows: (1) the increased metabolism of arginine to citrulline, (2) the increase of cGMP in the platelet/neutrophil system, and (3) the inhibitory action of the
l
-arginine (L-Arg)–competitive analogue L-NMMA, which was reversed by L-Arg. The effect of aspirin appeared to be related to cyclooxygenase inhibition, since it was reproduced by using indomethacin. The vasoconstricting peptide endothelin-1 (ET-1) reversed the effect of aspirin through the endogenous production of platelet-activating factor (PAF) by neutrophils, as judged by the marked inhibitory effect of the PAF antagonist BN-52021.

Conclusions
Our results show that a significant part of the effect of aspirin on platelet activation involves a neutrophil-mediated, NO/cGMP-dependent mechanism. The presence of ET-1 counterbalances these effects of neutrophils on platelet activation, therefore acting as an indirect proactivating agent. These results add new elements for interpreting the effects of aspirin on the interactions between blood cells, with special reference to high endothelin states (for example, ischemia/reperfusion processes).
One-Year Follow-up in the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT I)
Authors: Elliott John M. , Berdan Lisa G. , Holmes David R. , Isner Jeffrey M. , King Spencer B. , Keeler Gordon P. , Kearney Marianne , Califf Robert M. , Topol Eric J.
Published: June 2012

Background
Directional atherectomy is a frequently used percutaneous revascularization strategy, but its long-term outcomes have not previously been compared with those of balloon angioplasty in a prospective trial.

Methods and Results
The 1012 patients enrolled in the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT I) were followed for at least 1 year after randomization. Analyses of predetermined end points were performed, including a detailed analysis of the 14 patients who died. At 1 year, 11 patients had died in the atherectomy group compared with 3 in the angioplasty group (2.2% versus 0.6%,
P
=.035), with an excess of out-of-hospital deaths (2.2% versus 0.2%,
P
=.01) and late cardiac deaths (1.6% versus 0%,
P
=.01). Univariate predictors of death included age, abrupt closure, periprocedural enzyme elevation, and peripheral vascular complications. There was no evidence that the excess of deaths after atherectomy was linked to perforation, ectasia, or deep resection. Cumulative rates of myocardial infarction were higher in those who had been randomized to atherectomy than in those randomized to angioplasty (8.9% versus 4.4%,
P
=.005) with a trend toward excess Q-wave and non–Q-wave infarctions. By multivariate analysis, atherectomy was the only variable predictive of the combined end point of death or myocardial infarction. No clinical or angiographic characteristics added to this index. Rates of repeat percutaneous intervention at the target site (24.4% after atherectomy versus 25.9% after angioplasty), coronary artery bypass surgery (9.3% versus 9.1%), hospitalization (50% versus 47.1%), and stroke (1% in both groups) were not significantly different.

Conclusions
Long-term follow-up of the 1012 patients randomized to atherectomy or angioplasty has revealed a statistically significant excess of deaths after directional atherectomy that was not evident at 6 months. This difference could be due to the chance occurrence of a low mortality rate in those randomized to angioplasty. The excess of myocardial infarctions after atherectomy remains statistically significant at 1 year. Further investigation is warranted to improve the safety of atherectomy.
Increased Activity of Constitutive Nitric Oxide Synthase in Cardiac Endothelium in Spontaneous Hypertension
Authors: Nava Eduardo , Noll Georg , Lüscher Thomas F.
Published: June 2012

Background
We analyzed the activity of nitric oxide synthase in the rat heart to study whether this activity is affected by high blood pressure. Hearts from young (3 to 4 weeks old) and adult (15 to 25 weeks old) Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were excised and frozen in liquid nitrogen. The activities of Ca
2+
-dependent (cNOS) and Ca
2+
-independent (iNOS) were determined in homogenized tissues by measuring the conversion of [
14
C]-
l
-arginine to [
14
C]-
l
-citrulline in the presence or absence of either EGTA (1 mmol/L) or EGTA plus
N
G
-nitro-
l
-arginine methyl ester (L-NAME, 1 mmol/L each).

Methods and Results
Arterial pressure was higher in adult SHR than in young SHR and WKY rats of both ages (
P
<.01). The cNOS activity was two to three times higher in hypertensive than in normotensive hearts (
P
=.01 to
P
=.04). No significant activity of iNOS was detected in any tissue. Studies of the right and left ventricles demonstrated a higher cNOS activity in the left sides of the hearts of adult SHR (
P
<.05). No differences were found in hearts from WKY rats. Selective removal of endocardial or coronary endothelial cells in hearts of SHR and WKY rats substantially reduced cNOS activity (
P
<.01).

Conclusions
The cNOS activity is upregulated in cardiac endothelial cells of genetically hypertensive rats. The high activity of cardiac cNOS is related to increased arterial pressure of these animals. We propose that in the heart, endothelial cells respond with a higher production of nitric oxide as a compensatory mechanism against high blood pressure and its damaging effects in this organ.
In Vivo Gene Transfer Into Injured Carotid Arteries
Authors: Schulick Andrew H. , Newman Kurt D. , Virmani Renu , Dichek David A.
Published: June 2012

Background
Adenoviral vectors are very attractive agents for use in in vivo arterial gene transfer. In a previous study, we demonstrated high-efficiency adenovirus-mediated gene transfer into medial smooth muscle cells of balloon-injured rat carotid arteries. We now further characterize this system by investigating the reproducibility of recombinant gene expression, the presence of acute adenovirus-associated toxicity in the vessel wall, and the optimal virus concentration for transduction.

Methods and Results
Balloon-injured rat carotid arteries were incubated with (1) an adenovirus expressing a β-galactosidase gene (Av1LacZ4), (2) a related adenovirus without the recombinant gene (Addl312), or (3) control solutions. Recombinant gene expression was determined 3 days after gene transfer by measurement of β-galactosidase activity in vessel extracts and by counting of smooth muscle cells in microscopic sections that were histochemically stained to detect recombinant β-galactosidase activity. Adenovirus-associated toxicity was assessed in microscopic cross sections by counting of total smooth muscle cell nuclei in the media (to identify cell loss) and characterization of medial cellular infiltrates with histochemical stains for specific inflammatory cells (neutrophils, lymphocytes, macrophages, and monocytes). Maximum recombinant gene expression after incubation with Av1LacZ4 was produced by virus concentrations ranging from 2×10
10
to 5×10
10
plaque-forming units (pfu)/mL. Surprisingly, use of a higher concentration of Av1LacZ4 virus (1×10
11
pfu/mL) resulted in loss of recombinant gene expression. In addition, infusion of either Av1LacZ4 or Addl312 at 1×10
11
pfu/mL resulted in statistically significant decreases in medial smooth muscle cell number (53% decrease,
P
<0.01 for Av1LacZ4; 39% decrease,
P
<.05 for Addl312) compared with vessels infused with control solution. This decrease in smooth muscle cell number was not present after the infusion of virus at lower concentrations. The number of neutrophils in vessel cross sections was significantly increased (fivefold;
P
<.05) after infusion of Av1LacZ4 at 1×10
11
pfu/mL compared with vessels infused with control solution. Lymphocytes, macrophages, and monocytes were present only in low numbers in all vessel cross sections and were not increased consequent to adenovirus infusion.

Conclusions
This model of focal in vivo adenovirus-mediated gene transfer into the media of injured arteries is highly reproducible and allows high-level recombinant gene expression over a fairly narrow range of virus concentrations. Acute adenovirus-associated tissue toxicity, as demonstrated by medial smooth muscle cell loss and neutrophilic infiltrates, places an upper limit on virus concentration and associated recombinant gene expression and suggests the presence of a “window” of virus concentration in which either therapeutic or biological effects of recombinant genes can be studied in the absence of associated acute toxicity.
Role of Endogenous Endothelin-1 in Experimental Renal Hypertension in Dogs
Authors: Donckier Julian , Stoleru Liviu , Hayashida Wataru , Van Mechelen Henri , Selvais Philippe , Galanti Laurence , Clozel Jean-Paul , Ketelslegers Jean-Marie , Pouleur Hubert
Published: June 2012

Background
Endothelin-1, a vasoconstrictive peptide released by endothelium, may be involved in the pathophysiology of hypertension. The goal of the present study was to evaluate the role of endogenous endothelin-1 in renal hypertension in dogs. The model of hypertension consisted of silk tissue wrapping of the left kidney, which produced hypertension associated with perinephritis after 6 to 8 weeks.

Methods and Results
Thirty-two anesthetized open chest dogs were studied randomly: 8 dogs with perinephritic hypertension received the nonpeptidic ET
A
-ET
B
receptor antagonist bosentan (group 1); 8 other hypertensive dogs received the vehicle solution (group 2); 8 healthy dogs received bosentan (group 3); and 8 healthy dogs received the vehicle solution (group 4). Bosentan was injected as an intravenous bolus (3 mg/kg) followed by a 1-hour infusion at a rate of 7 mg · kg
−1
· h
−1
. In hypertensive dogs, bosentan produced a similar decrease (
P
=.0001) of both left ventricular systolic and mean aortic pressures, which averaged 38 mm Hg (−22% and −24%, respectively). These parameters remained unchanged with the vehicle solution. Left ventricular end-diastolic and left atrial pressures also declined significantly with bosentan (
P
=.0005 and
P
<.05, respectively). Left ventricular lengths tended to decrease. The other cardiovascular parameters (heart rate, peak [+]dP/dt, time constant of relaxation, and coronary vascular resistance) did not change significantly. In healthy dogs, bosentan decreased mean aortic pressure by 19 mm Hg (
P
=.004). Vehicle solution had no effect. Plasma endothelin-1 levels, similar under basal conditions in healthy and hypertensive dogs, increased 30-fold with bosentan (
P
=.0001).

Conclusions
Specific endothelin-1 receptor antagonism markedly lowers blood pressure in experimental hypertension but is less effective on blood pressure of healthy animals. This suggests that endothelin-1 plays a role in the pathophysiology of hypertension but contributes to a lesser extent to the maintenance of normal blood pressure. This role of endothelin-1 is unrelated to its plasma levels. The increase of plasma endothelin-1 with bosentan, due either to a displacement of endothelin-1 from its receptor or to a feedback mechanism, does not prevent this blood pressure reduction.
Basic Fibroblast Growth Factor Upregulates the Expression of Vascular Endothelial Growth Factor in Vascular Smooth Muscle Cells
Authors: Stavri George T. , Zachary Ian C. , Baskerville Paul A. , Martin John F. , Erusalimsky Jorge D.
Published: June 2012

Background
Vascular endothelial growth factor (VEGF) is a hypoxia-inducible direct angiogenic factor. Upregulation of VEGF is thought to mediate many of the angiogenic effects of growth factors that are not direct endothelial cell mitogens. Like VEGF, basic fibroblast growth factor (bFGF) is considered to induce angiogenesis by a direct effect on endothelial cells. This study investigated the possibility that bFGF may also act indirectly by regulating VEGF expression in vascular smooth muscle cells (VSMCs).

Methods and Results
Incubation of confluent and quiescent cultures of rabbit VSMCs with bFGF caused a time- and concentration-dependent increase in steady-state levels of VEGF mRNA, as analyzed by Northern blot hybridization. Exposure of VSMCs to a threshold hypoxic stimulus (2.5% O
2
) caused a modest increase in VEGF mRNA levels. However, the combination of 2.5% O
2
with bFGF had a marked synergistic effect. This effect was specific for VEGF as hypoxia did not enhance bFGF-induced expression of the proto-oncogene c-
myc
. Synergistic upregulation of VEGF mRNA expression also was observed between hypoxia and TGF-β
1
.

Conclusions
These results suggest that bFGF may promote angiogenesis both by a direct effect on endothelial cells and also indirectly by the upregulation of VEGF in VSMCs. The synergy demonstrated between hypoxia and either bFGF or TGF-β
1
suggests that multiple diverse stimuli may interact via the upregulation of VEGF expression in VSMCs to amplify the angiogenic response.
Molecular Analysis of Nondisjunction in Down Syndrome Patients With and Without Atrioventricular Septal Defects
Authors: Zittergruen Mark M. , Murray Jeffrey C. , Lauer Ronald M. , Burns Trudy L. , Sheffield Val C.
Published: June 2012

Background
Congenital heart disease is common in Down syndrome patients, with atrioventricular septal defects accounting for a majority of the abnormalities. The molecular mechanisms of meiotic nondisjunction resulting in Down syndrome were studied for associations with the presence of atrioventricular septal defects.

Methods and Results
Twenty highly polymorphic chromosome 21 microsatellite markers were used to genotype two groups of patients (group 1: Down syndrome with atrioventricular septal defects, n=43; and group 2: Down syndrome without cardiac defects, n=51) to determine (1) the parental origin of the extra chromosome, (2) the stage of meiotic nondisjunction resulting in the trisomy, (3) the presence or absence of disomic homozygosity or heterozygosity, and (4) the degree of recombination in the nondisjoined chromosomes. The parental origin of the nondisjoined chromosome was maternal in 86.2% of the families, with no significant differences between groups. The most centromeric marker was nonreduced, indicating a meiosis I nondisjunction in 76.5% of maternally derived trisomies, and reduced, indicating a meiosis II nondisjunction in 76.9% of paternally derived trisomies, with no significant differences between groups. There were no significant differences in the proportion of reduced markers at any locus between groups. The distribution of the number of crossovers was significantly different between groups (χ
2
=14.12,
P
<.001), with less recombination observed in group 1.

Conclusions
In Down syndrome patients, no association was found between the presence of an atrioventricular septal defect and the parent of origin, stage of meiotic nondisjunction, or disomic homozygosity or heterozygosity. A significant association was found between the presence of an atrioventricular septal defect and reduced frequency of recombination.
A Comparison of the Costs of and Quality of Life After Coronary Angioplasty or Coronary Surgery for Multivessel Coronary Artery Disease
Authors: Weintraub William S. , Mauldin Patrick D. , Becker Edmund , Kosinski Andrzej S. , King Spencer B.
Published: June 2012

Background
The Emory Angioplasty Versus Surgery Trial (EAST) is a randomized trial that compares, by intention to treat, the clinical outcome and costs of percutaneous transluminal coronary angioplasty (PTCA) and coronary surgery for multivessel coronary artery disease.

Methods and Results
The primary end point was a composite of death, Q-wave myocardial infarction, and a large reversible thallium defect at 3 years. Multiple measures of quality of life also were made. Charges were assessed from the hospital UB-82 bills; professional charges were assessed from the Emory Clinic. Hospital charges were reduced to cost through step-down accounting methods. All costs and charges were deflated to 1987 dollars. Costs were assessed for the initial hospitalization and the cumulative costs of the initial hospitalization and additional revascularization procedures for up to 3 years. There was no difference in mortality or the primary end point. Mean initial hospital charges were $12 654 for the PTCA group and $20 214 for the surgery group (
P
<.0001). Professional charges were $4538 for PTCA and $9426 for surgery (
P
<.0001). Three-year hospital charges were $19 047 for PTCA and $21 174 for coronary surgery (
P
<.0001). Three-year professional charges were $6412 for PTCA and $9861 for surgery (
P
<.0001). Three-year total charges were $25 458 for PTCA and $31 033 for surgery (
P
<.0001). Total 3-year costs were $23 734 for PTCA and $25 310 for coronary surgery (
P
<.0001). There were more hospitalizations for angina and more antianginal medications used in the PTCA group, which would further narrow the differences in cost.

Conclusions
There was no difference in the primary end point or its components at 3 years. Although the primary procedural costs of coronary surgery are more than for coronary angioplasty, this cost advantage is largely, although probably not completely, lost by 3 years because of more frequent additional procedures and other resource consumption after a first revascularization by PTCA.
Phenotypic Patterns of Mononuclear Cells in Dilated Cardiomyopathy
Authors: Holzinger Christoph , Schöllhammer Andrea , Imhof Martin , Reinwald Christian , Kramer Gero , Zuckermann Andreas , Wolner Ernst , Steiner Georg
Published: June 2012

Background
Immunological factors in the pathogenesis of idiopathic dilated cardiomyopathy (IDC) were suggested previously on the basis of the demonstration of mononuclear cell infiltrates and autoantibodies against the myocardium. The present study investigated whether tissue leukocyte subpopulations isolated from hearts with IDC (n=6) differ in phenotype from those of tissues without IDC (n=7).

Methods and Results
Leukocytes were quantified as reactive cells per square millimeter in perivascular, interstitial, and parenchymal tissue sections. Freshly isolated heart-tissue T cells and peripheral-blood T cells from the same patients were analyzed by triple staining and flow cytometry to identify T-cell subpopulations as well as their states of differentiation (expression of CD45RA and Leu-8 versus CD45RO) and activation (IL-2R, IL-7R, very late antigen–1, HLA-DR). All types of infiltrating cells (T cells, B cells, macrophages, granulocytes) are increased in hearts with IDC compared with normal hearts, but only CD8
+
T cells and macrophages are increased relative to the other leukocyte subpopulations. CD45RO
+
/CD45RA
−
/Leu-8
−
cells constitute the majority of heart-tissue T cells in both normal hearts and hearts with IDC. Strikingly, hearts with IDC are infiltrated by eightfold greater numbers of perivascularly located IL-2R
+
– (26% of all T cells) and CD45RO
+
–activated memory T cells; moreover, in contrast to normal heart, ≈40% of both CD4
+
and CD8
+
heart-tissue T cells express activation markers.

Conclusions
Both normal hearts and hearts with IDC are populated by leukocytes. The quantitative increase in IDC, associated with a dramatically altered activation status of heart-tissue T cells, suggests a direct role of infiltrating leukocytes in the pathogenesis of IDC.
A Prospective Randomized Evaluation of Implantable Cardioverter-Defibrillator Size on Unipolar Defibrillation System Efficacy
Authors: Jones Gregory K. , Poole Jeanne E. , Kudenchuk Peter J. , Dolack G. Lee , Johnson George , DeGroot Paul , Gleva Marye J. , Raitt Merritt , Bardy Gust H.
Published: June 2012

Background
The active can unipolar implantable cardioverter-defibrillator (ICD) has been shown to defibrillate efficiently, but its current 80-cc size limits use in the pectoral position in many patients. Decreasing can size will facilitate pectoral insertion and will soon be feasible as an inevitable consequence of technological advancements. However, decreasing the can size has the potential to compromise unipolar defibrillation efficacy. It is the purpose of this study, therefore, to prospectively and randomly compare unipolar defibrillation efficacy with 80-cc, 60-cc, and 40-cc can sizes in patients immediately before ICD surgery in anticipation of advances in technology that will make smaller ICDs possible.

Methods and Results
Twenty-four consecutive patients underwent prospective, randomized evaluation of the effect of ICD can size on defibrillation efficacy during standard ICD surgery. Each patient had the unipolar defibrillation threshold (DFT) measured with 80-cc, 60-cc, or 40-cc active can placed in the left subcutaneous infraclavicular region. The system included a 10.5F tripolar right ventricular electrode that served as the shock anode. The shock waveform used in each instance was a single capacitor biphasic 65% tilt pulse delivered from a 120-μF capacitor. Stored energy at the DFT for the 80-cc, 60-cc, and 40-cc cans were 8.1±4.7 J, 8.7±5.8 J, and 9.5±4.8 J, respectively. There was no statistical significant difference between the DFTs for the three unipolar can electrodes (
P
=.39). Leading edge voltage also did not differ significantly among the three unipolar cans (356±92 V, 365±110 V, and 387±94 V, respectively,
P
=.29). There was, however, a slight progressive increase in resistance with decreasing can size (57±7 Ω, 60±7 Ω, and 65±9 Ω, respectively,
P
<.001).

Conclusions
Decreasing can volume from 80 cc to 60 cc to 40 cc does not compromise unipolar defibrillation efficacy despite a slight rise in shock resistance. These findings indicate that technological advances that allow for smaller-volume ICDs will not compromise defibrillation efficacy for unipolar systems.
Hyperlipidemia and Coronary Disease
Authors: Lacoste Lucie , Lam Jules Y.T. , Hung Joseph , Letchacovski Glaci , Solymoss Charles B. , Waters David
Published: June 2012

Background
Hypercholesterolemia is a risk factor for coronary disease, and platelet reactivity is increased with hypercholesterolemia, suggesting a prethrombotic risk. The aim of this study was to measure mural platelet thrombus formation on an injured arterial wall in a model simulating vessel stenosis and plaque rupture in hypercholesterolemic coronary disease patients before and after cholesterol reduction.

Methods and Results
Thirty-two patients with stable coronary disease were studied. Platelet thrombus formation and serum lipids were measured in 16 hypercholesterolemic patients (cholesterol >5.2 mmol/L) before and after a mean of 2.5 months of pravastatin therapy (40 mg/d) and in 16 normocholesterolemic control patients. Thrombus formation was assessed by exposing porcine aortic media to the patient’s flowing venous blood for 3 minutes at a shear rate of 754 or 2546 s
−1
at 37°C in an ex vivo superfusion chamber. Quantitative morphometric platelet thrombus formation at baseline was higher in the hypercholesterolemic patients at both the high and low shear rates: 4.8±1.0 and 3.3±0.7 μm
2
/mm, respectively, compared with normocholesterolemic patients: 2.1±0.5 and 1.6±0.4 μm
2
/mm (both
P
<.05). In the hypercholesterolemic patients, pravastatin decreased total cholesterol from 6.5±0.2 to 4.5±0.2 mmol/L and LDL cholesterol from 4.5±0.2 to 2.8±0.1 mmol/L (both
P
<.05). Platelet thrombus formation at high and low shear rates decreased to 2.0±0.3 and 1.3±0.3 μm
2
/mm, respectively (both
P
<.05).

Conclusions
Thus, hypercholesterolemia is associated with an enhanced platelet thrombus formation on an injured artery, increasing the propensity for acute thrombosis. Platelet thrombus formation at both high and low shear rates decreased as total and LDL cholesterol levels were reduced with pravastatin. Cholesterol lowering may therefore reduce the risk of acute coronary events in part by reducing the thrombogenic risk.