bluuebunny/crossref_metadata_2025 huggingface dataset:
Fractional Flow Reserve
Authors: Pijls Nico H.J. , Van Gelder Berry , Van der Voort Pepijn , Peels Kathinka , Bracke Frank A.L.E. , Bonnier Hans J.R.M. , El Gamal Mamdouh I.H.
Published: June 2012

Background
Fractional flow reserve (FFR), defined as the ratio of maximum flow in the presence of a stenosis to normal maximum flow, is a lesion-specific index of stenosis severity that can be calculated by simultaneous measurement of mean arterial, distal coronary, and central venous pressure (P
a
, P
d
, and P
v
, respectively), during pharmacological vasodilation. The aims of this study were to define ranges of FFR values, whether associated with inducible ischemia or not, and to investigate FFR in normal coronary arteries.

Methods and Results
In 60 patients accepted for percutaneous transluminal coronary angioplasty (PTCA) of single-vessel disease, with a positive exercise test (ET) <24 hours before PTCA, FFR was determined during adenosine-induced hyperemia just before and 15 minutes after angioplasty. P
a
was measured by the guiding catheter, P
d
by an 0.018-in fiber-optic pressure-monitoring wire, and P
v
by a multipurpose catheter. The ET was repeated after 5 to 7 days, and only if this second ET had reverted to normal was the pre-PTCA value of FFR definitely considered to be associated with inducible ischemia and the post-PTCA value not.

Myocardial FFR (FFR
myo
) increased from 0.53±0.15 before PTCA to 0.88±0.07 after PTCA. Coronary FFR increased from 0.38±0.19 to 0.83±0.12. In all patients, values of FFR
myo
definitely associated with ischemia were ≤0.74, whereas all except two values not associated with inducible ischemia exceeded 0.74. Moreover, FFR
myo
in 18 coronary arteries in 5 normal patients equaled 0.98±0.03.

Conclusions
A value of FFR
myo
of 0.74 reliably discriminates coronary stenosis, whether associated with inducible ischemia or not. Therefore, FFR
myo
is a useful index to determine the functional significance of an epicardial coronary stenosis and may facilitate clinical decision making in patients with an equivocal coronary stenosis.
Induction of 15-Lipoxygenase mRNA and Protein in Early Atherosclerotic Lesions
Authors: Hiltunen Timo , Luoma Jukka , Nikkari Tapio , Ylä-Herttuala Seppo
Published: June 2012

Background
15-Lipoxygenase (15-LO) may be involved in atherogenesis and in oxidative modification of LDL. In this study, we investigated 15-LO expression in developing atherosclerotic lesions and verified the exact type of the atherosclerosis-associated LO at the nucleotide level.

Methods and Results
Quantitative reverse transcription–polymerase chain reaction, in situ hybridization, and immunocytochemistry were used in two models of experimental atherosclerosis. New Zealand White rabbits were given a 1% cholesterol diet for 0 (control group), 3, 6, or 14 weeks. 15-LO mRNA was undetectable in the aortic intima-medias of the control group, whereas it was clearly induced as early as after 3 weeks. 15-LO expression increased further in the 6- and 14-week groups. According to in situ hybridization and immunocytochemical studies, 15-LO was localized to macrophage-rich areas. In Watanabe heritable hyperlipidemic rabbits, 15-LO mRNA was undetectable in normal aortic intima-medias. 15-LO mRNA was markedly induced in fatty streaks but less so in more advanced lesions. Identification of the induced LO as reticulocyte-type 15-LO was done by cloning and sequencing. We also observed a distinct basal expression of copper-zinc and extracellular superoxide dismutases in normal aortic intima-medias, but no clear induction of these mRNAs was detected in atherosclerotic aortas.

Conclusions
The results show that, in contrast to copper-zinc and extracellular superoxide dismutases, the expression of reticulocyte-type 15-LO is markedly induced in rabbit fatty streaks. This may lead to an increase in the oxidative potential during the early phase of atherogenesis and contribute to the development of atherosclerotic lesions.
Effects of Pericardial Constraint on Left Ventricular Mechanoreceptor Activity in Cats
Authors: Wang Steven Y. , Sheldon Robert S. , Bergman Dale W. , Tyberg John V.
Published: June 2012

Background
The purpose of this study was to assess the effect of pericardial constraint on the activity of left ventricular (LV) mechanoreceptors with nonmyelinated vagal afferents.

Methods and Results
Single-unit activity of cervical vagal afferents (conduction velocity, 1.6±0.5 m/s) was recorded in six cats anesthetized with α-chloralose. Discharge frequency during diastole (DF
diastole
) and systole (DF
systole
) was determined after correction for conduction delay of the nerve action potential. When the pericardium was closed and LV end-diastolic pressure (LVEDP) was ≈5 mm Hg, DF
diastole
and DF
systole
were 1.3±1.0 and 0.3±0.1 impulses per second, respectively. Volume expansion increased LVEDP, LV transmural LVEDP, and segment length and was associated with a significant increase in DF
diastole
. At a given LVEDP, DF
diastole
was significantly greater in the absence of the pericardium than with the pericardium closed. Removal of the pericardium increased the slope of the relation between DF
diastole
and intracavitary LVEDP but did not alter the slope of the relations between DF
diastole
and transmural LVEDP and LV segment length.

Conclusions
These results suggest that, rather than the absolute value of intracavitary LVEDP, transmural LVEDP and distension appear to be more important determinants of diastolic LV mechanoreceptor activity and that pericardial constraint may attenuate mechanoreceptor activity by limiting cardiac distension.
Loading Sequence Plays an Important Role in Enhanced Load Sensitivity of Left Ventricular Relaxation in Conscious Dogs With Tachycardia-Induced Cardiomyopathy
Authors: Ishizaka Shinji , Asanoi Hidetsugu , Wada Osamu , Kameyama Tomoki , Inoue Hiroshi
Published: June 2012

Background
Left ventricular relaxation rate in the failing heart depends more on the systolic load than in the normal heart. To elucidate the mechanisms for the enhanced load sensitivity of left ventricular relaxation in heart failure, we examined the relative contributions of changes in end-systolic volume and loading sequence to the left ventricular relaxation rate.

Methods and Results
In seven conscious dogs, the time constant (T
d
) of left ventricular pressure decay, end-systolic volume, systolic circumferential force, and time to peak force during caval occlusion were compared before and after development of tachycardia-induced heart failure. Rapid ventricular pacing decreased the slope of the end-systolic pressure-volume relation from 4.5 to 2.8 mm Hg/mL (
P
<.01) and prolonged T
d
from 33 to 49 ms (
P
<.01). In normal conditions, caval occlusion reduced end-systolic force (−580 g,
P
<.01) and end-systolic volume (−7 mL,
P
<.01) but did not change T
d
or time to peak force. In heart failure, however, caval occlusion shortened T
d
(−11 ms,
P
<.01), with a concomitant decrease in the time to peak force (−30 ms,
P
<.01), while end-systolic volume and force declined slightly. Consequently, for a comparable reduction in end-systolic force, T
d
decreased more in heart failure than in normal hearts, suggesting enhanced load sensitivity. Moreover, changes in T
d
correlated well with those in the time to peak force (
r
=.79,
P
<.01) but not with those in end-systolic volume.

Conclusions
Loading sequence rather than elastic recoil seems to play the predominant role in the enhanced load sensitivity of left ventricular relaxation in heart failure.
Association of Left Ventricular Remodeling and Nonuniform Electrical Recovery Expressed by Nondipolar QRST Integral Map Patterns in Survivors of a First Anterior Myocardial Infarction
Authors: Dambrink Jan-Henk E. , SippensGroenewegen Arne , van Gilst Wiek H. , Peels Kathinka H. , Grimbergen Cornelis A. , Kingma J. Herre
Published: June 2012

Background
Progressive left ventricular dilatation after myocardial infarction is associated with a high mortality rate, the majority of which is arrhythmogenic in origin. The underlying mechanism of this relation remains unknown. It has been suggested, however, that left ventricular dilatation is accompanied by changes in repolarization characteristics that may facilitate the occurrence of life-threatening ventricular arrhythmias.

Methods and Results
We examined 62-lead body surface QRST integral maps during sinus rhythm in 78 patients at 349±141 days after thrombolysis for a first anterior myocardial infarction. Visual map analysis was directed at discriminating dipolar (uniform repolarization) from nondipolar (nonuniform repolarization) patterns. In addition, the nondipolar content of each map was assessed quantitatively with the use of eigenvector analysis. Nondipolar map patterns were present in almost one third of the patients (32%). Left ventricular end-systolic and end-diastolic volumes were assessed echocardiographically before discharge and after 3 and 12 months with the use of the modified biplane Simpson rule. The increase in left ventricular end-systolic volume 1 year after myocardial infarction was more pronounced in patients with nondipolar QRST integral map patterns (14.47±14.10 versus 4.22±8.44 mL/m
2
,
P
=.017). In patients with an increase in end-systolic volume of more than 16 mL/m
2
(upper quartile), the prevalence of nondipolar maps was 89% compared with 29% in patients with dilatation of less than 16 mL/m
2
. In addition, the nondipolar content of maps in patients in the upper quartile was significantly increased compared with the lower quartiles (49±14% versus 37±12%,
P
=.013). Logistic regression analysis revealed that an end-systolic volume of more than 42 mL/m
2
after 1 year contributed independently to the appearance of nondipolar maps. Patients with high-grade ventricular arrhythmias showed a higher nondipolar content (49±17% versus 39±10%,
P
=.013). QT
c
dispersion did not discriminate between patients with and those without high-grade ventricular arrhythmias. Also, the association between left ventricular remodeling and nondipolar map patterns was confirmed prospectively in an additional group of 15 patients.

Conclusions
Nondipolar map patterns are present in 32% of patients after thrombolysis for a first anterior myocardial infarction and are associated with increased left ventricular dilatation. These data support the hypothesis that left ventricular dilatation after myocardial infarction leads to changes in repolarization characteristics that may facilitate the occurrence of life-threatening ventricular arrhythmias.
A New Control Volume Method for Calculating Valvular Regurgitation
Authors: Walker Peter G. , Oyre Steen , Pedersen Erik M. , Houlind Kim , Guenet Frederique S. A. , Yoganathan Ajit P.
Published: June 2012

Background
The purpose of the present study was to develop a new method of measuring heart valvular regurgitation based on control volume theory and to verify its accuracy in vitro and in vivo. Current methods of quantifying valvular regurgitation rely too much on assumptions about the flow field and therefore are difficult to apply in vivo. In particular, the proximal isovelocity surface area (PISA) method oversimplifies the proximal velocity field by assuming hemispherical isovelocity contours proximal to the orifice. This severely limits the applicability of the PISA method. Use of the basic control volume theory, however, removes the need to assume the manner in which the proximal flow accelerates toward the regurgitant orifice, the shape and size of the orifice, the shape of the orifice plate, and the non-newtonian behavior of the fluid. Apart from a correction that is necessary if the orifice plate is moving, the control volume method assumes only the incompressibility of the fluid and therefore is a potentially more accurate approach. In addition, the use of magnetic resonance imaging (MRI) precludes the need for an acoustic window.

Methods and Results
MRI has been used to measure the three-dimensional velocity field proximal to regurgitant orifices, including single and multiple orifices and a cone-shaped orifice plate. Both steady (0 to 7.5 L/min) and pulsatile (2 and 3 L/min) flows were used. By integrating this velocity over a control volume surrounding the orifice, we calculated the flow rate through the orifice. As a validation, the cardiac output of a 50-kg pig also was measured and was compared with thermodilution measurements. It was found that MRI could be used to measure the three-dimensional flow proximal to regurgitant orifices. This enabled the calculation of the flow rate through the orifice by integrating the velocity over the surface of a control volume covering the orifice. This flow rate correlated well with the actual flow rate (0.992; correlation line slope, 1.01). Care had to be taken, however, to exclude from the integration regions of aliased velocity. The cardiac output of the pig measured using MRI was in close agreement with the thermodilution measurements.

Conclusions
Our new method of measuring valvular regurgitation has been shown to be very accurate in vitro and in vivo and therefore is a potentially accurate way to quantify valvular regurgitation.
Bioenergetic Consequences of Left Ventricular Remodeling
Authors: Zhang Jianyi , McDonald Kenneth M.
Published: June 2012

Background
Left ventricular (LV) remodeling is associated with LV dysfunction and decrease of coronary flow reserve. The underlying mechanisms responsible for these alterations are unclear. Changes in myocardial high-energy phosphate levels may be associated with these alterations.

Methods and Results
Twelve dogs with LV remodeling secondary to discrete necrosis produced by transmyocardial DC shock were compared with 8 normal dogs. LV mass and end-diastolic volume were measured by magnetic resonance imaging 7 days before and 12.9±1.3 months after DC shock. Transmurally localized
31
P nuclear magnetic resonance spectra from five layers across the LV wall were obtained simultaneously with transmural blood flow measurements (microspheres) under basal conditions and during pacing at 200 and 240 beats per minute. LV mass and end-diastolic volume were significantly increased after DC shock (33% and 26%, respectively, each
P
<.01). Under basal conditions, the subendocardial creatine phosphate (CP)/ATP ratio was significantly lower in remodeled LV compared with the control group (1.71±0.09 versus 2.04±0.09,
P
<.05). The subendocardial CP/ATP ratio was inversely correlated with both the increase in LV mass and LV end-diastolic volume (
r
=−.77 and
r
=−.70,
P
<.01 and
P
<.05, respectively). In remodeled myocardium, pacing induced a significant increase in LV end-diastolic pressure (from 8±1 to 20±3 mm Hg,
P
<.05), which was accompanied by a significant decrease of subendocardial/subepicardial (Endo/Epi) blood flow ratio (from 1.01±0.10 to 0.63±0.11,
P
<.05) and a significant decrease in subendocardial CP/ATP ratio (from 1.78±0.07 to 1.61±0.10,
P
<.05) and increase of ΔP
i
/ATP ratio (from 0 to 0.24±0.05,
P
<.01). The decrease in subendocardial CP/ATP ratio was correlated with the decrease in Endo/Epi blood flow ratio (
r
=.79,
P
<.05).

Conclusions
These results demonstrate that alterations in myocardial high-energy phosphate levels are correlated with the extent of LV remodeling. In remodeled hearts, pacing-induced tachycardia produces further changes of myocardial high-energy phosphate levels in the subendocardium that appear to be related to ventricular dysfunction and redistribution of blood flow away from the subendocardium.
Nonreentrant Mechanisms Underlying Spontaneous Ventricular Arrhythmias in a Model of Nonischemic Heart Failure in Rabbits
Authors: Pogwizd Steven M.
Published: June 2012

Background
The goal of this study was to define the mechanisms of spontaneously occurring ventricular arrhythmias in the setting of nonischemic heart failure.

Methods and Results
Three-dimensional cardiac mapping from 232 intramural sites was performed in four rabbits with heart failure induced by combined aortic regurgitation and aortic stenosis and in four control rabbits. During the development of heart failure, serial echocardiographic examination demonstrated a progressive increase in left ventricular (LV) chamber dimensions and a decrease in LV systolic function over 19±2 months. Serial Holter monitoring demonstrated spontaneously occurring premature ventricular complexes (PVCs) (up to 13 000 per day) and couplets in all four rabbits with heart failure, and runs of nonsustained ventricular tachycardia (VT) up to 26 beats long in three. Mapping of spontaneous rhythm was performed for up to 60 minutes. None of the control rabbits demonstrated spontaneous arrhythmias during mapping. Three rabbits with heart failure demonstrated isolated PVCs, and two demonstrated couplets and runs of nonsustained VT up to 4 beats long. The three-dimensional activation sequence of 50 sinus beats (42 from rabbits with heart failure; 8 from control rabbits), 19 PVCs, and 37 beats of couplets and nonsustained VT was determined and the mechanism of arrhythmia defined for all ventricular ectopic beats analyzed. Normal sinus beats from the failing rabbits activated rapidly, with a total activation time of 28±1 ms (
P
=.18 versus sinus beats from control hearts, 26±1 ms). Sinus beats preceding PVCs in the rabbits with heart failure activated in a similar fashion, with a total activation time of 26±1 ms. In each case, these PVCs initiated in the subendocardium by a nonreentrant mechanism based on the absence of intervening electrical activity between the termination of the preceding beat and the initiation of the next (225±7 ms), despite the presence of multiple intervening electrode recording sites. Couplets and monomorphic and polymorphic VTs were due to repetitive nonreentrant activation at the same or different subendocardial sites. Total activation time of beats of VT averaged 44±1 ms and did not differ from that of isolated PVCs (43±2 ms,
P
=.65). Pathological analysis of tissue demonstrated myocardial fiber hypertrophy, degenerative changes, and interstitial fibrosis throughout the failing hearts.

Conclusions
Spontaneously occurring PVCs, couplets, and VT in a model of nonischemic heart failure are due to nonreentrant mechanisms such as triggered activity or abnormal automaticity. Approaches to the treatment of spontaneously occurring ventricular arrhythmias in patients with nonischemic heart failure should be directed at nonreentrant mechanisms.
Maintenance of Coronary Patency After Fibrinolysis With Tissue Factor Pathway Inhibitor
Authors: Abendschein Dana R. , Meng Yuan Yuan , Torr-Brown Sheryl , Sobel Burton E.
Published: June 2012

Background
Pharmacological coronary fibrinolysis induces procoagulant effects that contribute to delayed recanalization and early reocclusion. This study was designed to determine whether brief inhibition of activation of the coagulation cascade with tissue factor pathway inhibitor, a physiological inhibitor of activated factor X and its activation by the tissue factor/factor VII complex, would facilitate fibrinolysis, sustain patency of recanalized arteries, or both.

Methods and Results
Platelet-rich coronary thrombi were induced with anodal current that elicited intimal injury in 21 conscious dogs. Each was randomized to human recombinant tissue-type plasminogen activator (rTPA 1.0 mg/kg IV over 1 hour) with infusion of 50 μg · kg
−1
· min
−1
of human recombinant tissue factor pathway inhibitor (rTFPI, n=7), 100 μg · kg
−1
· min
−1
of rTFPI (n=8), or 300 mmol/L arginine phosphate buffer as a control (n=6) concomitant with and for 1 hour after infusion of the plasminogen activator. Recanalization, verified with proximal Doppler flow probes, occurred in all but 1 dog given the high dose of rTFPI. It was not accelerated by conjunctive rTFPI. Reocclusion occurred within 90 minutes after infusion of rTPA in all 6 control dogs. However, reocclusion was delayed and patency was sustained for the entire 24-hour observation interval in 2 of 6 dogs (excluding 1 that did not survive) given the low dose and in 4 of 6 dogs (excluding 1 that did not receive the desired amount) given the high dose of rTFPI (
P
<.05 compared with controls). Cyclic flow variations indicative of platelet aggregation and disaggregation locally were virtually eliminated by rTFPI (3±4[SD]/h in dogs given the low dose and 2±2/h in those given the high dose of rTFPI compared with 13±12/h in controls,
P
<.05). In addition, rTFPI increased activated partial thromboplastin time and prothrombin time only at the high dose (1.4±0.3 and 2.1±0.9 times baseline) and had no effects on platelet aggregation assayed ex vivo and only minimal effects on bleeding time assayed in vivo.

Conclusions
Brief inhibition of the coagulation system by administration of rTFPI sustains patency of arteries recanalized by pharmacological fibrinolysis without markedly perturbing hemostatic mechanisms.
Kinetic Analysis of Technetium-99m-Labeled Nitroimidazole (BMS-181321) as a Tracer of Myocardial Hypoxia
Authors: Ng Chin K. , Sinusas Albert J. , Zaret Barry L. , Soufer Robert
Published: June 2012

Background
Experimental data have indicated that [
99m
Tc]- nitroimidazole (BMS-181321) is preferentially taken up in hypoxic tissue; its kinetics, however, has not been fully investigated. The purpose of this study was to address the relation between perfusate oxygen level and myocardial retention of [
99m
Tc]nitroimidazole.

Methods and Results
Bolus injection and constant infusion experiments were performed in Langendorff buffer–perfused rat hearts in normoxic and hypoxic conditions. Data were acquired with a pair of NaI detectors. The initial clearance rate of [
99m
Tc]nitroimidazole was approximately 20 seconds and independent of perfusate oxygen level. The slow clearance rate was greater than 3 hours in all perfusion conditions. The tissue retention of [
99m
Tc]nitroimidazole varied from 0.61±0.14% in normoxic conditions to 5.94±1.16% in the most severe hypoxic conditions. In addition, tissue retention was inversely proportional to perfusate oxygen level in a sigmoidal manner. The constant infusion experiments established that the binding rate at 25% oxygen level (1.94±0.38 mL of perfusate/min−g dry wt) was twofold of that at 40% and sevenfold at 100%. The binding rate of [
99m
Tc]nitroimidazole was independent of the perfusion sequence, suggesting irreversible binding.

Conclusions
These data indicate that [
99m
Tc]nitroimidazole may be a useful tracer for the identification of myocardial hypoxia. A sigmoidal relation was demonstrated for the uptake of the tracer, which suggests that a threshold level of hypoxia is necessary for the uptake of the tracer.
Fibrinolysis Inhibits Shear Stress–Induced Platelet Aggregation
Authors: Kamat Suraj G. , Michelson Alan D. , Benoit Stephen E. , Moake Joel L. , Rajasekhar Damodara , Hellums J. David , Kroll Michael H. , Schafer Andrew I.
Published: June 2012

Background
Shear stress–induced platelet aggregation may initiate arterial thrombosis at sites of pathological blood flow. Shear stress–induced platelet aggregation is mediated by von Willebrand factor (vWf) binding to platelet membrane glycoprotein (GP) Ib and GP IIb/IIIa. Tissue-type plasminogen activator (TPA) induces thrombolysis in coronary arteries through the local generation of plasmin. Plasmin also proteolyses GP Ib and plasma vWf.

Methods and Results
Because these effects could mitigate shear stress–induced platelet aggregation, we investigated the effect of fibrinolytic agents on platelet aggregation in response to a pathological shear stress of 120 dynes/cm
2
generated by a cone-and-platen rotational viscometer. Plasmin inhibited shear stress–induced aggregation of washed platelets, and this was associated with a decrease in GP Ib. TPA, at concentrations ≥2000 IU/mL, significantly inhibited shear stress–induced platelet aggregation of platelet-rich plasma without a decrease in platelet GP Ib. In plasma-platelet mixing experiments, we determined that the TPA effect was localized to plasma. Purified vWf multimer degradation by TPA (in the presence of exogenous plasminogen) was associated with the loss of the capacity of vWf to support shear stress–induced platelet aggregation.

Conclusions
These results demonstrate that TPA inhibits platelet aggregation in response to pathological shear stress by altering the multimeric composition of vWf. This effect of TPA on shear stress–induced platelet aggregation may contribute, along with fibrinolysis, to the therapeutic effect of TPA in restoring blood flow during acute coronary artery thrombosis.
Psychosocial Risk Factors and Nonfatal Myocardial Infarction
Authors: O’Connor Nancy J. , Manson JoAnn E. , O’Connor Gerald T. , Buring Julie E.
Published: June 2012

Background
Numerous psychosocial factors have been hypothesized to play a role in coronary heart disease. However, existing studies have yielded inconsistent results.

Methods and Results
The relations between type A personality as well as suppressed versus expressed anger and risk of nonfatal myocardial infarction (MI) were studied in 340 patients and 340 age-, sex-, and community-matched control subjects. Subjects were interviewed at home to assess behavioral and medical cardiovascular risk factors, and fasting blood samples were obtained. Type A personality was associated with nonfatal MI in crude matched-pair analysis (OR, 1.57; 95% CI, 1.12 to 2.20;
P
=.008). Adjusting for known cardiovascular risk factors (including treated hypertension, body mass index, treated diabetes, family history of premature MI, physical activity, smoking, alcohol, total calories per day, and saturated fat) did not substantially change the magnitude of the point estimate, although the finding was no longer statistically significant (OR, 1.43; 95% CI, 0.97 to 2.09;
P
=.069). Further adjustment for lipids, including total cholesterol, total HDL, its subfractions (HDL
2
, HDL
3
), LDL, VLDL, and triglycerides, markedly attenuated the association (OR, 1.12; 95% CI, 0.66 to 1.90;
P
=.687), an effect due almost entirely to HDL cholesterol. Suppressed anger was positively but not statistically significantly associated with increased risk of MI in crude matched-pair analysis (OR, 1.33; 95% CI, 0.98 to 1.81;
P
=.065), in analysis adjusted for behavioral and medical cardiovascular risk factors (OR, 1.26; 95% CI, 0.89 to 1.78;
P
=.193), or after adjustment for lipids (OR, 1.11; 95% CI, 0.67 to 1.82;
P
=.695).

Conclusions
These findings suggest a possible association of type A but not suppressed anger with risk of nonfatal MI that may be mediated by alterations in HDL cholesterol level. If decreases in HDL are not in the same causal pathway, then the apparent association between type A personality and risk of MI is due to confounding, principally by HDL.
Endocardial Carbon-Braid Electrodes
Authors: Alt Eckhard U. , Fotuhi Parwis C. , Callihan Richard L. , Mestre Edgar , Smith William M. , Ideker Raymond E.
Published: June 2012

Background
In the treatment of patients with life-threatening ventricular arrhythmia, transvenous implantable cardioverter/defibrillators provide significant advantages over devices requiring a thoracotomy. This study tested the hypothesis that a new carbon-fiber electrode, designed at the Technische Universität in Munich, Germany, has a lower defibrillation threshold (DFT) than standard transvenous defibrillation electrodes.

Methods and Results
In 8 mongrel dogs (weight, 25.2±0.8 kg; heart weight, 192±19 g), we examined the efficacy and electrical characteristics of a right ventricular endocardial carbon prototype defibrillation electrode (9.5F, 4.4-cm
2
surface) compared with a standard CPI 0062 Endotak electrode and a Medtronic 6966 Transvene endocardial right ventricular defibrillation electrode. The new electrode consists of 24 braided, tubular carbon filaments, each containing 1000 highly isotropic carbon fibers of 7-μm diameter, yielding a theoretical electrical surface of 480 cm
2
. The DFTs were determined in random order between each of the three right ventricular electrodes and a subcutaneous wire array anode placed on the left thorax. A standard step-down/-up DFT protocol of 20-V shock steps was applied. Two different biphasic waveforms with a 1-ms delay between phases were tested: 3.2-ms first phase/2.0-ms second phase, and 6.0-ms first phase/6.0-ms second phase. For the 3.2/2.0-ms waveform, we found a significantly lower DFT for the carbon lead (4.96±1.58 J) compared with the CPI 0062 (6.93±1.67 J) and the Medtronic 6966 (7.49±0.99 J) leads. For the 6.0/6.0-ms waveform, the DFT for the carbon electrode (5.97±2.09 J) was significantly lower than for the Medtronic 6966 lead (8.55±1.93 J) but not for the CPI 0062 lead (6.30±1.41 J). The impedance with carbon was lower than with the other two leads for the 6.0/6.0-ms waveform but not for the 3.2/2.0-ms waveform. For the carbon electrode, the 3.2/2.0-ms waveform had a lower DFT than the 6.0/6.0-ms waveform.

Conclusions
The present canine study found a lower DFT for a new carbon electrode compared with DFTs for endocardial defibrillation electrodes made of standard metal. Further long-term animal studies and clinical studies are needed to determine whether carbon materials and braided-lead technology are practical and beneficial in patients.
Inhibition of Platelet-Dependent Thrombosis by Local Delivery of Heparin With a Hydrogel-Coated Balloon
Authors: Nunes Gilberto L. , Thomas Clifford N. , Hanson Stephen R. , Barry James J. , King Spencer B. , Scott Neal A.
Published: June 2012

Background
Systemic administration of heparin can decrease mortality and morbidity of acute ischemic coronary syndromes such as unstable angina and myocardial infarction. Hemorrhage is the major limiting factor in the clinical use of systemic heparin. The objective of the present study was to determine whether local delivery of heparin could inhibit platelet-dependent thrombosis without altering systemic bleeding parameters.

Methods and Results
Hydrogel-coated angioplasty balloon catheters were dipped in a heparin solution, dried, and applied to a platelet-rich mural thrombus in a chronic ex vivo porcine arteriovenous shunt.
111
In-labeled platelet deposition was quantified by gamma camera imaging. In a separate series of experiments,
3
H-heparin was used to estimate the amount of heparin delivered to the thrombus with the coated balloon. Systemic heparin administration produced a dose-dependent decrease in platelet-dependent thrombus formation that was maximal at 200 units/kg. Bleeding times and activated partial thromboplastin times were prolonged at this dose. An equal inhibition of thrombus formation was achieved after the coated balloon was dipped in a heparin solution (10 000 units/mL) and deployed at the mural thrombus. In contrast to systemic heparin administration, there was no alteration in bleeding parameters associated with local heparin delivery. The estimated amount of heparin delivered with the coated balloon was 40 units.

Conclusions
Local delivery of heparin in amounts sufficient to inhibit platelet-dependent thrombosis can be accomplished with a hydrogel-coated coronary angioplasty balloon catheter. Local heparin delivery can inhibit thrombus formation in amounts that are several orders of magnitude lower than the required systemic dose. Local delivery of heparin was not associated with prolongation of bleeding parameters.
Functional Significance of Presynaptic α-Adrenergic Receptors in Failing and Nonfailing Human Left Ventricle
Authors: Parker John D. , Newton Gary E. , Landzberg Joel S. , Floras John S. , Colucci Wilson S.
Published: June 2012

Background
There are α-adrenergic receptors on human myocardium that exert positive inotropic effects. The effect of α-adrenergic receptor blockade on human left ventricular (LV) performance has not been fully explored. Although α-adrenergic receptor blockade might have effects on LV function that are mediated via blockade of postsynaptic myocardial α-adrenergic receptors, it is also possible that blockade of presynaptic α
2
-adrenergic receptors and subsequent increased release of norepinephrine would have effects on LV performance. In the present study, we explored the effects of nonselective α-adrenergic receptor blockade on LV performance and transcardiac norepinephrine concentrations in a group of patients with normal LV function and in a group of patients with congestive heart failure secondary to dilated cardiomyopathy.

Methods and Results
Using an intracoronary drug infusion technique, we administered the nonselective α-adrenergic antagonist phentolamine to 13 patients with normal LV function and 19 patients with congestive heart failure secondary to dilated cardiomyopathy. With a high-fidelity LV catheter, the systolic (+dP/dt) and diastolic (−dP/dt and Tau) LV function responses to intracoronary infusion of phentolamine (0.2 mg/min×5 minutes) were assessed. In 8 patients with normal ventricular function and 10 patients with congestive heart failure, arterial and coronary sinus blood samples were drawn to determine the effects of phentolamine on catecholamine concentrations. Phentolamine had no measurable effect on LV performance or catecholamine concentrations in the normal ventricular function group. In patients with congestive heart failure, intracoronary phentolamine caused a significant increase in +dP/dt and the rate of isovolumic LV relaxation (−dP/dt and Tau). These hemodynamic effects were accompanied by a significant increase in coronary sinus norepinephrine concentration but no change in arterial norepinephrine concentration.

Conclusions
Myocardial α-adrenergic receptor blockade causes significant inotropic and lusitropic effects in the failing but not the nonfailing human LV. These effects appear to be mediated by increased release of norepinephrine from cardiac nerves secondary to blockade of presynaptic α
2
-adrenergic receptors. Differences in the responses of the failing and nonfailing human LV appear to reflect the higher level of sympathetic activation that is seen in the group with congestive heart failure. This suggests that the presynaptic α
2
-adrenergic receptor exerts a tonic inhibitory effect on the release of norepinephrine from cardiac nerves in patients with congestive heart failure.
Spatial Features in Body-Surface Potential Maps Can Identify Patients With a History of Sustained Ventricular Tachycardia
Authors: Hubley-Kozey Cheryl L. , Mitchell L. Brent , Gardner Martin J. , Warren James W. , Penney Cindy J. , Smith Eldon R. , Horácek B. Milan
Published: June 2012

Background
Regional disparities of ventricular primary-repolarization properties contribute to an electrophysiological substrate for arrhythmias. Such disparities can be assessed from body-surface distributions of ECG QRST areas. Our objective was to isolate and test those features of QRST-area distributions that would be suitable for identifying patients at risk for life-threatening ventricular arrhythmias.

Methods and Results
We recorded ECGs simultaneously from 120 leads during sinus rhythm for 204 patients taking no antiarrhythmic drugs: half had had sustained ventricular tachycardia (VT); the other half, a myocardial infarction but no history of VT. For each patient, we calculated the QRST area in each lead and, using Karhunen-Loeve (K-L) expansion, reduced these data to 16 coefficients (each relating to one spatial feature, an eigenvector, derived from the total set of 204 QRST-area maps). Using stepwise discriminant analysis, we selected feature subsets that best discriminated between the two groups, and we estimated by a bootstrap procedure using 1000 trials how these subsets would perform on a prospective patient population. The mean diagnostic performance of the classifier for 1000 randomly selected training sets (n=102 in each, with both groups equally represented) increased monotonically with the number of features used for classification. The initial trend for the corresponding test sets (n=102 in each) was the same but reversed when the number of features exceeded eight. For an optimal set of eight spatial features, the sensitivity and specificity of the classifier for detecting patients with VT in 1000 test sets were (mean±SD) 90.3±4.3% and 78.0±6.1%, and its positive and negative predictive accuracies were 80.7±4.2% and 89.2±4.2%, respectively. Use of QRS duration as a supplementary feature to eight K-L coefficients can, in the test sets, increase specificity to 80.9±5.4% and positive predictive accuracy to 82.8±3.9% compared with the results for the optimal number of eight K-L features alone.

Conclusions
Multiple body-surface ECGs contain valuable spatial features that can identify the presence of an arrhythmogenic substrate in the myocardium of patients at risk for ventricular arrhythmias. Our results compare very favorably with those achieved by any other known test, invasive or noninvasive, for arrhythmogenicity.
Effects of Premature Beats on Repolarization of Postextrasystolic Beats
Authors: Burgess Mary Jo , Pollard Andrew E. , Spitzer Kenneth W. , Yang Lin
Published: June 2012

Background
A short-long-short sequence of cycle lengths predisposes to reentrant tachyarrhythmias. There is limited information about the effects of premature ventricular contractions (PVCs) on repolarization of postextrasystolic depolarizations (PEDs). Such information would contribute to understanding the mechanism for facilitating reentry with short-long-short cycle lengths.

Methods and Results
We introduced PVCs, over a range of coupling intervals and during a range of basic drive cycle lengths (BCLs), and determined PED repolarization. Our results from whole-animal experiments, isolated cell studies, and computer simulations are reported. In the whole-animal experiments, PED refractory periods (RPs) were longer than RP
BCL
. The greatest difference between RP
PED
and RP
BCL
(ΔRP
max
) occurred after short coupling interval PVCs and was 4.3±0.8, 4.2±0.8, and 2.1±0.5 ms (mean±SEM) during drives with short, intermediate, and long BCLs, respectively. The diastolic interval preceding the PED (DI
PED
) was inversely related to the coupling interval between the basic drive beat and the PVC and directly related to RP
PED
. PED action potential durations (APDs) of isolated canine myocytes were 9.8±4.9 ms (mean±SEM) longer than APD BCL (n=19). The DiFrancesco-Noble membrane equations were used in simulations of action potential propagation in a one-dimensional cable, with stimulation protocols duplicating those in the animal experiments. PVCs prolonged APD
PED
, and APD
PED
was prolonged more during short than during long BCL drives. There was a direct relation between DI
PED
and APD
PED
. Analysis of the membrane currents over the time course of the PVCs and PEDs suggested that the ionic basis for PED repolarization prolongation was the interaction of I
to
and I
K
. Hyperpolarizing constant-current injections introduced immediately after the spike of isolated myocyte action potentials caused APD prolongation. This observation is consistent with the I
to
and I
K
interaction causing PED repolarization prolongation.

Conclusions
PED repolarization prolongation could provide sites for unidirectional block to propagation of PVCs after PEDs and could facilitate initiation of reentrant tachyarrhythmias after short-long-short sequences of cycle lengths.
A Randomized Trial of Recombinant Staphylokinase Versus Alteplase for Coronary Artery Patency in Acute Myocardial Infarction
Authors: Vanderschueren Steven , Barrios Laurentino , Kerdsinchai Pitsanu , Van den Heuvel Paul , Hermans Luc , Vrolix Mathias , De Man Filip , Benit Edouard , Muyldermans Luc , Collen Désiré , Van de Werf Frans
Published: June 2012

Background
Recombinant staphylokinase (STAR) was shown recently to offer promise for coronary arterial thrombolysis in patients with evolving myocardial infarction. The present multicenter randomized open trial was designed to assess the thrombolytic efficacy, safety, and fibrin specificity of STAR relative to accelerated alteplase (recombinant tissue-type plasminogen activator [RTPA]).

Methods and Results
One hundred patients with evolving myocardial infarction of <6 hours’ duration and with ST-segment elevation were allocated to accelerated and weight-adjusted RTPA over 90 minutes (52 patients) or to STAR (the first 25 patients to 10 mg and the next 23 patients to 20 mg given intravenously over 30 minutes). All patients received aspirin and intravenous heparin. The main end points were coronary artery patency and plasma fibrinogen levels at 90 minutes. Thrombolysis in Myocardial Infarction (TIMI) perfusion grade 3 at 90 minutes was achieved in 62% of STAR patients versus 58% of RTPA patients (risk ratio, 1.1; 95% CI, 0.76 to 1.5). With 10 mg STAR, TIMI grade 3 patency was 50% (risk ratio, 0.86; 95% CI, 0.54 to 1.4 versus RTPA); with 20 mg STAR, it was 74% (risk ratio, 1.3; 95% CI, 0.90 to 1.8 versus RTPA). Residual fibrinogen levels at 90 minutes were 118±47% (mean±SD) of baseline with STAR and 68±42% with RTPA (
P
<.0005). STAR therapy was not associated with an excess mortality or electric, hemorrhagic, mechanical, or allergic complications. However, patients developed antibody-mediated STAR-neutralizing activity from the second week after STAR treatment. As an addendum to the randomized study, 5 patients were given 40 mg STAR over 30 minutes, resulting in TIMI perfusion grade 3 at 90 minutes in 4 patients without fibrinogen breakdown (residual levels at 90 minutes of 105±8% of baseline).

Conclusions
STAR appears to be at least as effective for early coronary recanalization as and significantly more fibrin-specific than accelerated RTPA in patients with evolving myocardial infarction.
Thrombolytic Therapy of Peripheral Arterial Occlusion With Recombinant Staphylokinase
Authors: Vanderschueren Steven , Stockx Luc , Wilms Guy , Lacroix Hendrik , Verhaeghe Raymond , Vermylen Jozef , Collen Désiré
Published: June 2012

Background
Recombinant staphylokinase (STAR) induces fibrin-specific coronary artery recanalization in patients with evolving myocardial infarction. The present pilot study evaluates its thrombolytic efficacy, safety, fibrin specificity, and immunogenicity in patients with peripheral arterial occlusive disease.

Methods and Results
Thirty patients (37 to 86 years of age) with angiographically documented thromboembolic peripheral arterial occlusion of recent origin (21±5.5 days, mean±SEM) were treated with heparin and intra-arterial STAR given as a 1-mg bolus followed by a 0.5-mg/h infusion in 20 patients or as a 2-mg bolus followed by a 1-mg/h infusion in 10 subsequent patients. With 7.0±0.7 mg STAR infused over 8.7±1.0 hours, recanalization was complete in 25 patients, partial in 2, and absent in 3. Two major hemorrhagic complications occurred: one fatal hemorrhagic stroke and one hypovolemic shock caused by bleeding at the angiographic puncture site. Administration of STAR did not induce fibrinogen breakdown or a significant prolongation of template bleeding time. STAR-neutralizing activity and anti-STAR IgG were low at baseline, increased markedly from the second week on, and remained elevated for several months.

Conclusions
Intra-arterial administration of STAR restores vessel patency in patients with peripheral arterial occlusion in the absence of fibrinogen degradation.
Vasodilatation to Arachidonic Acid in Humans
Authors: Bhagat Kiran , Collier Joe , Vallance Patrick
Published: June 2012

Background
Human endothelial and vascular smooth muscle cells synthesize prostanoids. Several of these have been implicated in the physiological and pathophysiological regulation of vascular tone; however, there is no direct evidence that human blood vessels synthesize sufficient prostanoid to alter vessel tone.

Methods and Results
We explored the effects of local infusions of arachidonic acid on the tone of preconstricted superficial hand veins in healthy volunteers. Aspirin was used to assess the contribution of prostanoids to the responses seen. Local infusion of arachidonic acid produced a dose-dependent dilatation of preconstricted veins. This was abolished by local infusion of aspirin. Oral aspirin was also effective: a high (anti-inflammatory) dose of aspirin (1 g) taken 2 hours before the experiment blocked the arachidonic acid–induced venodilatation; however, a low (cardioprotective) dose of aspirin (75 mg) did not. Unlike the responses to arachidonic acid, responses to glyceryltrinitrate and bradykinin were unaltered by aspirin (1 g). Ex vivo platelet aggregation was inhibited by aspirin in both high and low doses. Aspirin (1 g) inhibited arachidonic acid–induced venodilatation for up to 5 days. The time course was similar for vascular and platelet effects.

Conclusions
The present findings demonstrate that local generation of prostanoids in a human vessel in vivo alters vascular tone. The predominant prostanoid synthesized is a dilator and its synthesis can be blocked by an anti-inflammatory but not a cardioprotective dose of aspirin. The results suggest that selective inhibition of platelet aggregation by oral aspirin might be a function of dose rather than the interval between doses.
Late Outcome After Coronary Artery Bypass Graft Surgery in Patients <40 Years Old
Authors: French John K. , Scott Douglas S. , Whitlock Ralph M.L. , Nisbet Heather D. , Vedder Margaret , Kerr Alan R. , Smith Warren M.
Published: June 2012

Background
Randomized trials confirm the long-term efficacy of coronary artery bypass graft surgery (CABG), although there are no randomized data in patients <40 years old. Because these patients have been reported to have an early recurrence of symptoms, the long-term postoperative outcome was examined.

Methods and Results
The long-term outcome of patients (n=221) <40 years old undergoing CABG at Green Lane Hospital, New Zealand, from 1970 to 1992 was determined. The 30-day mortality rate was 1.8% for initial and 9.5% for redo CABG. The median times to angina or myocardial infarction (recurrent ischemic event), further intervention, and death were 6.0, 9.6, and 14.2 years, respectively. Factors associated with increased late mortality on univariate analysis included end-systolic volume (ESV) ≥80 mL (
P
=.004; 10-year mortality 19% versus 39% ESV ≥80 mL), no internal mammary conduit (
P
=.01), no lipid-modifying therapy (
P
=.005), and no postoperative aspirin use (
P
=.0002); the latter was also associated with increased recurrent ischemic events (
P
=.04) or increased reintervention (
P
=.02). On stepwise logistic regression analysis, factors associated with increased late mortality were increasing ESV (
P
=.004), no internal mammary artery conduit (
P
=.009), diabetes (
P
=.04), and no postoperative aspirin (
P
=.02); the latter was also associated with increased recurrent ischemic events (
P
=.02). Hypercholesterolemia (≥6.5 mmol/L) was present in 65% of patients at presentation and 45% at follow-up.

Conclusions
To attempt to prevent recurrent ischemia or late death, patients <40 years old who require CABG should receive internal mammary conduits, aspirin, lipid-modifying therapy, therapy to inhibit ventricular dilatation, and strict diabetes management.