bluuebunny/crossref_metadata_2025 huggingface dataset:
Abnormalities in Beat-to-Beat Dynamics of Heart Rate Before the Spontaneous Onset of Life-Threatening Ventricular Tachyarrhythmias in Patients With Prior Myocardial Infarction
Authors: Huikuri Heikki V. , Seppänen Tapio , Koistinen M. Juhani , Airaksinen K.E. Juhani , Ikäheimo M.J. , Castellanos Agustin , Myerburg Robert J.
Published: June 2012

Background
Beat-to-beat analysis of RR intervals can reveal patterns of heart-rate dynamics, which are not easily detected by summary measures of heart-rate variability. This study was designed to test the hypothesis that alterations in RR-interval dynamics occur before the spontaneous onset of ventricular tachyarrhythmias (VT).

Methods and Results
Ambulatory ECG recordings from 15 patients with prior myocardial infarction (MI) who had spontaneous episodes of sustained VT during the recording and VT inducible by programmed electrical stimulation (VT group) were analyzed by plotting each RR interval of a sinus beat as a function of the previous one (Poincaré plot). Poincaré plots were also generated for 30 post-MI patients who had no history of spontaneous VT events and no inducible VT (MI control subjects) and for 30 age-matched subjects without heart disease (normal control subjects). The MI control subjects and VT group were matched with respect to age and severity of underlying heart disease. All the healthy subjects and MI control subjects showed fan-shaped Poincaré plots characterized by an increased next-interval difference for long RR intervals relative to short ones. All the VT patients had abnormal plots: 9 with a complex pattern, 3 ball-shaped, and 3 torpedo-shaped. Quantitative analysis of the Poincaré plots showed the SD of the long-term RR-interval variability (SD2) to be smaller in all VT patients (52±14 ms; range, 31 to 75 ms) than in MI control subjects (110±24 ms; range, 78 to 179 ms,
P
<.001) or the normal control subjects (123±38 ms,
P
<.001), but the SD of the instantaneous beat-to-beat variability (SD1) did not differ between the groups. The complex plots were caused by periods of alternating sinus intervals, resulting in an increased SD1/SD2 ratio in the VT group. This ratio increased during the 1-hour period preceding the onset of 27 spontaneous VT episodes (0.43±0.20) compared with the 24-hour average ratio (0.33±0.19) (
P
<.01).

Conclusions
Reduced long-term RR-interval variability, associated with episodes of beat-to-beat sinus alternans, is a highly specific sign of a propensity for spontaneous onset of VT, suggesting that abnormal beat-to-beat heart-rate dynamics may reflect a transient electrical instability favoring the onset of VT in patients conditioned by structurally abnormal hearts.
Selective Attenuation by N-0861 (
N

6

-Endonorboran-2-yl-9-Methyladenine) of Cardiac A
1
Adenosine Receptor–Mediated Effects in Humans
Authors: Bertolet Barry D. , Belardinelli Luiz , Franco Elizabeth A. , Nichols Wilmer W. , Kerensky Richard A. , Hill James A.
Published: June 2012

Background
To determine the adenosine receptor subtype selectivity of the novel antagonist N-0861, the A
1
and A
2
receptor–mediated cardiac effects of adenosine were investigated in 13 patients during continuous intravenous infusion and boluses of adenosine before and after intravenous infusion of N-0861.

Methods and Results
Measurements of the atria-to-His (A-H) interval, chest pain severity, and coronary blood flow velocity were made before and after low-dose (69 μg · kg
−1
· min
−1
) intravenous infusion and bolus (2.5 mg) adenosine. Two doses of N-0861 were infused intravenously, and the adenosine protocol was repeated. N-0861 0.25 mg/kg abolished the negative dromotropic effect (A-H interval prolongation) and chest discomfort experienced during infusion of adenosine and attenuated discomfort observed during the boluses of adenosine; however, the increase in coronary blood flow velocity was not significantly affected.

Conclusions
These actions of N-0861 support the concept that the negative dromotropic effect and anginalike pain caused by adenosine are A
1
adenosine receptor–mediated, whereas the increase in coronary blood flow velocity is due to activation of A
2
adenosine receptors. N-0861 appears to be an effective and selective A
1
adenosine receptor antagonist in humans.
Aminoguanidine Prevents the Decreased Myocardial Compliance Produced by Streptozotocin-Induced Diabetes Mellitus in Rats
Authors: Norton Gavin R. , Candy Geoff , Woodiwiss Angela J.
Published: June 2012

Background
A decreased cardiac compliance is a major feature of the cardiomyopathy of diabetes mellitus. Either an increase in the resistance afterload to the LV or an increase in collagen cross-linking induced by the formation of advanced glycosylation end products (AGEs) of collagen may be responsible for the stiff myocardium. To evaluate these hypotheses, we examined the effect of captopril, an afterload-reducing agent, and aminoguanidine, a nucleophilic hydrazine that prevents the accumulation of collagen AGEs, on left ventricular end-diastolic (LVED) compliance after 4 months of streptozotocin (0.26 mmol/kg)–induced diabetes mellitus in rats.

Methods and Results
Diabetes mellitus produced a decrease in LV chamber compliance as a result of an increased myocardial stiffness (slope of the linearized LVED stress–LVED strain relation [unitless]: diabetes mellitus, 47±4; control, 27±3;
P
<.001) and an increase in blood pressure as a result of an elevated vascular resistance. LV end-systolic elastance was unaltered by diabetes mellitus. The stiff myocardium was not associated with changes in the myocardial collagen volume fraction or total hydroxyproline concentration but was associated with an increased myocardial collagen fluorescence (fluorescence units/μg hydroxyproline) (diabetes mellitus, 11±1.1; control, 6.6±0.7;
P
<.01). Captopril therapy (0.22 mmol ·kg
−1
·d
−1
), despite producing a decrease in blood pressure through alterations in vascular resistance, failed to decrease myocardial stiffness in rats with diabetes mellitus. Alternatively, administration of aminoguanidine (7.35 mmol·kg
−1
·d
−1
) prevented both the enhanced myocardial collagen fluorescence (7.1±1.2) and the increased slope of the linearized LVED stress–LVED strain relation (29±2) but did not change markers of blood glucose control.

Conclusions
These results demonstrate that diabetes mellitus can produce a stiff myocardium before the development of myocardial fibrosis. The stiff myocardium in the early stages of the development of the cardiomyopathy of diabetes mellitus is not a consequence of an increase in ventricular resistance afterload and in these circumstances is associated with the formation of collagen AGEs.
Noninvasive Quantification of Myocardial Blood Flow in Humans
Authors: Nitzsche Egbert U. , Choi Yong , Czernin Johannes , Hoh Carl K. , Huang Sung-Cheng , Schelbert Heinrich R.
Published: June 2012

Background
[
13
N]Ammonia has been validated in dog studies as a myocardial blood flow tracer. Estimates of myocardial blood flow by [
13
N]ammonia were highly linearly correlated to those by the microsphere and blood sample techniques. However, estimates of myocardial blood flow with [
13
N]ammonia in humans have not yet been compared with those by an independent technique. This study therefore tested the hypothesis that the [
13
N]ammonia positron emission tomographic technique in humans gives estimates of myocardial blood flow comparable to those obtained with the [
15
O]water technique.

Methods and Results
A total of 30 pairs of positron emission tomographic flow measurements were performed in 30 healthy volunteers; 15 volunteers were studied at rest and 15 during adenosine-induced hyperemia. Estimates of average and of regional myocardial blood flow by the [
13
N]ammonia and the [
15
O]water approaches correlated well (
y
=0.02+1.02
x
,
r
=.99,
P
<.001, SEE=0.023 for average and
y
=0.06+1.00
x
,
r
=.97,
P
<.001, SEE=0.025 for regional values) over a flow range of 0.45 to 4.74 mL·min
−1
·g
−1
. At rest, mean myocardial blood flow was 0.64±0.09 mL·min
−1
·g
−1
for [
13
N]ammonia and 0.66±0.12 mL·min
−1
·g
−1
for [
15
O]water (
P
=NS). For adenosine-induced hyperemia, mean myocardial blood flow was 2.63±0.75 mL·min
−1
·g
−1
for [
13
N]ammonia and 2.73±0.77 mL·min
−1
·g
−1
for [
15
O]water (
P
=NS). The coefficient of variation as an index of the observed heterogeneity of myocardial blood flow averaged, for [
13
N]ammonia, 9±4% at rest and 12±7% during stress and, for [
15
O]water, 14±11% at rest and 16±9% during stress. The coefficients of variation for [
15
O]water were significantly higher than those for [
13
N]ammonia (
P
=.004 at rest and
P
=.03 during stress).

Conclusions
The two approaches yield comparable estimates of myocardial blood flow in humans, which supports the validity of the [
13
N]ammonia method in human myocardium previously shown only in animals. However, the [
15
O]water approach reveals a greater heterogeneity (presumably method-related), which might limit the accuracy of sectorial myocardial blood flow estimates in humans.
Pericardial Blood Activates the Extrinsic Coagulation Pathway During Clinical Cardiopulmonary Bypass
Authors: Chung Judith H. , Gikakis Nicolas , Rao A. Koneti , Drake Thomas A. , Colman Robert W. , Edmunds L. Henry
Published: June 2012

Background
Coagulation during cardiopulmonary bypass (CPB) traditionally has been attributed to activation of the contact system of plasma proteins and the intrinsic coagulation pathway by blood contact with negatively charged surfaces not lined by endothelium. Recent studies have focused on the possible role of the extrinsic coagulation pathway during cardiac surgery. We postulated that the wound activates the extrinsic coagulation pathway during CPB by producing procoagulant cells and enzymes that enter the general circulation.

Methods and Results
Blood samples taken from 20 consenting patients who had elective cardiac surgery were assayed for peripheral blood mononuclear cell tissue factor (TF) expression, plasma F1.2, and factor VII and VIIa concentrations. Peripheral blood mononuclear cell TF expression increased in the perfusate after the surgical incision and after CPB was started and in monocytes that adhered to the perfusion circuit. TF on circulating monocytes, however, did not continue to rise during CPB. Peripheral blood mononuclear cell TF was elevated in cells isolated directly from blood in the pericardial cavity and was twice that detected in simultaneous samples from the perfusate (
P
<.05). F1.2 levels were highest in pericardial blood and increased progressively during CPB. Plasma factor VIIa concentrations, corrected for hemodilution, and ratios of factor VIIa to factor VII were highest in pericardial samples (
P
<.05) and increased progressively during and immediately after CPB. Pericardial biopsies obtained before and after CPB in 7 patients did not show TF expression by mesothelial cells.

Conclusions
These data provide direct evidence of TF expression, activation of the extrinsic coagulation pathway, and thrombin formation in the surgical wound. Addition of pericardial blood to the perfusate and expression of TF by both circulating and adherent monocytes strongly promote thrombus formation during open heart surgery.
Intramyocardial Injections and Protection Against Myocardial Ischemia
Authors: Whittaker Peter , Kloner Robert A. , Przyklenk Karin
Published: June 2012

Background
Although adenosine has been proposed to be a cardioprotective agent, direct examination of such protection is confounded by its short half-life and hemodynamic effects. We attempted to avoid these problems by injecting adenosine directly into cardiac muscle.

Methods and Results
We gave four adenosine injections (each 0.15 mL, 5 mg·mL
−1
saline) into the left ventricular wall of rat hearts before a 60-minute occlusion. Although infarcts were smaller in adenosine-treated hearts (29±6%) than in controls (52±5%;
P
<.05), injection of saline also reduced infarct size (29±7%). Infarcts in hearts subjected to needle insertion but no fluid injection differed neither from control nor from fluid-treated hearts (38±4%). Adenosine reduced ectopic beats and the incidence of ventricular tachycardia during occlusion. In contrast, saline injection prolonged the duration of arrhythmias. To examine the spatial relationship between protection and the injection site, we gave 18 saline injections (each 0.15 mL) into canine myocardium before a 60-minute occlusion. Infarcts were smaller in saline-treated hearts than in controls (
P
<.01). Because infarcts in four hearts occupied <3% of the risk region, we concluded that fluid injection did not itself cause appreciable necrosis and speculated that muscle was protected in the vicinity of the injection site. Previous work indicated that muscle can be protected by stretch. We examined this hypothesis by adding gadolinium chloride (a stretch-activated channel blocker) to the saline (0.008 g·mL
−1
) injection in rat hearts. We again found small infarcts after saline injection (26±5%); however, gadolinium blocked protection (50±7%;
P
<.03).

Conclusions
Although we were only partially successful in documenting adenosine-mediated cardioprotection, we found evidence for myocyte protection via a stretch-activated mechanism.
Angioscopic Predictors of Early Adverse Outcome After Coronary Angioplasty in Patients With Unstable Angina and Non–Q-Wave Myocardial Infarction
Authors: Waxman Sergio , Sassower Michael A. , Mittleman Murray A. , Zarich Stuart , Miyamoto Akira , Manzo Karen S. , Muller James E. , Abela George S. , Nesto Richard W.
Published: June 2012

Background
Clinical and angiographic criteria have a limited ability to predict adverse outcome in patients with unstable angina who are undergoing percutaneous transluminal coronary angioplasty (PTCA). We investigated whether the use of angioscopy can improve prediction of early adverse outcome after PTCA.

Methods and Results
Angioscopic characterization of the culprit lesion was performed before PTCA in 32 patients with unstable angina and 10 with non–Q-wave infarction. Seven patients (17%) had an adverse outcome (myocardial infarction, repeat PTCA, or need for coronary artery bypass graft surgery) within 24 hours after PTCA. Six of 18 patients with a yellow culprit lesion had an adverse outcome compared with 1 of 24 in whom the culprit lesion was white (
P
=.03). Six of 20 patients with plaque disruption suffered an adverse outcome compared with 1 of 22 with nondisrupted plaques (
P
=.04). Six of 17 patients with intraluminal thrombus had an adverse outcome, whereas only 1 of 25 patients without thrombus suffered an adverse outcome (
P
=.01). Yellow color, disruption, and thrombus at the culprit lesion site were associated with an eightfold increase in risk of adverse outcome after PTCA. The prediction of PTCA outcome based on characteristics of the plaque that were identifiable by angioscopy was superior to that estimated by the use of angiographic variables.

Conclusions
In patients with unstable angina and non–Q-wave infarction, angioscopic features of disruption, yellow color, or thrombus at the culprit lesion site can identify patients at high risk of early adverse outcome after PTCA. Angioscopy was superior to angiography for prediction of PTCA outcome.
Paired Comparison of Vascular Wall Reactions to Palmaz Stents, Strecker Tantalum Stents, and Wallstents in Canine Iliac and Femoral Arteries
Authors: Barth Klemens H. , Virmani Renu , Froelich Jens , Takeda Toshiaki , Lossef Steven V. , Newsome Joseph , Jones Russell , Lindisch David
Published: June 2012

Background
Palmaz stents, Strecker stents, and Wallstents, all used clinically, differ substantially in their physical characteristics, yet how differently the vascular wall reacts to them has not been demonstrated conclusively. We therefore undertook a side-by-side comparison.

Methods and Results
One stent was implanted into each canine external iliac and/or the flexing portion of the proximal femoral artery. In 9 dogs, Palmaz stents were placed vis-à-vis Strecker stents, with follow-up of 2 and 4 months. In 7 dogs, Palmaz stents were placed vis-à-vis Wallstents, with 4 months of follow-up. Angiographic midstent luminal diameters immediately after placement and at follow-up as well as midstent cross-sectional areas of neointima were compared for significant differences. In addition, neointimal maturation, medial atrophy, and stent-related trauma were assessed. Angiographically, all arteries remained open. The degree of luminal narrowing by recoil and neointima never reached 50% and was modest for Palmaz stents and Wallstents (
P
=.33) but significantly higher for Strecker stents (
P
<.0001 compared with Palmaz stents). This corresponded histologically to a significantly thicker neointima (
P
=.003) over Strecker than over Palmaz stents but not between Palmaz stents and Wallstents (
P
=.18). Neointimal buildup was generally more pronounced in the femoral artery segments than in the iliac segments. Maturation of the neointima over Palmaz stents was much further advanced than over Strecker stents and slightly more advanced than over Wallstents. Pressure-related atrophy of the tunica media was least for Strecker stents and more pronounced but similar for Wallstents and Palmaz stents. Wallstent wire ends caused some wall trauma; several femoral Palmaz stent struts protruded through the media.

Conclusions
The lower-hoop-strength, higher-profile tantalum Strecker stent is affected by vascular wall recoil and evokes a greater degree of neointima formation than the lower-profile, higher-hoop-strength Palmaz stent and Wallstent. Medial atrophy is pronounced outside the latter two stents. The rigid Palmaz stent can penetrate through the vascular wall in flexing arteries.
Identification of a Potential Role for the Adventitia in Vascular Lesion Formation After Balloon Overstretch Injury of Porcine Coronary Arteries
Authors: Scott Neal A. , Cipolla Gustavo D. , Ross Cheryl E. , Dunn Bradley , Martin Francis H. , Simonet Lizette , Wilcox Josiah N.
Published: June 2012

Background
In the present series of experiments, we examined the onset of cell proliferation and growth factor expression after balloon overstretch injury to porcine coronary arteries.

Methods and Results
Domestic juvenile swine underwent balloon overstretch injury to the left anterior descending and circumflex coronary arteries with standard percutaneous transluminal coronary angioplasty balloon catheters. To identify proliferating cells, 5-bromo-2-deoxyuridine (BrDU) was administered over a period of 24 hours before the animals were killed at either 1, 3, 7, or 14 days after injury. Immunohistochemistry was performed with monoclonal antibodies to BrDU and smooth muscle cell markers. Three days after injury, a large number of proliferating cells were located in the adventitia, with significantly fewer positive cells found in the media and lumen. Seven days after injury, proliferating cells were found primarily in the neointima, extending along the luminal surface. In situ hybridization for PDGF A-chain and β-receptor mRNAs revealed that the expression of these two genes was closely correlated with the sites of proliferation at each time point. Studies in which BrDU was injected between days 2 and 3 and the animals were killed on day 14 suggested that the proliferating adventitial cells may migrate into the neointima.

Conclusions
These data suggest that adventitial myofibroblasts contribute to the process of vascular lesion formation by proliferating, synthesizing growth factors, and possibly migrating into the neointima. Increased synthesis of α-smooth muscle actin observed in the adventitial cells after arterial injury may constrict the injured vessel and contribute to the process of arterial remodeling and late lumen loss after angioplasty.
Physical Training Improves Endothelial Function in Patients With Chronic Heart Failure
Authors: Hornig Burkhard , Maier Volker , Drexler Helmut
Published: June 2012

Background
Chronic heart failure is associated with endothelial dysfunction including impaired endothelium-mediated, flow-dependent dilation (FDD). Since endothelial function is thought to play an important role in coordinating tissue perfusion and modulating arterial compliance, interventions to improve endothelial dysfunction are imperative.

Methods and Results
To assess the potential of physical training to restore FDD, 12 patients with chronic heart failure were studied and compared with FDD of 7 age-matched normal subjects. With a recently developed high-resolution ultrasound system, diameters of radial artery were measured at rest, during reactive hyperemia (with increased flow causing endothelium-mediated dilation), and during sodium nitroprusside, causing endothelium-independent dilation. Determination of FDD was repeated after intra-arterial infusion of
N
G
-monomethyl-
l
-arginine (L-NMMA, 7 μmol/min) to inhibit endothelial synthesis and release of nitric oxide. The protocol was performed at baseline, after 4 weeks of daily handgrip training, and 6 weeks after cessation of the training program. FDD was impaired in heart failure patients compared with normal subjects. L-NMMA attenuated FDD, indicating that the endothelial release of nitric oxide is involved in FDD. Physical training restored FDD in patients with heart failure. In particular, the portion of FDD inhibited by L-NMMA (representing FDD mediated by nitric oxide) was significantly higher after physical training (8-minute occlusion: 8.0±1% versus 5.4±0.9%;
P
<.05; normal subjects: 9.2±1%).

Conclusions
These results indicate that physical training restores FDD in patients with chronic heart failure, possibly by enhanced endothelial release of nitric oxide.
Enhanced In Vivo Antithrombotic Effects of Endothelial Cells Expressing Recombinant Plasminogen Activators Transduced With Retroviral Vectors
Authors: Dichek David A. , Anderson Johanna , Kelly Andrew B. , Hanson Stephen R. , Harker Laurence A.
Published: June 2012

Background
The effects of regulating endothelial cell (EC) plasminogen activator production on thrombus accumulation in vivo are incompletely understood. By overexpressing plasminogen activators in ECs via gene transfer, the hypothesis was tested that increased levels of plasminogen activators inhibit the accumulation of thrombus in vivo.

Methods and Results
Cultured baboon ECs transduced with human cDNAs for wild-type tissue plasminogen activator (TPA) or for glycosylphosphatidylinositol-anchored urokinase-type plasminogen activator (a-UPA) were seeded onto collagen-coated segments of vascular graft (collagen segments) and exposed overnight to flow using an in vitro perfusion circuit. The antigenic levels of TPA and UPA each increased 10-fold in the media perfusing the corresponding transduced ECs compared with untransduced ECs (
P
≤.05 in both cases). In baboons the antithrombotic effects of TPA-transduced or a-UPA–transduced ECs were measured as
111
In-platelet deposition and
125
I-fibrin accumulation on collagen segments bearing sparsely attached ECs (transduced versus untransduced) interposed in exteriorized arteriovenous femoral shunts. Platelet-rich thrombus formed on the collagen segments with fibrin-rich thrombus propagated distally. The presence of TPA-transduced or a-UPA–transduced ECs on collagen segments at a density of 25 000 ECs/cm
2
decreased
111
In-platelet deposition and
125
I-fibrin accumulation on collagen surfaces compared with untransduced ECs present at equivalent density (
P
<.05 for platelet deposition with TPA-transduced ECs and
P
<.05 for platelet deposition on the propagated tail, as well as fibrin accumulation on the graft with a-UPA–transduced ECs). The systemic levels of fibrinopeptide A, thrombin-antithrombin complex,
d
-dimer, and both local and systemic levels of TPA and UPA were not increased by transduced ECs compared with untransduced ECs. The focal antithrombotic effects of transduced ECs appear to be due to local enhancement of thrombolysis.

Conclusions
ECs transduced with recombinant TPA and a-UPA enhance local antithrombotic activity in vivo. This strategy of attaching transduced ECs overexpressing plasminogen activators may be therapeutically useful by preventing thrombo-occlusive failure of implanted cardiovascular devices or mechanically denuded vessels.
Angiotensin II Receptor Antagonist TCV-116 Reduces Graft Coronary Artery Disease and Preserves Graft Status in a Murine Model
Authors: Furukawa Yutaka , Matsumori Akira , Hirozane Toshiro , Sasayama Shigetake
Published: June 2012

Background
Despite the current progress in immunosuppressive regimens, the incidence of graft coronary artery disease (CAD) after cardiac transplantation has not decreased. Recent study has revealed that angiotensin-converting enzyme (ACE) inhibition decreases CAD in rats; however, it is not clear whether this beneficial effect of ACE inhibition is due to a decrease in production of angiotensin II (Ang II) or inhibition of bradykinin degradation. To determine whether Ang II type 1 receptor (AT
1
-R) blockade has an inhibitory effect on CAD, we evaluated the effects of TCV-116, an AT
1
-R antagonist, in a murine model of cardiac transplantation.

Methods and Results
Hearts of DBA/2 mice (H-2
d
) were transplanted heterotopically to B10.D2 mice (H-2
d
). Recipients were treated orally with TCV-116 (10 mg/kg per day), captopril (100 mg/kg per day), or vehicle only. Graft status, as assessed by palpation and inspection at laparotomy 70 days after transplantation, was preserved better in the TCV-116–treated group (
P
<.005) and in the captopril-treated group (
P
<.05) than in the vehicle-treated group. Intimal area in the graft coronary arterial wall decreased to 31% in the TCV-116–treated group (
P
<.001 versus vehicle-treated group) and to 34% (
P
<.005) in the captopril-treated group but was 45% in the vehicle-treated group. Fibrotic lesions of the left ventricle were less prominent in the TCV-116–treated (31%;
P
<.01 versus vehicle-treated group) and captopril-treated groups (33%;
P
<.05) than in the vehicle-treated group (54%).

Conclusions
These findings show that AT
1
-R blockade is at least as effective as ACE inhibition in management of chronic allograft rejection and suggest that Ang II may play an important role in chronic allograft rejection.
Cellular Basis for the Electrocardiographic J Wave
Authors: Yan Gan-Xin , Antzelevitch Charles
Published: June 2012

Background
The J wave is a deflection that appears in the ECG as a late delta wave following the QRS or as a small secondary R wave (R′). Also referred to as an Osborn wave, the J wave has been observed in the ECG of animals and humans for more than four decades, yet the mechanism underlying its manifestation is poorly understood. The present study investigates the cellular basis for the J wave using an isolated arterially perfused preparation consisting of a wedge of canine right or left ventricle.

Methods and Results
A 12-lead ECG was initially recorded in vivo. After isolation and arterial perfusion of the right or left ventricular wedge, transmembrane action potentials were simultaneously recorded from epicardial, M region, and endocardial transmural sites with three floating microelectrodes. A transmural ECG was recorded concurrently. A J wave was observed at the R-ST junction of the ECG in 17 of 20 adult dogs, usually in leads II, III, aVR, and aVF and the mid to lateral precordial leads. The J wave in the transmural ECG recorded across the wedge was closely associated with the presence of a prominent action potential notch in epicardium but not endocardium. The shape and amplitude of the J wave were found to depend on (1) the transmural distribution of the action potential notch amplitude, (2) the relative time course of the early phases of the action potential (width of notch) at different sites within the wall, (3) sequence of activation, and (4) conduction time across the wall. A highly significant correlation was demonstrated between the amplitude of the epicardial action potential notch and the amplitude of the J wave recorded during interventions that alter the appearance of the electrocardiographic J wave, including hypothermia, premature stimulation, and block of the transient outward current by 4-aminopyridine. Ventricular activation from endocardium to epicardium, with epicardium activated last, was also an important prerequisite for the appearance of the J wave. This sequence permits the establishment of a voltage gradient of the early phases of the action potential after activation (ie, the QRS) is complete.

Conclusions
Our results provide the first direct evidence in support of the hypothesis that heterogeneous distribution of a transient outward current–mediated spike-and-dome morphology of the action potential across the ventricular wall underlies the manifestation of the electrocardiographic J wave. The presence of a prominent action potential notch in epicardium but not endocardium is shown to provide a voltage gradient that manifests as a J (Osborn) wave or elevated J-point in the ECG.
β Fibrinogen Gene Polymorphisms Are Associated With Plasma Fibrinogen and Coronary Artery Disease in Patients With Myocardial Infarction
Authors: Behague Isabelle , Poirier Odette , Nicaud Viviane , Evans Alun , Arveiler Dominique , Luc Gérald , Cambou Jean-Pierre , Scarabin Pierre-Yves , Bara Lucienne , Green Fiona , Cambien François
Published: June 2012

Background
Polymorphisms of the β fibrinogen gene have been shown to affect plasma fibrinogen levels and the risk of peripheral arterial disease. We now present the results of a detailed analysis of the β fibrinogen gene in relation to plasma fibrinogen and to the severity of coronary artery disease (CAD) in patients with myocardial infarction (MI) in the ECTIM Study.

Methods and Results
Ten polymorphisms of the β fibrinogen gene, including five new polymorphisms identified by single-strand conformation polymorphism analysis, and one polymorphism in the 3′ flanking region of the α fibrinogen gene were investigated in 565 patients with MI and 668 control subjects. The polymorphisms were in tight linkage disequilibrium and the genotype frequencies were similar in patients with MI and control subjects. In the multivariate analysis, only two polymorphisms, β
Hae
III (
P
<.0003) and β-854 (
P
<.01), were independently associated with plasma fibrinogen. The significant association between β fibrinogen polymorphisms and plasma fibrinogen was present in smokers but not in nonsmokers. In French MI patients, the number of coronary arteries with >50% stenosis was estimated by angiography and used as a criterion for severity of CAD. Presence of the less frequent allele of the β
Bcl
I (
P
<.0003) and of other polymorphisms was positively associated with the severity of CAD.

Conclusions
Genetic variants of the β fibrinogen gene are associated with an increased plasma level of fibrinogen, especially in smokers. The association with CAD appears to be the consequence of an increased risk of MI in subjects with severe CAD who carry the predisposing β fibrinogen genotypes.
Smoking, Serum Lipids, Blood Pressure, and Sex Differences in Myocardial Infarction
Authors: Njølstad Inger , Arnesen Egil , Lund-Larsen Per G.
Published: June 2012

Background
Few epidemiological studies have investigated the relative importance of major coronary risk factors in the two sexes within the same study population. In particular, it is not clear whether smoking carries a similar risk of coronary heart disease in men and women.

Methods and Results
The associations between smoking, serum lipids, blood pressure, and myocardial infarction were examined in a population-based prospective study of 11 843 men and women aged 35 to 52 years at entry. During 12 years, 495 cases of first myocardial infarction among men and 103 cases among women were identified. Myocardial infarction incidence was 4.6 times higher among men. The incidence was increased sixfold in women and threefold in men who smoked at least 20 cigarettes per day compared with never-smokers, and the rate in female heavy smokers exceeded that of never-smoking men. Multivariate analysis identified current smoking as a stronger risk factor in women (relative risk, 3.3; 95% confidence interval [CI], 2.1 to 5.1) than in men (relative risk, 1.9; 95% CI, 1.6 to 2.3). Among those under 45 years old at entry, the smoking-related sex difference was more pronounced (in women: relative risk, 7.1; 95% CI, 2.6 to 19.1) (in men: relative risk, 2.3; 95% CI, 1.6 to 3.2). Serum total cholesterol, HDL cholesterol, and systolic blood pressure were also highly significant predictors in both sexes.

Conclusions
Smoking was a stronger risk factor for myocardial infarction in middle-aged women than in men. Relative risks associated with serum lipids and blood pressure were similar despite large sex differences in myocardial infarction incidence rates.
Simultaneous Transmission/Emission Myocardial Perfusion Tomography
Authors: Ficaro Edward P. , Fessler Jeffrey A. , Shreve Paul D. , Kritzman James N. , Rose Patricia A. , Corbett James R.
Published: June 2012

Background
The purpose of the present study was to assess the diagnostic performance of attenuation-corrected (AC) stress
99m
Tc-sestamibi cardiac single-photon emission computed tomography (SPECT) for the identification of coronary heart disease (CHD).

Methods and Results
With a triple-detector SPECT system with a
241
Am transmission line source, simultaneous transmission/emission tomography (TCT/ECT) was performed on 60 patients with angiographic coronary disease and 59 patients with ≤5% likelihood of CHD. Iteratively reconstructed AC stress
99m
Tc-sestamibi perfusion images were compared with uncorrected (NC) filtered-backprojection images. Normal database polar maps were constructed from AC and NC images for quantitative analyses. From the low-likelihood patients, the visual and quantitative normalcy rates increased from 0.88 and 0.76 for NC to 0.98 and 0.95 for AC (
P
<.05). For the detection of CHD, the receiver operating characteristic curves for the AC images demonstrated improved discrimination capacity (
P
<.05), and sensitivity/specificity values increased from 0.78/0.46 (NC) to 0.84/0.82 (AC) with visual analysis and from 0.84/0.46 (NC) to 0.88/0.82 (AC) with quantitative analysis. For localization of stenosed vessels, visual and quantitative sensitivity values were 0.51 and 0.63 for NC and 0.64 and 0.78 for AC images (
P
<.05), respectively.

Conclusions
TCT/ECT myocardial perfusion imaging significantly improves the diagnostic accuracy of cardiac SPECT for the detection and localization of CHD. Clinical use of TCT/ECT imaging deserves serious consideration.
Anatomic Substrate for Idiopathic Left Ventricular Tachycardia
Authors: Thakur Ranjan K. , Klein George J. , Sivaram Chittur A. , Zardini Marco , Schleinkofer David E. , Nakagawa Hiroshi , Yee Raymond , Jackman Warren M.
Published: June 2012

Background
Idiopathic left ventricular tachycardia (ILVT) characterized by QRS complexes with right bundle-branch block (RBBB) morphology and left axis deviation is a distinct clinical syndrome that also demonstrates a characteristic response to verapamil and inducibility from the atrium in patients without structural heart disease. A false tendon has been described in the left ventricle in a patient with ILVT in whom surgical resection of the false tendon resulted in cure. We hypothesized that the false tendon is responsible for the genesis of similar ventricular tachycardia (VT) in others.

Methods and Results
We performed transthoracic (TTE) and/or transesophageal (TEE) two-dimensional echocardiograms in 15 patients undergoing catheter ablation for ILVT. There were 12 men and 3 women (mean age, 31±12 years, with average symptom duration of 11±9 years). The mean VT cycle length was 360±70 ms, and all had RBBB morphology with left axis deviation. Cardiac chamber sizes, left ventricular wall thickness, and wall motion were normal in all ILVT patients. TTE and/or TEE demonstrated a false tendon extending from the posteroinferior left ventricular free wall to the left ventricular septum in all ILVT patients. The false tendons were thick (≥2 mm maximal thickness) in 5 patients and thin (<2 mm maximal thickness) in 10 patients. We compared ILVT patients with a control group of 671 consecutive patients referred for echocardiography for other reasons. The mean age for the control group was 42 years. A false tendon was seen in the left ventricle in 34 of 671 (5%). In the control group patients with a false tendon, 2 patients had a history of VT (left bundle-branch block morphology) and 1 had ventricular fibrillation. The false tendons in the control patients were also oriented transversely across the ventricular cavity but were somewhat thinner (<2 mm maximal thickness in 32 of 34 patients). Catheter ablation with the use of radiofrequency and/or direct current applied to the posteroapical septum resulted in cure in 14 of 15 patients.

Conclusions
A false tendon extending from the posteroinferior left ventricle to the septum is a consistent finding in patients with ILVT and probably is responsible for this unique arrhythmia. The mechanism by which the false tendon precipitates tachycardia is speculative, but possibilities include conduction through the false tendon or by producing stretch in the Purkinje fiber network on the interventricular septum.
Quantitative Assessment of the Spatial Organization of Atrial Fibrillation in the Intact Human Heart
Authors: Botteron Gregory W. , Smith Joseph M.
Published: June 2012

Background
Atrial activation during atrial fibrillation (AF) is frequently described as random or chaotic. We propose that activation during AF is constrained by the principles of reentrant excitation; that these constraints impart a measurable spatial organization to activation during AF; and that the distance over which activation sequences remain well correlated can be readily measured and related both to the propensity of AF to sustain itself as well as to atrial tissue wavelength.

Methods and Results
We describe a novel signal-processing technique that quantifies the correlation in activation sequences recorded from five equally spaced sites in the right atrium in patients undergoing electrophysiology studies. In 20 patients in AF (12 with paroxysmal AF, 5 with chronic AF, and 3 with no clinical history of AF), the average correlation was 0.54±0.12 at 11 mm and 0.32±0.11 at 44 mm, compared with 0.95±.023 and 0.91±.023 in sinus rhythm. In AF, the correlation versus distance relation was monotonically decreasing, well fit by a decaying exponential function. The space constant of this exponential function, termed the activation space constant, provides a single objective metric of the spatial organization of activation during AF. The mean activation space constant for the group was 2.6±1.15 cm. Chronic AF had the lowest mean activation space constant (1.84±0.36 cm) and AF in patients with no prior history of AF had the highest (3.06±0.40 cm) (
P
<.05), with paroxysmal AF characterized by intermediate values (2.80±1.4 cm).

Conclusions
Using a novel method to measure the spatial organization of atrial activation during AF, we have demonstrated that AF in the intact human heart is organized over a length scale consistent with reentrant excitation. Preliminary results suggest a relationship between measured spatial organization and the clinical course of the arrhythmia. Further work is needed to determine whether measurement of spatial organization may be useful in prospective patient-specific selection of therapeutic options.
Angiotensin-Converting Enzyme Inhibition Preserves Endothelium-Dependent Coronary Microvascular Responses During Short-term Ischemia-Reperfusion
Authors: Piana Robert N. , Wang Steven Y. , Friedman Menachem , Sellke Frank W.
Published: June 2012

Background
Chronic angiotensin-converting enzyme (ACE) inhibition initiated days to weeks after acute myocardial infarction can reduce ventricular dilatation and improve patient survival. However, the effects on coronary vascular and myocardial function of very early ACE inhibitor therapy for acute myocardial infarction remain unresolved.

Methods and Results
Hemodynamics, segmental shortening, coronary blood flow, and in vitro coronary microvascular relaxation responses were studied in noninstrumented control pigs (n=8) and pigs subjected to 30 minutes of left anterior descending ischemia followed by administration of 30 mL IV normal saline (IR-saline, n=8), 5 mg/kg IV captopril (IR-captopril, n=6), or 1.5 mg/kg IV enalaprilat (IR-enalaprilat, n=6) before 1 hour of reperfusion. Hemodynamics were similar at baseline, end of ischemia, and end of reperfusion. However, coronary blood flow immediately on reperfusion was significantly enhanced in the IR-enalaprilat cohort (59±10 mL/min) compared with the IR-saline group (32±3 mL/min,
P
<.05). Segmental shortening in the dyskinetic ischemic region improved only minimally at the end of reperfusion to 1±2%, −7±3%, and −2±6% for the IR-saline, IR-captopril, and IR-enalaprilat groups, respectively (
P
<.05, IR-captopril versus IR-saline). Arteriolar microvascular endothelium-dependent responses to ADP (
P
<.01) and calcium ionophore A23187 (
P
<.01) were impaired after ischemia-reperfusion, whereas bradykinin responses were preserved (
P
=.95). Endothelium-dependent venular responses to ADP and serotonin were maintained despite ischemia-reperfusion. Endothelium-independent responses to sodium nitroprusside were unaltered in arterioles and venules. Either captopril or enalaprilat restored ADP and A23187 arteriolar responses to control levels and increased bradykinin responses above control levels.

Conclusions
Brief ischemia followed by reperfusion induces arteriolar microvascular endothelial dysfunction, while venular endothelial function is preserved in this porcine model. ACE inhibition enhances coronary blood flow at the time of reperfusion and can prevent impairment of endothelium-dependent arteriolar responses. However, ACE inhibition does not enhance ventricular segmental shortening acutely despite improved microvascular endothelial function and augmented postischemic coronary blood flow in this model of ischemia-reperfusion.
Estrogen Reduces Myointimal Proliferation After Balloon Injury of Rat Carotid Artery
Authors: Chen Shi-Juan , Li Huaibin , Durand Joan , Oparil Suzanne , Chen Yiu-Fai
Published: June 2012

Background
Vascular disease progresses more slowly in females with functional ovaries than in males. The mechanisms of this vasoprotective effect of female sex are incompletely understood. This study tested (1) whether there is a sex difference in the development of myointimal proliferation after balloon injury of the rat carotid artery in vivo, (2) whether this response is estrogen or androgen dependent, and (3) whether there is a sexual dimorphism in expression of the c-
myc
proto-oncogene in intact and/or damaged rat carotid arteries.

Methods and Results
Ten-week-old male and female Sprague-Dawley rats were either gonadectomized or studied intact. Gonadectomized rats of both sexes were implanted with estradiol, testosterone, or nothing (control) 3 days before vascular injury. Two weeks later, the rats were killed by overdose of pentobarbital, and the injured right and uninjured control left carotid arteries were fixed and subjected to morphometric analysis for evaluation of the degree of myointimal thickening. Separate groups of intact male and female rats were killed at 1 and 2 hours after vascular injury, and total RNA from injured and uninjured vessels was subjected to Northern blot analysis for assessment of steady state c-
myc
mRNA levels. Neointimal area and the ratio of neointimal to medial area were significantly less in intact female rats than in intact male rats (
P
<.05). Gonadectomy of female rats was associated with a greater increase in neointima formation after balloon injury than that observed in intact females (
P
<.05), but testosterone replacement did not further enhance this response. Estradiol treatment significantly inhibited myointimal proliferation after vascular injury in gonadectomized rats of both sexes (
P
<.05). Neither gonadectomy nor gonadectomy plus testosterone replacement altered the myointimal proliferative response to balloon injury in male rats. Steady state c-
myc
mRNA levels were detectable in undamaged carotid arteries in intact rats of both sexes and were significantly greater in males than in females; c-
myc
mRNA levels were increased in both sexes after carotid injury, but the response was significantly larger in magnitude and more rapid in males than in females.

Conclusions
These data indicate that the sex difference in myointimal proliferation after vascular injury is estrogen dependent. C-
myc
gene expression is greater in the undamaged carotid artery of the male than in that of the female, and the responsiveness of this gene to balloon injury of the artery is more rapid and more robust in the male than in the female rat. These findings have direct implications for the prevention and treatment of vascular disease in humans.
Value of Magnetic Resonance Imaging in Assessing Patency and Function of Coronary Artery Bypass Grafts
Authors: Galjee Michel A. , van Rossum Albert C. , Doesburg Teddo , van Eenige Machiel J. , Visser Cees A.
Published: June 2012

Background
Previous studies have demonstrated the high sensitivity and moderate specificity of standard magnetic resonance (MR) spin-echo (SE) and gradient-echo (GE) techniques in predicting the patency of coronary artery bypass grafts. These techniques, however, do not provide quantitative information. Therefore, the objectives of this study were first to investigate whether MR cine GE images, performed in addition to standard SE images, have additional value for the assessment of graft patency and second to assess the graft function by measuring the flow pattern and flow rate with MR phase velocity imaging.

Methods and Results
Forty-seven patients with previous histories of coronary artery bypass grafting underwent angiography and MR SE and cine GE phase velocity imaging. SE and GE images were evaluated by three independent observers blinded to the angiographic results. The spatial mean velocity and volume flow were measured and repeated for each image at consecutive 50-millisecond intervals throughout the cardiac cycle. The 47 patients had 98 proximal aortotomies, of which 60 were single and 38 sequential grafts. Seventy-three grafts were patent; 25 were occluded. Eighty-four grafts (86%) were eligible for comparison of the results of SE and GE images. Assessment of patency was inconclusive on SE images in 7 grafts (5 occluded by angiography) and on GE images in 7 grafts (2 occluded). A comparison of the results of contrast angiography and SE and GE MR imaging techniques showed that both techniques had a high sensitivity (both 98%) and somewhat lower specificity (85% and 88%, respectively) for graft patency. Combined analysis of the SE and GE images did not improve the accuracy. The strength of the interobserver agreement on GE images was good (κ=0.66), whereas on SE images the agreement was moderate (κ=0.51). Adequate MR phase velocity profiles were obtained in 62 (85%) of the 73 angiographically patent grafts. Graft flow was characterized by a balanced biphasic forward flow pattern. The volume flow of sequential grafts to 3 regions (136±106 mL/min) was significantly higher than in single grafts (63±41 mL/min,
P
<.01).

Conclusions
Considering the good interobserver agreement and the 85% success rate of quantitative flow measurements, cine GE phase velocity mapping is a promising clinical tool in the noninvasive assessment of graft patency and function.