bluuebunny/crossref_metadata_2025 huggingface dataset:
Simultaneous Multisite Mapping Studies During Induced Atrial Fibrillation in the Sterile Pericarditis Model
Authors: Kumagai Koichiro , Khrestian Celeen , Waldo Albert L.
Published: June 2012

Background
Chronic atrial fibrillation (AF) is thought to be due to multiple, simultaneously circulating wavelets. In the canine sterile pericarditis model, the mechanisms of maintenance of AF are not yet understood.

Methods and Results
During six induced AF episodes in six dogs with sterile pericarditis, 372 unipolar electrograms were recorded simultaneously from an electrode array placed around both atrial free walls, along with 10 to 24 electrodes from the atrial septum, by use of a multiplexing system. Activation maps during 12 consecutive 100-ms windows were analyzed from an episode of sustained AF in each dog (mean duration, 32±24 minutes). In two dogs, two such activation maps during the same episode of AF were analyzed. During AF, multiple unstable reentrant circuits (mean number, 1.4±0.1 per 100-ms analysis window) with very short cycle lengths (mean, 111±8 ms) present primarily in the atrial septum and right atrium were responsible for maintenance of AF. The unstable reentrant circuits frequently disappeared and re-formed. Wave fronts traveling from one atrium to the other and/or from the atrial septum play an important role in re-formation of unstable reentrant wave fronts.

Conclusions
In this model of paroxysmal AF, unstable reentrant circuits of very short cycle length principally involving the atrial septum appear to be critical for maintenance of AF. Some reentrant circuits disappear as others re-form, so that at least one reentrant circuit is always present. Because the atria cannot follow their very short cycle lengths in a 1:1 manner, AF is maintained.
Baseline Sodium-Lithium Countertransport and 6-Year Incidence of Hypertension
Authors: Laurenzi Martino , Cirillo Massimo , Panarelli Walter , Trevisan Maurizio , Stamler Rose , Dyer Alan R. , Stamler Jeremiah
Published: June 2012

Background
Sodium-lithium countertransport (Na-Li CT) activity is high in persons with hypertension. This study investigated whether high Na-Li CT relates to development of hypertension.

Methods and Results
At the baseline visit of the Gubbio Population Study, 4210 people of the 5376 surveyed were 18 to 74 years old; of these, 1599 were hypertensive (systolic pressure ≥140 mm Hg, or diastolic pressure ≥90 mm Hg, or on antihypertensive drug therapy). Of the 2611 nonhypertensives, 302 did not have Na-Li CT measured and 580 did not participate in 6-year follow-up. This analysis, therefore, deals with data collected on 1729 men 18 to 74 years old and women 18 to 74 years old who at baseline were nonhypertensive and had Na-Li CT measurement. Compared with individuals who were nonhypertensive at baseline and follow-up, individuals with incident hypertension at follow-up (systolic pressure ≥140 mm Hg, or diastolic pressure ≥90 mm Hg, or on antihypertensive drug therapy) had higher baseline values of Na-Li CT, blood pressure, age, body mass index, plasma cholesterol, and alcohol intake (
P
<.05). Baseline Na-Li CT was positively associated (
P
<.05) with development of hypertension in quartile analysis, with highest incidence of hypertension among men and women with Na-Li CT in the highest quartile (for men, ≥376 and for women, ≥311 μmol Li·L red blood cells
−1
·h
−1
). In univariate logistic regression, incidence of hypertension was related to baseline value of Na-Li CT, blood pressure, age, body mass index, plasma cholesterol, and alcohol intake (
P
<.05). In multiple logistic regression analysis, individuals with baseline Na-Li CT higher by 127 μmol (pooled SD for men and women) had 1.23 times greater risk of incident hypertension with control for sex and baseline age, body mass index, systolic pressure, and other confounders (
P
<.001).

Conclusions
Na-Li CT is a predictor of hypertension risk in adults.
l
-Arginine Reduces Human Monocyte Adhesion to Vascular Endothelium and Endothelial Expression of Cell Adhesion Molecules
Authors: Adams Mark R. , Jessup Wendy , Hailstones Deborah , Celermajer David S.
Published: June 2012

Background
Monocyte adhesion to endothelial cells is a key early event in atherogenesis. Because
l
-arginine has been shown to reduce atheroma and to decrease monocyte–endothelial cell adhesion in an animal model of atherosclerosis, we studied the effects of
l
-arginine on human monocyte adhesion to human endothelial cells and endothelial expression of cell adhesion molecules.

Methods and Results
Human umbilical vein endothelial cells (HUVECs) were grown to confluence, then incubated for 24 hours with arginine-deficient media to which was added saline (control), 100 or 1000 μmol/L
l
-arginine, 100 μmol/L
d
-arginine, 100 μmol/L
N
G
-monomethyl-
l
-arginine (L-NMMA), or 100 μmol/L
l
-arginine with 100 μmol/L L-NMMA. Human monocytes obtained by elutriation were incubated for 1 hour with HUVECs, and adhesion was measured by light microscopy. Compared with control, monocyte adhesion was reduced by
l
-arginine (59±10%,
P
=.01) and increased by L-NMMA (123±20%,
P
=.01). Surface expression of cell adhesion molecules by HUVECs was assessed by an ELISA under the above conditions with and without stimulation with interleukin-1β. Expression of ICAM-1 was reduced with both concentrations of
l
-arginine compared with control in both the basal (43±12%,
P
<.01), and stimulated (46±15%,
P
<.01) states, which correlated with decreased levels of mRNA. Expression of VCAM-1 was reduced only in the stimulated state and only in the presence of 1000 μmol/L
l
-arginine (72±24%,
P
=.02).

Conclusions
l
-Arginine reduces human monocyte adhesion to endothelial cells and decreases expression of certain endothelial cell adhesion molecules.
Attenuation by Gemfibrozil of Expression of Plasminogen Activator Inhibitor Type 1 Induced by Insulin and its Precursors
Authors: Nordt Thomas K. , Kornas Katharina , Peter Karlheinz , Fujii Satoshi , Sobel Burton E. , Ku¨bler Wolfgang , Bode Christoph
Published: June 2012

Background
Insulin and its precursors found in increased plasma concentrations in non–insulin-dependent diabetes mellitus (NIDDM) augment synthesis of plasminogen activator inhibitor type 1 (PAI-1) in Hep G2 cells in vitro and in rabbit liver in vivo. Reduced endogenous fibrinolysis secondary to increased PAI-1 activity may exacerbate atherogenesis. Recently, the reduction of the coronary heart disease incidence in the Helsinki Heart Study has implicated favorable modulation of endogenous fibrinolysis by gemfibrozil.

Methods and Results
In Hep G2 cells, 500 (700) μmol/L gemfibrozil decreased basal secretion of PAI-1 by 26% (43%) (
P
=.012 and
P
=.021, respectively) and attenuated insulin-induced (10 nmol/L) augmentation of PAI-1 in conditioned media by 61% (109%) (
P
=.010) within 24 hours. Inhibition was dependent on the duration of exposure (0 to 48 hours) and on the concentration of gemfibrozil (0 to 700 μmol/L) but not on the concentration of insulin (0.1 to 100 nmol/L). Gemfibrozil attenuated the augmentation of PAI-1 secretion induced by proinsulin (>100%), by des(31,32)proinsulin (75%), and by des(64,65)proinsulin (77%) as well (10 nmol/L each). The specificity of these effects was confirmed by the unaltered levels of newly synthesized protein (metabolic labeling) and of total protein (both in conditioned media and cell lysates). Secretion of fibrinogen by Hep G2 cells was not affected by gemfibrozil. Changes in PAI-1 protein levels reflected modulation of PAI-1 gene expression as manifested by changes in levels of 3.2-kb PAI-1 mRNA (Northern blots).

Conclusions
Gemfibrozil attenuated the augmentation of synthesis and secretion of PAI-1 induced by insulin and its precursors directly and specifically. Accordingly, gemfibrozil may exert favorable therapeutic effects normalizing impaired fibrinolysis in patients with hyperinsulinemia such as NIDDM.
A Tissue Plasminogen Activator/P-Selectin Fusion Protein Is an Effective Thrombolytic Agent
Authors: Fujise Kenichi , Revelle Bryan Mitch , Stacy Lowell , Madison Edwin L. , Yeh Edward T.H. , Willerson James T. , Beck Pamela J.
Published: June 2012

Background
P-selectin is expressed on the surface of activated endothelial cells and platelets. We hypothesized that a tissue plasminogen activator (TPA)/P-selectin fusion protein would have not only thrombolytic activity but also might target TPA to the thrombi. In addition, it seemed possible that this chimeric protein would competitively inhibit the binding of native P-selectin on endothelial cells and platelets to leukocytes and thus further promote thrombolysis.

Methods and Results
The full-length, plasminogen activator inhibitor-1–resistant form of TPA (TPA
IR
) together with two TPA
IR
/P-selectin fusion constructs (P280
IR
and P121
IR
) were expressed with the use of baculovirus vectors. After infection of Sf-21 cells with the recombinant baculovirus, recombinant TPA
IR
and P-selectin/TPA
IR
fusion proteins were purified with the use of metal ion chromatography. The intact protease activity of TPA
IR
and the ligand binding capability of P-selectin were confirmed through indirect chromogenic and cell binding assays, respectively. These molecules were assessed both in vitro and in vivo for thrombolytic activity. In vitro clot lysis assays indicated equal efficacy of TPA
IR
, P280
IR
, and P121
IR
(
P
>.5). The in vivo efficacy was tested in a cyclic flow variation model with the use of the rat mesenteric artery. Compared with saline control treatment, reduction in cyclic flow variations was significant (
P
<.05) and similar (
P
>.5) among TPA
IR
, P280
IR
, and P121
IR
. No significant bleeding was noted among treated animals.

Conclusions
Chimeric proteins P280
IR
and P121
IR
have clot lysis activities that are similar to TPA
IR
both in vitro and in vivo. These chimeric proteins also bind to P-selectin ligand in vitro. Thus, these proteins may provide an efficient method of targeting TPA to the thrombotic region. Further experimental analysis with the use of larger animal coronary occlusion models should help determine the future value of these proteins as clinical therapeutic agents.
In Vitro Identification of Angioplasty-Induced Injury by Use of Vascular Acoustic Emissions
Authors: Vonesh Michael J. , Mockros Lyle F. , Davidson Charles J. , Chandran Krishnan B. , McPherson David D.
Published: June 2012

Background
We have developed a novel method of diagnosing stress-induced vascular injury. This approach uses the sound energy released from atherosclerotic arterial tissue during in vitro balloon angioplasty to characterize type and severity of induced trauma.

Methods and Results
Thirty-two postmortem human peripheral arterial specimens 1.0 cm long were subjected to in vitro balloon angioplasty with simultaneous acoustic emission monitoring. Specimens were examined before and after angioplasty to ascertain the extent of angioplasty-induced injury. Gross observation was used to identify dissection. A three-dimensional intravascular ultrasound reconstruction technique was used to estimate the luminal surface area of the specimen. Change in luminal surface area (postangioplasty minus preangioplasty) was used to quantify induced injury. The energy content and spectral distribution of the digitally acquired vascular acoustic emission (VAE) signals were computed. Comparisons of angioplasty-induced trauma with VAE signal characteristics were made. Dissection (mural laceration of variable depth) was observed in 15 of 32 specimens. Eleven showed no evidence of induced dissection, and 6 had preexisting intimal disruptions. The energy content of the VAE signals collected from specimens with dissection was greater than that obtained from those in which dissection was absent: 845±89.4 mJ (mean±SEM; n=15) versus 128±40.8 mJ (n=11;
P
<.001). Comparison of induced trauma and VAE signal energy demonstrated a proportional relationship (
r
=.87,
P
<.001, n=32).

Conclusions
VAE signals contain information characterizing type and severity of angioplasty-induced arterial injury. Because vascular injury is related to adverse procedural outcome, development of VAE technology as an adjunct to conventional diagnostic modalities may facilitate optimal balloon angioplasty delivery and postprocedural care.
Post–Cardiopulmonary Bypass Pulmonary Hypertension in Lambs With Increased Pulmonary Blood Flow
Authors: Reddy V. Mohan , Hendricks-Munoz Karen D. , Rajasinghe Hiranya A. , Petrossian Edwin , Hanley Frank L. , Fineman Jeffrey R.
Published: June 2012

Background
After cardiopulmonary bypass (CPB), pulmonary hypertension and its associated increased vascular reactivity are a major source of morbidity, particularly for children with increased pulmonary blood flow. Although post-CPB pulmonary hypertension is well described, its mechanisms remain incompletely understood. Plasma levels of endothelin 1, a potent vasoactive substance implicated in pulmonary hypertension, are increased after CPB. The purpose of the present study was threefold: to characterize the changes in pulmonary vascular resistance and vascular reactivity induced by hypothermic CPB; to investigate the effects of preexisting increased pulmonary blood flow on these changes; and to better define the role of endothelin 1 in the pathogenesis of post-CPB pulmonary hypertension.

Methods and Results
Vascular pressures and blood flows were monitored in 14 1-month-old lambs with increased pulmonary blood flow (after in utero placement of an aortopulmonary shunt) and 6 age-matched control lambs. During the 2-hour study period after 105.3±20.6 minutes of hypothermic CPB, the increase in pulmonary vascular resistance was significantly augmented in lambs with increased pulmonary blood flow compared with control lambs (
P
<.05). Pretreatment with PD 145065 (a nonselective endothelin receptor blocker; 50 μg·kg
−1
·min
−1
) completely blocked this increase in pulmonary vascular resistance and blocked the increase in pulmonary vascular resistance in response to acute alveolar hypoxia after CPB (96.3±88.5% versus −9.7±16.4%;
P
<.05). Plasma endothelin 1 levels increased after CPB in all lambs.

Conclusions
Preexisting increased pulmonary blood flow alters the response of the pulmonary circulation to hypothermic CPB; the increase in pulmonary vascular resistance induced by CPB is augmented in lambs with increased pulmonary blood flow. Pretreatment with endothelin 1 receptor blockers eliminated the increase in pulmonary vascular resistance and the pulmonary vasoconstricting response to alveolar hypoxia, suggesting a role for endothelin 1 in post-CPB pulmonary hypertension. Endothelin 1 receptor blockers may decrease morbidity in children at risk for pulmonary hypertension after surgical repair with CPB and warrants further study.
Attenuated Cardiac Sympathetic Responsiveness During Dynamic Exercise in Patients With Heart Failure
Authors: Rundqvist Bengt , Eisenhofer Graeme , Elam Mikael , Friberg Peter
Published: June 2012

Background
Cardiac norepinephrine (NE) spillover is increased in patients with chronic heart failure. This elevation is partly due to augmented NE release but also to reduced capacity for cardiac NE removal processes. In patients with mild to moderate heart failure, it is not known whether the described alteration in cardiac sympathetic function also affects cardiac NE spillover during intense sympathetic activation and whether other organs respond in proportion to the heart.

Methods and Results
Twenty-two patients with heart failure and 15 age-matched healthy subjects were studied. Whole-body and regional (NE) spillovers from the heart and kidneys were assessed at baseline and during supine cycling exercise (10 minutes) with the use of steady-state infusions of tritiated NE (isotope dilution). Cardiac performance was evaluated by means of catheterization of the right side of the heart. Cardiac NE spillover was higher (
P
<.05) at baseline in the patient group than in healthy subjects, whereas renal and whole-body NE spillovers were similar between the study groups. During exercise, cardiac NE spillover increased 13-fold (
P
<.05) in healthy subjects but only 5-fold (
P
<.05) in the cardiac failure group, the latter reaching a lower peak value (
P
<.05). In contrast, there was no difference between the study groups in either renal or whole-body NE spillover responsiveness to exercise.

Conclusions
Patients with mild to moderate heart failure demonstrated a selective attenuation of cardiac sympathetic responsiveness during dynamic exercise. This attenuation may convey reduced inotropic and chronotropic support to the failing heart.
Long-term Follow-up of Cardioverter-Defibrillator Implanted Under Conscious Sedation in Prepectoral Subfascial Position
Authors: Pacifico Antonio , Wheelan Kevin R. , Nasir Nadim , Wells Peter J. , Doyle Timothy K. , Johnson Susan A. , Henry Philip D.
Published: June 2012

Background
Implantable cardioverter-defibrillators (ICDs) with intravenous electrode systems and downsized generators can be implanted by use of operative techniques similar to those employed for the insertion of permanent pacemakers. However, the safety, efficacy, and long-term follow-up of simplified implantation procedures remain to be evaluated. This report is a prospective long-term evaluation of nonselected patients receiving ICDs in the prepectoral subfascial position under conscious sedation.

Methods and Results
Clinical characteristics of the 231 consecutive patients included a mean age of 63 years, a male-to-female ratio of 6.4, a left ventricular ejection fraction of 0.34, a mild-to-moderate heart failure in 91%, coronary artery disease in 84%, and a history of aborted sudden cardiac death or refractory ventricular tachyarrhythmias. Insertion of transvenous leads and prepectoral subfascial ICD implantation were performed in electrophysiology laboratories under local anesthesia and conscious sedation with intravenous midazolam and propofol. Successful implantation in all patients (operation time, 80±32 minutes, mean±SD) irrespective of body size and skin thickness was free of major complications, including need for emergency intubation. After surgery, 1 pocket hematoma, 1 seroma, and 1 pneumothorax required treatment. There was no operative or first-month mortality. During long-term follow-up averaging 453±296 days, six leads required repositioning, but pocket erosions or infections did not occur. First-year total survival was 97%.

Conclusions
Implantation under conscious sedation of ICDs in the prepectoral subfascial position is a safe and effective procedure with low operative and postoperative morbidity and favorable long-term outcome.
Benefit of Active Compression-Decompression Cardiopulmonary Resuscitation as a Prehospital Advanced Cardiac Life Support
Authors: Plaisance Patrick , Adnet Fre´de´ric , Vicaut Eric , Hennequin Brigitte , Magne Philippe , Prudhomme Christophe , Lambert Yves , Cantineau Jean-Paul , Le´opold Catherine , Ferracci Catherine , Gizzi Mirella , Payen Didier
Published: June 2012

Background
We compared short-term prognosis of active compression-decompression (ACD) and standard (STD) cardiopulmonary resuscitation (CPR) in out-of-hospital cardiac arrests.

Methods and Results
We randomized advanced cardiac life support (ACLS) with ACD ACLS CPR on odd days and STD ACLS CPR on even days. We measured the rates of return of spontaneous circulation (ROSC), survival at 1 hour (H
1
), at 24 hours (H
24
), and at 1 month (D
30
); hospital discharge (HD); neurological outcome; and complications. Mean times from collapse to basic cardiac life support CPR was 9 minutes and from collapse to ACLS CPR was 21 minutes. Compared with the STD ACLS patients (n=258), ACD ACLS patients (n=254) had higher survival rates (ROSC, 44.9% versus 29.8%,
P
=.0004; H
1
, 36.6% versus 24.8%,
P
=.003; H
24
, 26% versus 13.6%,
P
=.002; HD without neurological impairment, 5.5% versus 1.9%,
P
=.03) and a trend for improvement in neurological outcome at D
30
(Glasgow-Pittsburgh Outcome Categories=1.6±0.8 versus 2.3±1.1,
P
=.09). Sternal dislodgments (2.9% versus 0.4%,
P
=.03) and hemoptysis (5.4% versus 1.3%,
P
=.01) were more frequent in the ACD ACLS group.

Conclusions
Despite long time intervals, ACD significantly improved short-term survival rates in out-of-hospital cardiac arrests compared with STD CPR.
Automatic Arrhythmia Identification Using Analysis of the Atrioventricular Association
Authors: Nair Mohan , Saoudi Nadir , Kroiss Daniel , Letac Brice
Published: June 2012

Background
Atrioventricular association is a key criterion for arrhythmia diagnosis. Its use in a defibrillator should significantly reduce the incidence of inappropriate shocks. Therefore, we evaluated the diagnostic accuracy of an algorithm that uses dual-chamber sensing and analysis of atrioventricular association to discriminate ventricular from supraventricular arrhythmias in a prototype of an implantable defibrillator.

Methods and Results
The algorithm performed a stepwise analysis of arrhythmias. The rhythm was first classified on the basis of cycle lengths. Each episode was then classified as supraventricular or ventricular in origin on the basis of the stability of cycle lengths and atrioventricular association. This algorithm was evaluated in 156 episodes of induced sustained tachycardias. Eighty-nine tachycardias were taken from the Ann Arbor electrogram library; the others were recorded in 50 patients during electrophysiological studies. The atrial and ventricular signals were stored on an external recorder and then injected into an external prototype of a defibrillator system. The algorithm correctly diagnosed 96% of ventricular tachycardia episodes, 100% of ventricular fibrillation episodes, and 92% of double-tachycardia episodes. The mean detection time for ventricular tachycardia was 2.6±0.8 seconds, and for ventricular fibrillation, it was 2.1±0.4 seconds. The positive predictive values for the diagnoses of atrial fibrillation and atrial flutter were 92% and 86%, respectively. For ventricular tachycardia and ventricular fibrillation, the values were 95% and 100%, respectively.

Conclusions
Analysis of atrioventricular association promotes reliable differentiation between ventricular and supraventricular tachycardias and should enhance the diagnostic capabilities of implantable defibrillators.
Hypertension and Borderline Isolated Systolic Hypertension Increase Risks of Cardiovascular Disease and Mortality in Male Physicians
Authors: O'Donnell Christopher J. , Ridker Paul M. , Glynn Robert J. , Berger Klaus , Ajani Umed , Manson JoAnn E. , Hennekens Charles H.
Published: June 2012

Background
The objective of this study was to examine whether definite hypertension and borderline isolated systolic hypertension predict subsequent cardiovascular disease and mortality.

Methods and Results
This was a prospective cohort study with a mean follow-up of 11.7 years. The subjects were a group of 18 682 apparently healthy US men, aged 40 to 84 years, participating in the Physicians' Health Study, a randomized trial of low-dose aspirin and β-carotene. The main outcome measures were total cardiovascular disease, myocardial infarction, stroke, cardiovascular death, and all-cause mortality. Hypertension was associated with substantially increased risks of total cardiovascular disease (relative risk [RR] 1.92; 95% confidence interval [CI], 1.70 to 2.18), myocardial infarction (RR, 1.78; 95% CI, 1.49 to 2.13), stroke (RR, 2.19; 95% CI, 1.78 to 2.69), and cardiovascular death (RR, 2.10; 95% CI, 1.68 to 2.63). Borderline isolated systolic hypertension was associated with significantly increased risks of cardiovascular disease (RR, 1.32; 95% CI, 1.09 to 1.59), stroke (RR, 1.42; 95% CI, 1.04 to 1.93), and cardiovascular death (RR, 1.56; 95% CI, 1.13 to 2.15), as well as a possible but nonsignificant increased risk of myocardial infarction (RR, 1.26; 95% CI, 0.95 to 1.67). Hypertension and borderline isolated systolic hypertension were associated with significantly increased risks of 41% and 22%, respectively, for all-cause mortality.

Conclusions
Hypertension as well as borderline isolated systolic hypertension are associated with elevated risks of cardiovascular diseases, especially stroke and cardiovascular death. Hypertension is associated with an increased risk of myocardial infarction, and borderline isolated systolic hypertension predicts a possible but more modest increase in risk. These data add to the existing evidence that hypertension is a major cardiovascular risk factor and extend the findings to borderline isolated systolic hypertension.
Presence of a Critical Coronary Artery Stenosis Does Not Abolish the Protective Effect of Ischemic Preconditioning
Authors: Kapadia Shaival J. , Terlato Joseph S. , Most Albert S.
Published: June 2012

Background
Episodic, severe coronary artery flow restriction preconditions the myocardium much like brief occlusions. The necessity for full reperfusion after a preconditioning intervention to elicit the preconditioning response is unclear. This study investigated in closed-chest swine the effect of a persistent critical coronary stenosis with moderate flow reduction on ischemic preconditioning.

Methods and Results
Farm pigs (n=23) assigned to one of four groups—(1) control, (2) stenosis, (3) preconditioned (PC), or (4) preconditioned plus stenosis (PC/S)—underwent percutaneous instrumentation with a percutaneous transluminal coronary angioplasty catheter advanced to the mid–left anterior descending coronary artery. An artificial coronary stenosis (82% diameter reduction) was mounted on the catheter just proximal to the balloon in the two stenosis groups. Preconditioning stimulus consisted of two 10-minute balloon occlusions followed by 15 minutes of reperfusion. All groups subsequently underwent 45 minutes of occlusion followed by 120 minutes of reperfusion. Baseline regional myocardial blood flow in the area at risk (AAR), measured with colored microspheres, was lowest in the stenosis groups, with flow expressed as a percentage of normal zone flow. Infarct size (percent of AAR), determined by staining slices of the heart with triphenyltetrazolium, was significantly reduced in PC compared with control pigs (15.1±5.9% versus 66.8±6.4%, respectively;
P
<.001). Infarct size in PC/S pigs was also significantly reduced (29.7±7.1%,
P
=.004 versus control) but was not different in degree from PC pigs (
P
=.6). The stenosis by itself conferred no preconditioning benefit (percent of AAR=69.0±5.4%).

Conclusions
A moderate flow-limiting stenosis did not prevent preconditioning but may have attenuated the effect. This may be analogous to the clinical scenario in which intermittent coronary occlusion and reperfusion superimposed on a critical stenosis precede a prolonged occlusion treated with thrombolysis.
Persistent Inhibition of Platelets During Continuous Nitroglycerin Therapy Despite Hemodynamic Tolerance
Authors: He´bert Daniel , Xiang Jian-Xin , Lam Jules Y.T.
Published: June 2012

Background
Nitroglycerin has been shown to possess antiplatelet properties in both animals and humans. Tolerance to the hemodynamic effects of nitroglycerin develops with continuous therapy, but it is unclear whether there is tolerance to its antiplatelet effect.

Methods and Results
Tolerance to nitroglycerin was studied by exposing porcine aortic media to flowing arterial blood from control pigs (n=9) or pigs treated with continuous nitroglycerin patches (Nitro-dur, 0.8 mg/h; n=11) at a shear rate of 3397 s
−1
for 3 minutes. Relative to baseline, mean arterial pressure fell by ≈10% at 3 and 24 hours (
P
<.05) but returned to baseline at 48 hours of continuous nitroglycerin treatment, whereas no significant changes were observed in control animals. Autologous
51
Cr-labeled platelet deposition (×10
6
/cm
2
) on the aortic media at baseline and 3, 24, and 48 hours remained stable in control animals, with mean values of 94.8±5.9, 89.4±8.3, 89.3±8.8, and 84.3±5.7, respectively. However, in pigs treated continuously with nitroglycerin for 48 hours, platelet deposition was reduced significantly at 3 (65.9±4.8), 24 (63.8±6.4), and 48 hours (56.5±7.3) of nitroglycerin treatment compared with baseline (93.1±3.6). Platelet aggregation induced by thrombin also decreased at 3 (12.4±1.3), 24 (12.6±1.7), and 48 hours (10.8±1.6) of nitroglycerin treatment compared with baseline (16.3±1.4) but remained unchanged in the control group. Also, nitroglycerin treatment increased intraplatelet cGMP at 3, 24, and 48 hours compared with baseline.

Conclusions
This study demonstrates the persistent inhibition of platelet function and platelet deposition on an injured arterial wall by continuous nitroglycerin therapy despite hemodynamic tolerance.
Relationship Between Spectral Components of Cardiovascular Variabilities and Direct Measures of Muscle Sympathetic Nerve Activity in Humans
Authors: Pagani Massimo , Montano Nicola , Porta Alberto , Malliani Alberto , Abboud Francois M. , Birkett Clay , Somers Virend K.
Published: June 2012

Background
Spectral analysis of RR interval and systolic arterial pressure variabilities may provide indirect markers of the balance between sympathetic and vagal cardiovascular control.

Methods and Results
We examined the relationship between power spectral measurements of variabilities in RR interval, systolic arterial pressure, and muscle sympathetic nerve activity (MSNA) obtained by microneurography over a range of blood pressures. In eight healthy human volunteers, MSNA, RR interval, intra-arterial pressure, and respiration were measured during blood pressure reductions induced by nitroprusside and during blood pressure increases induced by phenylephrine. Both low-frequency (LF; 0.10±0.01 Hz) and high-frequency (HF; 0.23±0.01 Hz) components were detected in MSNA variability. Increasing levels of MSNA were associated with a shift of the spectral power toward its LF component. Decreasing levels of MSNA were associated with a shift of MSNA spectral power toward the HF component. Over the range of pressure changes, the LF component of MSNA variability was positively and tightly correlated with LF components of RR interval (in normalized units;
P
<10
−6
) and of systolic arterial pressure variability (both in millimeters of mercury squared and normalized units;
P
<5×10
−5
and
P
<5×10
−6
, respectively). The HF component of MSNA variability was positively and tightly correlated with the HF component (in normalized units) of RR-interval variability (
P
<3×10
−4
) and of systolic arterial pressure variability (
P
<.01).

Conclusions
During sympathetic activation in normal humans, there is a predominance in the LF oscillation of blood pressure, RR interval, and sympathetic nerve activity. During sympathetic inhibition, the HF component of cardiovascular variability predominates. This relationship is best seen when power spectral components are normalized for total power. Synchronous changes in the LF and HF rhythms of both RR interval and MSNA during different levels of sympathetic drive are suggestive of common central mechanisms governing both parasympathetic and sympathetic cardiovascular modulation.
Regulation of Local Angiotensin II Formation in the Human Heart in the Presence of Interstitial Fluid
Authors: Kokkonen Jorma O. , Saarinen Juhani , Kovanen Petri T.
Published: June 2012

Background
Data from in vitro studies suggest that both chymase and ACE contribute to the local generation of angiotensin (Ang) II in the heart. The enzyme kinetics under in vivo conditions are unclear. We thus studied the generation of Ang II by cardiac tissue in the presence of interstitial fluid (IF) that contains a variety of naturally occurring protease inhibitors.

Methods and Results
Ang I was incubated with heart homogenate in the presence of IF. IF obtained from human skin contained substantial amounts of protease inhibitors and ACE activity, the concentration of α
1
-antitrypsin being 35% and the activity of ACE 24% of the corresponding serum values. When heart homogenate was incubated with Ang I, three enzymes were responsible for its metabolism: heart chymase and heart ACE converted Ang I to Ang II, and heart carboxypeptidase A (CPA)–like activity degraded Ang I to Ang-(1-9). Incubation of heart homogenate in the presence of IF led to practically full inhibition of heart chymase–mediated Ang II formation by the natural protease inhibitors present in IF. In contrast, heart CPA–like activity was not blocked, as reflected by the continued generation of Ang-(1-9). In addition, both heart ACE– and IF ACE–mediated Ang II formation were strongly inhibited. This inhibition was shown to be due to the Ang-(1-9) formed.

Conclusions
The present experimental study defines two novel inhibitory mechanisms of Ang II formation in the human heart interstitium. Heart chymase–mediated Ang II formation is strongly inhibited by the natural protease inhibitors present in the IF. Similarly, both heart ACE– and IF ACE–mediated Ang II formation appear to be inhibited by the endogenous inhibitor Ang-(1-9) formed by heart CPA–like activity. These inhibitory mechanisms provide additional information about how the Ang II concentration in the heart interstitium may be controlled.
Remodeling of the Left Ventricle in Primary Aldosteronism Due to Conn’s Adenoma
Authors: Rossi Gian Paolo , Sacchetto Alfredo , Pavan Edoardo , Palatini Paolo , Graniero Gian Rocco , Canali Cristina , Pessina Achille C.
Published: June 2012

Background
Since hyperaldosteronism has been experimentally related to myocardial interstitial fibrosis, we investigated the effects of hypertension and excess aldosterone due to aldosterone-producing adenomas (APAs) on the heart.

Methods and Results
In 52 hypertensive individuals, we performed Doppler echocardiography for estimation of left ventricular (LV) wall thickness and dimensions, transmitral LV filling flow velocity indexes, and 24-hour ambulatory blood pressure monitoring. Consecutive patients with APAs (n=26) and essential hypertension (EH, n=26) were individually matched for age, sex, race, body mass index, casual blood pressure, and known duration of hypertension. The matched groups were similar for demography, casual and 24-hour blood pressure values and variability, and duration of hypertension but differed for serum potassium, plasma renin activity, and aldosterone levels (all
P
<.001). A thicker interventricular septum (
P
=.015) and posterior wall (
P
=.009) and a higher LV mass index (118±5 versus 100±4 g/m
2
,
P
=.009) were observed in APA compared with EH patients. Both septum and posterior wall thicknesses had a significant direct relationship with age, plasma aldosterone, and mean blood pressure. The integral of the early diastolic filling wave (E
i
) (
P
=.011) and the ratio E
i
/A
i
(A wave integral) (
P
=.038) were lower and the atrial contribution to LV filling was higher (52±2% versus 46±2%,
P
=.038) in APA than in EH patients. The ratio E
i
/A
i
was significantly (
P
=.008) inversely related only to age and plasma aldosterone.

Conclusions
In APA patients, the excess aldosterone is associated with both increased LV wall thickness and mass and decreased early diastolic LV filling indexes compared with demographically similar EH with superimposable blood pressure values, profile, and variability.
Defibrillation Efficacy of Commercially Available Biphasic Impulses in Humans
Authors: Tomassoni Gery , Newby Keith , Deshpande Sanjay , Axtell Kathi , Sra Jasbir , Akhtar Masood , Natale Andrea
Published: June 2012

Background
Recent studies have shown that specifically shaped biphasic waveforms can lower energy requirements for ventricular defibrillation. We prospectively compared the defibrillation efficacy of three different biphasic wave shapes incorporated in three commercially available implantable defibrillators. The results led to the development of a second protocol in which the importance of negative-phase peak voltage and duration was investigated.

Methods and Results
Defibrillation threshold (DFT) testing using different biphasic waveforms was performed randomly on 42 patients undergoing implantation of a cardioverter-defibrillator for ventricular arrhythmias. In 23 patients (group 1), 3 waveforms were tested: a CPI waveform with 60% positive-phase (P1) tilt and 50% negative-phase (P2) tilt, a Medtronic waveform with 65% fixed tilt in both P1 and P2, and a Ventritex waveform with 60% P1 tilt and a P2 leading edge voltage equal to half of the P1 trailing edge voltage. In 19 patients (group 2), 3 biphasic waveforms with equal P1 tilt at 65% but shorter P2 duration or smaller P2 peak voltage were tested. The Endotak C 60 series lead system (CPI) was used in 11 patients in group 1 and 10 patients in group 2. A Transvene lead system (Medtronics) was used in the remaining patients. Stored energy required for defibrillation was significantly lower with the CPI waveform compared with the Ventritex waveform. In group 2, energy requirements were significantly increased for the waveform with a smaller P2 peak voltage, whereas a short P2 duration did not influence defibrillation success.

Conclusions
Our results suggest that specifically shaped biphasic waveforms delivered from commercially available devices can affect energy requirements for defibrillation. More importantly, the amplitude of the P2 peak voltage may be a more critical determinant than the P2 duration for defibrillation success of biphasic waveforms in humans.
Stroke Volume and Cardiac Output in Normotensive Children and Adults
Authors: de Simone Giovanni , Devereux Richard B. , Daniels Stephen R. , Mureddu GianFrancesco , Roman Mary J. , Kimball Thomas R. , Greco Rosanna , Witt Sandra , Contaldo Franco
Published: June 2012

Background
Relations between organs and body size are not linear but rather follow allometric (growth) relations characterized by their powers (exponents).

Methods and Results
Stroke volume (SV) by M-mode echocardiography was related to height, weight, body surface area (BSA), and ideal BSA (derived from ideal body weight for given height) in 970 normotensive individuals (1 day to 85 years old; 426 <18 years old; 204 overweight to obese; 426 female). In normal-weight children, adults, and the entire population, SV was related by allometric relations to BSA (power=0.82 to 1.19), body weight (power=0.57 to 0.71), and height (power=1.45 to 2.04) (all
P
<.0001). Relations of cardiac output to measures of body size had lower allometric powers than those for SV in the entire population (0.41 for body weight, 0.62 for BSA, and 1.16 for height). In overweight adults, observed SVs were 17% greater than predicted for ideal BSA, a difference that was approximated by normalization of SV for height to age-specific allometric powers. Similarly, observed cardiac output was 19% greater than predicted for ideal BSA, a difference that was accurately detected by use of cardiac output/height to age-specific allometric powers but not of BSA to the first power.

Conclusions
Indexations of SV and cardiac output for BSA are pertinent when the effect of obesity needs to be removed, because these indexations obscure the impact of obesity. To detect the effect of obesity on LV pump function, normalization of SV and cardiac output for ideal BSA or for height to its age-specific allometric power should be practiced.
99m
Tc-HL91
Authors: Okada Robert D. , Johnson Gerald , Nguyen Kiem N. , Edwards Barbara , Archer Colin M. , Kelly James D.
Published: June 2012

Background
99m
Tc-HL91 is a potential imaging agent that has demonstrated increased uptake in hypoxic tumor cells. The purpose of this study was to determine if
99m
Tc-HL91 demonstrates increased uptake and retention in ischemic and hypoxic myocardium.

Methods and Results
99m
Tc-HL91 (11.1 MBq) was infused over 10 minutes, followed by a 60-minute clearance phase. Activity was monitored by using an NaI detector. Three groups were studied using Krebs-Henseleit buffer (KH): controls (12 mL/min, n=6), low-flow ischemic (1 mL/min, n=7), and hypoxic (12 mL/min, n=8). Two groups were perfused with KH, red blood cells, and albumin: controls (6 mL/min, n=6) and low-flow ischemic (0.5 mL/min, n=6). For the KH hearts, the
99m
Tc-HL91 peak uptake progressively increased from control (6.3±0.5 μCi, mean±SEM) to hypoxic (9.1±1.0 μCi) to low flow (44.0±2.6 μCi;
P
<.01). The peak uptake low-flow/control ratio was 7:1. Final retention increased progressively from control (0.8±0.1 μCi) to hypoxic (2.9±0.5 μCi) to low flow (10.9±1.3 μCi;
P
<.01). The final low-flow/control activity ratio was 13.6:1. Similar results were observed in the red blood cell–perfused control and low-flow groups.

Conclusions
This study introduces a new myocardial “hot spot” imaging agent,
99m
Tc-HL91. This agent demonstrates increased myocardial uptake and retention in hypoxic and low-flow ischemic models. Further in vivo imaging studies are warranted to determine the clinical potential of this agent.
Genetic Polymorphism of 5,10-Methylenetetrahydrofolate Reductase (MTHFR) as a Risk Factor for Coronary Artery Disease
Authors: Morita Hiroyuki , Taguchi Jun-ichi , Kurihara Hiroki , Kitaoka Masao , Kaneda Hideaki , Kurihara Yukiko , Maemura Koji , Minamino Tohru , Ohno Minoru , Yamaoki Kazuhide , Ogasawara Ken , Aizawa Tadanori , Suzuki Shin , Yazaki Yoshio
Published: June 2012

Background
Epidemiological studies have identified hyperhomocyst(e)inemia as an independent risk factor for coronary artery disease (CAD). Recently, the alanine/valine (
A/V
) polymorphism of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, one of the key enzymes catalyzing remethylation of homocysteine, has been reported. The
VV
genotype correlates with increased plasma homocyst(e)ine levels as a result of the reduced activity and increased thermolability of this enzyme. In this study, we examined the distribution of the MTHFR genotypes in Japanese men and the association between the
VV
genotype and CAD.

Methods and Results
The diagnoses of CAD of all the studied patients were confirmed by coronary angiography. The MTHFR genotype was analyzed by PCR followed by
Hin
fI digestion. In 778 healthy male subjects, the frequency of the
V
allele was 0.33, comparable to that in a French Canadian population. In 362 patients with CAD, the
VV
genotype was significantly more frequent than in control subjects (16% versus 10%,
P
=.0067). The association of the
VV
genotype with CAD was further increased in patients with ≥99% stenotic lesions (18%,
P
=.0010), whereas no significant association with the
VV
genotype was observed in patients without a ≥99% stenosis. When the genotype frequency was compared among patients with different numbers of stenotic coronary arteries, the frequency of the
VV
genotype was significantly higher in patients with triple-vessel disease (26%) than in patients with single- or double-vessel disease (15% and 14%, respectively).

Conclusions
The
VV
genotype of MTHFR was also common in the Japanese population and was significantly associated with CAD. The frequency of this genotype in particular was correlated with the severity of disease. The
VV
genotype associated with a predisposition to increased plasma homocyst(e)ine levels may represent a genetic risk factor for CAD.
‘Cross Talk’ Between Opioid Peptide and Adrenergic Receptor Signaling in Isolated Rat Heart
Authors: Pepe Salvatore , Xiao Rui-Ping , Hohl Charlene , Altschuld Ruth , Lakatta Edward G.
Published: June 2012

Background
Cardiac myocyte sarcolemma contains both catecholamine and opioid peptide receptors (OPRs). Opioid peptides are coreleased with catecholamines from nerve terminals in the heart. We investigated whether OPR stimulation influences the effects of β-adrenergic receptor (β-AR) stimulation in the isolated, isovolumic rat heart and whether the mechanism of such an interaction involves both β-AR subtypes or an alteration in β-AR–mediated increase in cAMP.

Methods and Results
Norepinephrine (NE, 10
−7
mol/L) increased peak left ventricular systolic pressure (LVSP) and cAMP more than twofold compared with controls. The δ-OPR agonist leucine-enkephalin (LE, 10
−8
mol/L) markedly inhibited the β
1
-AR–induced positive inotropic effect and increase in cAMP but alone had no effect on basal LVSP or basal cAMP levels. The OPR antagonist naloxone 10
−8
mol/L added to LE+NE perfusate reversed the LE-induced decrease in cAMP and LVSP even though naloxone alone had no effect on LVSP and cAMP levels. LE could not counteract the twofold increase in LVSP produced by the nondegradable cAMP analog CPTcAMP 2.3×10
−5
mol/L or a high concentration of forskolin (10
−7
mol/L) but did reverse the 173±11.8% and 135±13.6% increases in LVSP stimulated by 10
−8
and 0.5×10
−8
mol/L forskolin, respectively. LE inhibited cAMP production at all concentrations of forskolin (10
−7
, 10
−8
, and 0.5×10
−8
mol/L). Pertussis toxin (PTX) pretreatment abolished LE effects on β
1
-AR stimulation. Zinterol 10
−5
and 10
−6
mol/L, a specific β
2
-AR agonist that elicits a cAMP-independent inotropic effect in rat heart, caused 225±14% and 182±5% increases in LVSP that could not be reversed by addition of LE.

Conclusions
Potent, inhibitory “cross talk” between δ-OPR and β
1
-AR signaling pathways occurs via a PTX-sensitive G
i/o
protein involved in adenylyl cyclase inhibition in rat heart.
Subendocardial and Intramural Temperature Response During Radiofrequency Catheter Ablation in Chronic Myocardial Infarction and Normal Myocardium
Authors: Kottkamp Hans , Hindricks Gerhard , Horst Eckehard , Baal Thomas , Fechtrup Christian , Breithardt Günter , Borggrefe Martin
Published: June 2012

Background
The ability of radiofrequency energy to extend across scar tissue is unknown. We investigated the effects of radiofrequency catheter ablation on intramural temperature in experimental chronic myocardial infarction.

Methods and Results
Myocardial infarction was induced in eight dogs by a transcatheter coronary artery occlusion-reperfusion technique. The dogs were reanesthetized after 15 to 24 days. Four additional dogs served as controls. The freshly excised preparations were cut and placed in a saline bath at 37°C. Temperature-guided energy applications with a preselected catheter tip temperature of 80°C were performed for 60 seconds with a 7F ablation catheter. Thermoelements were inserted into the ventricular muscle at depths of 2.5 to 3.0 mm (“subendocardial”) and 5.5 to 6.0 mm (“intramural”). Surviving muscle fibers were interspersed among the transmural scar tissue. The maximal temperatures did not differ significantly between normal hearts and chronic infarctions at the subendocardial (64.5±6.4°C versus 66.7±6.6°C) or intramural thermoelement (51.9±5.7°C versus 52.3±5.7°C). The myocardial temperature rise was slow, and steady-state temperatures had not been reached after 60 seconds. The intramural temperatures in chronic infarctions measured 49.0±4.3°C after 40 seconds of energy delivery and were still below the critical tissue temperature of 50°C that is necessary to induce permanent myocardial damage.

Conclusions
Temperature-guided radiofrequency ablation in a dog model of chronic myocardial infarction may induce tissue temperatures >50°C at a depth of 5.5 to 6.0 mm. The intramural temperature rise was slow, indicating that long energy applications might be necessary if the arrhythmogenic substrate is subepicardial.