bluuebunny/crossref_metadata_2025 huggingface dataset:
l
-Arginine and Substance P Reverse the Pulmonary Endothelial Dysfunction Caused by Congenital Heart Surgery
Authors: Schulze-Neick Ingram , Penny Daniel J. , Rigby Michael L. , Morgan Cliff , Kelleher Andrea , Collins Peter , Li Jia , Bush Andrew , Shinebourne Elliot A. , Redington Andrew N.
Published: June 2012

Background
—The increase in pulmonary vascular resistance (PVR) seen in children after cardiopulmonary bypass has been attributed to transient pulmonary endothelial dysfunction (PED). We therefore examined PED in children with congenital heart disease by assessing the
l
-arginine–nitric oxide (NO) pathway in terms of substrate supplementation (
l
-arginine [L-Arg]), stimulation of endogenous NO release (substance P [Sub-P]), and end-product provision (inhaled NO) before and after open heart surgery.

Methods and Results
—Ten patients (aged 0.62±0.27 years) with pulmonary hypertension undergoing cardiac catheterization who had not had surgery and 10 patients (aged 0.65±0.73 years) who had recently undergone cardiopulmonary bypass were examined. All were sedated and paralyzed and received positive-pressure ventilation. Blood samples and pressure measurements were taken from catheters in the pulmonary artery and the pulmonary vein or left atrium. Respiratory mass spectrometry was used to measure oxygen uptake, and cardiac output was determined by the direct Fick method. PVR was calculated during steady state at ventilation with room air, during F
io
2
of 0.65, then during additional intravenous infusion of L-Arg (15 mg · kg
−1
· min
−1
) and Sub-P (1 pmol · kg
−1
· min
−1
), and finally during inhalation of NO (20 ppm). In preoperative patients, the lack of an additional significant change of PVR with L-Arg, Sub-P, and inhaled NO suggests little preexisting PED. Postoperative PVR was higher, with an additional pulmonary endothelial contribution that was restorable with L-Arg and Sub-P.

Conclusions
—Postoperatively, the rise in PVR suggested PED, which was restorable by L-Arg and Sub-P, with no additional effect of inhaled NO. These results may indicate important new treatment strategies for these patients.
Insulin Stimulates Both Endothelin and Nitric Oxide Activity in the Human Forearm
Authors: Cardillo Carmine , Nambi Sridhar S. , Kilcoyne Crescence M. , Choucair Wassim K. , Katz Arie , Quon Michael J. , Panza Julio A.
Published: June 2012

Background
—The mechanism of the hemodynamic effect of insulin in the skeletal muscle circulation has not been fully elucidated. The purpose of this study was to assess whether the hemodynamic response to insulin involves the concurrent release of endothelin (ET-1) and nitric oxide (NO), 2 substances with opposing vasoactive properties.

Methods and Results
—Bioactivity of ET-1 and NO was assessed without insulin and during insulin infusion in the forearm circulation of healthy subjects by use of blockers of ET-1 receptors and by NO synthesis inhibition. In the absence of hyperinsulinemia, ET-1 receptor blockade did not result in any significant change in forearm blood flow from baseline (
P
=0.29). Intra-arterial insulin administration did not significantly modify forearm blood flow (
P
=0.88). However, in the presence of hyperinsulinemia, ET-1 receptor antagonism was associated with a significant vasodilator response (
P
<0.001). In the presence of ET-1 receptor blockade, the vasoconstrictor response to NO inhibition by
N
G
-monomethyl-
l
-arginine was significantly higher after insulin infusion than in the absence of hyperinsulinemia (
P
=0.006).

Conclusions
—These findings suggest that in the skeletal muscle circulation, insulin stimulates both ET-1 and NO activity. An imbalance between the release of these 2 substances may be involved in the pathophysiology of hypertension and atherosclerosis in insulin-resistant states associated with endothelial dysfunction.
Electrophysiological Effects of Dofetilide in an In Vitro Model of “Border Zone” Between Normal and Ischemic/Reperfused Myocardium
Authors: Rouet René , Picard Sandra , Libersa Christian , Ghadanfar Mathieu , Alabaster Colin , Gérard Jean-Louis
Published: June 2012

Background
—To evaluate both class III activity and antiarrhythmic action of dofetilide at the level of the “border zone,” we investigated its electrophysiological effects on guinea pig ventricular strips submitted partly to normoxia (normal zone, NZ) and partly to simulated severe ischemia, then reperfusion (altered zone, AZ).

Methods and Results
—Because of the differential class III effects of dofetilide in normal and ischemic regions, the dispersion of the action potential duration at 90% repolarization (APD
90
) between NZ and AZ was reduced by 5 nmol/L of drug during early ischemia (at 10 minutes, APD
90
NZ/APD
90
AZ was 1.68±0.22 versus 2.82±0.17 in control,
P
<0.05), whereas 50 nmol/L dofetilide worsened it during late ischemia (at 30 minutes, APD
90
NZ/APD
90
AZ was 4.62±0.76 versus 2.57±0.21 in control,
P
<0.05). Concomitantly, dofetilide at 5, 10, and 50 nmol/L abolished the early extrastimulus (ES)-induced arrhythmias, and at 10 and 50 nmol/L, it significantly enhanced the incidence of late spontaneous repetitive responses (in 86% and 75% of preparations treated with 10 and 50 nmol/L, respectively, versus 25% in control,
P
<0.05). During reperfusion, dofetilide at 5, 10, and 50 nmol/L exhibited concentration-dependent class III effects, as it did in the NZ, and did not modify the incidence of spontaneous arrhythmias.

Conclusions
—Dofetilide 5 nmol/L decreased APD
90
dispersion between NZ and AZ and reduced the early ES-induced arrhythmias. However, dofetilide 50 nmol/L increased APD
90
dispersion, and at 10 and 50 nmol/L, it increased the late spontaneous arrhythmias.
17β-Estradiol Restores Endothelial Nitric Oxide Release to Shear Stress in Arterioles of Male Hypertensive Rats
Authors: Huang An , Sun Dong , Koller Akos , Kaley Gabor
Published: June 2012

Background
—Endothelial nitric oxide (NO)–mediated responses are impaired in arterioles of male spontaneously hypertensive rats (SHR), but they are still present in female SHR. We hypothesized that in vitro incubation of arterioles of male SHR with estrogen will restore NO-mediated responses by upregulation of endothelial NO synthase.

Methods and Results
—Responses to increases in perfusate flow (from 0 to 25 μL/min) and to the calcium ionophore A23187 (5×10
−8
to 10
−6
mol/L), norepinephrine (NE; 10
−7
to 3×10
−7
mol/L), sodium nitroprusside (SNP; 10
−8
to 10
−6
mol/L), and adenosine (ADO; 10
−6
to 5×10
−5
mol/L) were studied in cannulated and pressurized gracilis muscle arterioles (≈75 μm in diameter) isolated from 12-week-old male SHR before and after incubation with 10
−9
mol/L 17β-estradiol (17β-E
2
) for 16 to 18 hours. After incubation with 17β-E
2
, basal diameter of arterioles was significantly increased (by ≈10%), and flow-induced dilation was significantly enhanced (79.8±2.9 versus 103.7±3.7 μm at 25 μL/min), resulting in a lowered shear stress (62.0±9.1 versus 32.5±4.2 dyne/cm
2
). Also, vasoconstrictions to A23187 were reversed to dilations (−18.7±2.2 versus 18.8±1.7 μm), and constrictions to NE were significantly attenuated (−30.7±3.0 versus −21.2±2.8 μm). These alterations were eliminated by ICI 182,780 (10
−7
mol/L), an estrogen receptor antagonist; 5,6-dichloro-1-β-
d
-ribofuranosylbenzimidazole (10
−5
mol/L), a transcription inhibitor; or
N
ω
-nitro-
l
-arginine methyl ester (10
−4
mol/L), an inhibitor of NO synthase, whereas they were not affected by aminoguanidine (5×10
−5
mol/L), a specific inhibitor of inducible NO synthase. Arteriolar responses were not altered by incubation with 17α-estradiol.

Conclusions
—Estrogen, via a receptor-mediated pathway, upregulates endothelial NO synthase gene expression, leading to increased NO production, and restores the regulation of wall shear stress in arterioles of male SHR.
New Body Surface Isopotential Map Evaluation Method to Detect Minor Potential Losses in Non–Q-Wave Myocardial Infarction
Authors: Medvegy Mihály , Préda István , Savard Pierre , Pintér Arnold , Tremblay Gaétan , Nasmith James B. , Palisaitis Donald , Nadeau Réginald A.
Published: June 2012

Background
—Potential losses caused by stable non–Q-wave myocardial infarction (MI) are too small to diagnose with the use of standard ECG. The aim of the present study was to obtain accurate diagnostic criteria for this prognostically important disease with the help of body surface mapping.

Methods and Results
—Body surface potentials were recorded with the use of 63 unipolar leads in 45 patients with a non–Q-wave MI (41 to 75 years old); 24 healthy adults, 42 patients with unstable angina, and 70 patients with Q-wave MI served as reference groups. Qualitative pathological features of the isopotential maps, such as onset time and site and magnitude of the first right-anterior/anterior minimum, as well as pathological negativities at that time, were defined in non–Q-wave MI cases. These features, which account for the activation sequence and the body surface projections of specific cardiac regions (Selvester classification), showed a 91% sensitivity and an 88% specificity for the detection of non–Q-wave MI. In comparison, the different departure maps (first third QRS, QRS, and QRST isoarea) resulted in less favorable specificities (50% to 58%). Concordance between the isopotential maps and the acute-phase ECG (90%), hypokinesis (64%), fixed perfusion defects (59%), and significant stenosis of the infarct-related coronary artery (87%) supported the concept that these isopotential map changes correspond to the supposed sites of MI. There were pathological features in 69% of patients with unstable angina, with similar concordances as in non–Q-wave MI.

Conclusions
—Isopotential maps revealed characteristic features that were suitable for the detection and localization of non–Q-wave MI in the clinical setting of unstable coronary artery disease.
Effects of Abciximab, Ticlopidine, and Combined Abciximab/Ticlopidine Therapy on Platelet and Leukocyte Function in Patients Undergoing Coronary Angioplasty
Authors: Fredrickson Becky J. , Turner Nancy A. , Kleiman Neal S. , Graziadei Nikki , Maresh Kelly , Mascelli Mary Ann , Effron Mark B. , McIntire Larry V.
Published: June 2012

Background
—Abciximab and ticlopidine reduce adverse cardiovascular events after percutaneous transluminal coronary angioplasty (PTCA). The goal of the current study was to determine if combined abciximab/ticlopidine therapy inhibits arterial thrombosis more effectively than either treatment alone. The effect of each therapy on platelet-leukocyte interactions was also investigated.

Methods and Results
—Whole blood samples from 14 patients undergoing PTCA who received abciximab therapy, ticlopidine therapy, or both treatments were evaluated using dynamic experimental systems. Mural thrombus formation under arterial shear conditions (1500 s
−1
) was determined in a parallel plate flow chamber. Shear-induced platelet aggregation was evaluated using a cone-and-plate viscometer at a shear rate of 3000 s
−1
. Of the 3 treatments, combined abciximab/ticlopidine therapy produced the most consistent reduction in shear-induced platelet aggregation and the most prolonged inhibition of mural thrombosis. Three days after PTCA, abciximab/ticlopidine treatment decreased mural thrombus formation to ≈50% of baseline values. Abciximab treatment alone inhibited mural thrombosis for only 1 day after PTCA, whereas ticlopidine treatment alone had no significant effect. Two hours after PTCA, abciximab therapy significantly decreased the number of circulating platelet-neutrophil aggregates but significantly enhanced P-selectin–mediated leukocyte adhesion on the collagen/von Willebrand factor–platelet surface.

Conclusions
—Combined therapy with abciximab and ticlopidine has a prolonged inhibitory effect on mural thrombosis formation relative to either treatment alone. Further, we demonstrated an unexpected effect of abciximab in enhancing P-selectin–mediated leukocyte adhesion.
Linear Ablation Lesions for Control of Unmappable Ventricular Tachycardia in Patients With Ischemic and Nonischemic Cardiomyopathy
Authors: Marchlinski Francis E. , Callans David J. , Gottlieb Charles D. , Zado Erica
Published: June 2012

Background
—Conventional activation mapping is difficult without inducible, stable ventricular tachycardia (VT).

Methods and Results
—We evaluated 16 patients with drug refractory, unimorphic, unmappable VT. Nine patients had ischemic and 7 had nonischemic cardiomyopathy. All patients had implantable defibrillators and had experienced 6 to 55 VT episodes during the month before treatment. Patients underwent bipolar catheter mapping during baseline rhythm. The amount of endocardium with an abnormal electrogram amplitude was estimated using fluoroscopy in 3 patients and a magnetic mapping system (CARTO) in 13 patients. For the magnetic mapping, normal endocardium was defined by an amplitude >1.5 mV; this measurement was based on sinus rhythm maps in 6 patients who did not have structural heart disease. Radiofrequency point lesions extended linearly from the “dense scar,” which had a voltage amplitude <0.5 mV, to anatomic boundaries or normal endocardium. To limit radiofrequency applications, 12-lead ECG during VT and pacemapping guided placement of linear lesions. No new antiarrhythmic drug therapy was added. The amount of endocardium demonstrating an abnormal electrogram amplitude ranged from 25 to 127 cm
2
. A total of 8 to 87 radiofrequency lesions (mean, 55) produced a median of 4 linear lesions that had an average length of 3.9 cm (range, 1.4 to 9.4 cm). Twelve patients (75%) have been free of VT during 3 to 36 months of follow-up (median, 8 months); 4 patients had VT episodes at 1, 3, 9, and 13 months, respectively. Only one of these patient had frequent VT.

Conclusions
—Radiofrequency linear endocardial lesions extending from the dense scar to the normal myocardium or anatomic boundary seem effective in controlling unmappable VT.
Profound Inhibition of Myogenic Tone in Rat Cardiac Allografts Is Due to eNOS- and iNOS-Based Nitric Oxide and an Intrinsic Defect in Vascular Smooth Muscle Contraction
Authors: Skarsgard Peter L. , Wang Xiaodong , McDonald Paul , Lui Amy H. , Lam Eugene K. , McManus Bruce M. , van Breemen Cornelis , Laher Ismail
Published: June 2012

Background
—The physiological consequences of inducible NO synthase (iNOS) expression were studied in allograft coronary arteries by pressure myography.

Methods and Results
—Septal coronary arteries (diameter, 200.6±3.3 μm) were harvested from allograft and isograft hearts, and their myogenic properties were measured before and after iNOS and nonselective NOS inhibition with aminoguanidine (AG, 100 μmol/L) and
N
G
-nitro-
l
-arginine methyl ester (L-NAME) (200 μmol/L). Fura 2 fluorescence microscopy was used to measure [Ca
2+
]
i
in isolated endothelial cells. Monoclonal anti-iNOS immunostains demonstrated iNOS protein in day 2, 7, 14, and 28 allograft vessels, but only in day 2 isograft vessels. Myogenic tone was profoundly inhibited in allograft vessels from day 4 onward. In day 4 allograft vessels, these differences were abolished by L-NAME but not AG, suggesting greater basal release of eNOS-based NO from allograft endothelium. Fluorescence measurements confirmed elevation of [Ca
2+
]
i
in day 4 allograft endothelium, providing a mechanism for enhanced eNOS activity. For days 7 to 28, AG potentiated myogenic tone in allograft but not isograft vessels, indicating that vasoactive iNOS-based NO was present. In mature vessels, constriction via agonist- and depolarization-mediated mechanisms showed parallel inhibition, suggesting an intrinsic defect in vascular smooth muscle cell contraction.

Conclusions
—Our data indicate that the profound inhibition of myogenic tone in allograft arteries involves direct vasodilation by eNOS- and iNOS-based NO, as well as an intrinsic defect in vascular smooth muscle contraction. The hemodynamic profile resulting from these changes in allograft resistance vessel function would favor movement of extracellular fluid from the intravascular space into the myocardial interstitium, resulting in edema, increased ventricular stiffness, and poor ventricular performance.
Pacing After Shocks Stronger Than the Upper Limit of Vulnerability
Authors: Chattipakorn Nipon , Fotuhi Parwis C. , Sreenan Catherine M. , White James B. , Ideker Raymond E.
Published: June 2012

Background
—After upper-limit-of-vulnerability (ULV) shocks of the same strength and coupling interval (CI) during the T wave, (1) the epicardial activation pattern (EAP) for the first postshock cycle is indistinguishable between shocks that do (VF) and do not (NoVF) induce ventricular fibrillation (VF) and (2) ≥3 cycles in rapid succession always occur during VF but not during NoVF episodes. To study the role of these rapid cycles, rapid pacing was performed after a shock stronger than the ULV that by itself did not induce rapid cycles and VF.

Methods and Results
—A 504-electrode sock was sutured to the heart in 6 pigs to map EAPs. The S2 shock strength and S1-S2 CI at the ULV were determined by T-wave scanning with an up/down protocol. Ten shocks 50 to 100 V above the ULV (aULV) were delivered at the same S1-S2 CI to confirm that VF was not induced. Then, the postshock interval after aULV shocks was scanned with an S3 pacing stimulus from the LV apex until the shortest S2-S3 CI that captured was reached. This was repeated for S4, S5, etc, until VF was induced. To induce VF, 3 pacing stimuli (S3-S5) with progressively shorter CIs were required; S3 or S3, S4 never induced VF. After cycle S5, which induced VF, 2 EAP types occurred: focal (74%) and reentrant (26%).

Conclusions
—At least 3 cycles with short CIs are necessary for VF induction after aULV shocks. Cycles S3-S4 may create the substrate for cycle S5 to initiate VF.
KB-R7943 Block of Ca
2+
Influx Via Na
+
/Ca
2+
Exchange Does Not Alter Twitches or Glycoside Inotropy but Prevents Ca
2+
Overload in Rat Ventricular Myocytes
Authors: Satoh Hiroshi , Ginsburg Kenneth S. , Qing Ke , Terada Hajime , Hayashi Hideharu , Bers Donald M.
Published: June 2012

Background
—The Na
+
/Ca
2+
exchange (NCX) extrudes Ca
2+
from cardiac myocytes, but it can also mediate Ca
2+
influx, load the sarcoplasmic reticulum with Ca
2+
, and trigger Ca
2+
release from the sarcoplasmic reticulum. In ischemia/reperfusion or digitalis toxicity, increased levels of intracellular [Na
+
] ([Na
+
]
i
) may raise levels of intracellular [Ca
2+
] ([Ca
2+
]
i
) via NCX, leading to cell injury and arrhythmia.

Methods and Results
—We used KB-R7943 (KBR) to selectively block Ca
2+
influx via NCX to study the role of NCX-mediated Ca
2+
influx in intact rat ventricular myocytes. Removing extracellular Na
+
caused [Ca
2+
]
i
to rise, due to Ca
2+
influx via NCX, and this was blocked by 90% with 5 μmol/L KBR. However, KBR did not alter [Ca
2+
]
i
decline due to NCX. Thus, we used 5 μmol/L KBR to selectively block Ca
2+
entry but not efflux via NCX. Under control conditions, 5 μmol/L KBR did not alter steady-state twitches, Ca
2+
transients, Ca
2+
load in the sarcoplasmic reticulum, or rest potentiation, but it did prolong the late low plateau of the rat action potential. When Na
+
/K
+
ATPase was inhibited by strophanthidin, KBR reduced diastolic [Ca
2+
]
i
and abolished the spontaneous Ca
2+
oscillations, but it did not prevent inotropy.

Conclusions
—In rat ventricular myocytes, Ca
2+
influx via NCX is not important for normal excitation-contraction coupling. Furthermore, the inhibition of Ca
2+
efflux alone (as [Na
+
]
i
rises) may be sufficient to cause glycoside inotropy. In contrast, Ca
2+
overload and spontaneous activity at high [Na
+
]
i
was blocked by KBR, suggesting that net Ca
2+
influx (not merely reduced efflux) via NCX is involved in potentially arrhythmogenic Ca
2+
overload.
Carvedilol for Prevention of Restenosis After Directional Coronary Atherectomy
Authors: Serruys Patrick W. , Foley David P. , Höfling Berthold , Puel Jacques , Glogar Helmut D. , Seabra-Gomes Ricardo , Goicolea Javier , Coste Pierre , Rutsch Wolfgang , Katus Hugo , Bonnier Hans , Wijns William , Betriu Amadeo , Hauf-Zachariou Ulrike , van Swijndregt Eline Montauban , Melkert Rein , Simon Rudiger
Published: June 2012

Background
—In addition to its known properties as a competitive, nonselective β and α-1 receptor blocker, carvedilol directly inhibits vascular myocyte migration and proliferation and exerts antioxidant effects that are considerably greater than those of vitamin E or probucol. This provides the basis for an evaluation of carvedilol for the prevention of coronary restenosis.

Methods and Results
—In a prospective, double-blind, randomized, placebo-controlled trial, 25 mg of carvedilol was given twice daily, starting 24 hours before scheduled directional coronary atherectomy and continuing for 5 months after a successful procedure. The primary end point was the minimal luminal diameter as determined during follow-up angiography 26±2 weeks after the procedure. Of 406 randomized patients, 377 underwent attempted atherectomy, and in 324 (88.9%), a ≤50% diameter stenosis was achieved without the use of a stent. Evaluable follow-up angiography was available in 292 eligible patients (90%). No differences in minimal luminal diameter (1.99±0.73 mm versus 2.00±0.74 mm), angiographic restenosis rate (23.4% versus 23.9%), target lesion revascularization (16.2 versus 14.5), or event-free survival (79.2% versus 79.7%) between the placebo and carvedilol groups were observed at 7 months.

Conclusions
—The maximum recommended daily dose of the antioxidant and β-blocker carvedilol failed to reduce restenosis after successful atherectomy. These findings are in contrast to those of the Multivitamins and Probucol Trial, which raises doubts regarding the validity of the interpretation that restenosis reduction by probucol was via antioxidant effects. The relationship between antioxidant agents and restenosis remains to be elucidated.
Long-Term Right Ventricular Volume Overload Increases Myocardial Fluorodeoxyglucose Uptake in the Interventricular Septum in Patients With Atrial Septal Defect
Authors: Otani Hiroki , Kagaya Yutaka , Yamane Yuriko , Chida Masanobu , Ito Kenta , Namiuchi Shigeto , Shiba Nobuyuki , Koseki Yoshito , Ninomiya Mototsugu , Ikeda Jun , Saito Haruo , Maruoka Shin , Fujiwara Takehiko , Ido Tatsuo , Ishide Nobumasa , Shirato Kunio
Published: June 2012

Background
—Several studies have shown that long-term right ventricular (RV) overload in animal models alters myocardial energy substrate metabolism. However, whether long-term RV volume overload alters this metabolism in the human is unclear.

Methods and Results
—We performed positron emission tomography with [
18
F]fluorodeoxyglucose (FDG) and single-photon emission tomography (SPECT) with [
201
Tl]TlCl (Tl) and [
123
I]15-(
p
-iodophenyl)-3-
R,S
-methylpentadecanoic acid (BMIPP) in 11 patients with atrial septal defect (ASD) and 11 control subjects. In the FDG study, we calculated myocardial metabolic rate of glucose (MMR) in interventricular septum (IVS) and left ventricular (LV) free wall. MMR was significantly increased in IVS compared with LV free wall in the ASD patients (420±35 versus 333±32 mol · kg
−1
· min
−1
;
P
<0.05) but not in the control group (347±27 versus 357±25 mol · kg
−1
· min
−1
). In both ASD and control groups, SPECT count was not significantly different between IVS and LV free wall in Tl (ASD, 160±11 versus 177±12; control, 141±12 versus 157±14 counts per 15 minutes) and BMIPP studies (ASD, 203±14 versus 212±18; control, 162±16 versus 176±16 counts per 15 minutes). MMR in the IVS/LV free wall ratio in the ASD group significantly correlated with indices related to RV volume overload.

Conclusions
—Given the assumption that long-term RV volume overload did not affect the lumped constant, the present study suggests that, unlike myocardial perfusion or fatty acid analogue uptake, myocardial glucose utilization in IVS relative to LV free wall is increased in relation to long-term RV volume overload in patients with ASD.
Stimulation of Bradykinin B
1
Receptors Induces Vasodilation in Conductance and Resistance Coronary Vessels in Conscious Dogs
Authors: Su Jin Bo , Hoüel Rémi , Héloire François , Barbe Fabrice , Beverelli Fabrizio , Sambin Lucien , Castaigne Alain , Berdeaux Alain , Crozatier Bertrand , Hittinger Luc
Published: June 2012

Background
—Constitutive bradykinin B
1
receptors have been identified in dogs; however, their physiological implications involving the coronary circulation remain to be determined. This study examined, in conscious dogs, the coronary response to des-Arg
9
-bradykinin (a B
1
receptor agonist) and the mechanisms involved.

Methods and Results
—Eleven dogs were instrumented with a left ventricular micromanometer, a circumflex coronary catheter, a cuff occluder, a Doppler flow probe, and ultrasonic crystals to measure coronary blood flow velocity (CBFv) and coronary diameter (CD). Intracoronary des-Arg
9
-bradykinin (3 to 100 ng/kg) and bradykinin (0.1 to 10 ng/kg) did not modify systemic hemodynamics but dose-dependently increased CBFv and CD. Des-Arg
9
-bradykinin was less potent than bradykinin. Hoe 140 (a B
2
antagonist, 10 μg/kg) abolished the effects of bradykinin but did not influence the effects of des-Arg
9
-bradykinin. When CBFv increase was prevented by the cuff occluder, CD responses to bradykinin and des-Arg
9
-bradykinin were maintained. Intracoronary lisinopril (0.75 mg) increased the CD response to bradykinin, with only minimal effect on CBFv, and extended the duration of the effect. Lisinopril did not alter des-Arg
9
-bradykinin responses. Intracoronary
N
ω
-nitro-
l
-arginine (2 mg/kg) decreased the CD effect of bradykinin and prevented the CBFv and CD effects of des-Arg
9
-bradykinin. The relaxing effect of des-Arg
9
-bradykinin on isolated coronary rings was prevented by des-Arg
9
,[Leu
8
]-bradykinin.

Conclusions
—In the conscious dog, B
1
receptors are present in coronary vessels, and their stimulation produces vasodilation in conductance and resistance vessels, which is mediated essentially by NO but not modulated by angiotensin-converting enzyme. However, the coronary vasodilation induced by B
1
receptor stimulation is not as great as that produced by B
2
receptor stimulation.
Relationship of Socioeconomic Status to the Incidence and Prehospital, 28-Day, and 1-Year Mortality Rates of Acute Coronary Events in the FINMONICA Myocardial Infarction Register Study
Authors: Salomaa Veikko , Niemelä Matti , Miettinen Heikki , Ketonen Matti , Immonen-Räihä Pirjo , Koskinen Seppo , Mähönen Markku , Lehto Seppo , Vuorenmaa Tapio , Palomäki Pertti , Mustaniemi Harri , Kaarsalo Esko , Arstila Matti , Torppa Jorma , Kuulasmaa Kari , Puska Pekka , Pyörälä Kalevi , Tuomilehto Jaakko
Published: June 2012

Background
—Low socioeconomic status (SES) is associated with increased coronary heart disease mortality rates. There are, however, very little data on the relation of SES to the incidence, recurrence, and prognosis of myocardial infarction (MI) events.

Methods and Results
—The FINMONICA MI Register recorded detailed information on all MI events among men and women aged 35 to 64 years in 3 areas of Finland during the period of 1983 to 1992. We carried out a record linkage of the MI register data with files of Statistics Finland to obtain information on indicators of SES, such as taxable income and education, for each individual who is registered. In the analyses, income was grouped into 3 categories (low, middle, and high), and education was grouped into 2 categories (basic and secondary or higher). Among men with their first MI event (n=6485), the adjusted incidence rate ratios were 1.67 (95% CI 1.57 to 1.78) and 1.84 (95% CI 1.73 to 1.95) in the low- and middle-income categories compared with the high-income category. For 28-day mortality rates, the corresponding rate ratios were 3.18 (95% CI 2.82 to 3.58) and 2.33 (95% CI 2.03 to 2.68). Significant differentials were observed for prehospital mortality rates, and they remained similar up to 1 year after the MI. Findings among the women were consistent with those among the men.

Conclusions
—The excess coronary heart disease mortality and morbidity rates among persons with low SES are considerable in Finland. To bring the mortality rates of low- and middle-SES groups down to the level of that of the high-SES group constitutes a major public health challenge.
Rate of Change in Aortic Valve Area During a Cardiac Cycle Can Predict the Rate of Hemodynamic Progression of Aortic Stenosis
Authors: Lester Steven J. , McElhinney Doff B. , Miller Joseph P. , Lutz Juergen T. , Otto Catherine M. , Redberg Rita F.
Published: June 2012

Background
—The ability to predict the rate of hemodynamic progression in an individual patient with valvular aortic stenosis has been elusive. The purpose of the present study was to evaluate whether the rate of change in aortic valve area (AVA) measured during the ejection phase of a cardiac cycle predicts the rate of hemodynamic progression in patients with asymptomatic aortic stenosis.

Methods and Results
—In 84 adults with initially asymptomatic aortic stenosis and a baseline AVA of ≥0.9 cm
2
, annual echocardiographic data were obtained prospectively (mean follow-up 2.8±1.3 years). With the initial echocardiogram, the ratio of AVA measured at mid-acceleration and mid-deceleration to the AVA at peak velocity was calculated. The primary outcome variable was the annual rate of change in AVA (rate of progression), with rate of progression classified as rapid (a reduction in AVA of ≥0.2 cm
2
/y) or slow (<0.2 cm
2
/y). Rapid progression was significantly associated with an AVA ratio of ≥1.25 (
P
=0.004, risk ratio 3.1, 95% CI 1.2 to 7.9). The sensitivity, specificity, and positive predictive value of AVA ratio of ≥1.25 for the prediction of rapid progression of valvar aortic stenosis was 64%, 72%, and 80% respectively. The decrease in ejection fraction measured from the initial to final echocardiogram was small but greater for patients with an AVA ratio of ≥1.25 (−4±7% versus +2±7%,
P
<0.001).

Conclusions
—A flow-dependent change in AVA can be measured during a routine transthoracic echocardiographic study. The rate of change in AVA is an additional measure of disease severity and may be used to predict an individual’s risk for subsequent rapid disease progression.
A Method for Determining the Reference Effective Flow Areas for Mechanical Heart Valve Prostheses
Authors: Shandas Robin , Kwon Jeffrey , Valdes-Cruz Lilliam
Published: June 2012

Background
—The anatomic opening area (AOA) is usually reported as the primary index of mechanical heart valve function. Because flow contracts immediately distal to an orifice as a result of the vena contracta effect, AOA may not be a good measure of true effective flow area.

Methods and Results
—Laser flow imaging was used to visualize the contraction in the jet flow stream as it passed through bileaflet mechanical valves under steady and pulsatile conditions. Such visualization allowed clear measurement of the individual vena contracta areas (VCAs) of the 3 valve orifices. VCAs for side orifices were larger (94±2% of AOA) than those through the central orifice (34±8%). Formation of large radial vortices around the leaflet tips constricted the central orifice flow stream and appeared to be the main reason for smaller central VCA. Total VCA remained constant until ≈0.5 orifice diameters (≈1.0 cm) downstream, beyond which cross-sectional area increased as a result of entrainment of receiving chamber flow. Total VCA was larger for steady flow (89.6±2.7% of AOA) than for pulsatile flow (76.3±5.0% of AOA).

Conclusions
—This study further clarifies flow dynamics through bileaflet mechanical valves and provides previously unavailable reference information on VCAs for these valves. Such information should aid clinicians in explaining Doppler-derived and catheter-measured pressure discrepancies, validating clinical techniques for quantifying effective flow areas, and optimizing valve size for implantation. The method should also be useful for comparative studies of different valve designs.
ST-Segment Recovery Adds to the Assessment of TIMI 2 and 3 Flow in Predicting Infarct Wall Motion After Thrombolytic Therapy
Authors: Andrews Jacqueline , Straznicky Ivan T. , French John K. , Green Cindy L. , Maas Arthur C. P. , Lund Mayanna , Krucoff Mitchell W. , White Harvey D.
Published: June 2012

Background
—Early resolution of ST-segment elevation (ST-segment recovery) is associated with an improved outcome after infarction. Whether this relation is present in patients with Thrombolysis In Myocardial Infarction (TIMI) grade 2 or 3 flow (ie, patent) infarct-related arteries is not known.

Methods and Results
—To examine the associations between time to achieve stable 50% ST-segment recovery assessed by continuous ECG monitoring, infarct artery flow, and infarct zone wall motion (at 48 hours), we studied 134 patients who underwent angiography at 99 (interquartile range 92 to 110) minutes after commencing streptokinase, initiated within 12 hours of onset of symptoms of myocardial infarction. Patients with TIMI 2 or 3 flow who failed to achieve early stable ST-segment recovery (50% ST-segment recovery sustained for ≥4 hours with <100 μV change in the peak lead) by 60 or 90 minutes had a higher fraction of chords in the infarct zone >2 SD below normal wall motion (TIMI 2: 55.5% vs 15.3%,
P
=0.006; and 56.5% vs 26.8%,
P
=0.01, respectively; and TIMI 3: 48.8% vs 28.3%,
P
=0.07; and 51.8% vs 29.9%,
P
=0.03, respectively). Time to stable ST-segment recovery was a multivariate predictor of infarct zone wall motion (
P
=0.04) independent of TIMI flow grade and the time from symptom onset to streptokinase therapy.

Conclusions
—In patients with TIMI 2 or 3 flow in infarct-related artery, early stable ST-segment recovery is associated with improved infarct zone wall motion at 48 hours. ST-segment recovery may provide additional information about the degree of myocyte reperfusion achieved in patients with a patent epicardial infarct-related artery after thrombolytic therapy.
CLA-1/SR-BI Is Expressed in Atherosclerotic Lesion Macrophages and Regulated by Activators of Peroxisome Proliferator-Activated Receptors
Authors: Chinetti Giulia , Gbaguidi Franck G. , Griglio Sabine , Mallat Ziad , Antonucci Micheline , Poulain Philippe , Chapman John , Fruchart Jean-Charles , Tedgui Alain , Najib-Fruchart Jamila , Staels Bart
Published: June 2012

Background
—The scavenger receptors are cell-surface receptors for native and modified lipoproteins that play a critical role in the accumulation of lipids by macrophages. CLA-1/SR-BI binds HDL with high affinity and is involved in the cholesterol reverse-transport pathway. Peroxisome proliferator–activated receptors (PPARs) are transcription factors regulating the expression of genes implicated in lipid metabolism, cellular differentiation, and inflammation. Here, we investigated the expression of CLA-1/SR-BI in macrophages and its regulation by PPARs.

Methods and Results
—CLA-1 is undetectable in human monocytes and is induced upon differentiation into macrophages. Immunohistological analysis on human atherosclerotic lesions showed high expression of CLA-1 in macrophages of the lipid core colocalizing with PPARα and PPARγ staining. Activation of PPARα and PPARγ resulted in the induction of CLA-1 protein expression in monocytes and in differentiated macrophages. Finally, SR-BI expression is increased in atherosclerotic lesions of apoE-null mice treated with either PPARγ or PPARα ligands.

Conclusions
—Our data demonstrate that CLA-1/SR-BI is expressed in atherosclerotic lesion macrophages and induced by PPAR activation, identifying a potential role for PPARs in cholesterol homeostasis in atherosclerotic lesion macrophages.
99m
Tc-N-NOET Myocardial Uptake Reflects Myocardial Blood Flow and Not Viability in Dogs With Reperfused Acute Myocardial Infarction
Authors: Vanzetto Gérald , Glover David K. , Ruiz Mirta , Calnon Dennis A. , Pasqualini Roberto , Watson Denny D. , Beller George A.
Published: June 2012

Background
—
N
-Ethoxy-
N
-ethyl-dithiocarbamato-nitrido-
99m
Tc (
99m
Tc-N-NOET) is a new neutral lipophilic
99m
Tc-labeled myocardial perfusion agent with a high first-pass extraction fraction and delayed redistribution kinetics after transient ischemia comparable to what is observed with
201
Tl. It is unknown whether the uptake of this tracer reflects myocardial viability or just reperfusion flow in the setting of a reperfused myocardial infarction.

Methods and Results
—In 13 anesthetized open-chest dogs, the left anterior descending coronary artery was occluded for 180 minutes, followed by 180 minutes of reperfusion.
201
Tl and
99m
Tc-N-NOET were injected after either 60 (group 1, n=9) or 175 (group 2, n=4) minutes of reperfusion. Myocardial blood flow was measured by radioactive microspheres, and
201
Tl and
99m
Tc-N-NOET tissue activities were determined by gamma-well counting. Normalized myocardial blood flow in the central infarct zone fell from 0.80±0.03 (SEM) and 0.89±0.01 at baseline to 0.18±0.04 and 0.13±0.02 during the occlusion in groups 1 and 2, respectively. Normalized
201
Tl activity in these segments was 0.39±0.04 and 0.43±0.04 and reflected myocardial viability rather than reperfusion flow (
P
<0.001). Normalized
99m
Tc-N-NOET activity in the same segments was 0.84±0.08 and 0.64±0.03, respectively (
P
<0.01 versus
201
Tl;
P
=NS versus reperfusion flow) and more accurately reflected reperfusion flow (0.99±0.17 and 0.70±0.04) than residual viability.

Conclusions
—The myocardial uptake of
99m
Tc-N-NOET reflects reperfusion myocardial blood flow and not viability in a canine model of reperfused acute myocardial infarction. The clinical use of early
99m
Tc-N-NOET imaging to assess the success of coronary reperfusion in patients with acute myocardial infarction should be investigated.
Mechanism of Ventricular Defibrillation
Authors: Gillis Anne M. , Fast Vladimir G. , Rohr Stephan , Kléber André G.
Published: June 2012

Background
—The geometry of the myocardium may influence changes in transmembrane potential (ΔVm) during defibrillation. To test this hypothesis, specific nonlinear structures (bifurcations, expansions, and curved strands or “bends”) were created in patterned cultures of neonatal rat myocytes.

Methods and Results
—Extracellular field stimuli (EFS; 7 to 11 V/cm field strength) were applied parallel to the strands. Changes in Vm were measured with microscopic resolution using optical mapping techniques. In bifurcations, EFS produced 2 ΔVm maxima (so-called secondary sources) at the shoulder of each limb that were separated by a decrease of either hyperpolarization or depolarization at the insertion of the stem strand. In expansions, EFS produced a significant decrease in ΔVm at the insertion site of the expansion compared with the ΔVm maxima measured at the lateral borders. In 50% of experiments, tertiary sources of opposite polarity appeared in the strand due to local electrotonic currents. New action potentials were propagated from the sites of ΔVm maxima located at the lateral borders of the expansions. In bends, the strand oriented in parallel to the field dominated electrotonically and partially cancelled the sources produced by the perpendicular segment.

Conclusions
—In electrically well-coupled nonlinear structures, EFS produced changes in Vm at resistive boundaries that were determined by the electrotonic interaction between sources of different, direction-dependent strength. In addition, the interaction between localized secondary sources at nonlinear boundaries generated local current circuits, which gave rise to further changes in Vm (tertiary sources).
Linkage of the Cholesteryl Ester Transfer Protein (
CETP
) Gene to LDL Particle Size
Authors: Talmud Philippa J. , Edwards Karen L. , Turner Clare M. , Newman Beth , Palmen Jutta M. , Humphries Steve E. , Austin Melissa A.
Published: June 2012

Background
—A preponderance of small, dense LDL particles, elevated levels of plasma triglycerides (TG), and low levels of HDL characterize the atherogenic lipoprotein phenotype, which is associated with increased coronary artery disease (CAD) risk. Genetic and environmental factors influence LDL size, cholesteryl ester transfer protein (
CETP
) being one of the candidate genes. CETP mediates the transfer of cholesteryl ester from HDL to apolipoprotein (apo) B–containing lipoproteins in exchange for TG, promoting reverse cholesterol transfer and remodeling of lipoprotein particles.

Methods and Results
—We have identified a tetranucleotide repeat (fragment sizes from 324 to 464 bp; heterozygosity index=0.74) within the
CETP
promoter and used it in quantitative sib-pair linkage analysis in 119 female dizygotic (DZ) twins. Linkage was found to LDL size (
P
<0.001), TG (
P
<0.005), and plasma apoB (
P
=0.02). The distribution of the tetranucleotide repeats was bimodal, and there was strong allelic association of the “short” alleles with the B2 allele of
CETP
TaqIB polymorphic site (
P
<0.001).

Conclusions
—This report of linkage of the
CETP
gene to LDL particle size adds to the list of candidate genes linked to LDL size, supporting the hypothesis of multigenic determination of LDL size heterogeneity. Whether this promoter variation is itself functional or is a marker for a functional site in the
CETP
gene remains to be determined.
Coronary Nitric Oxide Production in Response to Exercise and Endothelium-Dependent Agonists
Authors: Traverse Jay H. , Wang Yale L. , Du Ruisheng , Nelson Daniel , Lindstrom Paul , Archer Stephen L. , Gong Guangrong , Bache Robert J.
Published: June 2012

Background
—Endothelium-derived nitric oxide (NO) contributes to epicardial coronary artery vasodilation during exercise. However, blockade of NO production does not impair the increase in coronary blood flow (CBF) during exercise, suggesting that NO is not obligatory for exercise-induced coronary resistance vessel dilation. In contrast, the increases in CBF produced by endothelium-dependent agonists are decreased after NO blockade. Consequently, this study was performed to determine whether the increase in coronary NO production in response to agonists is greater than that which occurs during exercise.

Methods and Results
—We measured the oxidation products of NO (nitrate+nitrite=NO
x
) in aortic and coronary sinus plasma using chemiluminescence to assess NO
x
production across the coronary circulation in chronically instrumented dogs during a 3-stage treadmill exercise protocol and in response to intracoronary administration of the endothelium-dependent agonists acetylcholine (37.5 μg/min) and bradykinin (3.0 μg/min). No coronary NO
x
production could be detected at rest or during the first 2 stages of exercise; only at the highest level of exercise was a small increase in coronary NO
x
production measured. In contrast, coronary production of NO
x
was significantly increased in response to endothelium-dependent agonists.

Conclusions
—Coronary NO production in response to endothelium-dependent agonists is greater than in response to the increase in shear stress associated with exercise. These findings support previous studies suggesting that NO is not required for the coronary vasodilation that occurs in the normal heart during exercise.
Effect of Distension of the Gallbladder on Plasma Renin Activity in Anesthetized Pigs
Authors: Molinari Claudio , Grossini Elena , Mary David A. S. G. , Vacca Giovanni
Published: June 2012

Background
—Gallbladder pathology has been associated with cardiovascular disease. Recently, we showed that gallbladder distension in anesthetized pigs reflexly increased heart rate, arterial pressure, and coronary and renal vascular resistance through efferent sympathetic mechanisms. Renin release is affected by sympathetic output, and angiotensin liberation may result in vasoconstriction. This study was undertaken to determine whether gallbladder distension primarily causes a reflex change in plasma renin activity (PRA) and to assess its influence on observed pressor and coronary responses as well as on regional vascular resistance.

Methods and Results
—In 34 α-chloralose–anesthetized pigs, balloons positioned within the gallbladder were distended for 30 minutes with volumes of Ringer’s solution equal to those of withdrawn bile. In 19 pigs, gallbladder distension at constant heart rate, arterial pressure, and renal flow increased PRA in the absence of changes in urinary sodium excretion. This increase was abolished by cervical vagotomy, section of renal nerves, or blockade of β-adrenergic receptors. In another 15 pigs, blockade of angiotensin II receptors significantly attenuated the pressor and coronary, mesenteric, and iliac vasoconstriction responses to gallbladder distension.

Conclusions
—The present study showed that innocuous gallbladder distension primarily caused a reflex increase in PRA. This increase, which involved afferent vagal pathways and efferent sympathetic mechanisms related to β-adrenergic receptors, contributed significantly to the pressor and coronary, mesenteric, and iliac vasoconstriction responses to gallbladder distension.
Echocardiographic Destruction of Albumin Microbubbles Directs Gene Delivery to the Myocardium
Authors: Shohet Ralph V. , Chen Shuyuan , Zhou Yan-Ting , Wang Zhuowei , Meidell Robert S. , Unger Roger H. , Grayburn Paul A.
Published: June 2012

Background
—The noninvasive, tissue-specific delivery of therapeutic agents to the heart would be a valuable clinical tool. This study addressed the hypothesis that albumin-coated microbubbles could be used to effectively deliver an adenoviral transgene to rat myocardium by ultrasound-mediated microbubble destruction.

Methods and Results
—Recombinant adenovirus containing β-galactosidase and driven by a constitutive promoter was attached to the surface of albumin-coated, perfluoropropane-filled microbubbles. These bubbles were infused into the jugular vein of rats with or without simultaneous echocardiography. Additional controls included ultrasound of microbubbles that did not contain virus, virus alone, and virus plus ultrasound. One group underwent ultrasound-mediated destruction of microbubbles followed by adenovirus infusion. Rats were killed after 4 days and examined for β-galactosidase expression. The hearts of all rats that underwent ultrasound-mediated destruction of microbubbles containing virus showed nuclear staining with 5-bromo-4-chloro-3-indolyl-β-
d
-galactopyranoside substrate, indicating expression of the transgene. None of the control animals showed myocardial expression of the β-galactosidase transgene. By quantitative analysis, β-galactosidase activity was 10-fold higher in the treated group than in controls (
P
<0.0001).

Conclusions
—Ultrasound-mediated destruction of albumin-coated microbubbles is a promising method for the delivery of bioactive agents to the heart.