bluuebunny/crossref_metadata_2025 huggingface dataset:
Evidence for Preserved Cardiopulmonary Baroreflex Control of Renal Cortical Blood Flow in Humans With Advanced Heart Failure
Authors: Middlekauff Holly R. , Nitzsche Egbert U. , Hamilton Michèle A. , Schelbert Heinrich R. , Fonarow Gregg C. , Moriguchi Jaime D. , Hage Antoine , Saleh Saleh , Gibbs G. Gary
Published: June 2012

Background
The effect of cardiopulmonary baroreflexes on the renal circulation in healthy humans and patients with heart failure is unknown because of the technical limitations of studying the renal circulation. Positron emission tomography (PET) imaging is a new method to measure renal cortical blood flow in humans that is precise, rapid, reproducible, and noninvasive. The purpose of this study was to compare the effect of acute cardiopulmonary baroreceptor unloading by phlebotomy on regional blood flow in healthy humans and humans with advanced heart failure.

Methods and Results
We compared renal cortical blood flow and forearm blood flow in 10 healthy volunteers and 8 patients with heart failure (left ventricular ejection fraction, 0.24±0.02) during cardiopulmonary baroreceptor unloading with phlebotomy (450 mL). The major findings of this study are: (1) At rest, renal cortical blood flow is markedly diminished in humans with heart failure compared with healthy humans (heart failure, 2.4±0.1 versus healthy, 4.3±0.2 mL · min
−1
· g
−1
,
P
<.001). (2) In healthy humans, during phlebotomy, forearm blood flow decreased substantially (basal, 3.3±0.4 versus phlebotomy, 2.6±0.3 mL · min
−1
· 100 mL
−1
,
P
=.02) and renal cortical blood flow decreased slightly but significantly (basal, 4.3±0.2 versus phlebotomy, 4.0±0.3 mL · min
−1
· g
−1
,
P
=.01). (3) The small magnitude of reflex renal vasoconstriction is not explained by the inability of the renal circulation to vasoconstrict, since the cold pressor stimulus induced substantial decreases in renal cortical blood flow in healthy subjects (basal, 4.4±0.1 versus cold pressor, 3.7±0.1 mL · min
−1
· g
−1
,
P
=.003). (4) In humans with heart failure, during phlebotomy, forearm blood flow did not change (basal, 2.6±0.3 versus phlebotomy, 2.7±0.2 mL · min
−1
· 100 mL
−1
,
P
=NS), but renal cortical blood flow decreased slightly but significantly (basal, 2.4±0.1 versus phlebotomy, 2.1±0.1 mL · min
−1
· g
−1
,
P
=.01). (5) The cold pressor stimulus induced substantial decreases in renal cortical blood flow in patients with heart failure (basal, 2.9±0.1 versus cold pressor, 2.3±0.1 mL · min
−1
· g
−1
,
P
=.008). Thus, in patients with heart failure, there is an abnormality in cardiopulmonary baroreflex control of the forearm circulation but not the renal circulation.

Conclusions
This study demonstrates the power of PET imaging to study normal physiological and pathophysiological reflex control of the renal circulation in humans and describes the novel finding of selective dysfunction of cardiopulmonary baroreflex control of one vascular region but its preservation in another in patients with heart failure.
Cardiac Release of Cytokines and Inflammatory Responses in Acute Myocardial Infarction
Authors: Neumann Franz-Josef , Ott Ilka , Gawaz Meinrad , Richardt Gert , Holzapfel Heidi , Jochum Marianne , Schömig Albert
Published: June 2012

Background
In animal models of myocardial infarction (MI), inflammatory responses compromise microcirculation during reperfusion and restrict functional recovery. To investigate cardiac inflammatory responses in patients with acute MI, we examined the cardiac release of cytokines, the expression on neutrophils of the β
2
-integrin Mac-1 (CD11b/CD18) and L-selectin (CD62L), and the cardiac release of thrombomodulin as a marker of endothelial injury.

Methods and Results
In 12 patients with acute anterior MI, blood samples were obtained from the coronary sinus and from the aorta immediately before and after recanalization of the coronary occlusion by balloon angioplasty. Twelve patients undergoing elective balloon angioplasty served as control subjects. Plasma concentrations of interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor-α, and thrombomodulin were determined by immunoassay, and surface expression of CD11b and CD62L was assessed by flow cytometry. Differences in coronary sinus and arterial blood were found in IL-6 before (median, 6.3 ng/L,
P
=.01) and after (13.4 ng/L,
P
=.002) recanalization and in IL-8 after recanalization (10.7 ng/L,
P
=.02). The cardiac release of both cytokines significantly (
P
≤.03) increased with reperfusion. Cytokine release after reperfusion was associated with significant transcardiac gradients in surface expression on neutrophils of CD11b (10.1 mean channel of fluorescence intensity [mean fl],
P
=.01) and CD62L (−8.7 mean fl,
P
=.007) and with a thrombomodulin release (4.5 μg/L,
P
=.004). Transcardiac gradients in IL-1β and tumor necrosis factor-α were not found. None of the changes found in MI were detectable in the control group.

Conclusions
As evidence of cardiac inflammatory responses in reperfused acute MI, the study demonstrates cardiac neutrophil activation with signs of endothelial injury and a release of the proinflammatory cytokines IL-8 and IL-6. These findings may assist in the design of pharmacological interventions aimed at reducing microvascular reperfusion injury.
Repeat Dilation of Intravascular Stents in Congenital Heart Defects
Authors: Ing Frank F. , Grifka Ronald G. , Nihill Michael R. , Mullins Charles E.
Published: June 2012

Background
Intravascular (Palmaz) stents have been successfully implanted in patients with congenital and acquired branch pulmonary stenosis. Early results are excellent; however, there is no information on restenosis and repeat dilation in patients with congenital heart disease. The purpose of this study is to review the incidence of restenosis and demonstrate the safety and efficacy of repeat dilation of stents in this group of patients.

Methods and Results
Of 94 patients with 163 implanted stents in this single-center study, 43 patients with 73 implanted stents underwent recatheterization. Only 2 of 73 restudied stents (3%) developed significant restenosis. In 20 patients, 30 stents were redilated. At stent implantation, the mean age of this subgroup was 14.2 years, the mean intraluminal diameter increased from 4.9 to 10.7 mm (
P
=.0001), and the systolic gradient (mean) across the stent decreased from 52 to 11 mm Hg (
P
=.0001). At recatheterization (mean, 13 months), all stents were patent. The mean diameter decreased by 1.2 mm (
P
=.0001), but the increase in the gradient (mean, 3 mm Hg) was not significant (
P
=.11). After repeat dilation, the diameter increased from 9.5 to 12.2 mm (
P
=.0001), and the gradient decreased from 14 to 8 mm Hg (
P
=.0003). The 2 stents with restenosis were redilated successfully. Two patients underwent a successful second redilation of 3 stents at 18 and 26 months. There were no complications.

Conclusions
All stents remained patent. The occurrence of significant restenosis is low (3%), and these restenoses can be redilated and/or restented. Repeat dilation of the Palmaz stent implanted in branch pulmonary artery stenosis can be performed with safety and efficacy (94% success rate) up to 3 years after stent implantation.
Benefit of Thrombolytic Therapy Is Sustained Throughout Five Years and Is Related to TIMI Perfusion Grade 3 But Not Grade 2 Flow at Discharge
Authors: Lenderink Timo , Simoons Maarten L. , Van Es Gerrit-Anne , Van de Werf Frans , Verstraete Marc , Arnold Alf E.R.
Published: June 2012

Background
Long-term follow-up in patients treated with thrombolysis for acute myocardial infarction thus far has been reported in a few studies only, and no long-term follow-up is available for patients who underwent additional percutaneous transluminal coronary angioplasty (PTCA). This report describes 5-year survival as collected in patients who received placebo, recombinant tissue plasminogen activator (rTPA), or rTPA with additional immediate PTCA in two European Cooperative Study Group trials. Determinants for long-term survival were assessed in 1043 patients discharged alive.

Methods and Results
Five-year follow-up information on mortality was collected. Hospital mortality was lower after rTPA than placebo (2.5% versus 5.7%,
P
=.04) and higher after rTPA with immediate PTCA compared with rTPA without additional intervention (6.0% versus 2.2%,
P
=.07). Of the 1043 hospital survivors, data were available for 923 patients, of whom 109 died. In the placebo group, mortality after hospital discharge was 10.7% versus 11.0% in the comparative rTPA group. The patients treated with rTPA and immediate PTCA had a mortality rate of 10.5% versus 8.9% in the rTPA group without PTCA (all
P
=NS). Significant determinants of mortality in multivariate proportional hazards analysis were enzymatic infarct size, indicators of residual left ventricular function, number of diseased vessels and TIMI perfusion grade at discharge. Patients with TIMI grade 2 flow had mortality rates similar to those with TIMI flow grades 0 and 1, while prognosis was better in patients with TIMI flow grade 3.

Conclusions
The initial in-hospital benefit of thrombolysis with intravenous rTPA is maintained throughout 5 years, with no early or late beneficial effect of systematic immediate PTCA. Enzymatic infarct size, left ventricular function, and extent of coronary artery disease are predictors for long-term survival. TIMI perfusion grade 2 at discharge should be considered as an inadequate result of therapy.
Influence of Preexistent Donor Coronary Artery Disease on the Progression of Transplant Vasculopathy
Authors: Botas Javier , Pinto Fausto J. , Chenzbraun Adrian , Liang David , Schroeder John S. , Oesterle Stephen N. , Alderman Edwin L. , Popp Richard L. , Yeung Alan C.
Published: June 2012

Background
Transplant vasculopathy (TxCAD) limits long-term survival of allograft recipients. The possibility that preexistent donor coronary disease (PEDD) might accelerate this process is of concern. The serial progression of sites with and without PEDD as assessed by intravascular ultrasonic imaging is explored in this study.

Methods and Results
Thirty patients with baseline intravascular imaging within 3 weeks of cardiac transplantation who had at least one annual follow-up study were included in this study. Vessel luminal area (LA), total area (TA), intimal index (II=TA−LA/TA), mean intimal thickness (MIT), and Stanford classification were expressed for each image site and for each patient at each study. Progression of sites and of patients with and without PEDD on the baseline study was compared. Patients with PEDD (n=9) still had significantly more intimal disease than those without PEDD (n=21) at the first follow-up study (MIT=0.35±0.13 versus 0.13±0.11 mm; II=0.29±0.11 versus 0.11±0.1; class=3.7±0.5 versus 2.2±0.94;
P
<.001 for all comparisons). However, the increase in intimal thickness during the 1- year interval was not significantly different between the two groups. In 4 patients in whom both types of sites were present, no difference in progression was found. Data were similar for patients and sites studied over >1 year.

Conclusions
PEDD does not accelerate the progression of TxCAD within the first few years after cardiac transplantation. The pathophysiology of TxCAD is most likely immune mediated and does not seem to be accelerated by native coronary artery disease.
Smooth Muscle Cell Proliferation Is Proportional to the Degree of Balloon Injury in a Rat Model of Angioplasty
Authors: Indolfi Ciro , Esposito Giovanni , Di Lorenzo Emilio , Rapacciuolo Antonio , Feliciello Antonio , Porcellini Antonio , Avvedimento Vittorio E. , Condorelli Mario , Chiariello Massimo
Published: June 2012

Background
A variable degree of smooth muscle cell (SMC) proliferation after balloon injury has been reported in previous rat studies. It is unknown whether balloon injury induces c-
fos
expression and whether it is related to the degree of vascular injury in vivo. Therefore, we tested the hypothesis that proportional increases in neointimal formation and c-
fos
expression might be present after different degrees of balloon dilation.

Methods and Results
Angioplasty of the carotid artery was performed with a balloon catheter. Vascular injury was evaluated at 0, 0.5, 1.0, 1.5, and 2 atm (n=6 for all). In 40 additional rats, total RNA dot blots were performed to assess the effect of various degrees of balloon injury on c-
fos
expression. SMC proliferation proportional to the increases of inflation pressure was found between 0 and 2 atm with neointimal areas of 0.002±0.002, 0.069±0.014, 0.128±0.043, 0.190±0.010, and 0.255±0.041 mm
2
, respectively. When the degree of SMC proliferation (neointima and neointima/media ratio) was plotted against balloon inflation pressure, a linear relation was observed (
r
=.733,
P
<.001 and
r
=.755,
P
<.001, respectively). An increase in c-
fos
expression proportional to the degree of injury was found 30 minutes after injury.

Conclusions
Neointimal proliferation produced by balloon injury is related to balloon inflation pressure, supporting the concept of an SMC proliferative response proportional to the degree of injury. The increase in SMC proliferation is associated with a proportional increase in the early expression of the c-
fos
nuclear proto-oncogene.
VCL, an Antagonist of the Platelet GP1b Receptor, Markedly Inhibits Platelet Adhesion and Intimal Thickening After Balloon Injury in the Rat
Authors: Zahger Doron , Fishbein Michael C. , Garfinkel Leonard I. , Shah Prediman K. , Forrester James S. , Regnstrom Jan , Yano Juliana , Cercek Bojan
Published: June 2012

Background
Arterial injury is immediately followed by platelet adhesion at the site of injury, a process that requires the interaction of subendothelial von Willebrand factor with the platelet GP1b receptor. VCL, a recombinant von Willebrand factor GP1b binding domain, inhibits platelet binding to von Willebrand factor. The aim of this study was to determine whether VCL inhibits platelet adhesion at the site of arterial injury and affects neointimal thickening after injury in rats.

Methods and Results
Sprague-Dawley rats were randomized to receive VCL, 4 mg/kg bolus followed by a continuous infusion of 2 mg · kg
−1
· h
−1
for 72 hours, or an identical volume of saline. Balloon injury of the femoral artery was performed 15 minutes after the initial bolus injection of VCL. Scanning electron microscopy performed 1 and 3 days after injury indicated that VCL-treated rats had >80% reduction in the number of platelets adherent to the vessel wall at the site of injury compared with controls (
P
<.003). Histological examination at day 14 showed that, compared with controls, VCL-treated rats had a 60% reduction in the intima-media ratio (0.21±0.03 versus 0.53±0.06,
P
=.001) and a reduced luminal area stenosis (12±3% versus 38±10%,
P
=.04). At 28 days after injury, there was no rebound of neointimal thickening in VCL-treated rats (intima-media ratio, 0.19±0.04; luminal stenosis, 17±5%). The difference between VCL-treated rats and control rats persisted but was attenuated (intima-media ratio, 0.19±0.04 versus 0.28±.0.1,
P
=.162; luminal stenosis, 17±5% versus 31±5%,
P
=.058) as neointimal thickening regressed in untreated rats. With the use of proliferating cell nuclear antigen immunohistochemistry on day 3, VCL had no effect on smooth muscle cell (SMC) proliferation.

Conclusions
Antagonism of the platelet GP1b receptor by VCL profoundly decreased platelet deposition at the site of balloon injury in the rat femoral artery. This effect was associated with a persistent reduction in neointimal thickening. The lack of effect of VCL on SMC proliferation suggests that the decrease in neointimal thickening may have been mediated through inhibition of SMC migration and/or modulation of the extracellular matrix.
Isolated Systolic and Diastolic Ventricular Interactions in Pacing-Induced Dilated Cardiomyopathy and Effects of Volume Loading and Pericardium
Authors: Farrar David J. , Chow Edna , Brown Craig D.
Published: June 2012

Background
Interactions between the closely coupled right and left ventricles are known to play important roles as determinants of ventricular function, and the purpose of this study was to evaluate their effects in a model of heart failure.

Methods and Results
A dilated cardiomyopathy resulting in congestive heart failure (CHF) was produced in pigs by rapid ventricular pacing at 230 beats per minute for 1 week. Blood was rapidly withdrawn from the left ventricular (LV) apex into a prosthetic ventricle, and the instantaneous effects on the right ventricle were studied during volume loading and before and after pericardiectomy. The systolic interaction gain between the right and left ventricles (G
s
) was calculated as the ratio of changes in mean systolic pressure during isolated systolic LV unloading. Diastolic ventricular interaction gain (G
d
) was calculated as the ratio of changes in mean diastolic pressures during LV unloading in the last 150 ms of diastole. With the pericardium closed, all interaction gains were significantly increased during volume loading from a right ventricular end-diastolic pressure of 3 to 9 mm Hg: G
s
from 0.045±0.014 to 0.063±0.020 mm Hg/mm Hg (normal pigs) and from 0.077±0.040 to 0.103±0.019 (CHF pigs) and G
d
from 0.196±0.116 to 0.493±0.117 mm Hg/mm Hg (normal pigs) and from 0.174±0.101 to 0.341±0.165 (CHF pigs). When the pericardium was opened, G
d
was significantly reduced to 0.145±0.071 and 0.129±0.026 mm Hg/mm Hg (normal and CHF pigs, respectively), but G
s
showed no significant change (0.067±0.027 and 0.109±0.012 mm Hg/mm Hg for normal and CHF pigs, respectively), and both were also significantly increased during volume loading. G
s
was significantly greater in CHF versus normal pigs under all conditions, but there were no differences in G
d
between CHF and normal pigs.

Conclusions
These results suggest that dilated cardiomyopathy increases systolic but not diastolic interactions, that the pericardium increases diastolic but not systolic ventricular interactions, and that volume loading with and without the pericardium opened increases both systolic and diastolic interactions.
Blockade of Vasospastic Attacks by α
2
-Adrenergic but Not α
1
-Adrenergic Antagonists in Idiopathic Raynaud’s Disease
Authors: Freedman Robert R. , Baer Rachel P. , Mayes Maureen D.
Published: June 2012

Background
Idiopathic Raynaud’s disease is characterized by cold-induced digital vasospasms, but its origin has not been established. Previous research has shown that peripheral vascular α
2
-adrenergic receptors are hypersensitive to local cooling in these patients, but the role of α
1
-adrenergic receptors is not clear. Moreover, the role of adrenergic receptors in the production of actual vasospastic symptoms has not been investigated.

Methods and Results
We studied 23 patients with idiopathic Raynaud’s disease who were screened using conservative criteria. They were randomly assigned to receive brachial artery infusions of an α
1
-antagonist, an α
2
-antagonist, or both while vasospastic attacks were induced by cooling in the laboratory. Each patient’s hands were photographed, and the number of attacks in the infused hand was compared with the number in the contralateral hand. The number of fingers (mean±SEM) with attacks in infused hands was yohimbine 0.3±0.3, prazosin 2.3±0.3, and both drugs 0.6±0.2. The difference between prazosin and the other two drug groups was significant (
P
<.001).

Conclusions
These findings demonstrate that activation of α
2
-adrenergic receptors but not α
1
-adrenergic receptors is necessary for the production of vasospastic attacks in idiopathic Raynaud’s disease.
Double-Blind, Placebo-Controlled Study of the Long-term Efficacy of Carvedilol in Patients With Severe Chronic Heart Failure
Authors: Krum Henry , Sackner-Bernstein Jonathan D. , Goldsmith Rochelle L. , Kukin Marrick L. , Schwartz Brian , Penn Joshua , Medina Norma , Yushak Madeline , Horn Evelyn , Katz Stuart D. , Levin Howard R. , Neuberg Gerald W. , DeLong Greg , Packer Milton
Published: June 2012

Background
Clinical trials have shown that β-adrenergic blocking drugs are effective and well tolerated in patients with mild to moderate heart failure, but the utility and safety of these drugs in patients with advanced disease have not been evaluated.

Methods and Results
We enrolled 56 patients with severe chronic heart failure into a double-blind, placebo-controlled study of the vasodilating β-blocker carvedilol. All patients had advanced heart failure, as evidenced by a mean left ventricular ejection fraction of 0.16±0.01 and a mean maximal oxygen consumption of 13.6±0.6 mL · kg
−1
· min
−1
despite digitalis, diuretics, and an angiotensin-converting enzyme inhibitor (if tolerated). After a 3-week, open-label, up-titration period, 49 of the 56 patients were assigned (in a double-blind fashion using a 2:1 randomization) to receive either carvedilol (25 mg BID, n=33) or matching placebo (n=16) for 14 weeks, while background therapy remained constant. Hemodynamic and functional variables were measured at the start and end of the study. Compared with the placebo group, patients in the carvedilol group showed improved cardiac performance, as reflected by an increase in left ventricular ejection fraction (
P
=.005) and stroke volume index (
P
=.010) and a decrease in pulmonary wedge pressure, mean right atrial pressure, and systemic vascular resistance (
P
=.003, .002, and .017, respectively). In addition, compared with placebo, patients treated with carvedilol benefited clinically, as shown by an improvement in symptom scores (
P
=.002), functional class (
P
=.013), and submaximal exercise tolerance (
P
=.006). The combined risk of death, worsening heart failure, and life-threatening ventricular tachyarrhythmia was lower in the carvedilol group than in the placebo group (
P
=.028), but carvedilol-treated patients had more dizziness and advanced heart block.

Conclusions
Carvedilol produces clinical and hemodynamic improvement in patients who have severe heart failure despite treatment with angiotensin-converting enzyme inhibitors.
Myogenic Reactivity of Coronary Resistance Arteries After Cardiopulmonary Bypass and Hyperkalemic Cardioplegia
Authors: Wang Steven Y. , Friedman Menachem , Franklin Alvin , Sellke Frank W.
Published: June 2012

Background
Cardiopulmonary bypass (CPB) and cardioplegia are associated with systemic hypotension and altered vascular responses, suggesting a defect in the smooth muscle control of vascular tone. Previous studies demonstrated alteration in neurohumoral control of the systemic and coronary circulation after CPB and cardioplegia; however, effects of CPB and cardioplegia on the intrinsic control of the vascular smooth muscle, especially in the coronary microcirculation, remain to be determined.

Methods and Results
Pigs were placed on CPB. Selected hearts were arrested with a cold, hyperkalemic ([K
+
]=25 mmol/L) crystalloid cardioplegic solution for 1 hour. In another group, hearts were arrested and then reperfused with warm blood for 1 hour. Coronary arterioles (70 to 149 μm) were studied in a pressurized, no-flow state with video microscopy. Myogenic reactivity was examined to stepwise increases in intraluminal pressure from 10 to 100 mm Hg. The vessel diameter was normalized to the diameter at 50 mm Hg after application of papaverine (10
−4
mol/L). Myogenic reactivity of vessels from noninstrumented control pigs was not altered after mechanical denudation of the endothelium or pretreatment with
N
G
-nitro-
l
-arginine or indomethacin. In vessels from control pigs and vessels from the CPB group, myogenic contraction was observed with pressures >40 mm Hg. However, CPB significantly decreased intrinsic tone as the pressure-diameter relation shifted upward (
P
<.05 versus control). This decreased intrinsic tone was markedly attenuated by
N
G
-nitro-
l
-arginine, suggesting an increased basal release of nitric oxide. Cardioplegic arrest, with or without reperfusion, decreased myogenic contraction to pressures >40 mm Hg (
P
<.05 versus control). Pretreatment of vessels with glybenclamide normalized the cardioplegia-induced decrease in myogenic contraction (
P
<.05), suggesting that the reduced myogenic contraction is due to activation of ATP-sensitive potassium channels.

Conclusions
The result of the present study suggests that coronary microvascular myogenic reactivity and the intrinsic tone are reduced after hyperkalemic cardioplegia and that CPB preserves myogenic reactivity but reduces the intrinsic tone of the vascular smooth muscle.
Triggering of Acute Myocardial Infarction Onset by Episodes of Anger
Authors: Mittleman Murray A. , Maclure Malcolm , Sherwood Jane B. , Mulry Richard P. , Tofler Geoffrey H. , Jacobs Sue C. , Friedman Richard , Benson Herbert , Muller James E.
Published: June 2012

Background
Many anecdotes and several uncontrolled case series have suggested that emotionally stressful events, and more specifically, anger, immediately precede and appear to trigger the onset of acute myocardial infarction. However, controlled studies to determine the relative risk of myocardial infarction after episodes of anger have not been reported.

Methods and Results
We interviewed 1623 patients (501 women) an average of 4 days after myocardial infarction. The interview identified the time, place, and quality of myocardial infarction pain and other symptoms, the estimated usual frequency of anger during the previous year, and the intensity and timing of anger and other potentially triggering factors during the 26 hours before the onset of myocardial infarction. Anger was assessed by the onset anger scale, a single-item, seven-level, self-report scale, and the state anger subscale of the State-Trait Personality Inventory. Occurrence of anger in the 2 hours preceding the onset of myocardial infarction was compared with its expected frequency using two types of self-matched control data based on the case-crossover study design. The onset anger scale identified 39 patients with episodes of anger in the 2 hours before the onset of myocardial infarction. The relative risk of myocardial infarction in the 2 hours after an episode of anger was 2.3 (95% confidence interval, 1.7 to 3.2). The state anger subscale corroborated these findings with a relative risk of 1.9 (95% confidence interval, 1.3 to 2.7). Regular users of aspirin had a significantly lower relative risk (1.4; 95% confidence interval, 0.8 to 2.6) than nonusers (2.9; 95% confidence interval, 2.0 to 4.1) (
P
<.05).

Conclusions
Episodes of anger are capable of triggering the onset of acute myocardial infarction, but aspirin may reduce this risk. A better understanding of the manner in which external events trigger the onset of acute cardiovascular events may lead to innovative preventive strategies aimed at severing the link between these external stressors and their pathological consequences.
Soluble P-Selectin Is Released Into the Coronary Circulation After Coronary Spasm
Authors: Kaikita Koichi , Ogawa Hisao , Yasue Hirofumi , Sakamoto Tomohiro , Suefuji Hisakazu , Sumida Hitoshi , Okumura Ken
Published: June 2012

Background
The glycoprotein P-selectin is an adhesion molecule involved in the property change of leukocytes at the initiation of the inflammatory process. The purpose of the present study was to determine whether acute myocardial ischemia induced by coronary spasm causes an acute inflammatory response in the coronary circulation.

Methods and Results
We examined plasma soluble P-selectin levels in the coronary sinus and the aortic root simultaneously in 16 patients with coronary spastic angina before and after left coronary artery spasm induced by intracoronary injection of acetylcholine and in 15 patients with stable exertional angina before and after acute myocardial ischemia induced by rapid atrial pacing. Ten control patients with chest pain but normal coronary arteries and no coronary spasm also received intracoronary acetylcholine. Plasma soluble P-selectin levels were increased significantly in the coronary sinus (32.8±3.6 to 52.8±5.9 ng/mL,
P
<.001) and in the aortic root (34.6±3.7 to 41.9±4.4 ng/mL,
P
<.05) after the attacks in the coronary spastic angina group but remained unchanged in the stable exertional angina group after the attacks and in the control group after the administration of acetylcholine. Furthermore, the coronary sinus–arterial difference of soluble P-selectin increased significantly after the attacks in the coronary spastic angina group (−1.8±2.2 to 10.9±2.7 ng/mL,
P
<.001).

Conclusions
Our data indicate that soluble P-selectin is released into the coronary circulation after coronary artery spasm. We conclude that coronary artery spasm may induce the leukocyte adhesion in the coronary circulation and may lead to myocardial damage.
Insulin Resistance Associated With Compensatory Hyperinsulinemia as an Independent Risk Factor for Vasospastic Angina
Authors: Shinozaki Kazuya , Suzuki Masaaki , Ikebuchi Motoyoshi , Takaki Hiroshi , Hara Yasushi , Tsushima Motoo , Harano Yutaka
Published: June 2012

Background
It is generally believed that coronary artery spasm plays an important role in the progression of obstructive coronary artery disease. Since insulin resistance together with hyperinsulinemia plays an important role in the pathogenesis of coronary atherosclerosis, we investigated the association of hyperinsulinemia and insulin resistance with vasospastic angina (VAP).

Methods and Results
The study population consisted of 60 patients with VAP and 42 control subjects (62 subjects with normal glucose tolerance and 40 with impaired glucose tolerance). Insulin sensitivity was determined by the steady-state plasma glucose (SSPG) method for nondiabetic, normotensive, nonobese subjects (16 control subjects, 16 obstructive coronary artery disease patients, and 16 VAP patients). Compared with the control groups, the 2-hour insulin area (area under the plasma insulin concentration-time curve) during a 75-g oral glucose tolerance test was significantly higher in both VAP groups with normal and impaired glucose tolerance. A high frequency of vasospastic angina was observed in subjects with clustered risk factors for insulin resistance syndrome, suggesting a close association of VAP with this syndrome. In stepwise discriminant analysis, the 2-hour insulin area was significantly associated with VAP independent of other risk factors. SSPG level in VAP was about twofold over control, indicating the presence of insulin resistance in patients with VAP. However, no differences were found between patients with VAP and obstructive coronary artery disease with respect to mean SSPG level.

Conclusions
SSPG level was significantly elevated in patients with VAP and obstructive coronary artery disease compared with control subjects. This indicates that hyperinsulinemia is secondary to insulin resistance, both of which are thought to play important roles as risk factors for VAP in the early atheromatous lesion and in the future development of occlusive lesions when chronically present.
Socioeconomic Status and Carotid Atherosclerosis
Authors: Lynch John , Kaplan George A. , Salonen Riitta , Cohen Richard D. , Salonen Jukka T.
Published: June 2012

Background
There is a consistent body of evidence that socioeconomic status (SES) is importantly associated with cardiovascular morbidity and mortality. However, little information currently exists on the relationship between SES and early manifestations of atherosclerotic vascular disease.

Methods and Results
We investigated the association between education, income, and occupation and intima-media thickness (IMT) in a population-based sample of eastern Finnish men. Data from the Kuopio Ischemic Heart Disease Risk Factor Study were used to estimate mean IMT across levels of SES in 1140 men. The association between SES and IMT was examined in relation to atherosclerotic risk factors and was also stratified by degree of atherosclerotic progression and prevalent cardiovascular disease. There were significant, inverse, graded differences between levels of SES and IMT. For education, the age-adjusted mean IMTs for those with primary schooling or less, some high school, and completed high school or more were 0.96, 0.94, and 0.82 mm, respectively. The difference in mean IMT between the most extreme categories of education corresponds to a 15.4% increase in the risk of myocardial infarction. Similar patterns were found for each measure of SES, although the differences between the highest and lowest levels of SES were attenuated by adjustment for risk factors. In men who had no carotid stenosis or nonstenotic plaque and in men who had no indication of prevalent cardiovascular disease, a graded, inverse association between SES and IMT persisted, even after risk factor adjustment.

Conclusions
These findings demonstrate a strong association between SES and atherosclerosis in an unselected population. The results show that this association was mediated by known atherosclerotic risk factors, was evident in the early stages of atherosclerosis, and was apparent in a healthy subgroup. Our findings suggest that the impact of SES is evident early in the natural history of atherosclerotic vascular disease.
The Etiology of Syncope in Patients With Negative Tilt Table and Electrophysiological Testing
Authors: Krahn Andrew D. , Klein George J. , Norris Caro , Yee Raymond
Published: June 2012

Background
Patients with syncope of unknown etiology after negative noninvasive and electrophysiological testing may suffer from recurrent disability. Syncopal episodes are often too infrequent and unpredictable for detection by conventional ambulatory monitoring techniques.

Methods and Results
A long-term subcutaneous monitoring device was implanted in patients with negative ambulatory monitoring, tilt table and electrophysiological testing to establish cardiac rhythm during spontaneous syncope. Sixteen patients aged 57±19 years with a mean of 8.4±4.4 previous episodes of syncope underwent device implantation. Fifteen patients (94%) had recurrent syncope 4.4±4.2 months after implantation. The remaining patient has not had recurrent syncope and continues to be followed. A diagnosis was obtained in every patient who had recurrent episode. Syncope was secondary to sinus arrest in 5, atrioventricular block in 2, ventricular tachycardia in 1, supraventricular tachycardia in 1, and nonarrhythmic in 6. Successful therapy was implemented in all 15 patients, without recurrence of syncope during 13.0±8.4 months of follow-up.

Conclusions
Unexplained syncope in patients with negative investigations has a broad spectrum of etiologies, the most common of which is bradycardia. An implantable long-term monitoring device is useful for establishing a diagnosis when symptoms are recurrent but too infrequent for conventional monitoring techniques.
Role of Right Atrial Endocardial Structures as Barriers to Conduction During Human Type I Atrial Flutter
Authors: Olgin Jeffrey E. , Kalman Jonathan M. , Fitzpatrick Adam P. , Lesh Michael D.
Published: June 2012

Background
The importance of barriers in atrial flutter has been demonstrated in animals. We used activation and entrainment mapping, guided by intracardiac echocardiography (ICE), to determine whether the crista terminalis (CT) and eustachian ridge (ER) are barriers to conduction during typical atrial flutter in humans.

Methods and Results
In eight patients, ICE was used to guide the placement of 20-pole and octapolar catheters along the CT and interatrial septum and a roving catheter to nine sites: just posterior (1) and anterior (2) to the CT along the lateral right atrium, at the fossa ovalis (3), and just posterior and anterior to the ER at the low posterolateral (4 and 5), low posterior (6 and 7), and low posteromedial (8 and 9) right atrium. Entrainment was performed, and each site was considered within the flutter circuit if the postpacing interval–flutter cycle length (PPI−FCL) and the stimulus time–activation time (stim time−act time) were <10 msec. Split potentials were recorded along the CT with components activated in a low-to-high pattern and a high-to-low pattern. Conduction times, as percentage of FCL, were significantly different at sites on either side of the CT and ER: site 1 (33±13%) and site 2 (43±12%) (
P
=.02), site 4 (48±24%) and site 5 (75±8.9%) (
P
=.02), and site 6 (22±10%) and site 7 (82±5.3%) (
P
=.0009). During entrainment, no surface fusion was observed at sites 5, 7, or 9. The PPI−FCL and stim time−act time were not significantly different than 0 at sites 2, 7, 5, or 9, indicating that they were within the flutter circuit, whereas sites 1, 3, 4, and 6 were not.

Conclusions
ICE enabled the correlation of functional electrophysiological properties with specific anatomic landmarks, identifying the CT and ER as barriers to conduction during human atrial flutter.
Induction of Interleukin-6 Synthesis in the Myocardium
Authors: Kukielka Gilbert L. , Smith C. Wayne , Manning Anthony M. , Youker Keith A. , Michael Lloyd H. , Entman Mark L.
Published: June 2012

Background
Neutrophil-induced injury of myocardial cells requires the expression of intercellular adhesion molecule-1 (ICAM-1) on the myocyte surface and is mediated by ICAM-1–CD11b/CD18 adhesion. We have previously shown that interleukin-6 (IL-6) cytokine activity, present in cardiac lymph, induces ICAM-1 on isolated cardiac myocytes. Furthermore, in previous in vivo studies, we have also shown ICAM-1 mRNA induction in the myocardium within the first hour of reperfusion in the previously ischemic viable zone. We hypothesized that induction of IL-6 synthesis in the myocardium was an integral part of the reaction to injury resulting from ischemia and reperfusion and was associated with induction of ICAM-1 on myocardial cells.

Methods and Results
In this study, cloned canine IL-6 cDNA was used as a molecular probe to study the regulation of IL-6 in an awake canine model of myocardial ischemia and reperfusion. IL-6 mRNA was induced in ischemic and reperfused segments of myocardium preferentially in segments previously exposed to severe ischemia. Peak levels of IL-6 mRNA were reached within 3 hours of reperfusion. At the same time, IL-6 mRNA and ICAM-1 mRNA were found in the same myocardial segments. In contrast to hearts that were ischemic for 1 hour and reperfused for 3 hours, nonreperfused hearts after 4 hours of persistent ischemia demonstrated minimal induction of ICAM-1 or IL-6 despite similar degrees of injury and blood flow reductions during ischemia. After 24 hours of persistent ischemia, levels of IL-6 mRNA were comparable to those observed in hearts that were ischemic for 1 hour and subsequently reperfused for 24 hours.

Conclusions
Our results demonstrate induction of IL-6 mRNA in the myocardium and that this synthesis is accelerated by reperfusion. Evidence is also provided to show that peak IL-6 mRNA precedes that of ICAM-1 mRNA. These findings are compatible with our hypothesis that IL-6 is important in the induction of ICAM-1 in the area of ischemia. In addition, these studies suggest that the necessary factors to promote adhesive interactions between transmigrated neutrophils and cardiac myocytes are present in reperfused myocardium.
Superficial Accumulation of Plasminogen During Plasma Clot Lysis
Authors: Sakharov Dmitry V. , Rijken Dingeman C.
Published: June 2012

Background
Binding of plasminogen to partially degraded fibrin is an important step in fibrinolysis, influencing its rate and fibrin specificity. Little is known about the spatial distribution of plasminogen and of plasminogen-binding sites inside thrombi during lysis. In the present study, we investigated this problem, which is important for a better understanding of the local regulation of fibrinolysis and the rate-limiting factors of therapeutic thrombolysis.

Methods and Results
An experimental system was used that allowed continuous visualization and quantification by fluorescence microscopy of the spatial distribution of fluorescein-labeled plasminogen inside and outside model thrombi. Strong superficial accumulation of plasminogen was observed during lysis of a plasma clot induced by tissue-type or urokinase-type plasminogen activators in the surrounding plasma. A distinctly visible plasminogen-accumulating shell moved continuously with the reducing surface of the clot. The accumulation decreased in conditions of exhaustive activation of plasminogen in the outer plasma. It was found in a purified system that a thin superficial layer (≈50 μm wide) of a plasmin-treated fibrin clot exposes about 2.5 plasminogen-binding sites per fibrin monomer with a
K
d
of 2.2 μmol/L. At a physiological concentration of plasminogen (1.5 μmol/L) in the outer medium, plasminogen was concentrated about 10-fold in this layer. The binding was dose-dependently inhibited by ε-aminocaproic acid.

Conclusions
We conclude that the generation of potent surface-associated plasminogen-binding sites during thrombolysis results in a strikingly high plasminogen concentration at the dynamically changing surface of a lysing clot. The necessity of a continuous plasminogen supply from the plasma supports the use of fibrin-specific and plasminogen-sparing agents for thrombolytic therapy.
Normothermic Continuous Antegrade Blood Cardioplegia Does Not Prevent Myocardial Edema and Cardiac Dysfunction
Authors: Mehlhorn Uwe , Allen Steven J. , Adams Deborah L. , Davis Karen L. , Gogola Gloria R. , de Vivie E. Rainer , Laine Glen A.
Published: June 2012

Background
Normothermic continuous blood cardioplegia (BC) has been proposed to completely protect the myocardium during cardiac surgery. However, previous work from our laboratory suggests that BC could cause myocardial edema that produces cardiac dysfunction. The purpose of this present study was to evaluate the impact of BC on myocardial fluid balance and left ventricular function.

Methods and Results
In 11 dogs, myocardial water content (MWC) was determined by microgravimetry. Myocardial lymph flow rate was measured after cannulation of the major prenodal cardiac lymphatic. Preload recruitable stroke work (PRSW) was calculated by sonomicrometry and micromanometry. The dogs were placed on normothermic cardiopulmonary bypass (CPB), and BC was delivered at either 80 to 90 mm Hg (BC
high
; n=6) or 40 to 50 mm Hg (BC
low
; n=5) for 1 hour. Coronary sinus lactate and oxygen saturation monitoring demonstrated ischemia avoidance. BC was associated with substantial myocardial lymph flow rate decrease (
P
<.05) and myocardial edema development in both groups. MWC increased from 76.0±1.9% to 79.2±1.7% (
P
<.05) after 10 minutes of BC
high
and from 75.9±0.6% to 78.9±1.4% (
P
<.05) after 30 minutes of BC
low
. PRSW decreased to 63±19% (BC
high
) and 69±15% of control (BC
low
) at 30 minutes after CPB (
P
<.05). Myocardial lymph flow rate increases of threefold to fourfold that of control (
P
<.05) resulted in significant myocardial edema reduction associated with PRSW improvement to 71±17% (BC
high
) and to 78±11% (BC
low
) at 2 hours after CPB.

Conclusions
We conclude that BC is associated with compromised cardiac function despite ischemia avoidance. This cardiac dysfunction is due to myocardial edema caused by the combination of increased myocardial microvascular fluid filtration and decreased myocardial lymph flow rate during BC.
Trandolapril Decreases Prevalence of Ventricular Ectopic Activity in Middle-Aged SHR
Authors: Chevalier B. , Heudes D. , Heymes C. , Basset A. , Dakhli T. , Bansard Y. , Jouquey S. , Hamon G. , Bruneval P. , Swynghedauw B. , Carré F.
Published: June 2012

Background
Although severe arrhythmias are still a major problem in patients with left ventricular hypertrophy (LVH), the relationship between ventricular remodeling and its regression or prevention, and the prevalence of ventricular premature beats (VPB) or more sustained arrhythmias are still poorly explored in hypertensive heart disease.

Methods and Results
Holter monitoring was used to quantify supraventricular premature beats and VPB and heart rate (HR) in middle-aged spontaneously hypertensive rats (SHR) and Wistar rats treated for 3 months with trandolapril (ACE inhibitor, 0.3 mg/kg per day). Hypertrophy and fibrosis were morphometrically determined. Statistical analysis was performed with the use of simple regression and multivariate data analysis (cluster and correspondence analysis). SHR have higher cardiac mass and fibrosis, more VPB, and a decreased HR. Cluster analysis demonstrated that trandolapril was only effective in SHR. Trandolapril significantly reduced cardiac hypertrophy, fibrosis, and VPB incidence and increased the HR. Simple regression analysis showed that VPB incidence correlated to both hypertrophy and fibrosis. Correspondence analysis evidenced a strong correlation between hypertrophy, fibrosis, and VPB, but only for severe hypertrophy, and the correlation disappeared for moderate hypertrophy.

Conclusions
After trandolapril treatment, the regression of VPB incidence not only is linked to hypertrophy and fibrosis, but additional causal factors also are involved including the myocardial phenotype and new calcium metabolism. Our model of Holter monitoring in conscious middle-aged SHR and multivariate data analysis might be useful in correlating myocardial structural modifications and ectopic activity.
Atrial Fibrillation Begets Atrial Fibrillation
Authors: Wijffels Maurits C.E.F. , Kirchhof Charles J.H.J. , Dorland Rick , Allessie Maurits A.
Published: June 2012

Background
In this study we tested the hypothesis that atrial fibrillation (AF) causes electrophysiological changes of the atrial myocardium which might explain the progressive nature of the arrhythmia.

Methods and Results
Twelve goats were chronically instrumented with multiple electrodes sutured to the epicardium of both atria. Two to 3 Weeks after implantation, the animals were connected to a fibrillation pacemaker which artificially maintained AF. Whereas during control episodes of AF were short lasting (6±3 seconds), artificial maintenance of AF resulted in a progressive increase in the duration of AF to become sustained (>24 hours) after 7.1±4.8 days (10 of 11 goats). During the first 24 hours of AF the median fibrillation interval shortened from 145±18 to 108±8 ms and the inducibility of AF by a single premature stimulus increased from 24% to 76%. The atrial effective refractory period (AERP) shortened from 146±19 to 95±20 ms (−35%) (S
1
S
1
, 400 ms). At high pacing rates the shortening was less (−12%), pointing to a reversion of the normal adaptation of the AERP to heart rate. In 5 goats, after 2 to 4 weeks of AF, sinus rhythm was restored and all electrophysiological changes were found to be reversible within 1 week.

Conclusions
Artificial maintenance of AF leads to a marked shortening of AERP, a reversion of its physiological rate adaptation, and an increase in rate, inducibility and stability of AF. All these changes were completely reversible within 1 week of sinus rhythm.