bluuebunny/crossref_metadata_2025 huggingface dataset:
Feasibility of Intracoronary β-Irradiation to Reduce Restenosis After Balloon Angioplasty
Authors: Verin Vitali , Urban Philip , Popowski Youri , Schwager Michael , Nouet Philippe , Dorsaz Pierre A. , Chatelain Pascal , Kurtz John M. , Rutishauser Wilhelm
Published: June 2012

Background
With the aim of decreasing the incidence of restenosis after coronary balloon angioplasty, we developed a technique of intracoronary β-irradiation using an endoluminally centered pure metallic
90
Y source. The purpose of the present study was to evaluate the clinical feasibility and safety profile of this approach with a dose of 18 Gy delivered to the inner arterial surface.

Methods and Results
Between June 21 and November 15, 1995, fifteen patients (6 women and 9 men; mean age, 71±5 years) underwent intracoronary β-irradiation immediately after a conventional percutaneous transluminal coronary angioplasty (PTCA) procedure. The PTCA/irradiation procedure was technically feasible in all attempted cases, and the delivery of the 18 Gy dose was accomplished without complications. In 4 patients, the intervention was completed through intra-arterial stent implantation because of dissection induced by the initial PTCA. During the follow-up period of 178±17 days (range, 150 to 225 days), no complication occurred that could be attributed to radiation therapy. No aneurysm or angiographically detectable thrombus was observed in any of the irradiated arterial segments. The clinical event rate (4 of 15 patients underwent further target lesion revascularization) and the angiographic follow-up (6 of 15 patients had a >50%-diameter stenosis at the previously treated site) did not suggest a marked impact on the expected restenosis rate.

Conclusions
This early experience demonstrates that our approach is feasible, and no side effects attributable to radiation were noted during a 6-month period of follow-up. Whether higher doses of β-irradiation will favorably affect post-PTCA restenosis in patients must await further evaluation.
Results of a Consecutive Series of Patients Receiving Only Antiplatelet Therapy After Optimized Stent Implantation
Authors: Albiero Remo , Hall Patrick , Itoh Akira , Blengino Simonetta , Nakamura Shigeru , Martini Giovanni , Ferraro Massimo , Colombo Antonio
Published: June 2012

Background
Previous studies have shown that stents can be inserted in coronary arteries of patients who are subsequently treated safely with antiplatelet therapy only (ticlopidine and/or aspirin) with a low incidence of stent thrombosis, provided that stent expansion is adequate and there are no other flow-limiting lesions present. However, it is unknown whether ticlopidine combined with aspirin is superior to aspirin alone in preventing stent thrombosis.

Methods and Results
From March 1993 through July 1995, 801 consecutive patients assigned to receive either aspirin therapy alone (ASA, 264 patients, 348 lesions) or a combination of ticlopidine and aspirin (TIC-ASA, 537 patients, 737 lesions) after a successful stent insertion, in most accomplished with intravascular ultrasound guidance, were evaluated retrospectively. At 1 month, there was no difference in the ASA group compared with the TIC-ASA group in the rate of any stent thrombosis (1.9% versus 1.9%;
P
=1), subacute stent thrombosis (1.9% versus 1.3%;
P
=.5), cumulative major adverse clinical events (1.9% versus 2.0%;
P
=1), and peripheral vascular complications (0.5% versus 0.2%;
P
=.3). Medication side effects that required termination of antiplatelet therapy occurred only in 1.9% of patients in the TIC-ASA group (
P
=.04).

Conclusions
At 1-month clinical follow-up, stent thrombosis and other adverse clinical outcomes were not significantly different between the ASA and TIC-ASA groups. Medication side effects occurred only in patients treated with ticlopidine. These results provide further evidence of the safety of treatment with antiplatelet therapy only after optimal stent implantation and support the efficacy of aspirin alone in preventing stent thrombosis.
Basic Fibroblast Growth Factor as a Biochemical Marker of Exercise-Induced Ischemia
Authors: Gu Jian-Wei , Santiago Derek , Olowe Yetunde , Weinberger Judah
Published: June 2012

Background
Basic fibroblast growth factor (bFGF) is a mitogenic polypeptide that demonstrates enhanced expression and promotes angiogenesis in animal models of myocardial ischemia and infarction. Elevated levels of bFGF are present in the urine of humans with metastatic tumors, but its expression in human myocardial ischemia is unknown. Thus, we sought to determine whether urine levels of bFGF are altered by exercise-induced ischemia in humans.

Methods and Results
Eighty-six patients underwent exercise thallium studies for evaluation of anginal symptoms. Urine levels of bFGF (corrected for urine creatinine) were determined by ELISA immediately before and between 2 and 4 hours after exercise. The change in urine bFGF level was compared between 43 patients with and 43 patients without exercise-induced ischemia. Patients with ischemia had an increase in urine bFGF compared with nonischemic patients (1052±245 versus −278±130 pg/g creatinine,
P
<.0001). Exercise, demographic, and clinical variables were assessed and analyzed for possible effect on bFGF response to exercise. By univariate analysis, a history of hypertension was negatively associated with a change in bFGF level (
P
<.05). No other variables were associated. By multivariate analysis, only bFGF response (
P
<.001) and age (
P
<.05) were independently related to exercise-induced ischemia.

Conclusions
Significantly increased levels of bFGF are detected in the urine within hours of exercise-induced ischemia. Further studies are warranted to determine whether bFGF might serve as a useful circulating marker of myocardial ischemia in humans.
Selective Downregulation of the Angiotensin II AT
1
-Receptor Subtype in Failing Human Ventricular Myocardium
Authors: Asano Koji , Dutcher Darrin L. , Port J. David , Minobe Wayne A. , Tremmel Kelli D. , Roden Robert L. , Bohlmeyer Teresa J. , Bush Erik W. , Jenkin Matthew J. , Abraham William T. , Raynolds Mary V. , Zisman Lawrence S. , Perryman M. Benjamin , Bristow Michael R.
Published: June 2012

Background
The regulation of angiotensin II receptors and the two major subtypes (AT
1
and AT
2
) in chronically failing human ventricular myocardium has not been previously examined.

Methods and Results
Angiotensin II receptors were measured by saturation binding of
125
I-[Sar
1
,Ile
8
]angiotensin II in crude membranes from nonfailing (n=19) and failing human left ventricles with idiopathic dilated cardiomyopathy (IDC; n=31) or ischemic cardiomyopathy (ISC; n=21) and membranes from a limited number of right ventricles in each category. The AT
1
and AT
2
fractions were determined by use of an AT
1
-selective antagonist, losartan. β-Adrenergic receptors were also measured by binding of
125
I-iodocyanopindolol with the β
1
and β
2
fractions determined by use of a β
1
-selective antagonist, CGP20712A. AT
1
but not AT
2
density was significantly decreased in the combined (IDC+ISC) failing left ventricles (nonfailing: AT
1
4.66±0.48, AT
2
2.73±0.39; failing: AT
1
3.20±0.29, AT
2
2.70±0.33 fmol/mg protein; mean±SE). The decrease in AT
1
density was greater in the IDC than in the ISC left ventricles (IDC: 2.73±0.40,
P
<.01; ISC: 3.89±0.39 fmol/mg protein,
P
=NS versus nonfailing). β
1
but not β
2
density was decreased in the failing left ventricles. AT
1
density was correlated with β
1
density in all left ventricles (
r
=.43). AT
1
density was also decreased in IDC right ventricles. In situ reverse transcription–polymerase chain reaction in sections of nonfailing and failing ventricles indicated that AT
1
mRNA was present in both myocytes and nonmyocytes.

Conclusions
AT
1
receptors are selectively downregulated in failing human ventricles, similar to the selective downregulation of β
1
receptors. The relative lack of AT
1
downregulation in ISC hearts may be related to differences in the degree of ventricular dysfunction.
Increased Restenosis in Diabetes Mellitus After Coronary Interventions Is Due to Exaggerated Intimal Hyperplasia
Authors: Kornowski Ran , Mintz Gary S. , Kent Kenneth M. , Pichard Augusto D. , Satler Lowell F. , Bucher Theresa A. , Hong Mun K. , Popma Jeffrey J. , Leon Martin B.
Published: June 2012

Background
The increased risk of restenosis after catheter-based coronary interventions in diabetic patients has not been determined. Intravascular ultrasound (IVUS) has shown that the decrease in arterial area is responsible for most of the late lumen loss in nonstented lesions and that intimal hyperplasia is responsible for all of the late lumen loss in stented lesions.

Methods and Results
Serial (postintervention and follow-up at 5.6±3.3 months) IVUS was used to study 251 native coronary lesions in 241 patients; 63 patients had treated diabetes mellitus (oral hypoglycemic drugs or insulin). Interventional procedures included percutaneous transluminal coronary angioplasty, directional or rotational atherectomy, excimer laser angioplasty, or Palmaz-Schatz stents. The external elastic membrane (EEM), stent, and lumen areas were measured. The plaque+media (P+M) area in nonstented lesions was calculated as EEM minus lumen area, and the intimal hyperplasia (IH) area in stented lesions was calculated as stent minus lumen area. The anatomic slice selected for serial analysis had an axial location within the target lesion at the smallest follow-up lumen area. Nonstented lesions in diabetics and nondiabetics had a similar decrease in EEM cross-sectional area (CSA; 1.9±2.8 versus 1.8±4.2 mm
2
;
P
=.6350). However, nonstented lesions in diabetics had a greater increase in P=M CSA (1.3±2.8 versus 0.6±2.5 mm
2
,
P
=.0720), and the increase in P=M CSA contributed a greater percentage to the decrease in lumen CSA. In stented lesions, the decrease in lumen CSA (5.2±2.5 versus 2.0±2.3 mm
2
) and the increase in IH CSA (5.0±2.8 versus 1.8±2.0 mm
2
) were greater in diabetics than nondiabetics (
P
=.0009 and
P
=.0007, respectively). These findings were even more striking in (nonstented and stented) restenotic lesions.

Conclusions
Serial IVUS analysis showed that the main reason for increased restenosis in diabetes mellitus was exaggerated intimal hyperplasia in both stented and nonstented lesions.
Safety and Accuracy of Dobutamine-Atropine Stress Echocardiography for the Detection of Residual Stenosis of the Infarct-Related Artery and Multivessel Disease During the First Week After Acute Myocardial Infarction
Authors: Smart Steven C. , Knickelbine Thomas , Stoiber Thomas R. , Carlos Michael , Wynsen John C. , Sagar Kiran B.
Published: June 2012

Background
The safety of dobutamine-atropine echocardiography early after acute myocardial infarction is unknown. Its accuracy for the early detection of infarct artery stenosis and multivessel coronary artery disease is also unclear. The objective of the present study was to document its safety and accuracy during the first week after acute myocardial infarction.

Methods and Results
Multistage dobutamine-atropine stress echocardiography was performed in 232 patients (age, 58±13 years; 58 women) at 5±2 days after acute myocardial infarction. The peak heart rate was 116±20 bpm. There were no episodes of sustained ventricular tachycardia, myocardial infarction, or death. Atropine with dobutamine was tolerated well. Coronary angiography was performed in 206 patients (89%). There were 171 patients (83%) with infarct artery stenosis of ≥50% and 114 patients (55%) with multivessel disease. Ischemic or biphasic responses in the infarction zone were 82% (140 of 171) sensitive and 80% (28 of 35) specific for residual stenosis. Sensitivity was similar for occluded arteries (77%, 36 of 47) and patent but stenotic arteries (84%, 104 of 124). Wall motion abnormalities outside the infarction zone were specific (97%, 89 of 92) and moderately sensitive (68%, 77 of 114) for multivessel disease. The only determinant of sensitivity for residual infarct artery stenosis was improved wall motion at low dose (
P
<.01). The determinants of sensitivity for multivessel disease were peak heart rate and infarct size (
P
<.01).

Conclusions
Dobutamine-atropine stress echocardiography was safely used to detect residual infarct artery stenosis and multivessel disease during the first week after acute myocardial infarction. The test may be very effective for evaluating patients with acute myocardial infarction because sensitivity for residual stenosis and multivessel disease was maximal in the high-risk subsets of patients with viable, jeopardized myocardium and large infarct size.
Dobutamine Stress Echocardiography for Risk Stratification After Myocardial Infarction
Authors: Carlos Michael E. , Smart Steven C. , Wynsen John C. , Sagar Kiran B.
Published: June 2012

Background
Because dobutamine stress echocardiography (DSE) provides assessment of left ventricular function and ischemia at a distance, the major determinants of adverse outcome after acute myocardial infarction (AMI), we undertook this study to determine the role of DSE in risk stratification after AMI.

Methods and Results
A graded DSE in 5-minute stages was performed in 214 patients (age, 57±13 years [mean±SD]) at 2 to 7 days after AMI. Coronary angiography was performed in 193 patients. Follow-up data regarding major cardiac events were obtained through telephone interviews and chart reviews. All patients were followed for ≥500 days or until a hard cardiac event occurred. The mean follow-up interval was 494±182 days after AMI. Peak heart rate and systolic blood pressure were 115±21 bpm and 135±29 mm Hg, respectively. An adverse outcome occurred in 80 of 214 patients; cardiac death occurred in 15, nonfatal AMI occurred in 15, sustained or symptomatic ventricular arrhythmia occurred in 5, congestive heart failure occurred in 14, and unstable angina occurred in 31. Significant predictors of adverse outcome by univariate analysis were prior myocardial infarction (
P
=.005), anterior infarction (
P
=.006), multivessel coronary artery disease (
P
<.0001), global resting left ventricular wall motion score index (
P
<.0001), infarction zone nonviability based on akinesis unresponsive to low-dose dobutamine (
P
<.0001), and ischemia/infarction at a distance (
P
<.0001). Furthermore, the extent of infarct zone and nonviability correlated with the severity of the cardiac event. Multivariate analysis of clinical, angiographic, and DSE variables revealed that the only independent predictors of adverse outcome were ischemia/infarction at a distance (
P
<.0001) and infarction zone nonviability (
P
<.0001). Multivessel disease identified through DSE was more predictive of adverse outcome than was angiographically determined multivessel disease.

Conclusions
DSE can be used to predict adverse outcomes after AMI.
Coexistence of Anti-Phospholipid Antibodies and Endothelial Perturbation in Systemic Lupus Erythematosus Patients With Ongoing Prothrombotic State
Authors: Ferro Domenico , Pittoni Valerio , Quintarelli Claudio , Basili Stefania , Saliola Mirella , Caroselli Costantino , Valesini Guido , Violi Francesco
Published: June 2012

Background
Anti-phospholipid antibodies (aPLs) were associated with an ongoing prothrombotic state in patients with systemic lupus erythematosus (SLE). Because aPLs are able to shift endothelial function toward procoagulant activity in vitro, we investigated the relationship among aPLs, ongoing prothrombotic state, and endothelial perturbation in SLE patients.

Methods and Results
We measured aPLs, anti-EC antibodies, circulating levels of prothrombin fragment F1+2 (F1+2), tumor necrosis factor-α (TNF-α), tissue-type plasminogen activator (TPA), and von Willebrand factor (vWF) in 43 SLE patients and 25 healthy subjects. Patients positive for aPLs (n=23) had a higher prevalence of anti-EC antibodies (
P
=.02) and higher levels of F1+2 (
P
=.003) than aPL(−) patients. Endothelial perturbation, defined by elevated plasma levels of both TPA and vWF, was significantly associated with aPL positivity (
P
=.001). F1+2 >1 nmol/L (mean+2 SD of controls) was detected in all but one patient in whom aPL positivity and endothelial perturbation coexisted and in no aPL(+) patient without endothelial perturbation (
P
=.0039). F1+2 was significantly correlated with vWF (ρ=.6,
P
=.004) and TPA (114 =.70,
P
=.0006) only in aPL(+) patients. Endothelial perturbation was closely associated with high values of TNF-α (
P
=.0001), anti-phospholipid (
P
=.001), and anti-EC antibodies (
P
=.012). In 31 patients without a clinical history of thrombosis followed up for 3 years, aPL(+) patients with endothelial perturbation showed higher F1+2 and TNF-α values than aPL(+) patients without endothelial dysfunction.

Conclusions
This study shows that in SLE patients, aPL positivity is associated with an ongoing prothrombotic state only in the presence of endothelial perturbation. Our findings also suggest that aPLs and TNF-α might cooperate in inducing endothelial perturbation.
Absence of Low-Frequency Variability of Sympathetic Nerve Activity in Severe Heart Failure
Authors: van de Borne Philippe , Montano Nicola , Pagani Massimo , Oren Ron , Somers Virend K.
Published: June 2012

Background
In normal humans, variability of blood pressure, RR interval, and sympathetic activity occurs predominantly at a low frequency (LF; 0.04 to 0.14 Hz) and a high frequency (HF; ±0.25 Hz). In conditions that increase sympathetic activation in normal humans, the LF component is increased relative to the HF component. Patients with heart failure have high levels of sympathetic activity. We tested the hypothesis that the LF component of sympathetic nerve activity variability is increased in heart failure.

Methods and Results.
We performed spectral analysis of simultaneous recordings of resting muscle sympathetic nerve activity (MSNA) and RR interval in 21 patients with chronic heart failure and 12 age-matched control subjects. MSNA was higher in patients with heart failure (62±4 bursts per minute) than in the normal subjects (39±4 bursts per minute;
P
<.01). LF components of RR interval and MSNA variability were lower in the heart failure patients versus the control subjects (
P
<.01). HF variability of RR interval and MSNA was preserved, at least in part, in heart failure. There was close coherence between variability patterns of RR interval and MSNA. Furthermore, in 14 heart failure patients who had no LF variability in MSNA compared with 7 heart failure patients who did manifest LF variability in MSNA, RR interval was shorter, the variance of RR interval was lower, MSNA was higher, respiratory rate was faster, and left ventricular ejection fraction was lower (all
P
<.05). At a median follow-up of 12 months, 4 heart failure patients had died, all of whom had had absent LF oscillations in MSNA and RR interval.

Conclusions
The LF variability of sympathetic nerve activity is absent in patients with severe heart failure. This disturbed pattern of variability is closely coherent with the abnormal variability of RR interval. These disturbances of rhythmic oscillations of autonomic outflow, evident in both RR interval and MSNA, suggest a central autonomic regulatory impairment in heart failure and may have important prognostic implications.
Ambulatory Blood Pressure Is Superior to Clinic Blood Pressure in Predicting Treatment-Induced Regression of Left Ventricular Hypertrophy
Authors: Mancia Giuseppe , Zanchetti Alberto , Agebiti-Rosei Enrico , Benemio Giuseppe , De Cesaris Raffaele , Fogari Roberto , Pessino Achille , Porcellati Carlo , Salvetti Antonio , Trimarco Bruno
Published: June 2012

Background
In cross-sectional studies, ambulatory blood pressure (ABP) correlates more closely than clinic BP with the organ damage of hypertension. Whether ABP predicts development or regression of organ damage over time better than clinic BP, however, is unknown.

Methods and Results
In 206 essential hypertensive subjects with left ventricular hypertrophy (LVH), we measured clinic supine BP, 24-hour ABP, and left ventricular mass index (LVMI, echocardiography) before and after 12 months of treatment with lisinopril (20 mg UID) without or with hydrochlorothiazide (12.5 or 25 mg UID). Measurements included random-zero, clinic orthostatic, and home BP. In all, 184 subjects completed the 12-month treatment period. Before treatment, clinic supine BP was 165±15/105±5 mm Hg (systolic/diastolic), 24-hour average BP was 149±16/95±11 mm Hg, and LVMI was 158±32 g/m
2
. At the end of treatment, they were 139±12/87±7 mm Hg, 131±12/83±10 mm Hg, and 133±26 g/m
2
, respectively (
P
<.01 for all). Before treatment, LVMI did not correlate with clinic BP, but it showed a correlation with systolic and diastolic 24-hour average BP (
r
=.34/.27,
P
<.01). The LVMI reduction was not related to the reduction in clinic BP, but it was related to the reduction in 24-hour average BP (
r
=.42/.38,
P
<.01). Treatment-induced changes in average daytime and nighttime BPs correlated with LVMI changes as strongly as 24-hour BP changes. No substantial advantage over clinic supine BP was shown by clinic orthostatic, random-zero, and home BP.

Conclusions
In hypertensive subjects with LVH, regression of LVH was predicted much more closely by treatment-induced changes in ABP than in clinic BP. This provides the first longitudinally controlled evidence that ABP may be clinically superior to traditional BP measurements.
Inhibition of Intimal Hyperplasia After Balloon Injury by Antibodies to Intercellular Adhesion Molecule-1 and Lymphocyte Function–Associated Antigen-1
Authors: Yasukawa Hideo , Imaizumi Tsutomu , Matsuoka Hidehiro , Nakashima Akihiko , Morimatsu Minoru
Published: June 2012

Background
Although intercellular adhesion molecule-1 (ICAM-1) is known to be expressed in balloon-injured arteries, it remains unknown whether ICAM-1 plays a role in the progression of intimal hyperplasia (IH) induced by balloon injury.

Methods and Results
We examined the ICAM-1 expression in rat carotid arteries at 1, 2, 5, 7, 10, and 14 days after injury by immunohistochemistry. Medial smooth muscle cells (SMC) expressed ICAM-1 intensely at 1 to 2 days after injury. The regenerating endothelial cells expressed ICAM-1 more than did those of intact carotid arteries. To investigate the effects of monoclonal antibodies (MAbs) on IH, we examined the intima/medial ratio of arteries at 2 weeks after injury in five treatment groups: nonimmune IgG, anti-membrane glycoprotein MAb, anti–lymphocyte function–associated antigen-1 (LFA-1) MAb, anti–ICAM-1 MAb, and anti–ICAM/LFA-1 MAb. Treatments were administered intravenously into rats for 6 consecutive days after injury. MAb against LFA-1 alone or membrane glycoprotein had no effect on IH. The intima/media ratios in anti–ICAM-1 MAb–treated and anti–ICAM-1/LFA-1 MAb–treated animals were significantly less than those in nonimmune IgG–treated and anti–membrane glycoprotein MAb–treated animals (
P
<.05).

Conclusions
Balloon injury induced or upregulated the ICAM-1 expression on vascular SMC and on regenerating endothelial cells. MAb against ICAM-1 or ICAM-1/LFA-1 attenuated IH. These results suggest that ICAM-1 may play a role in the progression of IH after injury in rats.
Experimental Study of Thrombogenicity and Foreign Body Reaction Induced by Heparin-Coated Coronary Stents
Authors: De Scheerder Ivan , Wang Kai , Wilczek Krzysztof , Meuleman Dirk , Van Amsterdam Ronald , Vogel Gerard , Piessens Jan , Van de Werf Frans
Published: June 2012

Background
Results of recent randomized clinical trials have revealed a significant reduction in angiographic restenosis rate when adjunctive stenting was performed after conventional coronary balloon angioplasty. The thrombogenicity of metal stents, however, remains a concern. In the present study, we compare the thrombogenicity of heparin-coated coronary stents with that of bare metallic coronary stents.

Methods and Results
Thrombogenicity of metallic coronary stents (four heparin-coated and eight bare stents) was studied in a rat arteriovenous shunt model with the use of
125
I-labeled fibrinogen and
51
Cr-labeled platelets. Total clot weight after 30-minute follow-up was significantly lower in the heparin-coated stents compared with the bare stents (8.1±3.7 versus 25.8±4.6 mg;
P
<.001). Relative
125
I and
51
Cr activities in the stents were significantly higher in the bare stents than in the heparin-coated stents (
125
I, 1.03±0.43 versus 0.18±0.04,
P
=.003;
51
Cr, 17.5±6.8 versus 4.4±1.0,
P
=.004). Subsequently, heparin-coated and bare stents were randomly implanted in the right coronary artery of 20 domestic pigs. Angiographic parameters were similar between both groups at baseline and after 6-week follow-up. Morphometry also did not show a significant difference in lumen area (bare, 1.03±0.83 mm
2
; heparin-coated, 1.12±0.73 mm
2
;
P
=NS) or neointimal hyperplasia (bare, 1.01±0.81 mm
2
; heparin-coated, 1.21±0.57 mm
2
;
P
=NS).

Conclusions
Heparin coating of metallic coronary stents decreases their thrombogenicity but does not improve late vessel patency and neointimal hyperplasia at follow-up in a porcine coronary model.
β
2
-Adrenergic Dilation of Resistance Coronary Vessels Involves K
ATP
Channels and Nitric Oxide in Conscious Dogs
Authors: Ming Zhi , Parent Robert , Lavallée Michel
Published: June 2012

Background
We considered that β
2
-adrenergic stimulation may dilate resistance coronary vessels by opening ATP-sensitive potassium (K
ATP
) channels, thereby triggering NO formation.

Methods and Results
In conscious instrumented dogs after β
1
-adrenergic blockade, intracoronary (IC) injections of acetylcholine (ACh), nitroglycerin (NTG), and pirbuterol (PIR), a selective β
2
-adrenergic agonist, were performed before and after blockade of NO formation with IC
N
ω
-nitro-
l
-arginine methyl ester (L-NAME, 50 μg·kg
−1
·min
−1
×12 minutes) or blockade of K
ATP
channels with IC glibenclamide (25 μg·kg
−1
·min
−1
×12 minutes followed by 2 μg·kg
−1
·min
−1
). PIR (50.0 ng/kg) increased coronary blood flow (CBF) by 32±6 from 43±7 mL/min and by only 11±2 (
P
<.01) from 40±7 mL/min after L-NAME. Increases in CBF to ACh were also reduced by L-NAME, but NTG responses were not. Before glibenclamide, PIR increased CBF by 33±5 from 45±7 mL/min and by only 14±3 (
P
<.01) from 36±5 mL/min thereafter. CBF responses to ACh and NTG were maintained after glibenclamide. Lemakalim, a selective opener of K
ATP
channels, caused dose-dependent increases in CBF that were partially inhibited by L-NAME. In experiments in which CBF was controlled, the fall in distal coronary pressure caused by PIR was less after L-NAME or glibenclamide than before.

Conclusions
β
2
-Adrenergic dilation of resistance coronary vessels involves both the opening of K
ATP
channels and NO formation. L-NAME antagonized lemakalim responses consistent with a link between the opening of K
ATP
channels and NO formation in canine resistance coronary vessels.
Interrelation of Hyperhomocyst(e)inemia, Factor V Leiden, and Risk of Future Venous Thromboembolism
Authors: Ridker Paul M. , Hennekens Charles H. , Selhub Jacob , Miletich Joseph P. , Malinow M. Rene , Stampfer Meir J.
Published: June 2012

Background
Because patients with rare familial homocystinuria who also carry factor V Leiden have an increased incidence of venous thromboembolism (VTE), we hypothesized an interrelation of moderate hyperhomocyst(e)inemia, factor V Leiden, and risk of VTE in the general population.

Methods and Results
In a large prospective cohort, we determined total homocysteine level and factor V Leiden mutation in baseline blood samples from 145 initially healthy men who subsequently developed VTE and among 646 men who remained free of vascular disease during a 10-year follow-up period. Hyperhomocyst(e)inemia was defined as a total homocysteine level above the 95th percentile (17.25 μmol/L). Compared with men with normal total homocysteine levels, those with hyperhomocyst(e)inemia had no increase in risk of any VTE but were at increased risk of idiopathic VTE (relative risk [RR]=3.4,
P
=.002). Compared with men without Leiden mutation, those with mutation were at increased risk of developing any VTE (RR=2.3,
P
=.005) as well as idiopathic VTE (RR=3.6,
P
=.0002). Compared with men with neither abnormality, those affected by both disorders had a 10-fold increase in risk of any VTE (RR=9.65,
P
=.009) and a 20-fold increase in risk of idiopathic VTE (RR=21.8,
P
=.0004).

Conclusions
Apparently healthy men with coexistent hyperhomocyst(e)inemia and Leiden mutation are at substantially increased risk of developing future VTEs, particularly those events considered idiopathic. In these data, the risk of VTE among doubly affected individuals was far greater than the sum of the individual risks associated with either abnormality alone.
Vascular Effects of Acute Hyperglycemia in Humans Are Reversed by
l
-Arginine
Authors: Giugliano Dario , Marfella Raffaele , Coppola Ludovico , Verrazzo Giovanni , Acampora Rita , Giunta Riccardo , Nappo Francesco , Lucarelli Carmela , D’Onofrio Felice
Published: June 2012

Background
Acute hyperglycemia may increase vascular tone in normal humans via a glutathione-sensitive, presumably free radical–mediated pathway. The objective of this study was to investigate whether or not the vascular effects of hyperglycemia are related to reduced availability of nitric oxide.

Methods and Results
Acute hyperglycemia (15 mmol/L, 270 mg/dL) was induced in 12 healthy subjects with an artificial pancreas. Systolic and diastolic blood pressures, heart rate, and plasma catecholamines showed significant increases (
P
<.05) starting after 30 minutes of hyperglycemia; leg blood flow decreased significantly (15%;
P
<.05) at 60 and 90 minutes. Platelet aggregation to ADP and blood viscosity also showed significant increments (
P
<.05). The infusion of
l
-arginine (n=7, 1 g/min) but not
d
-arginine (n=5, 1 g/min) or
l
-lysine (n=5, 1 g/min) in the last 30 minutes of the hyperglycemic clamp completely reversed all hemodynamic and rheological changes brought about by hyperglycemia. Infusion of
N
G
-monomethyl-
l
-arginine (L-NMMA; 2 mg/min) to inhibit endogenous nitric oxide synthesis in 8 normal subjects produced vascular effects qualitatively similar to those of hyperglycemia but quantitatively higher (
P
<.05); however, heart rate and plasma catecholamine levels decreased during L-NMMA infusion, presumably as a consequence of baroreflex activation. Infusion of L-NMMA during hyperglycemia produced changes not different from those obtained during infusion of L-NMMA alone.

Conclusions
The results show that acute hyperglycemia in normal subjects causes significant hemodynamic and rheological changes that are reversed by
l
-arginine. Moreover, the effects of hyperglycemia are mimicked to a large extent, but not entirely, by infusion of L-NMMA. This suggests that hyperglycemia may reduce nitric oxide availability in humans.
Endogenous Basic Fibroblast Growth Factor Displaced by Heparin From the Lumenal Surface of Human Blood Vessels Is Preferentially Sequestered by Injured Regions of the Vessel Wall
Authors: Medalion Benjamin , Merin Gideon , Aingorn Helena , Miao Hua-Quan , Nagler Arnon , Elami Amir , Ishai-Michaeli Rivka , Vlodavsky Israel
Published: June 2012

Background
Proliferation of smooth muscle cells (SMCs) of the arterial wall in response to local injury is an important factor in vascular proliferative disorders. Among the growth factors that promote SMC proliferation is basic fibroblast growth factor (bFGF), which is characterized by a high affinity for heparin and is associated with heparan sulfate on cell surfaces and extracellular matrices. We investigated whether heparin can displace endogenous active bFGF from the lumenal surface of blood vessels, whether bFGF is preferentially bound to injured blood vessels, and whether a synthetic, polyanionic, heparin-mimicking compound (RG-13577) can prevent sequestration of bFGF by the vessel wall.

Methods and Results
Injured and noninjured saphenous vein segments were perfused with or without heparin, in the absence or presence of
125
I-bFGF and/or RG-13577 (a polymer of 4-hydroxyphenoxy acetic acid). Heparin displaced bFGF from the lumenal surface of the vein, and the released bFGF stimulated proliferation of SMCs. Likewise, systemic administration of heparin during open heart surgery resulted in a marked increase in plasma bFGF levels. Injured veins sequestered
125
I-bFGF to a much higher extent than noninjured vein segments, both in the absence and presence of heparin. This sequestration was inhibited by compound RG-13577.

Conclusions
Despite its beneficial effects, heparin may displace active bFGF, which subsequently may be preferentially deposited on injured vessel walls, thus contributing to the pathogenesis of restenosis. This effect may be prevented by a synthetic heparin-mimicking compound.
Fast
23
Na Magnetic Resonance Imaging of Acute Reperfused Myocardial Infarction
Authors: Kim Raymond J. , Lima Joao A. C. , Chen Enn-Ling , Reeder Scott B. , Klocke Francis J. , Zerhouni Elias A. , Judd Robert M.
Published: June 2012

Background
The ability of the myocyte to maintain an ionic concentration gradient is perhaps the best indication of myocardial viability. We studied the relationship of
23
Na MRI intensity to viability and explored the potential of fast-imaging techniques to reduce
23
Na imaging times in rabbits and dogs.

Methods and Results
Eighteen rabbits underwent in situ coronary artery occlusion and reperfusion. The hearts were then either imaged following isolation and perfusion with cardioplegic solution (n=6), imaged in vivo (n=6), or analyzed for
23
Na content and relaxation times (n=12). Normal rabbits (n=6) and dogs (n=4) were imaged to examine the effect of animal size on
23
Na image quality.
23
Na imaging times were 7, 11, and 4 minutes for isolated rabbits, in vivo rabbits, and in vivo dogs, respectively. Infarcted, reperfused regions, identified by triphenyltetrazolium chloride staining, showed a significant elevation in
23
Na image intensity compared with viable regions (isolated, 42±5%,
P
<.02; in vivo, 95±6%,
P
<.001), consistent with increased tissue sodium content. Similarly,
23
Na MR spectroscopy showed that [Na
+
] was higher in nonviable than viable myocardium (isolated, 99±4 versus 61±2 mmol/L; in vivo, 91±2 versus 38±1 mmol/L;
P
<.001 for both). Image signal-to-noise ratios were higher in dogs than rabbits despite shorter imaging times, primarily due to larger voxels.

Conclusions
Following acute infarction with reperfusion, a regional increase in
23
Na MR image intensity is associated with nonviable myocardium. Fast gradient-echo imaging techniques reduce
23
Na imaging times to a few minutes, suggesting that
23
Na MR imaging has the potential to become a useful experimental and clinical tool.
α
2
-Antiplasmin Causes Thrombi to Resist Fibrinolysis Induced by Tissue Plasminogen Activator in Experimental Pulmonary Embolism
Authors: Butte Anjum N. , Houng Aiilyan K. , Jang Ik-Kyung , Reed Guy L.
Published: June 2012

Background
In patients with pulmonary embolism, thrombi resist fibrinolysis induced by plasminogen activators. Because the molecular basis of this thrombus resistance is poorly understood, we used a potent inhibitor to examine the potential role of α
2
-antiplasmin (α2AP) in experimental pulmonary embolism.

Methods and Results
Lysis of experimental pulmonary emboli was measured 4 hours after embolization in anesthetized ferrets. All animals received heparin (100 U/kg). Five experimental groups were studied: (1) no recombinant tissue plasminogen activator (rTPA); (2) rTPA at 1 mg/kg; (3) rTPA at 2 mg/kg; (4) rTPA at 1 mg/kg plus a control monoclonal antibody (MAb); and (5) rTPA at 1 mg/kg plus an α2AP inhibitor (MAb 77A3). In comparison with ferrets receiving no rTPA (15.6±10.5% lysis, mean±SD), rTPA–treated groups showed significantly greater lysis (
P
<.01). Animals treated with rTPA and α2AP inhibitor (56.2±4.7% lysis) showed significantly greater lysis than all other treatment groups, including ferrets treated with the same dose of rTPA alone (38.5±6.3%,
P
<.01), with twice the rTPA dose alone (45.0±6.5%,
P
<.05), or with a control MAb (35.2±4.6%,
P
<.01). The combination of rTPA treatment and α2AP inhibition caused no consumption of fibrinogen.

Conclusions
Inhibition of α2AP significantly amplified the lysis of experimental pulmonary emboli by rTPA without increasing fibrinogen consumption. These results suggest that α2AP may play an important role in thrombus resistance in patients with venous thromboembolism.
Improvement of Alveolar–Capillary Membrane Diffusing Capacity With Enalapril in Chronic Heart Failure and Counteracting Effect of Aspirin
Authors: Guazzi Marco , Marenzi Giancarlo , Alimento Marina , Contini Mauro , Agostoni Piergiuseppe
Published: June 2012

Background
KII ACE, the enzyme that converts angiotensin I and inactivates bradykinin, is highly concentrated in the lungs; its blockade reduces exposure to angiotensin II and enhances exposure to prostaglandins generated by local kinin hyperconcentration. Our hypothesis is that ACE inhibitors improve pulmonary function in chronic heart failure (CHF) by readjusting lung vessel tone and permeability or alveolar–capillary membrane diffusion.

Methods and Results
In 16 CHF patients and 16 normal volunteers or mild untreated hypertensives, pulmonary function and exercise tests with respiratory gas analysis were assessed on placebo, enalapril (10 mg BID), enalapril plus aspirin (325 mg/d), or aspirin, in random order and double blind, for 15 days each. In CHF, enalapril increased pulmonary carbon monoxide diffusion (DLCO), oxygen consumption (V̇
o
2
), and exercise tolerance and reduced the ratio of dead space to tidal volume (V
d
/V
t
) and the ventilatory equivalent for carbon dioxide production V̇
e
/V̇
co
2
). On enalapril, V̇
o
2
(
r
=.80,
P
<.0001) and V
d
/V
t
(
r
=−.69,
P
=.003) changes from placebo correlated with those in DLCO. These effects were inhibited by aspirin and were absent in control subjects. In 8 additional patients, hydralazine–isosorbide dinitrate, as an alternative treatment for reducing pulmonary capillary wedge pressure (PCWP) and increasing exercise capacity, were more effective than enalapril for the PCWP but did not affect DLCO and V̇
e
/V̇
co
2
; amelioration in V̇
o
2
and V
d
/V
t
was unrelated to DLCO and was not modified by aspirin.

Conclusions
ACE inhibition improved pulmonary diffusion in CHF. Hydralazine–isosorbide dinitrate failed to provide this result. Counteraction by aspirin, a prostaglandin inhibitor, bespeaks prostaglandin participation while on enalapril that might readjust capillary permeability or alveolar–capillary membrane diffusion.
Unanticipated Lessening of the Rise in Extracellular Potassium During Ischemia by Pinacidil
Authors: Kanda Akihiro , Watanabe Ichiro , Williams Marcus L. , Engle Connie L. , Li Shu , Koch Gary G. , Gettes Leonard S.
Published: June 2012

Background
The efflux of potassium (K) through the ATP- sensitive K channel is considered an important cause of the rise in extracellular K ([K
+
]
e
) during no-flow ischemia. We postulated that agents that enhance K conductance in this channel would enhance the rise in [K
+
]
e.

Methods and Results
We studied the effects of 10 and 25 μmol/L pinacidil, an ATP-sensitive K channel opener that provides metabolic protection to the ischemic myocardium, on the rise in [K
+
]
e
recorded by K-sensitive electrodes, the change in action potential duration (APD) recorded by microelectrodes, and the changes in activation during ischemia in in situ pig hearts and Tyrode-perfused rabbit interventricular septa. Pinacidil 25 μmol/L unexpectedly lessened the rise in [K
+
]
e
and the activation delay in both preparations. Pinacidil 10 μmol/L had no effect in the rabbit and only a slight effect in the pig. Both concentrations significantly exaggerated the APD shortening induced by ischemia. By varying stimulation frequency, we demonstrated that the rise in [K
+
]
e
during ischemia, both before and after pinacidil, correlated with the time that the action potential was at its plateau voltage.

Conclusions
Our results indicate that the rise in [K
+
]
e
during ischemia is due to multiple factors, including K conductance across membrane channels, K driving force as reflected by the time that the action potential is at its plateau voltage, and the metabolic effects of ischemia. The unanticipated lessening of the rise in [K
+
]
e
by pinacidil reflects the balance of its effects on these several parameters.
The White Blood Cell Adhesion Molecule E-Selectin Predicts Restenosis in Patients With Intermittent Claudication Undergoing Percutaneous Transluminal Angioplasty
Authors: Belch J.J.F. , Shaw J.W. , Kirk G. , McLaren M. , Robb R. , Maple C. , Morse P.
Published: June 2012

Background
Experimental studies have shown that endothelial dysfunction is an early event preceding restenosis. Monocytes and neutrophils have been shown to bind to damaged endothelium via the cell adhesion molecules (CAMs). The selectins are involved in capturing the leukocytes and tethering them to the endothelium. E-selectin is a CAM that is only expressed on activated endothelial cells. Its ligands are expressed on monocytes and neutrophils and it has been found to exist in a soluble form. This soluble form may represent a marker for endothelial damage and may be a precursor of smooth muscle proliferation.

Methods and Results
Fifty-four patients who were undergoing peripheral arterial balloon angioplasty had blood sampled before angioplasty. E-selectin was measured in plasma with the use of an ELISA. At follow-up angiogram, 30% (n=14) of the patients had restenosed at 1 year. There was a significant difference in baseline E-selectin levels in patients who restenosed compared with those who did not (65.3 ng/mL [58.25 to 78.05] versus 52.3 [34.2 to 62.1], Mann-Whitney
U
,
P
<.007). Endothelial activation with subsequent adherence of white blood cells is an important step in restenosis.

Conclusions
We have shown an increased level of shed E-selectin in patients destined for restenosis and suggest that this work further supports a role for white blood cell/endothelial interaction in restenosis after angioplasty.
Asymptomatic Cardiac Ischemia Pilot (ACIP) Study Two-Year Follow-up
Authors: Davies Richard F. , Goldberg A. David , Forman Sandra , Pepine Carl J. , Knatterud Genell L. , Geller Nancy , Sopko George , Pratt Craig , Deanfield John , Conti C. Richard
Published: June 2012

Background
Patients with ischemia during stress testing and ambulatory ECG monitoring have an increased risk of cardiac events, but it is not known whether their prognosis is improved by more aggressive treatment with anti-ischemic drugs or revascularization.

Methods and Results
The Asymptomatic Cardiac Ischemia Pilot study randomized 558 such patients who had coronary anatomy suitable for revascularization to three treatment strategies: angina-guided drug therapy (n=183), angina plus ischemia–guided drug therapy (n=183), or revascularization by angioplasty or bypass surgery (n=192). Two years after randomization, the total mortality was 6.6% in the angina-guided strategy, 4.4% in the ischemia-guided strategy, and 1.1% in the revascularization strategy (
P
<.02). The rate of death or myocardial infarction was 12.1% in the angina-guided strategy, 8.8% in the ischemia-guided strategy, and 4.7% in the revascularization strategy (
P
<.04). The rate of death, myocardial infarction, or recurrent cardiac hospitalization was 41.8% in the angina-guided strategy, 38.5% in the ischemia-guided strategy, and 23.1% in the revascularization strategy (
P
<.001). Pairwise testing revealed significant differences between the revascularization and angina-guided strategies for each comparison.

Conclusions
A strategy of initial revascularization appears to improve the prognosis of this population compared with angina-guided medical therapy. A larger long-term study is needed to confirm this benefit and to adequately test the potential of more aggressive drug therapy.
Systemic Infection Related to Endocarditis on Pacemaker Leads
Authors: Klug Didier , Lacroix Dominique , Savoye Christine , Goullard Luc , Grandmougin Daniel , Hennequin Jean Luc , Kacet Salem , Lekieffre Jean
Published: June 2012

Background
Endocarditis related to pacemaker (PM)-lead infection is a rare but serious complication of permanent transvenous pacing. To determine in which situations the diagnosis should be evoked and to determine optimal management, we reviewed our experience with endocarditis related to PM-lead infection.

Methods and Results
Fifty-two patients were admitted for endocarditis related to PM-lead infection. The presentation was acute in 14 patients, with onset of symptoms in the first 6 weeks after the last procedure on the implant site, and chronic in 38 patients. Fever occurred in 86.5%. Clinical and/or radiological evidences of pulmonary involvement were observed in 38.4%. Pulmonary scintigraphy disclosed pulmonary infarcts in 31.2%. Local complications were found in 51.9%. Elevated C-reactive protein was found in 96.2%. A germ was isolated in 88.4% of patients and was a
Staphylococcus
in 93.5%. Transthoracic echocardiography demonstrated vegetations in only 23% of patients, whereas transesophageal echocardiography disclosed abnormal appearances on the PM lead in 94%. We systematically tried to ablate all the material. Two techniques were used: percutaneous ablation or surgical removal during extracorporeal circulation. All patients were treated with antibiotics after removal of the infected material. Two patients died before lead removal and 2 after surgical removal; the predischarge mortality was 7.6%, and the overall mortality was 26.9% after a follow-up of 20.1±13 months.

Conclusions
The diagnosis of endocarditis related to PM-lead infection should be suspected in the presence of fever, complications, or pulmonary lesions after PM insertion. Transesophageal echocardiography should be performed to look for vegetations. Staphylococci are involved in the majority of these infections. The endocardial system must be entirely removed and appropriate antibiotic therapy pursued for 6 weeks.