bluuebunny/crossref_metadata_2025 huggingface dataset:
In Vitro Responses of Human Peripheral Small Arteries in Hypercholesterolemia and Effects of Therapy
Authors: Goode Grahame K. , Heagerty Anthony M.
Published: June 2012

Background
Studies in both animals and humans with raised lipid levels have demonstrated abnormalities in vascular function usually manifested by an impairment in endothelium-dependent vasorelaxation. This is believed to be an early event in atheroma formation. There are few data on the effects on vascular function in humans of lowering serum lipids. We conducted a study to investigate the effects of cholesterol reduction on the in vitro function of human peripheral small arteries in middle-aged patients with hypercholesterolemia.

Methods and Results
Subcutaneous gluteal fat biopsies were taken from 18 hypercholesterolemic (HC) patients (mean±SEM serum total cholesterol, 9.7±0.57 mmol/L) and 16 age- and sex-matched control subjects (mean cholesterol, 4.69±0.18 mmol/L). Subcutaneous small arteries (internal diameter, <330 μm) were dissected and mounted on a wire myograph for isometric tension measurements. The HC patients showed impaired relaxation to acetylcholine (10
−9
to 10
−6
mol/L) after preconstriction with the thromboxane A
2
analogue
U46619
(10
−6
mol/L, mean maximum relaxation, 42.9±5.4%) compared with control subjects (85.7±4.0%,
P
<.00001). Incubation with the nitric oxide substrate
l
-arginine (3 mmol/L) improved the endothelium-dependent vasorelaxation response to acetylcholine (70.9±6.0%,
P
<.01) in patients but not in control subjects. Also, there was a smaller but significant difference in responses to the endothelium-independent agent sodium nitroprusside (10
−9
to 10
−6
mol/L) between the HC group (mean maximum relaxation, 76.9±6.0%) and the control subjects (89.7±6%;
P
<.01). A total of 10 patients had a second gluteal skin biopsy and repeat functional studies after successful cholesterol-lowering therapy after a mean period of 9.9±4.7 months. A significant reduction in total and LDL cholesterol was achieved (5.29±0.2 and 3.23±0.21 mmol/L, respectively;
P
<.001). This restored vasorelaxation to control values in response to both acetylcholine (mean maximum relaxation, 83.3±3.8%;
P
<.0001) and sodium nitroprusside (87.9±4.8%,
P
<.01). Although both groups were normotensive, there were significantly higher blood pressures in the HC group compared with control subjects (139±4.1 versus 123±3.0 mm Hg systolic,
P
<.01; 84±1.3 versus 75±2.2 mm Hg diastolic,
P
<.01). There was no difference in initial blood pressures between the entire group of 18 and the 10 patients who had repeat biopsies. The blood pressures fell to control values after cholesterol reduction (129.33±4.93 mm Hg systolic and 72.33±2.93 diastolic mm Hg,
P
<.02 relative to pretreatment values).

Conclusions
These results demonstrate abnormalities of both endothelium-dependent and -independent relaxation in human peripheral small arteries that are normalized with effective lipid lowering. The changes in blood pressure may have been secondary to the improvement in vascular function.
Failure of Heparin to Inhibit Intimal Hyperplasia in Injured Baboon Arteries
Authors: Geary Randolph L. , Koyama Noriyuki , Wang Trevina W. , Vergel Selina , Clowes Alexander W.
Published: June 2012

Background
Heparin is a potent inhibitor of smooth muscle cell (SMC) growth and intimal hyperplasia in animal models but has been ineffective in inhibiting restenosis in humans. This difference may relate to flaws in clinical study design or, alternatively, to interspecies differences in SMC response to heparin. To determine whether heparin could inhibit intimal hyperplasia in a species more closely related to humans, we studied the effect of a low-molecular-weight heparin (LMWH) on baboon SMC proliferation and migration in culture and in arteries subjected to experimental angioplasty.

Methods and Results
LMWH or saline was infused continuously after experimental angioplasty of baboon peripheral arteries (six animals per group). After 28 days, bromodeoxyuridine (BrdU) was given to label proliferating cells, and balloon-injured arteries were perfusion-fixed in situ and removed for analysis. All arteries had reendothelialized (Evans blue dye exclusion). LMWH increased partial thromboplastin time (LMWH, 81.7±8.4 seconds versus saline, 34.7±0.8 seconds [mean±SEM];
P
=.004) but failed to inhibit intimal thickening or SMC proliferation (intimal area: LMWH, 0.19±0.03 mm
2
versus saline, 0.21±0.03 mm
2
; BrdU labeling: LMWH, 2.9±0.6% versus saline, 2.4±0.4%;
P
=NS). In culture, LMWH and standard heparin (100 μg/mL) significantly inhibited serum-induced but not platelet-derived growth factor (PDGF-BB)–induced SMC proliferation (% control, serum: LMWH, 60.5±4.0%,
P
=.0002; standard heparin, 29.4±8.2%,
P
=.0001; % control, PDGF-BB: LMWH, 117.7±11.3%,
P
=NS; standard heparin, 90.9±14.4%,
P
=NS) and SMC migration (% control, serum: LMWH, 15.3±1.9%,
P
=.0198; standard heparin, 26.4±13.8%,
P
=.0032; % control, PDGF-BB: LMWH, 98.5±14.3%,
P
=NS; standard heparin, 100.0±13.5%,
P
=NS).

Conclusions
LMWH failed to inhibit intimal hyperplasia in a baboon angioplasty model. Furthermore, LMWH blocked serum-induced but not PDGF-BB–induced SMC proliferation and migration in culture. Thus, heparin-sensitive and -insensitive pathways exist for SMC activation. The relative importance of each pathway induced by injury may vary between species and thus account for different responses to heparin.
Absence of Lethal Reperfusion Injury After 3 Hours of Reperfusion
Authors: Zahger Doron , Yano Juliana , Chaux Aurelio , Fishbein Michael C. , Ganz William
Published: June 2012

Background
Whether reperfusion can cause necrosis of previously viable myocytes (lethal reperfusion injury) remains controversial. Numerous studies examined the ability of various agents to prevent or limit reperfusion injury, but the results were contradictory. In a single-canine-heart model of ischemia-reperfusion, we previously demonstrated that 5 minutes of reperfusion does not increase the transmural extent of necrosis. Since the 5-minute period of reperfusion is considered by some to be too short for the full manifestation of reperfusion injury, we reexamined the issue of lethal reperfusion injury using a modification of the single-heart model of ischemia-reperfusion that allowed extending the reperfusion period to 3 hours.

Methods and Results
In anesthetized, open-chest dogs, the distal half of the left anterior descending coronary artery (LAD) segment between the last diagonal branch and the apex was perfused via a shunt from the left carotid artery. The shunt was closed for periods of 90 to 180 minutes, depending on the ECG severity of ischemia, and reperfused for 3 hours. While the distal region was perfused from the carotid artery, the LAD was occluded proximal to the last diagonal branch for the same period of time as the distal region had been earlier. The time of occlusion was chosen such that the end of the occlusion period coincided with the end of the experiment. Thus, both regions of the LAD territory were subjected to identical periods of ischemia, but only the distal region was reperfused. At the end of the experiment, the boundary between the proximal (nonreperfused) and distal (reperfused) area was delineated by blue dye, and the heart was arrested, cut into slices 1 cm thick parallel to the LAD, and placed in triphenyltetrazolium chloride. The epicardial edges of necrosis in the reperfused and the nonreperfused regions were examined for any shift that might suggest a difference in the transmurality of necrosis. The areas of necrotic and viable myocardium were measured by planimetry within 1 cm on either side of the boundary. In all 14 dogs, the epicardial edges of necrosis ran as a single line across the boundary, and no shift was present. There was also no difference in the transmurality of necrosis between the reperfused and nonreperfused regions (64.9±20.7% versus 66.1±17.0% of left ventricular wall thickness, respectively;
P
=.32 by paired
t
test).

Conclusions
In a single-canine-heart model of ischemia-reperfusion, there was no evidence of lethal reperfusion injury after 3 hours of reperfusion.
Endovascular Stent Design Dictates Experimental Restenosis and Thrombosis
Authors: Rogers Campbell , Edelman Elazer R.
Published: June 2012

Background
Vascular interventions that maximize initial lumen diameter provoke extensive neointimal hyperplasia but minimize its effects, causing long-term lumen size to be greater. Nevertheless, interventions such as endovascular stents, which increase lumen size above that achieved with balloon angioplasty, are subject to frequent thrombosis and restenosis. It has been unclear whether the response to stent-induced injury is determined solely by the degree of stent-induced arterial expansion or whether the geometric configuration of the stent or the material left in contact with the vessel wall also contribute.

Methods and Results
We examined the vascular response to steel stents deployed in denuded rabbit iliac arteries for 14 days. In one set of experiments, the effects of stent configuration were examined, holding diameter, mass, surface area, and stent surface material constant. In another set, stent surface material was changed, with mass, configuration, and diameter unaltered. Changing stent configuration to reduce strut-strut intersections by 29% without affecting mass or surface area reduced vascular injury by 42%, thrombosis by 69%, and neointimal hyperplasia by 38%. Monocyte adhesion to stented arteries correlated linearly with vascular trauma and neointimal hyperplasia (
r
=.96,
P
<.01 for each). When the stainless steel surface was coated with an inert polymer material, vascular injury and neointimal hyperplasia were unchanged, but thrombosis was eliminated.

Conclusions
Surface material and geometric configuration of stents may be more important than postplacement diameter in determining neointimal hyperplasia and thrombosis. Alterations in configuration affect vascular injury and neointimal hyperplasia, while surface material plays a greater role in thrombosis. Monocytes may be important modulators of stent-induced intimal thickening. Clinical confirmation of these findings may alter coronary stent deployment techniques and future stent designs.
A DNA Variant at the Angiotensin-Converting Enzyme Gene Locus Associates With Coronary Artery Disease in the Caerphilly Heart Study
Authors: Mattu Raj K. , Needham Edward W. A. , Galton David J. , Frangos Evanthia , Clark Adrian J. L. , Caulfield Mark
Published: June 2012

Background
We analyzed an insertion/deletion (I/D) polymorphism of the angiotensin I–converting enzyme (ACE) gene in 1226 subjects from the Caerphilly Prospective Heart Disease Study. Amplification of genomic DNA using the polymerase chain reaction yielded the genotypes II, ID, and DD. Distribution of the polymorphism was analyzed among the whole group and within subgroups (specified following multiple risk factor analysis) for coronary artery disease (CAD) and against multiple risk factors.

Methods and Results
Allele frequencies were I=0.413 and D=0.587. No association was observed between the polymorphism and CAD in the whole group. Among subjects defined at lower risk of CAD by total cholesterol/HDL cholesterol (TC/HDL) ratios, we found significant associations of the DD genotype with CAD (
P
<.0053, n=586 for TC/HDL <5.654 [median] and
P
<.009, n=385 for TC/HDL <5.0 [clinical threshold]). On further exclusion of subjects with blood pressures ≥140/90 or on hypotensive medications, the DD genotype still associated with CAD (
P
<.07, n=210, TC/HDL <5.654 and
P
<.016, n=135, TC/HDL <5.0). Further stratification of risk incorporating other risk factors, except body mass index, did not alter or enhance this association. Although similar association was observed when risk was specified by using HDL and apo B levels instead of TC/HDL, this association was lost when body mass index was included in the low-risk stratification.

Conclusions
The DD genotype is a linkage marker for an etiologic mutation at or near the ACE gene that may confer risk of CAD detectable in subjects previously unidentifiable with “classic” risk factors. However, this risk may be quantitatively small among the general male population.
Effect of Cigarette Smoking on Outcome After Thrombolytic Therapy for Myocardial Infarction
Authors: Grines Cindy L. , Topol Eric J. , O’Neill William W. , George Barry S. , Kereiakes Dean , Phillips Harry R. , Leimberger Jeffrey D. , Woodlief Lynn H. , Califf Robert M.
Published: June 2012

Background
Smoking is known to be a strong risk factor for premature atherosclerosis, myocardial infarction, and sudden cardiac death. Unexpectedly, in the reperfusion era, investigators have reported that patients who smoke have a more favorable prognosis after thrombolysis compared with nonsmokers. Since smoking is associated with a relatively hypercoagulable state, we hypothesized that the coronary occlusion responsible for infarction may be primarily thrombotic, with improved outcome relating to enhanced patency or the absence of a residual stenosis after thrombolytic therapy.

Methods and Results
To examine this issue, we evaluated 1619 patients treated with TPA, urokinase, or both in six consecutive myocardial infarction trials, of whom 878 (54%) were currently smoking. Patients underwent 90-minute and predischarge catheterizations, which were quantified blinded to the patients’ smoking status. As expected, baseline fibrinogen (2.8 [2.5, 3.6] versus 2.7 [2.4, 3.5] g/dL,
P
=.003) and hematocrit (44% [41%, 47%] versus 43% [40%, 45%],
P
=.0001) levels were greater in smokers. Although there were no differences between smokers and nonsmokers with regard to 90-minute patency (73% versus 74%), smokers were more likely to have TIMI-3 flow (41.1% versus 34.6%,
P
=.034), with a larger minimum lumen diameter of the infarct stenosis both acutely (0.82 [0.51, 1.11] versus 0.72 [0.43, 1.04] mm,
P
=.0432) and at follow-up (1.2 [0.8, 1.74] versus 1.0 [0.7, 1.5],
P
=.002). Although smokers tended to have reduced in-hospital mortality compared with nonsmokers in univariate analysis (4.0% versus 8.9%,
P
=.0001), after adjustment for baseline differences between smokers and nonsmokers in age (54 [47, 62] versus 60 [54, 68] years,
P
<.0001), inferior infarct location (60% versus 53%,
P
<.0001), three-vessel disease (16% versus 22%,
P
<.001), and baseline ejection fraction (53% [44%, 60%] versus 50% [42%, 58%],
P
=.0069), smoking history was of no independent prognostic significance.

Conclusions
Therefore, smokers have a relatively hypercoagulable state, documented by increased hematocrit and fibrinogen levels. Quantitative coronary angiographic analysis suggests that the mechanism of infarction in smokers is more often thrombosis of a less critical atherosclerotic lesion compared with nonsmokers. Enhanced perfusion status, as well as favorable baseline clinical and angiographic characteristics, may be responsible for the more benign prognosis of current smokers.
Endothelin-1 in Pulmonary Hypertension Associated With High-Altitude Exposure
Authors: Goerre Stefan , Wenk Markus , Bärtsch Peter , Lüscher Thomas F. , Niroomand Feraydoon , Hohenhaus Elke , Oelz Oswald , Reinhart Walter H.
Published: June 2012

Background
Endothelin-1 is involved in chronic pulmonary hypertension. Its role in acute pulmonary hypertension due to hypoxia in humans is not clear. We therefore studied the influence of hypoxia caused by exposure to high altitude on plasma endothelin-1 levels, arterial blood gases, and pulmonary arterial pressure in subjects taking nifedipine or placebo.

Methods and Results
Twenty-two healthy volunteers were investigated at low altitude (490 m) and high altitude (4559 m). Arterial blood gases were analyzed immediately, endothelin-1 was measured by radioimmunoassay, and pulmonary artery pressure was assessed by Doppler echocardiography. After baseline investigations, the mountaineers were allocated in a randomized double-blind fashion to receive either placebo or nifedipine (20 mg TID) during rapid ascent to high altitude within 22 hours. Tests were repeated at the high-altitude research laboratories located in the Capanna “Regina Margherita” (Italy, 4559 m). Plasma endothelin-1 was increased twofold at high altitude (5.9±2.2 pg/mL compared with 2.9±1.1 pg/mL,
P
<.05), was inversely related to arterial P
o
2
(
r
=−.46,
P
<.001), and correlated with pulmonary artery pressure (
r
=.52,
P
<.002). At high altitude, arterial endothelin-1 was lower (4.3±1.6 pg/mL) than venous endothelin-1 (5.9±2.2 pg/mL,
P
<.001), indicating either predominant production in the venous vasculature or pronounced clearance in the pulmonary circulation. The calcium antagonist nifedipine, which lowered pulmonary artery pressure at high altitude (32±5 versus 42±11 mm Hg,
P
<.05), had no influence on plasma endothelin-1 levels. The administration of 35% O
2
at high altitude normalized arterial P
o
2
, tended to decrease endothelin-1, and decreased pulmonary artery pressure accordingly.

Conclusions
We conclude that plasma endothelin-1 is increased at high altitude, but whether or not it represents an important pathogenetic factor for pulmonary hypertension remains to be investigated.
Cardioprotective Effects of a C1 Esterase Inhibitor in Myocardial Ischemia and Reperfusion
Authors: Buerke Michael , Murohara Toyoaki , Lefer Allan M.
Published: June 2012

Background
Myocardial injury after ischemia and reperfusion can be attributed largely to the effects of polymorphonuclear leukocytes (PMN). The complement system plays an important role as a chemotactic agent, affecting adhesion molecule expression and neutrophil accumulation.

Methods and Results
In the present study, the cardioprotective effects of C1 esterase inhibitor (C1 INH) were examined in a feline model of myocardial ischemia and reperfusion (90 minutes of ischemia followed by 270 minutes of reperfusion). C1 INH (15 mg/kg) administered 10 minutes before reperfusion significantly attenuated myocardial necrosis compared with vehicle (10±2% and 29±2% necrosis as a proportion of area at risk, respectively;
P
<.01). Myocardial preservation was also related to reduced plasma accumulation of creatine kinase activity. C1 INH treatment resulted in improved recovery of cardiac contractility and preservation of coronary vascular endothelial function, as assessed by relaxation in response to acetylcholine, compared with contractility and preservation of endothelial function in vehicle-treated animals (69±6% and 20±4% relaxation, respectively;
P
<.01). In addition, cardiac myeloperoxidase activity (an index of PMN accumulation) in the ischemic area was significantly reduced after C1 INH treatment. Furthermore, immunohistochemical analysis of ischemic-reperfused myocardial tissue demonstrated deposition of the first component of the classic complement pathway, C1q, on cardiac myocytes and coronary vessels.

Conclusions
Blocking of the classic complement pathway by C1 INH appears to be an effective means of preserving ischemic myocardium from reperfusion injury. The mechanism of this cardioprotective effect appears to be inhibition of PMN-endothelium interaction; this inhibition leads to preservation of normal endothelial function, which results in reduced cardiac necrosis.
American Heart Association–Bugher Foundation Centers for Molecular Biology in the Cardiovascular System
Authors: Morgan Howard E. , Paul Sheryl R.
Published: June 2012

Background
The American Heart Association (AHA) and the Henrietta B. and Frederick H. Bugher Foundation in 1985 entered into a partnership to establish a group of Centers for Molecular Biology in the Cardiovascular System. The goal was to recruit and train young scientists with medical training to apply molecular and cellular biology knowledge and techniques to cardiovascular problems.

Methods and Results
Six Centers have been awarded (three in 1986 and three in 1991), and a total of 110 trainees have been involved as of June 30, 1994. Of these trainees, 77 were recruited and trained by the 1986 Centers. As of June 1994, 88% of these trainees remained in academic medicine and 54% progressed to higher academic ranks; 79% published papers in science and 66% in molecular biology; and 36% obtained extramural funding for their work. On this basis, the 1986 trainees appear to be well on their way to becoming successful academic cardiologists.

Conclusions
The AHA–Bugher Foundation Center program has produced a cadre of cardiovascular scientists who are applying molecular biology knowledge to both basic and clinical problems.
Maximal Coronary Flow Reserve and Metabolic Coronary Vasodilation in Patients With Diabetes Mellitus
Authors: Nahser Philip J. , Brown Ronald E. , Oskarsson Helgi , Winniford Michael D. , Rossen James D.
Published: June 2012

Background
Structural and functional abnormalities of the coronary microcirculation have been reported in experimental diabetes mellitus. The purpose of this study was to evaluate coronary microvascular function in human diabetes.

Methods and Results
Twenty-four diabetic and 31 nondiabetic patients were studied during cardiac catheterization. A Doppler catheter or guidewire was used to measure changes in coronary blood flow velocity in a nonstenotic artery. Maximal coronary blood flow reserve was determined by using intracoronary adenosine or papaverine. Coronary dilation in response to an increase in myocardial metabolic demand was assessed by using rapid atrial pacing. Maximal vasodilator responses to papaverine and adenosine were compared in 12 diabetic patients. Maximal pharmacologic coronary flow reserve was depressed in diabetic (2.8±0.2, n=19) compared with nondiabetic (3.7±0.2, n=21,
P
<.001) patients. During atrial pacing, the decrease in coronary vascular resistance was attenuated in the diabetic (−14±3%) compared with the nondiabetic (−24±2%,
P
<.05) patients. Differences in coronary microvascular function between diabetic and nondiabetic patients were not attributable to differences in drug therapy, resting hemodynamics, or incidence of hypertension. In 12 diabetic patients the maximal coronary vasodilator responses to papaverine and adenosine were similar.

Conclusions
This study demonstrates both reduced maximal coronary vasodilation and impairment in the regulation of coronary flow in response to submaximal increases in myocardial demand in patients with diabetes mellitus. These microvascular abnormalities may lead to myocardial ischemia in the absence of epicardial coronary atherosclerosis in some circumstances, and thus contribute to adverse cardiovascular events in diabetic patients.
Temporal Changes in Myocardial Perfusion Patterns in Patients With Reperfused Anterior Wall Myocardial Infarction
Authors: Ito Hiroshi , Iwakura Katsuomi , Oh Hidemasa , Masuyama Tohru , Hori Masatsugu , Higashino Yorihiko , Fujii Kenshi , Minamino Takazo
Published: June 2012

Background
Several studies demonstrated ischemic microvascular damage in patients with acute myocardial infarction (AMI). In this study, myocardial contrast echocardiography (MCE) was used to assess the temporal changes in myocardial perfusion after reflow and to investigate the relation between MCE findings and myocardial viability.

Methods and Results
MCE was performed with the intracoronary injection of sonicated microbubbles before and shortly after coronary reflow and 1 month later in 45 patients with anterior wall AMI. MCE before reflow was analyzed to determine the risk area as an area of contrast defect in the apical long-axis view. MCE images after reperfusion were analyzed to determine peak contrast intensity, which should be in proportion to the concentration of microbubbles within the microvasculature and in the infarcted and normal myocardium, and the ratio of these (PI ratio) was used to assess microvascular integrity. Areas of residual contrast defect were expressed as a ratio to those of left ventricular myocardium (RCD ratio) to assess the spatial extent of the MCE “no reflow.” Regional wall motion (RWM, SD per chord) in the territory of the left anterior descending coronary artery was determined by the centerline method in both the acute and late stages. Although the PI ratio was extremely low shortly after coronary reflow, it increased in the late stage of AMI with the improvement in regional contractile function (RWM, −3.2±0.5 versus −2.6±1.0,
P
<.01; PI ratio, 0.44±0.25 versus 0.60±0.29,
P
<.01). Reduction in the RCD ratio was observed even in 15 patients with MCE no reflow in the acute stage (0.33±0.09 versus 0.16±0.11,
P
<.01). Then we investigated the relation between residual contractile function and microvascular integrity in the late stage. A significant correlation was found between the PI ratio and RWM (
r
=.73,
P
<.001) in the late stage of the AMI.

Conclusions
(1) Recovery from ischemic microvascular damage is generally observed in the late stage of AMI in association with improvement in myocardial contractile function. The degree of improvement in contractile function and microvascular integrity, however, varies among patients. (2) Contrast peak intensity in the late stage of infarction may provide a useful estimate of myocardial viability.
Comparison of Five Antihypertensive Monotherapies and Placebo for Change in Left Ventricular Mass in Patients Receiving Nutritional-Hygienic Therapy in the Treatment of Mild Hypertension Study (TOMHS)
Authors: Liebson Philip R. , Grandits Greg A. , Dianzumba Sinda , Prineas Ronald J. , Grimm Richard H. , Neaton James D. , Stamler Jeremiah
Published: June 2012

Background
Increased left ventricular mass (LVM) by echocardiography is associated with increased risk of cardiovascular disease. Thus, it is of interest to compare the effects of both pharmacological and nonpharmacological approaches to the treatment of hypertension on reduction of LVM.

Methods and Results
Changes in LV structure were assessed by M-mode echocardiograms in a double-blind, placebo-controlled clinical trial of 844 mild hypertensive participants randomized to nutritional-hygienic (NH) intervention plus placebo or NH plus one of five classes of antihypertensive agents: (1) diuretic (chlorthalidone), (2) β-blocker (acebutolol), (3) α-antagonist (doxazosin mesylate), (4) calcium antagonist (amlodipine maleate), or (5) angiotensin-converting enzyme inhibitor (enalapril maleate). Echocardiograms were performed at baseline, at 3 months, and annually for 4 years. Changes in blood pressure averaged 16/12 mm Hg in the active treatment groups and 9/9 mm Hg in the NH only group. All groups showed significant decreases (10% to 15%) in LVM from baseline that appeared at 3 months and continued for 48 months. The chlorthalidone group experienced the greatest decrease at each follow-up visit (average decrease, 34 g), although the differences from other groups were modest (average decrease among 5 other groups, 24 to 27 g). Participants randomized to NH intervention only had mean changes in LVM similar to those in the participants randomized to NH intervention plus pharmacological treatment. The greatest difference between groups was seen at 12 months, with mean decreases ranging from 35 g (chlorthalidone group) to 17 g (acebutolol group) (
P
=.001 comparing all groups). Within-group analysis showed that changes in weight, urinary sodium excretion, and systolic BP were moderately correlated with changes in LVM, being statistically significant in most analyses.

Conclusions
NH intervention with emphasis on weight loss and reduction of dietary sodium is as effective as NH intervention plus pharmacological treatment in reducing echocardiographically determined LVM, despite a smaller decrease in blood pressure in the NH intervention only group. A possible exception is that the addition of diuretic (chlorthalidone) may have a modest additional effect on reducing LVM.
Marfan Syndrome
Authors: Finkbohner Rebecca , Johnston Dennis , Crawford E. Stanley , Coselli Joseph , Milewicz Dianna M.
Published: June 2012

Background
Development of surgical therapy for aortic aneurysms and dissections has led to treatment of the life-threatening cardiovascular complications associated with Marfan syndrome. The present study determines the effect of surgical therapy on the life expectancy of patients with Marfan syndrome and the clinical course of these patients after aortic aneurysm repair.

Methods and Results
Medical records were reviewed on 192 patients with Marfan syndrome who underwent aortic aneurysm repair during the past 26 years; 103 patients were interviewed, and complete preoperative and postoperative medical information was obtained. Survival curves were generated, and data were analyzed. The median cumulative probability of survival was 61 years, significantly increased compared with the median survival of 47 years for patients with Marfan syndrome determined 30 years ago (
P
<.0006). The majority of patients (53%) had second surgeries to repair subsequent aneurysms or dissections at other sites, the vast majority of which involved the aorta. The most common pattern of aneurysm repair was proximal ascending aortic aneurysm repair, followed by descending thoracic aneurysm surgery. The following variables predicted patients requiring second vascular surgeries: presence of acute or chronic dissection at the time of the first surgery, hypertension after the first surgery, and a history of smoking.

Conclusions
The life expectancy of patients with Marfan syndrome undergoing surgical repair of aortic aneurysms has improved and is consistent with increased survival. After initial repair of an ascending aortic aneurysm, a significant number of patients have subsequent surgeries at other sites throughout the aorta, indicating Marfan syndrome is a disease involving the entire aorta. Patients who had a dissection at the time of the first aortic surgery were more likely to require subsequent aortic surgery than were patients who underwent prophylactic composite graft repair of an aortic aneurysm.
Induction of Plasminogen Activator Inhibitor Type-1 (PAI-1) by Proinsulin and Insulin In Vivo
Authors: Nordt Thomas K. , Sawa Hirofumi , Fujii Satoshi , Sobel Burton E.
Published: June 2012

Background
Fasting hyperinsulinemia (reflected by elevations in immunoreactive “insulin”) is typical of patients with non–insulin-dependent diabetes mellitus (NIDDM) and is often associated with obesity and hypertension. The elevated concentrations detected are indicative not only of insulin but also of its immunologically cross-reactive precursors, including proinsulin. Fasting hyperinsulinemia appears to be associated with decreased fibrinolytic activity in blood, which results from increased activity of plasminogen activator inhibitor type-1 (PAI-1), a potential independent risk factor for coronary artery disease. Patients who were given proinsulin in a previous clinical study by others exhibited an increased incidence of cardiovascular events. Thus, a “proinsulin–PAI-1 axis” may predispose to coronary thrombosis. To define the possible presence of such an axis, this study was designed to determine whether insulin, its precursors, or both increase the concentrations of PAI-1 in rabbits in vivo.

Methods and Results
Equimolar proinsulin (n=10), insulin (n=11), C-peptide (n=4), or vehicle alone (n=10) was administered intravenously over 1 hour to euglycemic, conscious rabbits. Plasma PAI-1 activity increased 3.8-fold with proinsulin (
P
=.002) and 3.6-fold with insulin (
P
=.002). By contrast, no increase occurred after C-peptide or vehicle was administered. The increased PAI-1 activity was shown to be attributable to PAI-1 protein by reverse fibrin autography. As judged from changes in mRNA in tissues, proinsulin and insulin increased PAI-1 gene expression within 3 hours by 2.1- and 2.1-fold, respectively, in aorta (
P
=.025 each) and by 1.9- and 2.4-fold in liver (
P
=.015 and
P
=.001), with return of values to baseline within 24 hours (n=4 experiments in each case).

Conclusions
These results extend our previous observations from studies in vitro and suggest that hyperinsulinemia attributable to augmented concentrations of proinsulin and insulin in plasma increase plasma PAI-1 activity and may contribute to acceleration of atherosclerosis and impairment of coronary thrombolysis in patients with NIDDM.
Administration of Wine and Grape Juice Inhibits In Vivo Platelet Activity and Thrombosis in Stenosed Canine Coronary Arteries
Authors: Demrow Heather S. , Slane Peter R. , Folts John D.
Published: June 2012

Background
Moderate daily consumption of alcoholic beverages is a negative risk factor for the development of atherosclerosis and coronary artery disease (CAD), especially in France and other Mediterranean areas where red wine is regularly consumed with meals. Platelets contribute to the development of atherosclerosis, CAD, and acute arterial thrombus formation.

Methods and Results
Anesthetized dogs were prepared with the Folts model of mechanically stenosed coronary arteries and intimal damage. Periodic acute platelet-mediated thrombus formation occurred, causing cyclic flow reductions (CFRs) in coronary blood flow. The CFRs were eliminated by the administration of 1.62±1.12 mL/kg red wine intravenously (IV) and 4.0 mL/kg intragastrically (IG). The CFRs were abolished by 2.04±1.42 mL/kg of grape juice IV and 10 mL/kg IG. White wine did not have significant results in eliminating the CFRs, either IV (2.0 mL/kg) or IG (4.0 mL/kg), decreasing the slopes of the CFRs only slightly.

Conclusions
Pure ethanol has been shown to inhibit platelet aggregation in vitro, ex vivo, and in vivo, although a blood alcohol content (BAC) of ≥0.2 g/dL is usually required. The BAC of dogs administered the red wine–saline solution intravenously was 0.028 g/dL, much less than is usually necessary for platelet inhibition with pure ethanol. Because red wine and grape juice, but not white wine, abolished the CFRs, this suggests there are compounds present in red wine and grape juice that are not present or are present in a lower concentration in white wine. Wine and grape juice contain a wide variety of naturally occurring compounds, including fungicides, tannins, anthocyanins, and phenolic flavonoids (including flavonols and flavones). These compounds have shown platelet inhibition in vitro by a variety of proposed mechanisms. Perhaps the biological activity of these compounds can explain the platelet-inhibitory properties of red wine and grape juice that are observed without high levels of ethanol.
Tissue Endothelin-1 Immunoreactivity in the Active Coronary Atherosclerotic Plaque
Authors: Zeiher Andreas M. , Goebel Heike , Schächinger Volker , Ihling Christian
Published: June 2012

Background
The pathomorphological substrate of complicated coronary atherosclerotic lesions underlying unstable angina is characterized by a localized chronic inflammatory process. Functionally, coronary lesions associated with unstable angina demonstrate an enhanced vasoreactivity. Endothelin-1 is a potent vasoconstrictor peptide produced not only by endothelial cells but also by macrophages and polymorphonuclear leukocytes, the cell types characteristic of inflammation.

Methods and Results
By use of immunohistochemical techniques, we examined the presence of endothelin-1 in coronary atherosclerotic plaque tissue obtained by directional coronary atherectomy of primary lesions from 50 consecutive patients. The tissue specimens of 43 of 50 patients (86%) demonstrated endothelin-1–like immunoreactivity. Endothelin-1–like immunoreactivity preferentially localized to macrophage-rich areas, to hypercellular regions rich in microvessels, and to plaque areas with evidence of prior hemorrhage. Double-immunolabeling revealed that both macrophages (HAM56 positive) and intimal smooth muscle cells (α-actin positive) demonstrated cytoplasmic immunostaining for endothelin-1. Semiquantitative analysis of endothelin-1–like immunostaining revealed significantly (
P
<.005) higher staining grades in active (1.86±0.15, n=40) compared with nonactive lesions (0.78±0.35, n=10): endothelin-1 staining grades were significantly (
P
<.001) lower in patients with stable angina (0.69±0.19, n=13) than in patients with crescendo angina (1.82±0.30, n=11), with angina at rest (2.08±0.21, n=12), or with angina after myocardial infarction (2.0±0.26, n=14).

Conclusions
Endothelin-1 immunostaining of atherosclerotic tissue localizes predominantly with plaque components indicative of chronic inflammatory processes. The increased tissue endothelin-1–like immunoreactivity in active coronary atherosclerotic lesions may provide a clue to the mechanisms of increased vasoreactivity of the culprit lesion in acute ischemic syndromes, which is the clinical substrate of the active coronary atherosclerotic plaque.
Molecular Variant of Angiotensinogen Gene Is Associated With Coronary Atherosclerosis
Authors: Ishigami Tomoaki , Umemura Satoshi , Iwamoto Tamio , Tamura Kouichi , Hibi Kiyoshi , Yamaguchi Satoshi , Nyuui Nobuo , Kimura Kazuo , Miyazaki Naomichi , Ishii Masao
Published: June 2012

Background
A positive association was previously reported between angiotensin-converting enzyme (ACE) gene polymorphism and several cardiovascular diseases, such as myocardial infarction, left ventricular hypertrophy, and restenosis after percutaneous transluminal coronary angioplasty. Plasma ACE activity and carotid-wall thickening measured by ultrasonography were related, and it was postulated that long-term exposure to high levels of plasma ACE could be involved in structural changes of the arterial wall. In addition, angiotensinogen gene mutation was recently reported to be associated with essential hypertension and preeclampsia. There exists a possibility that the renin-angiotensin system plays an important role in the progress of cardiovascular diseases in humans. Therefore, we examined the association between the molecular variant of the angiotensinogen gene and coronary atherosclerosis.

Methods and Results
This study included 82 patients who had coronary atherosclerosis and 160 control subjects; all study participants were Japanese. All patients with coronary atherosclerosis had at least one coronary artery with >25% luminal diameter obstruction on average according to multiple coronary angiographic views. Angiotensinogen gene molecular variants were designated
AA
,
Aa
, and
aa
. The
a
allele indicated thymine-cytosine transition at nucleotide 704 in exon 2. Genomic DNA was extracted from peripheral blood leukocytes. Polymerase chain reaction was performed to amplify the concerned region of the angiotensinogen gene. After restriction enzyme digestion, it was possible to distinguish the molecular variant of the angiotensinogen gene. The frequencies of these genotypes were 7.3%, 26.8%, and 65.9% in the patients and 18.8%, 31.9%, and 49.3% in the control subjects for the
AA
,
Aa
, and
aa
allelles, respectively. There was an excess in the
a
allele among patients (
P
<.01).

Conclusions
We found a significant association between coronary atherosclerosis and a molecular variant of the angiotensinogen gene. The results suggested that the molecular variant of the angiotensinogen gene could be a new risk factor for coronary atherosclerosis.
Local Lesion-Related Factors and Restenosis After Coronary Angioplasty
Authors: de Groote Pascal , Bauters Christophe , McFadden Eugène P. , Lablanche Jean-Marc , Leroy Fabrice , Bertrand Michel E.
Published: June 2012

Background
Restenosis rates are high when coronary angioplasty is performed in patients with unstable angina. The relative contributions of local and systemic factors to this excess risk of restenosis are unclear. To assess these, we compared changes in minimal lumen diameter and the incidence of restenosis, determined by quantitative coronary angiography, after coronary angioplasty at culprit and nonculprit lesions dilated in the course of a single procedure in patients with unstable angina.

Methods and Results
We identified 67 consecutive patients with unstable angina in whom two lesions, in different vessels, were dilated during the same procedure. Lesions were designated as culprit or nonculprit on the basis of the location of ECG changes during chest pain combined with assessment of the angiographic characteristics of the lesions. With these criteria, 43 patients had identifiable culprit lesions. Stenosis severity before and immediately after angioplasty and at follow-up was assessed with quantitative angiography. Angiographic follow-up was performed in 91% (39 patients) of this subgroup. Culprit lesions were more severe (
P
<.02) than nonculprit lesions. The late loss at culprit lesions (0.87±0.75 mm) was significantly (
P
<.01) greater than the equivalent value for nonculprit lesions (0.33±0.69 mm). With a categorical definition (>50% stenosis at follow-up), restenosis occurred at 67% of culprit lesions and at 32% of nonculprit lesions (
P
<.01).

Conclusions
The greater loss in minimal lumen diameter and the consequent higher rate of restenosis at culprit compared with nonculprit lesions suggest that local “lesion-related” factors are an important determinant of the high rate of restenosis when coronary angioplasty is performed in patients with unstable angina.
Depression and 18-Month Prognosis After Myocardial Infarction
Authors: Frasure-Smith Nancy , Lespérance François , Talajic Mario
Published: June 2012

Background
We previously reported that major depression in patients in the hospital after a myocardial infarction (MI) substantially increases the risk of mortality during the first 6 months. We examined the impact of depression over 18 months and present additional evidence concerning potential mechanisms linking depression and mortality.

Methods and Results
Two-hundred twenty-two patients responded to a modified version of the National Institute of Mental Health Diagnostic Interview Schedule (DIS) for a major depressive episode at approximately 7 days after MI. The Beck Depression Inventory (BDI), which measures depressive symptomatology, was also completed by 218 of the patients. All patients and/or families were contacted at 18 months to determine survival status. Thirty-five patients met the modified DIS criteria for major in-hospital depression after the MI. Sixty-eight had BDI scores ≥10, indicative of mild to moderate symptoms of depression. There were 21 deaths during the follow-up period, including 19 from cardiac causes. Seven of these deaths occurred among patients who met DIS criteria for depression, and 12 occurred among patients with elevated BDI scores. Multiple logistic regression analyses showed that both the DIS (odds ratio, 3.64; 95% confidence interval [CI], 1.32 to 10.05;
P
=.012) and elevated BDI scores (odds ratio, 7.82; 95% CI, 2.42 to 25.26;
P
=.0002) were significantly related to 18-month cardiac mortality. After we controlled for the other significant multivariate predictors of mortality in the data set (previous MI, Killip class, premature ventricular contractions [PVCs] of ≥10 per hour), the impact of the BDI score remained significant (adjusted odds ratio, 6.64; 95% CI, 1.76 to 25.09;
P
=.0026). In addition, the interaction of PVCs and BDI score marginally improved the model (
P
=.094). The interaction showed that deaths were concentrated among depressed patients with PVCs of ≥10 per hour (odds ratio, 29.1; 95% CI, 6.97 to 122.07;
P
<.00001).

Conclusions
Depression while in the hospital after an MI is a significant predictor of 18-month post-MI cardiac mortality. Depression also significantly improves a risk-stratification model based on traditional post-MI risks, including previous MI, Killip class, and PVCs. Furthermore, the risk associated with depression is greatest among patients with ≥10 PVCs per hour. This result is compatible with the literature suggesting an arrhythmic mechanism as the link between psychological factors and sudden cardiac death and underscores the importance of developing screening and treatment programs for post-MI depression.
Late Lumen Loss After Coronary Angioplasty Is Associated With the Activation Status of Circulating Phagocytes Before Treatment
Authors: Pietersma Anneke , Kofflard Marcel , Wit L. Elly A. de , Stijnen Theo , Koster Johan F. , Serruys Patrick W. , Sluiter Wim
Published: June 2012

Background
The purpose of this pilot study was to identify biological risk factors for restenosis after percutaneous transluminal coronary angioplasty (PTCA) to predict the long-term outcome of PTCA before treatment.

Methods and Results
To investigate whether blood granulocytes and monocytes could determine luminal renarrowing after PTCA, several characteristics of these phagocytes were assessed before angioplasty in 32 patients who underwent PTCA of one coronary artery and who had repeat angiograms at 6-month follow-up. The plasma levels of interleukin (IL)-1β, tumor necrosis factor-α, IL-6, fibrinogen, C-reactive protein, and lipoprotein(a) before angioplasty were assessed as well. We found that the expression of the membrane antigens CD64, CD66, and CD67 by granulocytes was inversely associated with the luminal renarrowing normalized for vessel size (relative loss) at 6 months after PTCA, while the production of IL-1β by stimulated monocytes was positively associated with the relative loss. Next, these univariate predictors were corrected for the established clinical risk factors of dilation of the left anterior descending coronary artery and current smoking, which were statistically significant classic predictors in our patient group. Only the expression of CD67 did not predict late lumen loss independent of these established clinical risk factors. Multiple linear regression analysis showed that luminal renarrowing could be predicted reliably (
R
2
=.65;
P
<.0001) in this patient group on the basis of the vessel dilated and only two biological risk factors that reflect the activation status of blood phagocytes, ie, the expression of CD66 by granulocytes and the production of IL-1β by stimulated monocytes.

Conclusions
The results of the present study indicate that activated blood granulocytes prevent luminal renarrowing after PTCA, while activated blood monocytes promote late lumen loss. To validate this new finding, further study in an independent patient group is required.
Angioscopic Prediction of Successful Dilatation and of Restenosis in Percutaneous Transluminal Coronary Angioplasty
Authors: Itoh Akira , Miyazaki Shunichi , Nonogi Hiroshi , Daikoku Satoshi , Haze Kazuo
Published: June 2012

Background
Coronary angiography has been used to assess the anatomy of coronary artery and intraluminal pathological changes. However, it has several limitations in its diagnostic quality and sensitivity in the detection of intraluminal details. Angioscopy has enabled coronary artery lumens to be visualized directly and fine intraluminal morphological changes to be detected. The information obtained by angioscopy is expected to provide new insights into the mechanisms and pathophysiology of transluminal coronary angioplasty.

Methods and Results
Forty-seven patients (39 men and 8 women) with stable angina were enrolled in the present study. Angioscopy was performed before and after angioplasty with a 0.68-mm angioscope with a double–guiding catheter system. The patients who were successfully evaluated by angioscopy were divided into two groups according to the color of the lesion: group 1, mainly yellow; and group 2, white. Angiographic, angioscopic, and clinical parameters in the two groups were compared. Detailed angioscopic findings were obtained in 36 of the 47 patients (77%) before percutaneous transluminal coronary angioplasty (PTCA) and in 24 of the 47 (51%) after PTCA. Yellow plaque were found in 13 of 36 (36%). Age, sex, presence of coronary risk factors, serum cholesterol level, and duration of angina showed no correlation with plaque color. The incidence rates of dissection and thrombi after angioplasty also were not different. Successful dilatation was achieved in 13 of 13 patients (100%) in group 1 and in 21 of 23 (91%) in group 2. The restenosis rate of group 1 was significantly lower than that in group 2 (16.7% versus 57.9%,
P
<.05). Cox proportional hazards model revealed that plaque color was the independent variable associated with restenosis after PTCA (
P
=.03).

Conclusions
The restenosis rate after successful balloon angioplasty differs, with the color of the target lesion being significantly higher in patients with solely white plaque. Therefore, angioscopic findings are highly predictive of restenosis.