bluuebunny/crossref_metadata_2025 huggingface dataset:
Pulmonary Release and Coronary and Peripheral Consumption of Big Endothelin and Endothelin-1 in Severe Heart Failure
Authors: Stangl Karl , Dschietzig Thomas , Richter Christoph , Laule Michael , Stangl Verena , Tanis Elsa , Baumann Gert , Felix Stephan B.
Published: June 2012

Background
—We investigated plasma endothelin (ET) levels in patients with congestive heart failure (CHF) during treatment for acute decompensation; we also measured imbalances in ET peptides across the pulmonary, coronary, and peripheral circulation.

Methods and Results
—In patients with severe CHF (n=21; cardiac index [CI], 1.9±0.2 L · min
−1
· m
−2
; pulmonary capillary wedge pressure [PCWP], 31±1 mm Hg), vasodilation was achieved with the nitric oxide donor sodium nitroprusside (n=11) or with the α
1
-antagonist urapidil (nitric oxide–independent, n=10). ET concentrations were determined from arterial blood and blood from the pulmonary artery, coronary sinus, and antecubital vein. Depending on sites of measurement, baseline big ET and ET-1 levels were, respectively, 12 to 16 times and 5 to 11 times higher than in controls (n=11), and 4 to 6 times and 2 to 3 times higher than in patients with moderate CHF (n=10; CI, 2.7±0.3 L · min
−1
· m
−2
; PCWP, 14±2 mm Hg). Patients with severe CHF demonstrated pulmonary net release and coronary and peripheral net consumption of both peptides (ie, arterial levels [big ET, 7.3±1.3 pmol/L; ET-1, 1.8±0.1 pmol/L] were higher than levels in the pulmonary artery [6.7±1.2 pmol/L; 1.3±0.1 pmol/L], coronary sinus [6.4±1.0 pmol/L; 1.4±0.1 pmol/L], and antecubital vein [6.6±1.1 pmol/L; 1.3±0.1 pmol/L]). In these patients, sodium nitroprusside (SNP) and urapidil resulted in comparable hemodynamic improvement after 6 hours (CI: SNP, 63±2%; urapidil, 72±3%; PCWP: SNP, −50±2%; urapidil, −47±2%) and a maximum decrease in ET peptides by >50%. After 3 hours, pulmonary net release and coronary and peripheral net consumption were no longer detectable.

Conclusions
—In patients with severe CHF, the lungs act as a producer and the heart and the periphery act as consumers of elevated circulating ETs. Short-term vasodilator therapy decreases ETs and restores their pulmonary, coronary, and peripheral balance.
Abnormal Pulmonary Artery Pressure Response in Asymptomatic Carriers of Primary Pulmonary Hypertension Gene
Authors: Grünig Ekkehard , Janssen Bart , Mereles Derliz , Barth Ulrike , Borst Mathias M. , Vogt Ina R. , Fischer Christine , Olschewski Horst , Kuecherer Helmut F. , Kübler Wolfgang
Published: June 2012

Background
—Familial primary pulmonary hypertension (PPH) is an autosomal-dominant inherited disease with incomplete penetrance and poor prognosis. This study was performed to examine whether asymptomatic carriers of a mutated PPH gene can be identified at an early stage by their pulmonary artery systolic pressure (PASP) response to exercise.

Methods and Results
—Stress Doppler echocardiography during supine bicycle exercise and genetic linkage analysis were performed on 52 members of 2 families with PPH. In 4 PPH patients, the mean PASP was increased at rest (73±16 mm Hg). Fourteen additional family members with normal PASP at rest revealed an abnormal PASP response to exercise (from 23±4 to 56±11 mm Hg) without secondary cause (abnormal response [AR] group). Twenty-seven other members (NR group) revealed a normal PASP response (maximal pressure <40 mm Hg) to exercise (from 24±4 to 37±3 mm Hg,
P
<0.0001). All 14 AR but only 2 NR members shared the risk haplotype with the PPH patients. The molecular genetic analysis supported linkage to chromosome 2q31-32 with a logarithm of the odds score of 4.4 when the 4 patients and the 14 AR members were classified as affected.

Conclusions
—We conclude that the pathological rise of PASP in asymptomatic family members is linked to chromosome 2q31-32 and is probably an early sign of PPH. Therefore, stress Doppler echocardiography may be a useful tool to identify persons at risk for PPH even before pulmonary artery pressures at rest are elevated.
Myocardial Strain by Doppler Echocardiography
Authors: Urheim Stig , Edvardsen Thor , Torp Hans , Angelsen Bjørn , Smiseth Otto A.
Published: June 2012

Background
—Myocardial strain is a measure of regional deformation, and by definition, negative strain means shortening and positive strain, elongation. This study investigates whether myocardial strain can be measured by Doppler echocardiography as the time integral of regional velocity gradients, using sonomicrometry as reference method.

Methods and Results
—In 13 anesthetized dogs, myocardial longitudinal strain was measured on apical images as the time integral of regional Doppler velocity gradients. Ultrasonic segment-length crystals were placed near the left ventricular (LV) apex and near the base. Apical ischemia was induced by occluding the left anterior descending coronary artery (LAD), and preload was increased by saline. Percentage systolic strain by Doppler correlated well with strain by sonomicrometry (
y
=0.82
x
−1.79,
r
=0.92,
P
<0.01). During LAD occlusion, apical myocardium became dyskinetic, as indicated by positive strain values and negative Doppler velocities. At the LV base, myocardial strain by Doppler, strain by sonomicrometry, and velocity of shortening by sonomicrometry (dL/dt) were unchanged during apical ischemia. However, myocardial Doppler velocities at the base decreased from 4.2±0.7 (±SEM) to 2.7±0.4 cm/s (
P
<0.05), probably reflecting loss of motion caused by tethering to apical segments. Volume loading increased myocardial Doppler velocities from 2.2±0.3 to 4.1±0.8 cm/s (
P
<0.05) and Doppler-derived strain from −12±1% to −22±2% (
P
<0.05), whereas peak LV elastance remained unchanged.

Conclusions
—Myocardial strain by Doppler echocardiography may represent a new, powerful method for quantifying regional myocardial function and is less influenced by tethering effects than Doppler tissue imaging. Like myocardial Doppler velocities, strain is markedly load-dependent.
Bolus Endovascular PDGFR-β Antisense Treatment Suppressed Intimal Hyperplasia in a Rat Carotid Injury Model
Authors: Noiseux Nicolas , Boucher Caroline H. , Cartier Raymond , Sirois Martin G.
Published: June 2012

Background
—Intimal thickening in accelerated arteriopathies relies on the migration of medial vascular smooth muscle cells (VSMCs) and their proliferation within the neointima. Activation of platelet-derived growth factor receptor-β (PDGFR-β) expressed in injured VSMCs is responsible for the migration of medial VSMCs to the intima. In the present study, we wanted to assess whether a single local endovascular delivery of antisense PDGFR-β in injured rat carotid arteries would be sufficient to prevent intimal hyperplasia and how it might contribute to the vascular healing process.

Methods and Results
—A bolus of antisense PDGFR-β delivered into injured rat carotid arteries reduced PDGFR-β protein overexpression by >90% from day 3 to 28 after injury. At day 28 after injury, compared with injured untreated carotids, treatment with antisense PDGFR-β reduced intimal hyperplasia by 58% and medial VSMC migration by 49% and improved vascular reendothelialization by 100% and vascular reactivity (EC
50
) to acetylcholine by 5-fold.

Conclusions
—A single-bolus luminal delivery of antisense PDGFR-β to injured rat carotids reduced intimal hyperplasia, improved the reendothelialization process, and led to the recovery of endothelium-dependent regulation of vascular tone.
Clinical Trials in Coronary Angiogenesis: Issues, Problems, Consensus
Authors: Simons Michael , Bonow Robert O. , Chronos Nicolas A. , Cohen David J. , Giordano Frank J. , Hammond H. Kirk , Laham Roger J. , Li William , Pike Marylin , Sellke Frank W. , Stegmann Thomas J. , Udelson James E. , Rosengart Todd K.
Published: June 2012

Abstract
—The rapid development of angiogenic growth factor therapy for patients with advanced ischemic heart disease over the last 5 years offers hope of a new treatment strategy based on generation of new blood supply in the diseased heart. However, as the field of therapeutic coronary angiogenesis is maturing from basic and preclinical investigations to clinical trials, many new and presently unresolved issues are coming into focus. These include in-depth understanding of the biology of angiogenesis, selection of appropriate patient populations for clinical trials, choice of therapeutic end points and means of their assessment, choice of therapeutic strategy (gene versus protein delivery), route of administration, and the side effect profile. The present article presents a summary statement of a panel of experts actively working in the field, convened by the Angiogenesis Foundation and the Angiogenesis Research Center during the 72nd meeting of the American Heart Association to define and achieve a consensus on the challenges facing development of therapeutic angiogenesis for coronary disease.
Tissue Doppler Imaging Consistently Detects Myocardial Contraction and Relaxation Abnormalities, Irrespective of Cardiac Hypertrophy, in a Transgenic Rabbit Model of Human Hypertrophic Cardiomyopathy
Authors: Nagueh Sherif F. , Kopelen Helen A. , Lim Do-Sun , Zoghbi William A. , Quiñones Miguel A. , Roberts Robert , Marian Ali J.
Published: June 2012

Background
—Hypertrophic cardiomyopathy (HCM) is diagnosed clinically by the presence of left ventricular hypertrophy (LVH). However, LVH is absent in a significant number of genotype-positive patients. Because myocyte dysfunction and disarray are the primary abnormalities in HCM, we reasoned that tissue Doppler imaging could identify contraction and relaxation abnormalities, irrespective of hypertrophy, in a transgenic rabbit model of human HCM.

Methods and Results
—M-mode, 2D, Doppler echocardiography and tissue Doppler imaging were performed in nontransgenic (n=24), wild-type β-myosin heavy chain-arginine
403
(n=14), and mutant β-myosin heavy chain-glutamic acid
403
(n=24) transgenic rabbits. Mean septal thicknesses were 2.0±0.3, 2.0±0.25, and 2.75±0.3 mm in the 3 groups, respectively (
P
=0.001). LVH was absent in 9 of the 24 mutant rabbits. Left ventricular dimensions, systolic function, heart rate, mitral inflow velocities, and time intervals were similar in the groups. However, the difference between atrial reversal and transmitral A wave duration was increased in the mutant rabbits (
P
<0.001). More importantly, systolic and early diastolic tissue Doppler velocities were significantly lower in all mutant rabbits (7.45±2.2 versus 10.8±2.3 cm/s in nontransgenic and 9.0±0.76 cm/s in wild-type;
P
<0.001), including the 9 without LVH. A systolic velocity <8.5 cm/s had an 86% sensitivity and 100% specificity in identifying the mutant transgenic rabbits.

Conclusions
—Myocardial contraction and relaxation were reduced in the mutant β-myosin heavy chain-glutamic acid
403
transgenic rabbit model of human HCM, irrespective of the presence or absence of LVH. In addition, tissue Doppler imaging is more sensitive than conventional echocardiography for HCM screening.
Regular Aerobic Exercise Prevents and Restores Age-Related Declines in Endothelium-Dependent Vasodilation in Healthy Men
Authors: DeSouza Christopher A. , Shapiro Linda F. , Clevenger Christopher M. , Dinenno Frank A. , Monahan Kevin D. , Tanaka Hirofumi , Seals Douglas R.
Published: June 2012

Background
—In sedentary humans endothelium-dependent vasodilation is impaired with advancing age contributing to their increased cardiovascular risk, whereas endurance-trained adults demonstrate lower age-related risk. We determined the influence of regular aerobic exercise on the age-related decline in endothelium-dependent vasodilation.

Methods and Results
—In a cross-sectional study, 68 healthy men 22 to 35 or 50 to 76 years of age who were either sedentary or endurance exercise–trained were studied. Forearm blood flow (FBF) responses to intra-arterial infusions of acetylcholine and sodium nitroprusside were measured by strain-gauge plethysmography. Among the sedentary men, the maximum FBF response to acetylcholine was 25% lower in the middle aged and older compared with the young group (
P
<0.01). In contrast, there was no age-related difference in the vasodilatory response to acetylcholine among the endurance-trained men. FBF at the highest acetylcholine dose was almost identical in the middle aged and older (17.3±1.3 mL/100 mL tissue per minute) and young (17.7±1.4 mL/100 mL tissue per minute) endurance-trained groups. There were no differences in the FBF responses to sodium nitroprusside among the sedentary and endurance- trained groups. In an exercise intervention study, 13 previously sedentary middle aged and older healthy men completed a 3-month, home-based aerobic exercise intervention (primarily walking). After the exercise intervention, acetylcholine-mediated vasodilation increased ≈30% (
P
<0.01) to levels similar to those in young adults and middle aged and older endurance-trained men.

Conclusions
—Our results indicate that regular aerobic exercise can prevent the age-associated loss in endothelium-dependent vasodilation and restore levels in previously sedentary middle aged and older healthy men. This may represent an important mechanism by which regular aerobic exercise lowers the risk of cardiovascular disease in this population.
Randomized Comparison of GR-II Stent and Palmaz-Schatz Stent for Elective Treatment of Coronary Stenoses
Authors: Lansky Alexandra J. , Roubin Gary S. , O’Shaughnessy Charles D. , Moore Paul B. , Dean Larry S. , Raizner Albert E. , Safian Robert D. , Zidar James P. , Kerr Jennifer L. , Popma Jeffrey J. , Mehran Roxana , Kuntz Richard E. , Leon Martin B.
Published: June 2012

Background
—This prospective multicenter randomized clinical trial was designed to evaluate the long-term angiographic and clinical outcomes of elective treatment with the GR-II stent compared with the Palmaz-Schatz (PS) stent in patients with coronary stenoses.

Methods and Results
—Seven hundred fifty-five patients with myocardial ischemia and de novo native coronary stenoses in 3- to 4-mm vessels were randomly assigned to the PS (375 patients) or the GR-II stent (380 patients). The primary end point was 12-month target lesion revascularization (TLR)-free survival. Angiography was performed at baseline and at follow-up in the first 300 consecutive patients to assess the frequency of angiographic restenosis. Procedure success was 98.5% for the GR-II stent and 99.4% for the PS stent (
P
=0.19). At 30 days, patients assigned to the GR-II stent had a higher stent thrombosis rate (3.9% versus 0.3% for PS stent,
P
<0.001) and TLR rate (3.9% versus 0.5% for PS stent,
P
<0.001). The GR-II group had a higher follow-up restenosis frequency (47.3% versus 20.6% for the PS group,
P
<0.001) and a lower 12-month TLR-free survival rate (71.7% versus 83.9% for the PS group,
P
<0.001). Multivariate logistic regression analysis identified a smaller final stent minimal lumen diameter (odds ratio [OR] 2.49, 95% CI 1.56 to 3.98;
P
<0.001), diabetes mellitus (OR 2.14, 95% CI 1.42 to 3.22;
P
<0.001), and use of the GR-II stent (OR 1.78, 95% CI 1.20 to 2.64;
P
<0.01) as independent determinants of 12-month TLR.

Conclusions
—On the basis of these long-term follow-up data, we conclude that use of the GR-II stent should be limited to the acute treatment of abrupt or threatened closure after failed conventional balloon angioplasty procedures.
Lisinopril-Mediated Regression of Myocardial Fibrosis in Patients With Hypertensive Heart Disease
Authors: Brilla Christian G. , Funck Reinhard C. , Rupp Heinz
Published: June 2012

Background
—In arterial hypertension, left ventricular hypertrophy (LVH) includes myocyte hypertrophy and fibrosis, which leads to LV diastolic dysfunction and, finally, heart failure. In spontaneously hypertensive rats, myocardial fibrosis was regressed and LV diastolic function was improved by treatment with the angiotensin-converting enzyme inhibitor lisinopril. Whether this holds true for patients with hypertensive heart disease was addressed in this prospective, randomized, double-blind trial.

Methods and Results
—A total of 35 patients with primary hypertension, LVH, and LV diastolic dysfunction were treated with either lisinopril (n=18) or hydrochlorothiazide (HCTZ; n=17). At baseline and after 6 months, LV catheterization with endomyocardial biopsy, Doppler echocardiography with measurements of LV peak flow velocities during early filling and atrial contraction and isovolumic relaxation time, and 24-hour blood pressure monitoring were performed. Myocardial fibrosis was measured by LV collagen volume fraction and myocardial hydroxyproline concentration. With lisinopril, collagen volume fraction decreased from 6.9±0.6% to 6.3±0.6% (
P
<0.05 versus HCTZ) and myocardial hydroxyproline concentration from 9.9±0.3 to 8.3±0.4 μg/mg of LV dry weight (
P
<0.00001 versus HCTZ); this was associated with an increase in the early filling and atrial contraction LV peak flow velocity ratio from 0.72±0.04 to 0.91±0.06 (
P
<0.05 versus HCTZ) and a decrease in isovolumic relaxation time from 123±9 to 81±5 ms (
P
<0.00002 versus HCTZ). Normalized blood pressure did not significantly change in either group. No LVH regression occurred in lisinopril-treated patients, whereas with HCTZ, myocyte diameter was reduced from 22.1±0.6 to 20.7±0.7 μm (
P
<0.01 versus lisinopril).

Conclusions
—In patients with hypertensive heart disease, angiotensin-converting enzyme inhibition with lisinopril can regress myocardial fibrosis, irrespective of LVH regression, and it is accompanied by improved LV diastolic function.
Initial Clinical Experience With Ambulatory Use of an Implantable Atrial Defibrillator for Conversion of Atrial Fibrillation
Authors: Daoud Emile G. , Timmermans Carl , Fellows Chris , Hoyt Robert , Lemery Robert , Dawson Kathy , Ayers Gregory M.
Published: June 2012

Background
—A recent study has shown that the implantable atrial defibrillator can restore sinus rhythm in patients with recurrent atrial fibrillation when therapy was delivered under physician observation. The objective of this study was to evaluate the safety and efficacy of ambulatory use of the implantable atrial defibrillator.

Methods and Results
—An atrial defibrillator was implanted in 105 patients (75 men; mean age, 59±12 years) with recurrent, symptomatic, drug-refractory atrial fibrillation. After successful 3-month testing, patients could transition to ambulatory delivery of shock therapy. Patients completed questionnaires regarding shock therapy discomfort and therapy satisfaction using a 10-point visual-analog scale (1 represented “not at all,” 10 represented “extremely”) after each treated episode of atrial fibrillation. During a mean follow-up of 11.7 months, 48 of 105 patients satisfied criteria for transition and received therapy for 275 episodes of atrial fibrillation. Overall shock therapy efficacy was 90% with 1.6±1.2 shocks delivered per episode (median, 1). Patients rated shock discomfort as 5.2±2.4 for successful therapy and 4.2±2.2 for unsuccessful therapy (
P
>0.05). The satisfaction score was higher for successful versus unsuccessful therapy (3.4±3.3 versus 8.7±1.3,
P
<0.05). There was no ventricular proarrhythmia observed throughout the course of this study.

Conclusions
—Ambulatory use of an implantable atrial defibrillator can safely and successfully convert most episodes of atrial fibrillation, often requiring only a single shock. Successful therapy is associated with high satisfaction and only moderate discomfort.
Angiogenesis Is Impaired by Hypercholesterolemia
Authors: Jang James J. , Ho Hoai-Ky V. , Kwan Helen H. , Fajardo Luis F. , Cooke John P.
Published: June 2012

Background
—Many angiogenic factors require endothelium-derived nitric oxide (NO) to exert their effects. Recently, an endogenous competitive antagonist of NO synthase has been characterized: asymmetric dimethylarginine (ADMA). Elevated plasma levels of ADMA reduce NO synthesis in hypercholesterolemia. Accordingly, we hypothesized that hypercholesterolemia impairs angiogenesis by an ADMA-dependent mechanism.

Methods and Results
—Angiogenesis was assessed with the use of a disk angiogenesis system implanted subcutaneously in normal (E
+
) mice or apolipoprotein (apo)E-deficient hypercholesterolemic (E
−
) mice. After 2 weeks, the disks were removed, and the fibrovascular growth area was used as an index of angiogenesis. Basal and fibroblast growth factor–stimulated angiogenesis was impaired in E
−
mice, associated with an elevation in plasma ADMA. Oral administration of
l
-arginine reversed the impairment of angiogenesis in E
−
mice. By contrast, oral administration of
l
-nitroarginine (an exogenous antagonist of NO synthase) reduced angiogenesis. When added directly to the disk, ADMA dose-dependently inhibited basal and fibroblast growth factor–induced angiogenesis, an effect that was reversed by oral administration of
l
-arginine.

Conclusions
—The derangement of the NO synthase pathway that occurs in hypercholesterolemia is associated with an impairment of angiogenesis. The lipid-induced impairment of angiogenesis can be reversed by oral administration of
l
-arginine and can be mimicked in normocholesterolemic animals by administration of an NO synthase antagonist. The data are consistent with the hypothesis that ADMA is an endogenous inhibitor of angiogenesis.
Suppression of Inflammation in Primary Systemic Vasculitis Restores Vascular Endothelial Function: Lessons for Atherosclerotic Disease?
Authors: Raza K. , Thambyrajah J. , Townend J. N. , Exley A. R. , Hortas C. , Filer A. , Carruthers D. M. , Bacon P. A.
Published: June 2012

Background
—Chronic inflammatory rheumatic disorders are associated with excess cardiovascular mortality. This may result from arteriosclerosis following inflammatory damage to the vessel wall by vasculitis. Our hypothesis that vasculitis results in arteriosclerosis by causing vascular endothelial dysfunction was tested in patients with primary systemic necrotizing vasculitis (SNV).

Methods and Results
—Endothelial function was assessed in cross-sectional and longitudinal studies of patients with primary SNV by measuring flow-mediated, endothelium-dependent brachial artery vasodilatation. These patients exhibited marked endothelial dysfunction compared with controls. Remission induction in patients with active primary SNV restored endothelial function.

Conclusions
—Endothelial function is significantly impaired in adults with primary SNV, supporting the hypothesis that premature arteriosclerosis in chronic inflammatory rheumatic disorders results from endothelial dysfunction secondary to vasculitis. Normalization of endothelial function after the treatment of primary SNV suggests that early suppression of disease activity in chronic inflammatory rheumatic disorders may reduce long-term vascular damage. The role of inflammation in atheroma formation is increasingly appreciated; this work raises questions regarding the potential for anti-inflammatory therapy in atherosclerosis itself.
Explanation for the Decline in Coronary Heart Disease Mortality Rates in Auckland, New Zealand, Between 1982 and 1993
Authors: Capewell Simon , Beaglehole Robert , Seddon Mary , McMurray John
Published: June 2012

Background
—We sought to determine how much of the recent, substantial fall in coronary heart disease (CHD) mortality rates in New Zealand can be attributed to “evidence-based” medical and surgical treatments and how much can be attributed to cardiovascular risk factor reductions.

Methods and Results
—A cell-based mortality model was developed and refined. This model combined (1) the published effectiveness of cardiological treatments and risk factor reductions with (2) data on all medical and surgical treatments administered to all CHD patients and (3) trends in population cardiovascular risk factors (principally smoking, cholesterol, and hypertension) from 1982 to 1993 in Auckland, New Zealand (population 996 000). Between 1982 and 1993, CHD mortality rates fell by 23.6%, with 671 fewer CHD deaths than expected from baseline mortality rates in 1982. Forty-six percent of this fall was attributed to treatments (acute myocardial infarction 12%, secondary prevention 12%, hypertension 7%, heart failure 6%, and angina 9%), and 54% was attributed to risk factor reductions (smoking 30%, cholesterol 12%, population blood pressure 8%, and other, unidentified factors 4%). These proportions remained relatively consistent after a robust sensitivity analysis.

Conclusions
—Approximately half the CHD mortality rate fall in Auckland, New Zealand, was attributed to medical therapies, and approximately half was attributed to reductions in major risk factors. These findings emphasize the importance of a comprehensive strategy that maximizes the population coverage of effective treatments and actively promotes a prevention program, particularly for smoking, diet, and blood pressure reduction.
Cardiac Endothelin System Impairs Left Ventricular Function in Renin-Dependent Hypertension via Decreased Sarcoplasmic Reticulum Ca
2+
Uptake
Authors: Rothermund Lars , Pinto Yigal M. , Hocher Berthold , Vetter Roland , Leggewie Stefan , Koßmehl Peter , Orzechowski Hans-Dieter , Kreutz Reinhold , Paul Martin
Published: June 2012

Background
—We evaluated the role of the cardiac endothelin (ET) system in compensated hypertensive left ventricular (LV) hypertrophy (LVH) and after the transition toward LV dysfunction.

Methods and Results
—Hypertensive transgenic rats overexpressing the
Ren2
gene (Ren2 rats) were investigated between the ages of 10 and 30 weeks (Ren2-10 and Ren2-30 groups, respectively) and compared with age-matched normotensive Sprague-Dawley (SD) rats (SD-10 and SD-30 groups, respectively). Systolic blood pressure and LV weight were elevated in both Ren2 groups compared with their age-matched SD control groups (
P
<0.0001). In Ren2-30 rats, LV end-diastolic pressure increased and −dP/dt
max
decreased compared with the values in SD-30 and Ren2-10 rats (
P
<0.05). This was paralleled by an activation of LV mRNA expression of preproET-1 and ET-converting enzyme-1 and ET subtype A (ETA) receptor binding in Ren2-30 compared with Ren2-10 rats (
P
<0.001). Cardiac fibrosis was increased and sarcoplasmic reticulum (SR) Ca
2+
reuptake was reduced in Ren2-30 compared with SD-30 and Ren2-10 rats (
P
<0.05). Treatment of Ren2 rats with the selective ETA receptor antagonist
Lu135252
between 10 and 30 weeks of age did not lower systolic blood pressure, heart weight, or cardiac fibrosis but completely prevented the deterioration of LV end-diastolic pressure and abolished alterations in −dP/dt
max
and SR Ca
2+
reuptake compared with no treatment in Ren2-30 and SD-30 rats (
P
<0.05).

Conclusions
—Activation of the cardiac ET system accounts at least in part for the LV dysfunction that gradually develops in LVH. The protective effect of ETA antagonism can be attributed to the improvement of diastolic LV function that is due to normalization of impaired SR Ca
2+
uptake.
Effect of Renal Artery Stenting on Renal Function and Size in Patients with Atherosclerotic Renovascular Disease
Authors: Watson Paul S. , Hadjipetrou Peter , Cox Stephen V. , Piemonte Thomas C. , Eisenhauer Andrew C.
Published: June 2012

Background
—Renal artery stenting is widely performed, but little is known about its effectiveness in preserving renal function and size in patients with renovascular disease and chronic renal insufficiency. We studied the effect of renal artery stenting on renal function and size in patients with obstructive renovascular disease and chronic renal insufficiency.

Methods and Results
—Stent deployment was performed in patients with chronic renal insufficiency (creatinine >1.5 mg · dL
−1
) and global renovascular obstruction (bilateral renal artery stenosis or unilateral stenosis in the presence of a solitary or single functional kidney). The effect of renal artery stenting on renal function was assessed by comparing the slopes of the regression lines derived from the reciprocal of serum creatinine versus time plotted before and after stent deployment. Renal size was assessed by serial ultrasound of pole-to-pole kidney length. Stenting was successful in all 61 vessels in 33 patients. Twenty-five patients had complete follow-up (mean 20±11 months). Before stent deployment, all patients exhibited a negative slope, indicating progressive renal insufficiency. After stent deployment, the slopes were positive in 18 and less negative in 7 patients. Thus, the mean slope increased from −0.0079 to 0.0043 dL · mg
−1
· mo
−1
(
P
<0.001). Ultrasonography on 41 kidneys revealed preservation of size, with the kidney length measuring 10.4±1.4 cm at baseline and 10.4±1.1 cm at last follow-up (
P
=NS). Patient survival at 20±11 months was 90%.

Conclusions
—In patients with chronic renal insufficiency and global obstructive atherosclerotic renovascular disease, renal artery stenting improves or stabilizes renal function and preserves kidney size.
Direct Evidence for Cytokine Involvement in Neointimal Hyperplasia
Authors: Rectenwald John E. , Moldawer Lyle L. , Huber Thomas S. , Seeger James M. , Ozaki C. Keith
Published: June 2012

Background
—Tumor necrosis factor-α (TNF-α) and interleukin 1 (IL-1) are proximal inflammatory cytokines that stimulate expression of adhesion molecules and induce synthesis of other proinflammatory cytokines. In addition, TNF-α and IL-1 influence vascular smooth muscle cell migration and proliferation in vitro. In view of the inflammatory nature of neointimal hyperplasia (NIH), we tested the hypothesis that endogenous TNF-α and IL-1 modulate low shear stress–induced NIH.

Methods and Results
—Mice underwent unilateral common carotid artery (CCA) ligation. Low shear stress in the patent ligated CCA has previously been shown to result in remodeling and NIH. Reverse transcriptase–polymerase chain reaction for TNF-α and IL-1α mRNA demonstrated both TNF-α and IL-1α mRNA in ligated CCAs, whereas normal and sham-operated CCAs had none. Mice lacking functional TNF-α (TNF−/−) developed 14-fold less neointimal area than WT controls (
P
<0.05). p80 IL-1 type I receptor knockout (IL-1RI−/−) mice tended to develop less (7-fold,
P
>0.05) neointimal area than WT controls. Furthermore, no IL-1α mRNA expression was detected in CCAs from TNF−/− mice; however, TNF-α mRNA expression was found in the IL-1RI−/− mice. Mice that overexpress membrane-bound TNF-α but produce no soluble TNF-α display an accentuated fibroproliferative response to low shear stress (
P
<0.05).

Conclusions
—These results directly demonstrate that TNF-α and IL-1 modulate NIH induced by low shear stress. NIH can proceed by way of soluble TNF-α–independent mechanisms. Specific anti–TNF-α and anti–IL-1 therapies may lessen NIH.
Long-Term Effects of Cholesterol Lowering and Angiotensin-Converting Enzyme Inhibition on Coronary Atherosclerosis
Authors: Teo Koon K. , Burton Jeffrey R. , Buller Christopher E. , Plante Sylvain , Catellier Diane , Tymchak Wayne , Dzavik Vladimir , Taylor Dylan , Yokoyama Shinji , Montague Terrence J.
Published: June 2012

Background
—This long-term, multicenter, randomized, double-blind, placebo-controlled, 2×2 factorial, angiographic trial evaluated the effects of cholesterol lowering and angiotensin-converting enzyme inhibition on coronary atherosclerosis in normocholesterolemic patients.

Methods and Results
—There were a total of 460 patients: 230 received simvastatin and 230, a simvastatin placebo, and 229 received enalapril and 231, an enalapril placebo (some subjects received both drugs and some received a double placebo). Mean baseline measurements were as follows: cholesterol level, 5.20 mmol/L; triglyceride level, 1.82 mmol/L; HDL, 0.99 mmol/L; and LDL, 3.36 mmol/L. Average follow-up was 47.8 months. Changes in quantitative coronary angiographic measures between simvastatin and placebo, respectively, were as follows: mean diameters, −0.07 versus −0.14 mm (
P
=0.004); minimum diameters, −0.09 versus −0.16 mm (
P
=0.0001); and percent diameter stenosis, 1.67% versus 3.83% (
P
=0.0003). These benefits were not observed in patients on enalapril when compared with placebo. No additional benefits were seen in the group receiving both drugs. Simvastatin patients had less need for percutaneous transluminal coronary angioplasty (8 versus 21 events;
P
=0.020), and fewer enalapril patients experienced the combined end point of death/myocardial infarction/stroke (16 versus 30;
P
=0.043) than their respective placebo patients.

Conclusions
—This trial extends the observation of the beneficial angiographic effects of lipid-lowering therapy to normocholesterolemic patients. The implications of the neutral angiographic effects of angiotensin-converting enzyme inhibition are uncertain, but they deserve further investigation in light of the positive clinical benefits suggested here and seen elsewhere.
Both β
2
- and β
1
-Adrenergic Receptors Mediate Hastened Relaxation and Phosphorylation of Phospholamban and Troponin I in Ventricular Myocardium of Fallot Infants, Consistent With Selective Coupling of β
2
-Adrenergic Receptors to G
s
-Protein
Authors: Molenaar Peter , Bartel Sabine , Cochrane Andrew , Vetter Donathe , Jalali Homayoun , Pohlner Peter , Burrell Kylie , Karczewski Peter , Krause Ernst-Georg , Kaumann Alberto
Published: June 2012

Background
—In adult human heart, both β
1
- and β
2
-adrenergic receptors mediate hastening of relaxation; however, it is unknown whether this also occurs in infant heart. We compared the effects of stimulation of β
1
- and β
2
-adrenergic receptors on relaxation and phosphorylation of phospholamban and troponin I in ventricle obtained from infants with tetralogy of Fallot.

Methods and Results
—Myocardium dissected from the right ventricular outflow tract of 27 infants (age range 21/2 to 35 months) with tetralogy of Fallot was set up to contract 60 times per minute. Selective stimulation of β
1
-adrenergic receptors with (−)-norepinephrine (NE) and β
2
-adrenergic receptors with (−)-epinephrine (EPI) evoked phosphorylation of phospholamban (at serine-16 and threonine-17) and troponin I and caused concentration-dependent increases in contractile force (−log EC
50
[mol/L] NE 5.5±0.1, n=12; EPI 5.6±0.1, n=13 patients), hastening of the time to reach peak force (−log EC
50
[mol/L] NE 5.8±0.2; EPI 5.8±0.2) and 50% relaxation (−log EC
50
[mol/L] NE 5.7±0.2; EPI 5.8±0.1). Ventricular membranes from Fallot infants, labeled with (−)-[
125
I]-cyanopindolol, revealed a greater percentage of β
1
- (71%) than β
2
-adrenergic receptors (29%). Binding of (−)-epinephrine to β
2
-receptors underwent greater GTP shifts than binding of (−)-norepinephrine to β
1
-receptors.

Conclusions
—Despite their low density, β
2
-adrenergic receptors are nearly as effective as β
1
-adrenergic receptors of infant Fallot ventricle in enhancing contraction, relaxation, and phosphorylation of phospholamban and troponin I, consistent with selective coupling to G
s
-protein.
Adoptive Transfer of β
2
-Glycoprotein I–Reactive Lymphocytes Enhances Early Atherosclerosis in LDL Receptor–Deficient Mice
Authors: George Jacob , Harats Dror , Gilburd Boris , Afek Arnon , Shaish Aviv , Kopolovic Juri , Shoenfeld Yehuda
Published: June 2012

Background
—It has been proposed that autoimmune factors can influence the progression of atherosclerosis. We have previously shown that immunization of LDL receptor–deficient (LDL-RD mice) with β
2
-glycoprotein I (β2GPI; a principal target of “autoimmune” antiphospholipid antibodies) enhances early atherosclerosis. In the present study, we tested the hypothesis that adoptive transfer of β2GPI-reactive T cells can accelerate fatty streak formation in LDL-RD mice.

Methods and Results
—LDL-RD mice were immunized with human β2GPI. An additional group of mice were immunized with β2GPI and boosted with the same antigen 3 weeks later. Control mice with immunized with human serum albumin. Lymphocytes obtained from the draining lymph node cells or from splenocytes of β2GPI- or human serum albumin–immunized mice were stimulated in vitro with β2GPI or with the mitogen concavalin A, respectively. The cultured lymphocytes were transferred intraperitoneally to syngenic LDL-RD mice, and the mice were fed a high-fat “Western” diet for 5 weeks until death. Mice injected with lymphocytes from draining lymph nodes or spleens of β2GPI-immunized animals displayed larger fatty streaks than those induced by control treated animals. T-cell–depleted splenocytes from β2GPI were unable to promote lesion formation in the mice.

Conclusions
—The present study provides the first direct evidence for a role of antigen (β2GPI)-reactive T cells in the promotion of fatty streaks in mice.
Chronic Exercise Reduces Sympathetic Nerve Activity in Rabbits With Pacing-Induced Heart Failure
Authors: Liu Jun-Li , Irvine Scott , Reid Ian A. , Patel Kaushik P. , Zucker Irving H.
Published: June 2012

Background
—Chronic exercise (EX) improves the quality of life and increases the survival of patients with chronic heart failure (CHF). Because sympathetic nerve activity is elevated in the CHF state, it is possible that EX is beneficial in this disease due to a decrease in sympathetic outflow.

Methods and Results
—We evaluated arterial baroreflex function and resting renal sympathetic nerve activity (RSNA) in EX normal and CHF rabbits before and after angiotensin II type 1 (AT
1
) receptor blockade. Four groups of rabbits were studied: a normal non-EX group, a normal EX group, a CHF non-EX group, and a CHF EX group. EX lowered resting RSNA in rabbits with CHF but not in normal rabbits. In addition, EX increased arterial baroreflex sensitivity in the CHF group (heart rate slope: CHF 1.7±0.3 bpm/mm Hg, EX CHF 4.9±0.3 bpm/mm Hg;
P
<0.01; RSNA slope: CHF 2.2±0.2%max/mm Hg, EX CHF 5.7±0.4%max/mm Hg;
P
<0.01. AT
1
receptor blockade enhanced baroreflex sensitivity in the non-EX CHF rabbits but had no effect in EX CHF rabbits. Concomitant with this effect, EX lowered the elevated plasma angiotensin II concentration in the CHF group. A significant positive correlation was observed between sympathetic nerve activity and plasma angiotensin II.

Conclusions
—-These data strongly suggest that EX reduces the sympathoexcitatory state in the setting of CHF. Enhanced arterial baroreflex sensitivity may contribute to this reduction. In addition, EX lowers plasma angiotensin II concentration in CHF. These data further suggest that the lowering of angiotensin II may contribute to the decrease in sympathetic nerve activity after EX in the CHF state.
Genome-Wide Linkage Analysis of Systolic and Diastolic Blood Pressure
Authors: Rice Treva , Rankinen Tuomo , Province Michael A. , Chagnon Yvon C. , Pérusse Louis , Borecki Ingrid B. , Bouchard Claude , Rao D. C.
Published: June 2012

Background
—Blood pressure (BP), an important risk factor for coronary heart disease, is a complex trait with multiple genetic etiologies. While some loci affecting BP variation are known (eg, angiotensinogen), there are likely to be novel signals that can be detected with a genome scan approach.

Methods and Results
—A genome-wide scan was performed in 125 random and 81 obese families participating in the Québec Family Study. A multipoint variance-components linkage analysis of 420 markers (353 microsatellites and 67 restriction fragment length polymorphisms) revealed several signals (
P
<0.0023) for systolic BP on 1p (D1S551, ATP1A1), 2p (D2S1790, D2S2972), 5p (D5S1986), 7q (D7S530), 8q (CRH), and 19p (D19S247). Suggestive evidence (0.0023<
P
<0.01) was found on 3q, 10p, 12p, 14q, and 22q. The results were encouraging for HSD3B1 (
P
<0.03), AGT (
P
<0.03), ACE (
P
<0.02), and adipsin (
P
<0.005) but null with regard to other candidates (eg, renin, and glucocorticoid and adrenergic receptors).

Conclusions
—Multiple linkage regions support the notion that risk for hypertension is due to multiple (ie, oligogenic) susceptibility loci. Comparisons across the complete, random, and obese samples suggest that some regions are specific to BP and others may involve obesity (eg, pleiotropy, epistasis, or gene-environment interaction). Some of these areas harbor known candidates. Others involve novel regions, some of which replicate previous reports and provide a focus for future studies to identify novel genes that influence interindividual variation in BP.
Cardiac Troponin T Predicts Mortality in Patients With End-Stage Renal Disease
Authors: Dierkes Jutta , Domröse Ute , Westphal Sabine , Ambrosch Andreas , Bosselmann Hans-Peter , Neumann Klaus Hinrich , Luley Claus
Published: June 2012

Background
—Patients with end-stage renal disease have a high risk of premature death, mainly as the result of cardiovascular disease (CVD), which is not sufficiently explained by the conventional risk factors. We therefore prospectively investigated total mortality and cardiovascular events in 102 patients on hemodialysis and assessed the prognostic value of baseline disease status and laboratory variables including total homocysteine and cardiac troponin T.

Methods and Results
—Patients were followed for 2 years or until their first event of CVD (for outcome variable cardiovascular events, n=33) or death (for outcome variable total mortality, n=28). Survival was computed by the Kaplan-Meier method. Cox proportional hazards model was used to determine independent predictors of CVD events or total mortality. Cardiac troponin T emerged as the most powerful predictor of mortality, resulting in an almost 7-fold risk increase at concentrations >0.10 ng/mL (hazard ratio 6.85, 95% CI 3.04 to 15.45). Total homocysteine level greater than median was also associated with mortality (hazard ratio 2.44, 95% CI 1.10 to 5.40). These hazard ratios did not change substantially after adjustment for other risk factors. Significant predictors for CVD events were baseline diabetes, cerebrovascular disease, serum glucose, and triglycerides. After adjustment, only glucose and triglycerides remained significantly related to CVD events (hazard ratio with 95% CI 1.33 [1.12 to 1.57] and 1.14 [1.04 to 1.26], respectively, for a 1-mmol/L increase in concentration).

Conclusions
—We conclude that total homocysteine and particularly cardiac troponin T are important predictors of mortality in patients with end-stage renal disease, whereas other laboratory variables and baseline disease status have less prognostic value.
Pulmonary Capillary Endothelium-Bound Angiotensin-Converting Enzyme Activity in Acute Lung Injury
Authors: Orfanos Stylianos E. , Armaganidis Apostolos , Glynos Constantinos , Psevdi Ekaterini , Kaltsas Panagiotis , Sarafidou Paulina , Catravas John D. , Dafni Urania G. , Langleben David , Roussos Charis
Published: June 2012

Background
—Pulmonary capillary endothelium-bound (PCEB) angiotensin-converting ectoenzyme (ACE) activity alteration is an early, sensitive, and quantifiable lung injury index in animal models. We hypothesized that (1) PCEB-ACE alterations can be found in patients with acute lung injury (ALI) and (2) PCEB-ACE activity correlates with the severity of lung injury and may be used as a quantifiable marker of the underlying pulmonary capillary endothelial dysfunction.

Methods and Results
—Applying indicator-dilution techniques, we measured single-pass transpulmonary hydrolysis of the synthetic ACE substrate
3
H-benzoyl-Phe-Ala-Pro (BPAP) in 33 mechanically ventilated, critically ill patients with a lung injury score (LIS) ranging from 0 (no lung injury) to 3.7 (severe lung injury) and calculated the kinetic parameter A
max
/K
m
. Both parameters decreased early during the ALI continuum and were inversely related to APACHE II score and LIS. Hydrolysis decreased with increasing cardiac output (CO), whereas 2 different patterns were observed between CO and A
max
/K
m
.

Conclusions
—PCEB-ACE activity decreases early during ALI, correlates with the clinical severity of both the lung injury and the underlying disease, and may be used as a quantifiable marker of underlying pulmonary capillary endothelial dysfunction.
Altered Myocardial Microvascular 3D Architecture in Experimental Hypercholesterolemia
Authors: Rodriguez-Porcel Martin , Lerman Amir , Ritman Erik L. , Wilson Stephanie H. , Best Patricia J. M. , Lerman Lilach O.
Published: June 2012

Background
—Experimental hypercholesterolemia (HC) impairs intramyocardial microvascular function. However, whether this is associated with alterations in microvascular architecture remained unknown. Using a novel 3D micro-CT scanner, we tested the hypothesis that HC is associated with an alteration in the microvascular architecture.

Methods and Results
—Pigs were euthanized after 12 weeks of either normal (n=6) or 2% HC (n=6) diet. The hearts were excised and the coronary arteries injected with a radiopaque contrast material. Myocardial samples were scanned with micro-CT, and 3D images were reconstructed with 21-μm cubic voxels. The myocardium was tomographically subdivided into subepicardium and subendocardium, and microvessels (<500 μm in diameter) were counted in situ within each region. In the subendocardium of HC pigs, the intramyocardial density of microvessels was significantly higher than in normal animals (1221.4±199.7 versus 758.3±90.8 vessels/cm
3
,
P
<0.05) because of an increase in the number of microvessels <200 μm in diameter (1214.4±199.7 versus 746.6±101.5 vessels/cm
3
,
P
<0.05). The subepicardial vascular density was similar in both groups.

Conclusions
—HC has differential effects on the spatial density of the subendocardial microvasculature that may play a role in regulation and/or spatial distribution of myocardial blood flow. This study also demonstrates the feasibility of studying myocardial microvascular architecture with micro-CT in pathophysiological states.
TIMI Risk Score for ST-Elevation Myocardial Infarction: A Convenient, Bedside, Clinical Score for Risk Assessment at Presentation
Authors: Morrow David A. , Antman Elliott M. , Charlesworth Andrew , Cairns Richard , Murphy Sabina A. , de Lemos James A. , Giugliano Robert P. , McCabe Carolyn H. , Braunwald Eugene
Published: June 2012

Background
—Considerable variability in mortality risk exists among patients with ST-elevation myocardial infarction (STEMI). Complex multivariable models identify independent predictors and quantify their relative contribution to mortality risk but are too cumbersome to be readily applied in clinical practice.

Methods and Results
—We developed and evaluated a convenient bedside clinical risk score for predicting 30-day mortality at presentation of fibrinolytic-eligible patients with STEMI. The Thrombolysis in Myocardial Infarction (TIMI) risk score for STEMI was created as the simple arithmetic sum of independent predictors of mortality weighted according to the adjusted odds ratios from logistic regression analysis in the Intravenous nPA for Treatment of Infarcting Myocardium Early II trial (n=14 114). Mean 30-day mortality was 6.7%. Ten baseline variables, accounting for 97% of the predictive capacity of the multivariate model, constituted the TIMI risk score. The risk score showed a >40-fold graded increase in mortality, with scores ranging from 0 to >8 (
P
<0.0001); mortality was <1% among patients with a score of 0. The prognostic discriminatory capacity of the TIMI risk score was comparable to the full multivariable model (c statistic 0.779 versus 0.784). The prognostic performance of the risk score was stable over multiple time points (1 to 365 days). External validation in the TIMI 9 trial showed similar prognostic capacity (c statistic 0.746).

Conclusions
—The TIMI risk score for STEMI captures the majority of prognostic information offered by a full logistic regression model but is more readily used at the bedside. This risk assessment tool is likely to be clinically useful in the triage and management of fibrinolytic-eligible patients with STEMI.