bluuebunny/crossref_metadata_2025 huggingface dataset:
Baroreflex Sensitivity in Patients With Vasovagal Syncope
Authors: Thomson Helen L. , Wright Karen , Frenneaux Michael
Published: June 2012

Background
In the present study, we tested the hypothesis that baroreflex sensitivity is reduced in patients with vasovagal syncope compared with normal control subjects.

Methods and Results
We investigated 30 patients with vasovagal syncope (mean age, 43.6±16.7 years; 14 men and 16 women) and 32 normal control subjects (mean age, 41.8±17.0 years; 24 men and 8 women). Cardiopulmonary baroreceptor sensitivity was assessed by measuring the change in forearm vascular resistance during subhypotensive lower body negative pressure (LBNP). Carotid baroreflex sensitivity was assessed by measuring the change in RR interval during the manipulation of carotid transmural pressure. Phenylephrine baroreceptor sensitivity was assessed on the basis of the linear regression slope of the RR interval versus systolic arterial blood pressure during the increment in blood pressure after intravenous administration of phenylephrine. In patients with vasovagal syncope, during the application of −10 mm Hg LBNP, forearm vascular resistance decreased by 0.7±11.6 U versus an increase of 8.3±6.2 U in control subjects (
P
=.002). Phenylephrine baroreceptor sensitivity was 11±7 ms/mm Hg in patients versus 14±6 ms/mm Hg in control subjects (
P
=NS). Carotid baroreflex sensitivity was 4±6 versus 4±2 ms/mm Hg in patients and control subjects, respectively (
P
=NS).

Conclusions
In patients with vasovagal syncope, during the application of subhypotensive LBNP, there is impaired forearm vasoconstriction or paradoxical forearm vasodilation. This suggests impaired cardiopulmonary baroreceptor inactivation or paradoxical activation of these receptors and is consistent with reduced cardiopulmonary baroreceptor sensitivity.
Low-Flow Ischemia Leads to Translocation of Canine Heart GLUT-4 and GLUT-1 Glucose Transporters to the Sarcolemma In Vivo
Authors: Young Lawrence H. , Renfu Yin , Russell Raymond , Hu Xiaoyue , Caplan Michael , Ren Jianming , Shulman Gerald I. , Sinusas Albert J.
Published: June 2012

Background
Myocardial ischemia increases heart glucose utilization in vivo. However, whether low-flow ischemia leads to the translocation of glucose transporter (GLUT)-4 and/or GLUT-1 to the sarcolemma in vivo is unknown.

Methods and Results
In a canine model, we evaluated myocardial glucose metabolism in vivo and the distribution of GLUT-4 and GLUT-1 by use of immunoblotting of sarcolemma and intracellular membranes and immunofluorescence localization with confocal microscopy. In vivo glucose extraction increased fivefold (
P
<.001) and was associated with net lactate release in the ischemic region. Ischemia led to an increase in the sarcolemma content of both GLUT-4 (15±2% to 30±3%,
P
<.02) and GLUT-1 (41±4% to 58±3%,
P
<.03) compared with the nonischemic region and to a parallel decrease in their intracellular contents. Immunofluorescence demonstrated the presence of both GLUT-4 and GLUT-1 on cardiac myocytes. GLUT-1 had a more prominent cell surface pattern than GLUT-4, which was primarily intracellular in the nonischemic region. However, significant GLUT-4 surface labeling was found in the ischemic region.

Conclusions
Translocation of the insulin-responsive GLUT-4 transporter from an intracellular storage pool to the sarcolemma occurs in vivo during acute low-flow ischemia. GLUT-1 is also present in an intracellular storage pool from which it undergoes translocation to the sarcolemma in response to ischemia. These results indicate that both GLUT-1 and GLUT-4 are important in ischemia-mediated myocardial glucose uptake in vivo.
In Vitro Effects of the Platelet Glycoprotein IIb/IIIa Receptor Antagonist c7E3 Fab on the Activated Clotting Time
Authors: Ammar Tameshwar , Scudder Lesley E. , Coller Barry S.
Published: June 2012

Background
In the Evaluation of 7E3 for the Prevention of Ischemic Complications study (EPIC), the activated coagulation (clotting) times (ACTs) were longer in heparinized patients treated with c7E3 Fab than in those treated with placebo. The present study was designed to further investigate this observation by assessing whether the in vitro addition of c7E3 Fab to blood would affect the ACT.

Methods and Results
Native or heparinized blood obtained from normal volunteers was preincubated with antibodies c7E3 Fab (anti-GPIIb/IIIa and anti-α
v
β
3
), 10E5 (anti-GPIIb/IIIa), or LM609 (anti-α
v
β
3
). The ACTs of the heparinized, but not native samples were significantly prolonged by the addition of c7E3 Fab and 10E5 but not LM609, indicating that the prolongation was due to GPIIb/IIIa blockade. The addition of c7E3 Fab also significantly prolonged the ACTs of blood anticoagulated with the direct thrombin inhibitors hirudin and
d
-phenylalanyl-
l
-prolyl-
l
-arginyl chloromethyl ketone, indicating that the effect of c7E3 Fab was not exclusively related to decreased release of PF4, a heparin-neutralizing factor, from platelets.

Conclusions
These data support the conclusion that the prolongation of the ACT in patients in EPIC was due to c7E3 Fab blockade of GPIIb/IIIa receptors. This raises the possibility that in vivo c7E3 Fab functions not only as an antiplatelet agent but also as an anticoagulant; direct in vivo data will, however, be required for assessment of this possibility.
Antisense Oligonucleotide Inhibition of PDGFR-β Receptor Subunit Expression Directs Suppression of Intimal Thickening
Authors: Sirois Martin G. , Simons Michael , Edelman Elazer R.
Published: June 2012

Background
The elucidation of molecular mechanisms of vascular cell biology has markedly influenced our thinking on the pathophysiology of vascular disease. Antisense oligonucleotide gene therapy has helped identify proteins critical to cell-cycle progression and proliferation and possible therapeutic strategies to combat human disease. This approach, however, has not yet been used to examine the contribution of chemotactic proteins and/or their receptors. Platelet-derived growth factor-BB (PDGF-BB) released from activated platelets adherent to subendothelial connective tissue is a principal smooth muscle cell chemotactic factor.

Methods and Results
A series of experiments was performed to assess the capacity of antisense oligonucleotides to reduce PDGF-β receptor subunit (PDGFR-β) expression and the contribution of PDGFR-β in neointimal formation. Sustained, direct, and local perivascular administration of two different antisense oligonucleotide sequences complementary to PDGFR-β mRNA almost completely abolished the expression of PDGFR-β protein in the intima and media of injured carotid arteries and decreased neointimal formation by 80% and 60%, respectively. Furthermore, neointimal formation correlated precisely with PDGFR-β expression in an exponential fashion.

Conclusions
Thus, myointimal proliferation depends on both PDGFR-β overexpression and its activation by PDGF-BB. Removal of either of these two elements can suppress neointimal formation.
Inhibitors of Arterial Relaxation Among Components of Human Oxidized Low-Density Lipoproteins
Authors: Deckert Vale´rie , Perse´gol Laurence , Viens Laurence , Lizard Ge´rard , Athias Anne , Lallemant Christian , Gambert Philippe , Lagrost Laurent
Published: June 2012

Background
Oxidized low-density lipoproteins (LDLs) are known to impair arterial relaxation. The aim of the present study was to identify the components of oxidized LDL that may account for inhibition of endothelium-dependent relaxation.

Methods and Results
LDLs from 12 healthy subjects were either maintained at 4°C (native LDL) or incubated at 37°C in the presence of copper sulfate (oxidized LDL). Unlike pretreatment with native LDL, pretreatment with oxidized LDL reduced significantly the acetylcholine-mediated relaxation of rabbit aortic segments compared with control segments incubated in Krebs' buffer (maximal relaxation [E
max
], 72.0±6.7% versus 94.1±0.8%, respectively,
P
<.01; negative logarithm of the concentration required to produce a half-maximal relaxing effect [pD
2
], 6.6±0.1 versus 7.2±0.1, respectively,
P
<.001). The absolute difference between E
max
values obtained with oxidized and native LDL (ΔE
max
) correlated significantly with the formation of 7-ketocholesterol, 7α-hydroxycholesterol, and 7β-hydroxycholesterol. In contrast, ΔE
max
did not correlate with the amount of lipoperoxides or lysophosphatidylcholine formed, and the difference of pD
2
values measured with oxidized and native LDL (ΔpD
2
) did not correlate significantly with any of the oxidation-derived LDL compounds. When added individually, 7-ketocholesterol and 7β-hydroxycholesterol reduced E
max
values but not pD
2
values in a time- and concentration-dependent manner.

Conclusions
Cholesterol derivatives in oxidized LDL can reduce maximal arterial relaxation through a specific effect on vascular endothelial cells.
Academic Cardiology Division in the Era of Managed Care
Authors: Feldman Arthur M. , Greenhouse Pamela K. , Reis Steven E. , Sevco Mark S.
Published: June 2012

Abstract The ability of academic divisions of cardiology to pursue educational and research missions in an era of market-driven managed care is being increasingly jeopardized. Indeed, several academic medical centers have been sold to for-profit entities, and many cardiology divisions have been forced to decrease staff and faculty reimbursements. Despite these threats, the academic division has unique strengths: (1) premium quality of care, (2) a single employer, (3) a somewhat uniform practice culture, (4) high-volume operators performing interventional procedures, (5) expertise in highly technical aspects of cardiology, and (6) the availability of physicians for outreach ventures. Therefore, we hypothesized that the cardiology division could be strengthened by collaborating with the medical center in the development of an aggressive and proactive managed care strategy. To this end, we developed a cardiovascular network having the academic center as its central focus but including a group of high-quality and geographically dispersed community-based physicians. These physicians were attracted by an economic package that provided protection from downside risk, participation in our managed care initiatives, and geographic exclusivity in an overcrowded market. In turn, the community-based physicians increasingly used the academic medical center for tertiary care, resulting in increased volumes and incremental profitability. Using this paradigm, we have now recruited ≈40 community cardiologists. The resulting network provides access to a university cardiologist in most of the surrounding urban and rural counties and will allow us to compete effectively for capitated contracts.
Video Imaging of Atrial Defibrillation in the Sheep Heart
Authors: Gray Richard A. , Ayers Gregory , Jalife Jose´
Published: June 2012

Background
The effects of defibrillatory shocks on the organization of atrial fibrillation (AF) have not been studied previously. In this study, we examined the events that precede, accompany, and follow the application of atrial defibrillatory shocks.

Methods and Results
We used video imaging to study the sequence of activation on the surface of the atria in the Langendorff-perfused sheep heart. We recorded transmembrane potentials simultaneously from >20 000 sites on the epicardium during AF as well as during and after biphasic shocks applied by a programmable atrial defibrillator. Defibrillatory shocks (1.2±0.6 J; n=6) depolarized all epicardial regions of the atria, and asynchronous repolarization occurred. The shocks resulted in four types of responses: (1) immediate cessation of epicardial activity, (2) single postshock activation, (3) organized activation for 0.8 to 1.5 seconds followed by termination, and (4) organized activity followed by degeneration back into AF. Types 2 through 4 involved a quiescent period lasting 110±28 ms immediately after the shock, then an activation sequence similar to those observed during sinus rhythm. The first cycle length after the shock for types 3 and 4 (170±36 ms) was longer than during AF (144±33 ms). Repolarization time after a shock was significantly longer for successful compared with unsuccessful shocks.

Conclusions
These results indicate that the shock depolarized the entire atrial epicardial surface, followed by a quiescent period, after which organized activation emanated from the sinoatrial pacemaker region.
Is Worrying Bad for Your Heart?
Authors: Kubzansky Laura D. , Kawachi Ichiro , Spiro Avron , Weiss Scott T. , Vokonas Pantel S. , Sparrow David
Published: June 2012

Background
Worry is an important component of anxiety, which recent work suggests is related to increased incidence of coronary heart disease (CHD). Chronic worry has also been associated with decreased heart rate variability. We hypothesized that high levels of worry may increase CHD risk.

Method and Results
We examined prospectively the relationship of worry with CHD incidence in the Normative Aging Study, an ongoing cohort of older men. In 1975, 1759 men free of diagnosed CHD completed a Worries Scale, indicating the extent to which they worried about each of five worry domains: social conditions, health, financial, self-definition, and aging. During 20 years of follow-up, 323 cases of incident CHD occurred: 113 cases of nonfatal myocardial infarction (MI); 86 cases of fatal CHD; and 124 cases of angina pectoris. Worry about social conditions was the domain most strongly associated with incident CHD. Compared with men reporting the lowest levels of social conditions worry, men reporting the highest levels had multivariate adjusted relative risks of 2.41 (95% CI, 1.40 to 4.13) for nonfatal MI and 1.48 (95% CI, 0.99 to 2.20) for total CHD (nonfatal MI and fatal CHD). A dose-response relation was found between level of worry and both nonfatal MI (
P
for trend, .002) and total CHD (
P
for trend, .04).

Conclusions
These results suggest that high levels of worry in specific domains may increase the risk of CHD in older men.
Hypobetalipoproteinemia Is Associated With Low Levels of Hemostatic Risk Factors in the Framingham Offspring Population
Authors: Welty Francine K. , Mittleman Murray A. , Wilson Peter W.F. , Sutherland Patrice A. , Matheney Travis H. , Lipinska Izabella , Muller James E. , Levy Daniel , Tofler Geoffrey H.
Published: June 2012

Background
Given the importance of thrombosis in causation of acute coronary syndromes, it is possible that the beneficial effect of low lipid levels on the risk of coronary events is achieved by lowering thrombotic potential of the blood. Hypobetalipoproteinemia is characterized by plasma concentrations of apolipoprotein B and LDL cholesterol that are one third of those observed in the general population. The aim of this study was to utilize subjects with hypobetalipoproteinemia to examine the relation between thrombotic potential and low levels of LDL cholesterol.

Methods and Results
Hemostatic risk factors were measured in 1878 individuals (1003 women and 875 men) participating in cycle 5 of the Framingham Offspring Study. The subjects were divided into five groups on the basis of LDL cholesterol level. Subjects with hypobetalipoproteinemia (LDL cholesterol <70 mg/dL) had the lowest levels of fibrinogen, plasminogen activator inhibitor–1 antigen, and tissue plasminogen activator antigen. As LDL cholesterol increased, there was a significant increase in the levels of the hemostatic risk factors, with the exception of von Willebrand factor antigen. Adjustment with multivariate regression analyses for the covariates age, sex, body mass index, diabetes mellitus, smoking, alcohol intake, triglyceride level, and use of antihypertensive medication did not materially alter the results.

Conclusions
Decreasing levels of LDL cholesterol are associated with decreasing levels of hemostatic risk factors. Subjects with hypobetalipoproteinemia have the lowest levels of hemostatic risk factors and may be protected against thrombotic complications of atherosclerotic cardiovascular disease because of reduced thrombotic potential. One mechanism by which lipid-lowering therapy may decrease clinical cardiac events is through a reduction in thrombotic tendency.
Human Connective Tissue Growth Factor Is Expressed in Advanced Atherosclerotic Lesions
Authors: Oemar Barry S. , Werner Annick , Garnier Jean-Marie , Do Dai-Do , Godoy Nelson , Nauck Markus , Ma¨rz Winfried , Rupp Joachim , Pech Michael , Lu¨scher Thomas F.
Published: June 2012

Background
Atherosclerosis affects certain but not all vascular beds of the human circulation. Its molecular mechanisms are only partially understood. Human connective tissue growth factor (hCTGF) is a novel cysteine-rich, secreted polypeptide. hCTGF is implicated in connective tissue formation, which may play an important role in atherosclerosis.

Methods and Results
By using a differential cloning technique, we isolated a cDNA clone from a human aorta cDNA library, which is identical to hCTGF. Northern analysis shows that hCTGF mRNA was expressed at 50- to 100-fold higher levels in atherosclerotic blood vessels compared with normal arteries. In vascular smooth muscle cells, high-level expression of hCTGF mRNA was induced by transforming growth factor-β1. Using in situ hybridization and immunohistochemistry, we found that all advanced atherosclerotic lesions of human carotid arteries (eight patients; mean age, 69; age range, 57 to 85 years) and femoral arteries (two patients; mean age, 71.5 years) that we tested expressed high levels of both hCTGF mRNA and protein. hCTGF expression was localized mainly to smooth muscle cells in the plaque lesions that are negative for proliferating cell nuclear antigen staining. In addition, some CD-31–positive endothelial cells of plaque vessels expressed high levels of hCTGF mRNA and protein. hCTGF-positive cells were found predominantly in areas with extracellular matrix accumulation and fibrosis. In contrast, in normal arteries, we were unable to detect either hCTGF mRNA or immunoreactive hCTGF protein.

Conclusions
In the present study, we have shown for the first time that both hCTGF mRNA and protein are expressed in human arteries in vivo and that hCTGF may represent a novel factor expressed at high levels specifically in advanced lesions and may play a role in the development and progression of atherosclerosis.
Detection and Quantification of Dysfunctional Myocardium by Magnetic Resonance Imaging
Authors: Holman Eduard R. , Buller Vincent G.M. , de Roos Albert , van der Geest Rob J. , Baur Leo H.B. , van der Laarse Arnoud , Bruschke Albert V.G. , Reiber Johan H.C. , van der Wall Ernst E.
Published: June 2012

Background
Regional left ventricular dysfunction is a major consequence of myocardial ischemia, and its extent determines long-term prognosis. Accurate and reproducible analysis of left ventricular dysfunction is therefore useful for risk stratification and patient management.

Methods and Results
Short-axis cardiac cine magnetic resonance (MR) imaging was performed in 25 patients after anterior myocardial infarction at 21±2.1 days after the acute onset. The MR images were analyzed with the use of a dedicated analytical software package (MASS version 1.0), which includes a modified centerline method and a new three-dimensional analysis approach. A database of 48 healthy volunteers was constructed to objectively depict myocardial dysfunction in the patients; this database was compared with enzymatically determined infarct size. The mean (±SEM) quantity of dysfunctional myocardium and enzymatically calculated infarct size equaled 24.0±3.0 and 22.3±2.9 g, respectively (
P
=.69). Enzymatically determined infarct size correlated strongly with left ventricular dysfunction determined by cine MR imaging (
y
=0.90
x
+3.7;
r
=.92,
P
<.0001). Segments related to the distribution of the left anterior descending coronary artery showed a significantly lower percentage wall thickening in patients than did corresponding segments of 48 normal subjects (46.0±8.22% versus 87.1±3.45%, mean±SEM, respectively;
P
<.001). The mean (±SEM) end-diastolic wall thickness of the infarcted segment did not differ from that of corresponding normal segments (7.4±0.33 versus 7.5±0.15 mm;
P
=.75).

Conclusions
We conclude that the use of three-dimensional quantitative analysis of cine MR images accurately quantifies the extent of regional left ventricular dysfunction in the infarcted heart. This method of analysis may be useful in assessing the effect of interventional therapies.
Evaluation of Superficial Femoral Artery Compromise and Limb Growth Retardation After Transfemoral Artery Balloon Dilatations
Authors: Lee Hae Y. , Reddy S. Chandra Bose , Rao P. Syamasundar
Published: June 2012

Background
Abnormalities of arterial pulse and limb growth after retrograde femoral arterial catheterization have been well documented. However, the magnitude of such complications after transfemoral artery balloon dilatation has not been thoroughly investigated. This study sought to evaluate the prevalence of these abnormalities in children who have undergone transfemoral artery balloon dilatation.

Methods and Results
Data on 43 consecutive patients (1 day to 15.5 years old at the time of balloon dilatation) seen on follow-up (42±23 months) (group 1) were compared with those of 35 patients undergoing retrograde femoral arterial catheterization (group 2) and 47 control patients. Interventional ankle/control ankle blood pressure index (AAI), ratio of interventional/control lower limb length (LLI), and leg length difference (LLD) were measured. Ages and weights at study were similar in all three groups, as were the ages and weights at intervention and duration of follow-up in groups 1 and 2. The AAI was lower (
P
=.023) in group 1 (0.95±0.13) than in groups 2 (1.0±0.1) and 3 (1.01±0.09). The prevalence of subjects with AAI ≤0.9 was higher (
P
=.003) in group 1 than in the other two groups. The LLI and LLD were similar (
P
>.1) in all three groups. AAI and LLD in the balloon group are not significantly associated with age and weight at intervention, duration of follow-up, or size of the balloon or balloon catheter shaft.

Conclusions
Transfemoral artery balloon dilatation procedures produce superficial femoral artery compromise, but there was no significant limb growth retardation at a 3.5-year mean follow-up, which may be related to development of collateral circulation. Study of a larger number of children at a longer follow-up interval may be necessary to further confirm these observations.
Clinical and Prognostic Usefulness of Supine Bicycle Exercise Echocardiography in the Functional Evaluation of Patients Undergoing Elective Percutaneous Transluminal Coronary Angioplasty
Authors: Dagianti Armando , Rosanio Salvatore , Penco Maria , Dagianti Alessandra , Sciomer Susanna , Tocchi Monica , Agati Luciano , Fedele Francesco
Published: June 2012

Background
Supine bicycle exercise echocardiography (SBEE) has never been used before and early after percutaneous transluminal coronary angioplasty (PTCA) for assessing the functional outcome of the procedure and predicting late restenosis.

Methods and Results
We selected 76 subjects with stable angina, normal wall motion at rest, and exercise-induced wall-motion abnormalities before PTCA. SBEE with peak exercise imaging and the use of a 16-segment, four-grade score model was performed 54±15 hours after PTCA. No exercise-related adverse events occurred. Patients were grouped according to SBEE results: group 1 (n=35, 46%) with negative exercise ECG and echo; group 2 (n=19, 25%) with a positive exercise ECG but normal echo; and group 3 (n=22, 29%) with a positive exercise echo with either a positive (n=7, 32%) or negative (n=15, 68%) ECG. Exercise performance significantly improved in all groups. In group 3, peak wall-motion score index decreased from 1.27±0.11 before to 1.15±0.06 after PTCA (
P
<.05), and duration of wall-motion abnormalities went from 81±24 to 47±19 seconds (
P
<.05). The rate of clinical restenosis (ie, angina recurrence or positive 6-month SBEE in asymptomatic patients, both associated with angiographic restenosis >50%) was 37%. By multiple logistic regression analysis, clinical restenosis was associated with a positive post-PTCA exercise echo (odds ratio [OR] 3.08, 95% confidence interval [CI] 1.66 to 5.72;
P
=.0004) and with increasing values of pre-PTCA wall-motion score index (OR 2.86, 95% CI 1.92 to 4.27;
P
=.005) and duration of wall-motion abnormalities (OR 2.12, 95% CI 1.07 to 4.20;
P
=.04).

Conclusions
SBEE is a safe and reliable tool to demonstrate changes in exercise-induced wall-motion abnormalities after PTCA and provides prognostic information in the risk assessment of clinical restenosis.
Potent and Long-Lasting Vasodilatory Effects of Adrenomedullin in Humans
Authors: Nakamura Motoyuki , Yoshida Hiroaki , Makita Shinji , Arakawa Naoshi , Niinuma Hiroyuki , Hiramori Katsuhiko
Published: June 2012

Background
Adrenomedullin (ADM) is a recently discovered hypotensive peptide that has been isolated from human pheochromocytoma cells. Observations that ADM is produced from cardiovascular tissue and is found in plasma suggest that it may be important in the regulation of regional vascular resistance.

Methods and Results
Limb vascular responses to ADM were examined in 10 healthy subjects and compared with those in 18 patients with chronic heart failure (CHF). The peptide increased forearm blood flow (FBF) from 2.7±0.3 to 11.8±0.9 mL·min
−1
·100 mL
−1
in the control group and from 2.4±0.3 to 6.5±0.7 mL·min
−1
·100 mL
−1
in the CHF group. The ADM-induced FBF increase was significantly impaired in the CHF group (
P
<.01). After cessation of the infusion, an increased FBF level was sustained for >60 minutes in the control group, whereas in the CHF group the response returned to the baseline in <30 minutes. The ADM infusion increased forearm skin blood flow in both groups (
P
<.05), whereas the skin blood flow response was impaired in the CHF group (
P
<.01). The role of nitric oxide in ADM-induced vasorelaxation was also studied in 11 healthy subjects and 6 patients with CHF. FBF and skin blood flow responses during ADM administration were significantly attenuated by
N
G
-monomethyl-
l
-arginine administration in healthy control subjects (
P
<.05), whereas both flow responses remained the same in the CHF group.

Conclusions
These observations demonstrate that ADM exerts a potent and long-lasting vasodilatory effect on skeletal muscle arteries with involvement of nitric oxide–dependent mechanisms in normal human peripheral vasculature and that these vascular effects are significantly attenuated in patients with CHF, in part because of impaired production of nitric oxide in the forearm resistance vessels.
cGMP-Elevating Agents Suppress Proliferation of Vascular Smooth Muscle Cells by Inhibiting the Activation of Epidermal Growth Factor Signaling Pathway
Authors: Yu Sheu-Meei , Hung Li-Man , Lin Chia-Chih
Published: June 2012

Background
Abnormal proliferation of vascular smooth muscle cells (VSMC) is a key event in the pathogenesis of atherosclerosis and many vascular diseases. It is known that nitric oxide released from the endothelium participates in the regulation of VSMC proliferation via a cyclic 3′,5′-guanosine monophosphate (cGMP)-mediated mechanism. In a series of experiments, sodium nitroprusside (SNP) and
A02131
-1 were evaluated for their antiproliferative effect and the mechanism of their cGMP-elevating action.

Methods and Results
The effect of SNP and A02131-1 on epidermal growth factor (EGF)-stimulated proliferation of rat aortic smooth muscle cells (VSMC) was examined. Cell proliferation was measured in terms of [
3
H]thymidine incorporation, flow cytometry, and the cell number. Further, their effect on the EGF-activated signal transduction pathway was assessed by measuring mitogen-activated protein kinases (MAPK), MAPK kinase (MEK), Raf-1 activity, and the formation of active form of
Ras
. SNP and A02131-1 inhibited EGF-induced DNA synthesis and subsequent proliferation of VSMC. These two increased cGMP but only a little cAMP in VSMC. A similar antiproliferative effect was observed with 8-bromo-cGMP. The antiproliferative effect of the two was reversed by KT5823 but not by dideoxyadenosine nor Rp-cAMPS. SNP and A02131-1 blocked the EGF-inducible cell cycle progression at the G1/S phase. Further experiments indicated that the two cGMP-elevating agents primarily blocked the activation of Raf-1 by EGF-activated
Ras
.

Conclusions
These results demonstrate that cGMP-elevating agents inhibit [
3
H]thymidine incorporation and thus the growth of VSMC, and this inhibition appears to attenuate EGF-activated signal transduction pathway by preventing
Ras
-dependent activation of Raf-1.
Increased Tolerance of the Chronically Hypoxic Immature Heart to Ischemia
Authors: Baker John E. , Curry Brian D. , Olinger Gordon N. , Gross Garrett J.
Published: June 2012

Background
Hypoxia from birth in immature rabbits increases the tolerance of isolated hearts to ischemia compared with age-matched normoxic rabbits. We determined whether this increased tolerance to ischemia was due to an alteration in the ATP-sensitive potassium (K
ATP
) channel and whether increased K
ATP
channel activation was associated with increases in intracellular lactate.

Methods and Results
Isolated immature rabbit hearts (7 to 10 days old) were perfused with bicarbonate buffer at 39°C in the Langendorff mode at a constant pressure. Saline-filled latex balloons were placed in the left and right ventricles for measurement of developed pressure. A K
ATP
channel agonist (bimakalim) or a K
ATP
channel antagonist (glibenclamide) was added 15 minutes before a global ischemic period of 18 minutes, followed by 35 minutes of reperfusion. Rabbits raised from birth in hypoxic conditions (F
io
2
=0.12) displayed significantly enhanced recovery of developed pressure. The right ventricle was more tolerant of ischemia than the left ventricle in normoxic and hypoxic hearts. Bimakalim (1 μmol/L) increased the recovery of left ventricular developed pressure in normoxic hearts to values not different from those of hypoxic controls (43±3% to 67±5%) and slightly increased developed pressure in hypoxic hearts (67±5% to 72±5%). Glibenclamide (3 μmol/L) abolished the cardioprotective effect of hypoxia (67±5% to 43±5%). Constant-flow studies indicated that the effects of bimakalim and glibenclamide were independent of their actions on coronary flow. Ventricular lactate and lactate dehydrogenase concentrations were elevated in hypoxic hearts compared with normoxic control hearts.

Conclusions
Increased tolerance to ischemia exhibited by chronically hypoxic rabbit hearts is associated with increased activation of the K
ATP
channel. This increased K
ATP
activity may be the result of increased intracellular concentrations of lactate.
Phased Chest and Abdominal Compression-Decompression
Authors: Tang Wanchun , Weil Max Harry , Schock Robert B. , Sato Yoji , Lucas John , Sun Shijie , Bisera Joe
Published: June 2012

Background
We describe a new manual method of phased chest and abdominal compression-decompression with a Lifestick resuscitator for cardiopulmonary resuscitation (CPR).

Methods and Results
Ventricular fibrillation (VF) was induced in 20 domestic pigs. After either 5 or 7 minutes of untreated VF, either phased chest and abdominal compression-decompression (Lifestick resuscitator) or precordial compression was initiated. Defibrillation was attempted at 2 minutes after the start of CPR. For the animals in which VF was untreated for 7 minutes, epinephrine was administered in doses of 20 μg/kg at 2 minutes after start of CPR. The coronary perfusion pressure generated by the Lifestick resuscitator was more than twofold greater (
P
<.01) than that generated by conventional precordial compression. Of 5 control animals, none were resuscitated after 5 minutes of VF. However, each of 5 animals treated with the Lifestick resuscitator was resuscitated (
P
<.01) and survived after 48 hours (
P
<.01). When untreated VF was prolonged to 7 minutes and epinephrine was administered, only 2 of the 5 control animals were resuscitated, and none of them survived for more than 4 hours. However, each of the Lifestick-treated animals was resuscitated and survived for more than 48 hours (
P
<.01).

Conclusions
Phased chest and abdominal compression-decompression substantially increased hemodynamic efficacy of CPR and outcome in terms of successful resuscitation, 48-hour survival, and cerebral recovery.
Greater Incidence of Hospitalized Myocardial Infarction Among Mexican Americans Than Non-Hispanic Whites
Authors: Goff David C. , Nichaman Milton Z. , Chan Wenyaw , Ramsey David J. , Labarthe Darwin R. , Ortiz Carmen
Published: June 2012

Background
Since Mexican Americans have adverse patterns of risk factors for myocardial infarction relative to non-Hispanic whites, the incidence of myocardial infarction should be greater among Mexican Americans than among non-Hispanic whites. This expectation conflicts with reports generated from death certificate registries.

Methods and Results
Data regarding myocardial infarction attacks and incident events were collected for a 4-year period in the Corpus Christi Heart Project, a population-based surveillance project for hospitalized coronary heart disease events. For both women and men, Mexican Americans experienced greater hospitalization rates for both attacks and incident events than non-Hispanic whites. Age-adjusted attack rate ratios comparing Mexican Americans with non-Hispanic whites were 1.59 (95% CI, 1.05 to 2.41) and 1.31 (95% CI, 1.18 to 1.45) among women and men, respectively. Corresponding incidence ratios were 1.52 (95% CI, 1.28 to 1.80) and 1.25 (95% CI, 1.10 to 1.42).

Conclusions
This is the first report documenting greater incidence of hospitalized myocardial infarction among Mexican Americans than among non-Hispanic whites, a biologically plausible finding given the risk factor patterns observed in the Mexican-American population. Public health planners and clinicians should be aware of the importance of myocardial infarction as a health problem in the Mexican-American population. Culturally appropriate prevention strategies should be developed for and tested in Mexican-American populations.
Bridge Experience With Long-term Implantable Left Ventricular Assist Devices
Authors: Oz MehmetC. , Argenziano Michael , Catanese Katharine A. , Gardocki Michael T. , Goldstein Daniel J. , Ashton Robert C. , Gelijns Annetine C. , Rose Eric A. , Levin Howard R.
Published: June 2012

Background
If long-term use of left ventricular assist devices (LVADs) as bridges to transplantation is successful, the issue of permanent device implantation in lieu of transplantation could be addressed through the creation of appropriately designed trials. Our medium-term experience with both pneumatically and electrically powered ThermoCardiosystems LVADs is presented to outline the benefits and limitations of device support in lieu of transplantation.

Methods and Results
Detailed records were kept prospectively for all patients undergoing LVAD insertion. Fifty-eight LVADs were inserted over 5 years, with a survival rate of 74%. Mean patient age was 50 years, and duration of support averaged 98 days. Although common, both preexisting infection and infection during LVAD support were not associated with increased mortality or decreased rate of successful transplantation. Thromboembolic complications were rare, occurring in only three patients (5%) despite the absence of anticoagulation. Ventricular arrhythmias were well tolerated in all patients except in cases of early perioperative right ventricular failure, with no deaths. Right ventricular failure occurred in one third of patients and was managed in a small percentage by right ventricular assist device (RVAD) support and/or inhaled nitric oxide therapy. There were no serious device malfunctions, but five graft-related hemorrhages resulted in two deaths. Finally, a variety of noncardiac surgical procedures were performed in LVAD recipients, with no major morbidity and mortality.

Conclusions
Over all, our medium-term experience with implantable LVAD support is encouraging. Although additional areas of investigation exist, improvements in patient selection and management together with device alterations that have reduced the thromboembolic incidence and facilitated patient rehabilitation lead us to believe that a prospective, randomized trial is indicated to study the role that LVADs may have as an alternative to medical management.
Local Intramural Delivery of
l
-Arginine Enhances Nitric Oxide Generation and Inhibits Lesion Formation After Balloon Angioplasty
Authors: Schwarzacher Severin P. , Lim Tai T. , Wang Bingyin , Kernoff Robert S. , Niebauer Josef , Cooke John P. , Yeung Alan C.
Published: June 2012

Background
Long-term oral administration of
l
-arginine has been shown to enhance production of nitric oxide (NO) and to reduce lesion formation. The goal of this study was to determine whether local intramural administration of
l
-arginine could enhance NO generation and reduce intimal thickening.

Methods and Results
New Zealand White rabbits (n=27) received a 1% cholesterol diet. For the short-term study, after 1 week of diet, both iliac arteries were balloon injured. Four weeks later, vasoreactivity was assessed angiographically during infusion of acetylcholine (Ach) before and after delivery of
l
-arginine or saline into the right or left iliac artery (800 mg/5 mL; 0.2 mL/min, 15 minutes) by use of a local drug-delivery balloon. Vessels were then harvested for measurements of NO. For the long-term study, after balloon injury, drugs were delivered as above into the iliac arteries. Two and 4 weeks after
l
-arginine delivery, vasoreactivity was determined. Subsequently, the iliac arteries were harvested for histomorphometric analysis and measurements of NO. In the short-term study, local delivery of
l
-arginine restored endothelium-dependent vasodilatation (Ach 10
−5
mol/L;
l
-arginine +35±10%; saline −14±5%;
P
<.001) and enhanced local production of nitrogen oxides (
l
-arginine 152±28; saline 78±12 nmol/L per milligram of tissue per hour;
P
<.04). In the long-term study, local administration of
l
-arginine enhanced vascular NO production as long as 1 week after the injury (
l
-arginine 394.4±141.6; saline 86.3±34.3 nmol/L per milligram of tissue per hour;
P
<.01) and reduced intimal thickening 4 weeks later (intima/media ratio:
l
-arginine 0.56±0.1; saline 1.40±0.2;
P
<.001), largely due to suppression of macrophage accumulation.

Conclusions
A single intramural administration of
l
-arginine enhances vascular NO generation and inhibits lesion formation. Local augmentation of NO production at the site of balloon angioplasty may be a novel strategy to prevent restenosis.
Different Effects of Thrombin Receptor Activation on Endothelium and Smooth Muscle Cells of Human Coronary Bypass Vessels
Authors: Yang Zhihong , Ruschitzka Frank , Rabelink Ton J. , Noll Georg , Julmy Friedgard , Joch Hana , Gafner Verena , Aleksic Ivan , Althaus Ulrich , Lüscher Thomas F.
Published: June 2012

Background
Thrombin is implicated in coronary bypass graft disease; it cleaves its receptor’s extracellular N-terminal domain and unmasks a new N-terminus as a tethered ligand. We studied the effects of thrombin receptor activation in human internal mammary artery (IMA) and saphenous vein (SV).

Methods and Results
To study the effects of thrombin receptor activation on vasomotion, isolated blood vessels were suspended for isometric tension recording, and the effects on cell proliferation were studied in cultured smooth muscle cells (SMCs) of IMA and SV. Thrombin receptor expression in IMA and SV was analyzed by reverse transcription polymerase chain reaction and immunohistology. Receptor function was studied by analyzing the activation of mitogen-activated protein kinase (p42
MAPK
). In IMA thrombin evoked endothelium-dependent relaxations (65±5%) that were mimicked by thrombin receptor agonist peptide (TRAP) and reduced by the thrombin inhibitors recombinant (r-) hirudin and
d
-Phe-Pro-Arg-chloromethyl ketone (PPACK) (
P
<.05). In SV thrombin caused contractions (36±5% of 100 mmol/L KCl) that were inhibited by r-hirudin or PPACK (
P
<.05) but not mimicked by TRAP. In SMCs thrombin induced more pronounced [
3
H]thymidine incorporation (inhibited by r-hirudin or PPACK) in SV than IMA (
P
<.05), but activation of p42
MAPK
was similar in both vessels. TRAP induced weaker activation of p42
MAPK
than thrombin and did not stimulate [
3
H]thymidine incorporation in SMCs of SV or IMA. Immunohistology and RT-PCR demonstrated that the endothelium and SMCs of IMA and SV express thrombin receptor.

Conclusions
Functional thrombin receptors are present on endothelium and SMCs of IMA and SV. Endothelial thrombin receptors mediate relaxation in IMA but not SV. Thrombin causes much more pronounced contraction and proliferation in SMCs of SV than IMA independent of tethered receptors, suggesting other thrombin receptors exist. These differences of thrombin receptor activation in IMA and SV may be important in the development of and therapy for graft disease.
Intermediate-Density Lipoproteins and Progression of Carotid Arterial Wall Intima-Media Thickness
Authors: Hodis Howard N. , Mack Wendy J. , Dunn Meleana , Liu Chao-ran , Liu Ci-hua , Selzer Robert H. , Krauss Ronald M.
Published: June 2012

Background
Although LDL cholesterol (LDL-C) is generally accepted to be a major risk factor for progression of atherosclerosis, the traditional measurement of LDL-C includes measurement of IDL. Little is known about the relationship between IDL and progression of atherosclerosis. Therefore, we investigated the association of plasma lipoprotein subclasses with progression of preintrusive carotid artery atherosclerosis in the Monitored Atherosclerosis Regression Study (MARS).

Methods and Results
MARS was a randomized, double-blind, placebo-controlled serial arterial imaging trial conducted in subjects 37 to 67 years old with angiographically defined coronary artery disease. Analytical ultracentrifugation was used to determine lipoprotein subclasses, including LDL (S
f
0 to 12), IDL (S
f
12 to 20), VLDL (S
f
20 to 400), and HDL (F
1.20
0 to 9) in 188 subjects. Subjects were randomized to a cholesterol-lowering diet plus placebo or lovastatin 80 mg/d. The outcome measure, the annual progression rate of the distal common carotid artery far wall intima-media thickness determined by high resolution B-mode ultrasonography, was determined at baseline and every 6 months on trial. When the major apolipoprotein B–containing lipoproteins were measured independently, IDL (
r
=.21,
P
<.005) but not VLDL (
r
=−.09,
P
=.24) or LDL (
r
=.09,
P
=.26) was associated with the progression of carotid artery intima-media thickness.

Conclusions
These data provide further evidence for the role of triglyceride-rich lipoproteins in the progression of atherosclerosis and support the evidence that indicates that the risk of atherosclerosis attributable to LDL-C may in part be the result of lipoproteins in the IDL fraction (S
f
12 to 20) that is included within the traditional measurements of LDL-C.
Differential Effects of Captopril and Nitrates on Muscle Sympathetic Nerve Activity in Volunteers
Authors: Noll Georg , Wenzel René R. , de Marchi Stefano , Shaw Sidney , Lüscher Thomas F.
Published: June 2012

Background
The sympathetic nervous system (SNS) is an important regulator of cardiovascular function. Activation of SNS plays an important role in the pathophysiology and the prognosis of cardiovascular diseases such as heart failure, acute coronary syndromes, arrhythmia, and possibly hypertension. Vasodilators such as adenosine and sodium nitroprusside are known to activate SNS via baroreflex mechanisms. Because vasodilators are widely used in the treatment of patients with cardiovascular diseases, the aim of the present study was to assess the influence of clinically used dosages of isosorbide dinitrate and captopril on sympathetic nerve activity at rest and during stimulatory maneuvers.

Methods and Results
Twenty-eight healthy volunteers were included in this double-blind placebo-controlled study, and muscle sympathetic nerve activity (MSA; with microelectrodes in the peroneal nerve), blood pressure, heart rate, and neurohumoral parameters were measured before and 90 minutes after the oral administration of 40 mg isosorbide dinitrate or 6.25 mg captopril. Furthermore, a 3-minute mental stress test and a cold pressor test were performed before and 90 minutes after drug administration. Resting MSA did not change after captopril and decreased compared with placebo (
P
<.05 versus placebo), whereas isosorbide dinitrate led to a marked increase in MSA (
P
<.05). Systolic blood pressure was reduced by isosorbide dinitrate (
P
<.05), whereas captopril decreased diastolic blood pressure (
P
<.05). The increases in MSA, blood pressure, and heart rate during mental stress were comparable before and after drug administration regardless of the medication. During cold pressor test, MSA and systolic and diastolic blood pressures increased to the same degree independent of treatment, but after isosorbide dinitrate, the increase in MSA seemed to be less pronounced. Heart rate did not change during cold stimulation. Plasma renin activity increased after captopril and isosorbide dinitrate (
P
<.05), whereas placebo had no effect. Endothelin-1 increased after placebo and isosorbide dinitrate (
P
<.05) but not after captopril.

Conclusions
Thus, captopril suppressed MSA despite lowering of diastolic blood pressure but allowed normal adaptation of the SNS during mental or physical stress. In contrast, the nitrate strongly activated the SNS under baseline conditions. These findings demonstrate that vasodilators differentially interact with the SNS, which could be of importance in therapeutic strategies for the treatment of patients with cardiovascular diseases.
Coronary Stenting After Rotational Atherectomy in Calcified and Complex Lesions
Authors: Moussa Issam , Di Mario Carlo , Moses Jeffrey , Reimers Bernhard , Di Francesco Lucia , Martini Giovanni , Tobis Jonathan , Colombo Antonio
Published: June 2012

Background
Treatment of calcified (in contrast to simple) lesions with PTCA has been associated with a lower success rate and more procedural complications. Rotablation can improve acute results, but the high restenosis rate remains a problem. The purpose of this study was to evaluate the clinical and angiographic outcome of patients with complex and calcified lesions treated with a combination of rotablation and stenting.

Methods and Results
Seventy-five consecutive patients with 106 lesions had rotablation prior to coronary stenting. Intravascular ultrasound–guided stenting was used without subsequent anticoagulation in 93% of patients. Procedural success was achieved in 93.4% of lesions. Acute stent thrombosis occurred in two lesions (1.9%), and subacute stent thrombosis in one lesion (0.9%). Angiographic follow-up was performed in 82.5% of lesions at 4.6±1.9 months with an angiographic restenosis rate of 22.5%. Clinical follow-up was performed in all patients at 6.4±3 months; target lesion revascularization was needed in 18% of lesions, Q-wave myocardial infarction occurred in 1.3%, coronary bypass surgery in 4.0%, and death in 1.3%.

Conclusions
Optimal coronary stenting after rotablation in calcified and complex lesions can be performed with a high success rate, an acceptable rate of procedural complications, and a low rate of stent thrombosis. This approach was associated with a low incidence of angiographic restenosis compared with results usually obtained with other interventional strategies in calcified and complex lesion subsets.