bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased Release of NO During Ischemia Reduces Myocardial Contractility and Improves Metabolic Dysfunction
Authors: Node Koichi , Kitakaze Masafumi , Kosaka Hiroaki , Komamura Kazuo , Minamino Tetsuo , Inoue Michitoshi , Tada Michihiko , Hori Masatsugu , Kamada Takenobu
Published: June 2012

Background
We have reported that myocardial ischemia increases nitric oxide (NO) production. Several lines of evidence suggest that NO reduces myocardial contraction. Therefore, we tested whether endogenous NO decreases the inotropic response of the ischemic myocardium and whether endogenous NO is beneficial in the metabolic function of ischemic myocardium.

Methods and Results
The left anterior descending coronary artery was perfused with blood from the left carotid artery in 72 dogs. An infusion of
N
G
-nitro-
l
-arginine methyl ester (L-NAME), an inhibitor of NO synthase, did not affect fractional shortening (FS) under nonischemic conditions. After reduction of perfusion pressure so that coronary blood flow decreased to 60% of the control value, FS of the perfused area decreased, and intravenous infusion of isoproterenol increased FS. Before and during intravenous infusion of isoproterenol under conditions of coronary hypoperfusion, FS was significantly increased in the L-NAME group compared with the untreated group. Both lactate extraction ratio and the pH in coronary venous blood were significantly lower in the L-NAME–treated group than in the untreated group during coronary hypoperfusion. Infusion of
l
-arginine prevented the effects of L-NAME in the ischemic myocardium.

Conclusions
These results indicate that endogenous NO reduces myocardial contractile function and improves myocardial metabolic function in the ischemic heart. The myocardial energy–sparing effect as well as coronary vasodilation due to NO may be beneficial to the ischemic myocardium.
Relation Between Activated Clotting Time During Angioplasty and Abrupt Closure
Authors: Narins Craig R. , Hillegass William B. , Nelson Charlotte L. , Tcheng James E. , Harrington Robert A. , Phillips Harry R. , Stack Richard S. , Califf Robert M.
Published: June 2012

Background
The purpose of this study was to determine whether the degree of heparin anticoagulation during coronary angioplasty, as measured by the activated clotting time, is related to the risk of abrupt vessel closure.

Methods and Results
Sixty-two cases of in- and out-of-laboratory abrupt closure in patients in whom intraprocedure activated clotting times were measured were identified from a population of 1290 consecutive patients who underwent nonemergency coronary angioplasty. This group was compared with a matched control population of 124 patients who did not experience abrupt closure. Relative to the control population, patients who experienced abrupt closure had significantly lower initial (median, 350 seconds [25th to 75th percentile, 309 to 401 seconds] versus 380 seconds [335 to 423 seconds],
P
=.004) and minimum (345 seconds [287 to 387 seconds] versus 370 seconds [321 to 417 seconds],
P
=.014) activated clotting times. Higher activated clotting times were not associated with an increased likelihood of major bleeding complications. Within this population, a strong inverse linear relation existed between the activated clotting time and the probability of abrupt closure.

Conclusions
This study demonstrates a significant inverse relation between the degree of anticoagulation during angioplasty and the risk of abrupt closure. A minimum target activated clotting time could not be identified; rather, the higher the intensity of anticoagulation, the lower the risk of abrupt closure.
Differential Cardiac Effects of Growth Hormone and Insulin-like Growth Factor1 in the Rat
Authors: Cittadini Antonio , Strömer Hinrik , Katz Sarah E. , Clark Ross , Moses Alan C. , Morgan James P. , Douglas Pamela S.
Published: June 2012

Background
Despite their increasing clinical use and recent evidence that growth hormone (GH) and insulin-like growth factor–1 (IGF-1) target the heart, there has been no systematic investigation of the effects of GH and IGF-1 on the cardiovascular system.

Methods and Results
Sixty normal but growing adult female rats were randomized to receive 4 weeks of treatment with GH (3.5 mg · kg
−1
· d
−1
), IGF-1 (3 mg · kg
−1
· d
−1
), a combination of the two, or placebo. Transthoracic echocardiograms were performed at baseline and at 2 weeks and 4 weeks of treatment. After the final echocardiography, rats underwent either closed-chest left ventricular (LV) catheterization or Langendorff perfusion studies. Myocyte diameter and interstitial tissue fraction were assessed by morphometric histology. Echocardiographic and ex vivo data demonstrated a LV hypertrophic response in all three groups of treated animals that was most marked in the GH group, which alone exhibited a concentric growth pattern (relative wall thickness, 0.52 versus 0.42 to 0.44 in the other groups;
P
<.001). At 4 weeks, cardiac index was significantly higher and total systemic vascular resistance was lower in all groups of treated animals than in control animals (both
P
<.001), whereas arterial blood pressure did not differ significantly. All indexes of in vivo and in vitro cardiac function were higher in GH- and IGF-1–treated rats than in control animals, whereas combination therapy yielded a blunted effect. Myocyte diameter was increased in all three treated groups without an increase in interstitial tissue.

Conclusions
Exogenous administration of GH and IGF-1 in the normal adult rat induces a cardiac hypertrophic response without development of significant fibrosis. Cardiac performance is increased both in vivo and in the isolated heart.
Increased Activation of Sympathetic Nervous System and Endothelin by Mental Stress in Normotensive Offspring of Hypertensive Parents
Authors: Noll Georg , Wenzel René R. , Schneider Martin , Oesch Valerie , Binggeli Christian , Shaw Sidney , Weidmann Peter , Lüscher Thomas F.
Published: June 2012

Background
The pathogenesis of essential hypertension is still uncertain, but genetic factors and the sympathetic nervous system are likely to be involved. Sympathetic nerve activity and hormonal circulatory control mechanisms, however, are affected by blood pressure itself. Hence, early functional changes are best investigated in normotensive subjects at risk to develop hypertension, such as normotensive offspring of hypertensive parents.

Methods and Results
Muscle sympathetic nerve activity (MSA) was measured in the peroneal nerve of 10 normotensive offspring of parents with essential hypertension and 8 offspring of normotensive parents. Measurements were performed under resting conditions, during a 10-minute period of hypoxia (12.5% O
2
/87.5% N
2
), and during a 3-minute mental stress test. The tests were separated by a 30-minute resting period. Plasma samples for determination of norepinephrine and endothelin were collected before and after the tests. Baseline values of MSA were comparable in offspring of hypertensive and normotensive parents. During hypoxia, MSA, heart rate, and norepinephrine and endothelin plasma levels increased in offspring of hypertensive and normotensive parents to a comparable degree, whereas no significant changes in blood pressure and plasma norepinephrine levels were observed in either group. During mental stress, MSA and plasma norepinephrine and endothelin increased only in offspring of hypertensive parents (
P
<.001 to .01). In parallel, blood pressure increased significantly only in offspring of hypertensive parents (
P
<.001 to .05), but heart rate increased in both groups (
P
<.001 to .05).

Conclusions
The activity of the sympathetic nervous system and plasma norepinephrine and endothelin levels are increased during mental stress only in offspring of hypertensive parents, whereas the response to hypoxia was similar in offspring of hypertensive and normotensive parents, suggesting a genetically determined abnormal regulation of the sympathetic nervous system to certain stressful stimuli in offspring of hypertensive parents. This may play a role in the pathogenesis of essential hypertension.
Activated Partial Thromboplastin Time and Outcome After Thrombolytic Therapy for Acute Myocardial Infarction
Authors: Granger Christopher B. , Hirsh Jack , Califf Robert M. , Col Jacques , White Harvey D. , Betriu Amadeo , Woodlief Lynn H. , Lee Kerry L. , Bovill Edwin G. , Simes R. John , Topol Eric J.
Published: June 2012

Background
Although intravenous heparin is commonly used after thrombolytic therapy, few reports have addressed the relationship between the degree of anticoagulation and clinical outcomes. We examined the activated partial thromboplastin time (aPTT) in 29 656 patients in the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO-I) trial and analyzed the relationship between the aPTT and both baseline patient characteristics and clinical outcomes.

Methods and Results
Intravenous heparin was administered as a 5000-U bolus followed by an initial infusion of 1000 U/h, with dose adjustment to achieve a target aPTT of 60 to 85 seconds. aPTTs were collected 6, 12, and 24 hours after thrombolytic administration. Higher aPTT at 24 hours was strongly related to lower patient weight (
P
<.00001) as well as older age, female sex, and lack of cigarette smoking (all
P
<.0001). At 12 hours, the aPTT associated with the lowest 30-day mortality, stroke, and bleeding rates was 50 to 70 seconds. There was an unexpected direct relationship between the aPTT and the risk of subsequent reinfarction. There was a clustering of reinfarction in the first 10 hours after discontinuation of intravenous heparin.

Conclusions
Although the relationship between aPTT and clinical outcome was confounded to some degree by the influence of baseline prognostic characteristics, aPTTs higher than 70 seconds were found to be associated with higher likelihood of mortality, stroke, bleeding, and reinfarction. These findings suggest that until proven otherwise, we should consider the aPTT range of 50 to 70 seconds as optimal with intravenous heparin after thrombolytic therapy.
Novel Human Vascular Endothelial Growth Factor Genes VEGF-B and VEGF-C Localize to Chromosomes 11q13 and 4q34, Respectively
Authors: Paavonen Karri , Horelli-Kuitunen Nina , Chilov Dimitri , Kukk Eola , Pennanen Sari , Kallioniemi Olli-Pekka , Pajusola Katri , Olofsson Birgitta , Eriksson Ulf , Joukov Vladimir , Palotie Aarno , Alitalo Kari
Published: June 2012

Background
Vascular endothelial growth factor (VEGF) is an important regulator of endothelial cell proliferation, migration, and permeability during embryonic vasculogenesis as well as in physiological and pathological angiogenesis. The recently isolated VEGF-B and VEGF-C cDNAs encode novel growth factor genes of the VEGF family.

Methods and Results
Southern blotting and polymerase chain reaction analysis of somatic cell hybrids and fluorescence in situ hybridization (FISH) of metaphase chromosomes were used to assess the chromosomal localization of VEGF-B and VEGF-C genes. The VEGF-B gene was found on chromosome 11q13, proximal to the cyclin D1 gene, which is amplified in a number of human carcinomas. However, VEGF-B was not amplified in several mammary carcinoma cell lines containing amplified cyclin D1. The VEGF-C gene was located on chromosome 4q34, close to the human aspartylglucosaminidase gene previously mapped to 4q34-35.

Conclusions
The VEGF-B locus in 11q13 and the VEGF-C locus in 4q34 are candidate targets for mutations that lead to vascular malformations or cardiovascular diseases.
Ascorbic Acid Reverses Endothelial Vasomotor Dysfunction in Patients With Coronary Artery Disease
Authors: Levine Glenn N. , Frei Balz , Koulouris Spyridon N. , Gerhard Marie D. , Keaney John F. , Vita Joseph A.
Published: June 2012

Background
In the setting of atherosclerosis, endothelial vasomotor function is abnormal. Increased oxidative stress has been implicated as one potential mechanism for this observation. We therefore hypothesized that an antioxidant, ascorbic acid, would improve endothelium-dependent arterial dilation in patients with coronary artery disease.

Methods and Results
Brachial artery endothelium-dependent dilation in response to hyperemia was assessed by high-resolution vascular ultrasound before and 2 hours after oral administration of either 2 g ascorbic acid or placebo in a total of 46 patients with documented coronary artery disease. Plasma ascorbic acid concentration increased 2.5-fold 2 hours after treatment (46±8 to 114±11 μmol/L,
P
=.001). In the prospectively defined group of patients with an abnormal baseline response (<5% dilation), ascorbic acid produced marked improvement in dilation (2.0±0.6% to 9.7±2.0%), whereas placebo had no effect (1.1±1.5% to 1.7±1.5%,
P
=.003 for ascorbic acid versus placebo). Ascorbic acid had no effect on hyperemic flow or arterial dilation to sublingual nitroglycerin.

Conclusions
Ascorbic acid reverses endothelial vasomotor dysfunction in the brachial circulation of patients with coronary artery disease. These findings suggest that increased oxidative stress contributes to endothelial dysfunction in patients with atherosclerosis and that endothelial dysfunction may respond to antioxidant therapy.
Patency of Infarct-Related Artery
Authors: Mortara Andrea , Specchia Giuseppe , La Rovere Maria Teresa , Bigger J. Thomas , Marcus Frank I. , Camm John A. , Hohnloser Stefan H. , Nohara Ryuji , Schwartz Peter J.
Published: June 2012

Background
In post–myocardial infarction (MI) patients, the restoration of anterograde flow in the infarct-related artery (IRA) significantly improves survival. Limitation of infarct size and increased electrical stability of the myocardium are likely operating mechanisms for this beneficial effect. We tested the hypothesis that patency of the IRA may enhance vagal reflexes, a factor known to affect electrical stability of the infarcted myocardium.

Methods and Results
Analysis of angiographic data was performed in 359 of 1284 post-MI patients enrolled in a multicenter prospective study within 8 weeks after the index MI. All the patients underwent baroreflex sensitivity (BRS) assessment by the phenylephrine method. The BRS of the entire population averaged 8.2±5.5 ms/mm Hg and was significantly related to age but not to ejection fraction (EF). One-, two-, and three-vessel disease was present in 138, 96, and 99 patients, respectively, while no coronary stenosis was observed in 26. IRA patency was documented in 234 patients (65%), while in the remaining 125 (35%), the artery remained occluded. Patients with occluded IRAs had more extensive coronary disease (2 to 3 vessels, 71% versus 46%,
P
<.01) and more depressed left ventricular (LV) function (LVEF, 48±13% versus 53±12%,
P
<.001). Patency of the IRA was associated with higher BRS values (BRS, 8.9±5.8 versus 7.1±4.7 ms/mm Hg,
P
<.005) and with a lower incidence (9% versus 18%,
P
<.02) of markedly depressed BRS (<3 ms/mm Hg), a condition suggested by preliminary studies to be associated with an increased risk of post-MI mortality. The association between IRA patency and BRS was more evident in anterior than in inferior MI. Multivariate regression analysis showed that age of the patient and patency of the IRA were the major independent determinants of BRS, while LVEF was weakly related to BRS and only when analyzed as a categorized variable.

Conclusions
The presence of an open IRA is associated with a higher baroreflex sensitivity, and this effect is largely independent of limitation of infarct size by IRA patency. These data offer new insights into the mechanisms by which coronary artery patency may affect cardiac electrical stability and survival.
Contributions of Frequency Distribution Analysis to the Understanding of Coronary Restenosis
Authors: Lehmann Kenneth G. , Melkert Rein , Serruys Patrick W.
Published: June 2012

Background
Clinical restenosis after balloon angioplasty can be categorized by use of dichotomous terms based on the presence or absence of recurrent myocardial ischemia. In contrast, recent investigations have concluded that late luminal renarrowing, documented through angiographic imaging, occurs to a variable extent in nearly all stenoses. This process has been characterized by a gaussian or normal frequency distribution, with restenosis simply representing an extreme form of this delayed remodeling. In the current study, frequency distribution analysis was used to examine the process of coronary restenosis in a large cohort of patients at risk.

Methods and Results
Quantitative coronary angiographic analysis was applied to 9279 cineangiograms obtained in 3093 patients before and immediately after angioplasty and after 6-month follow-up. Late loss, defined as the change in minimum lumen diameter of the target stenosis from postdilation to follow-up, did not statistically conform to a normal distribution (
P
<.0001 by both χ
2
statistic and Kolmogorov-Smirnov test), even after the exclusion of the 236 stenoses that displayed total occlusions at follow-up angiography. Examination of deviations from a normal curve revealed an excessively high frequency of stenoses that experienced either little change (0.0±0.3 mm) or marked change (1.0 to 2.0 mm) in late loss, with a low frequency of stenoses with intermediate values (0.3 to 1.0 mm). Similarly, although the distribution of percent diameter stenosis of the target lesion was statistically normal immediately after dilation, this gaussian distribution disappeared during the follow-up period. Other angiographic indexes of restenosis also failed to approximate a normal curve. In an attempt to improve the goodness of fit, a probabilistic model of late loss was created on the basis of deconvolution of the observed data distribution. Two theoretical, discrete populations of stenoses were identified, one with and one without overall late luminal narrowing. Unlike the gaussian distribution, this model provided a good representation of the observed data (
P
=NS for lack of fit).

Conclusions
The frequency distributions of angiographic indexes of restenosis often superficially resemble a gaussian curve, an appearance that is artifactually enhanced by the measurement imprecision of current quantitative techniques. Nevertheless, standard indexes of coronary restenosis fail to conform statistically to a normal distribution. The pattern of deviations observed supports the possible existence of discrete subpopulations of lesions, each with a different propensity toward the development of restenosis after coronary intervention.
Direct Evidence That Initial Oxidative Stress Triggered by Preconditioning Contributes to Second Window of Protection by Endogenous Antioxidant Enzyme in Myocytes
Authors: Zhou Xiaobo , Zhai Xiaolin , Ashraf Muhammad
Published: June 2012

Background
We tested the hypothesis that late preconditioning is associated with increased antioxidant enzyme activity induced by initial oxidative stress.

Methods and Results
Isolated rat myocytes were preconditioned either with two cycles of 5 minutes of anoxia and 5 minutes of reoxygenation or with exogenous superoxide anion (O
2
−
) generated by reaction of xanthine oxidase with xanthine. Myocytes were allowed to recover for 60 minutes or 24 hours, after which they were subjected to 60 minutes of anoxia and 60 minutes of reoxygenation. After 60 minutes or 24 hours, the protection was evidenced by decreased O
2
−
production, increased Mn superoxide dismutase (Mn-SOD) activity, increased cell viability, decreased LDH release, reduced malondialdehyde formation, high-energy phosphate preservation, and improved cell morphology in preconditioned and O
2
−
-treated myocytes. Immediately after treatment with O
2
−
or repetitive, brief anoxia, O
2
−
production was increased in myocytes. Longer anoxia resulted in loss of Mn-SOD activity in anoxic controls 24 hours later, whereas it was significantly increased in preconditioned and O
2
−
-treated myocytes. O
2
−
production was inhibited in preconditioned and O
2
−
-treated myocytes. Myocytes treated with Mn-SOD during short, intermittent anoxia exhibited decreased activity of Mn-SOD and increased O
2
−
production 24 hours later. Mn-SOD activity in late preconditioning was considerably higher than that in classic preconditioning.

Conclusions
These results suggest that a burst of oxygen free radicals generated during the initial periods of brief, repetitive anoxia increases myocardial antioxidant activity 24 hours later and that it contributes to the late cardioprotective effect of preconditioning.
Effect of Thrombin Inhibition With Desulfatohirudin on Early Kinetics of Cellular Proliferation After Balloon Angioplasty in Atherosclerotic Rabbits
Authors: Ragosta Michael , Barry William L. , Gimple Lawrence W. , Gertz S. David , McCoy Kyle W. , Stouffer George A. , McNamara Coleen A. , Powers Eric R. , Owens Gary K. , Sarembock Ian J.
Published: June 2012

Background
Thrombin may have a pivotal role in restenosis after angioplasty. Hirudin, a potent thrombin inhibitor, reduces luminal narrowing by plaque after angioplasty in a rabbit model of atherosclerosis. Because cellular proliferation is believed to be an important mechanism for restenosis and thrombin has been shown to be a potent smooth muscle cell mitogen in vitro, we hypothesized that the mechanism of the effect of hirudin on limiting luminal narrowing by plaque occurs via inhibition of cellular proliferation.

Methods and Results
Femoral atherosclerosis was induced in 108 rabbits, and balloon angioplasty was performed. At angioplasty, group 1 rabbits (n=38) were treated with a 2-hour infusion of hirudin, and group 2 rabbits (n=41) were treated with heparin. Group 3 rabbits (n=29) were treated with hirudin (n=15) or heparin (n=14) and killed at 7 or 28 days to determine cross-sectional area narrowing by plaque and cellular proliferation with the use of bromodeoxyuridine labeling. At 29, 71, or 167 hours after angioplasty, group 1 and 2 rabbits were injected with
3
H-thymidine and killed 1 hour later, and labeling indexes were determined. A significant increase in the index of
3
H-thymidine–labeled nuclei was observed in the intima of “ballooned” arteries compared with “nonballooned” atherosclerotic arteries at both 30 hours (0.06±0.05 versus 0.01±0.01,
P
<.01) and 72 hours (0.10±0.06 versus 0.004±0.004,
P
<.01). By 7 days, the index of labeled cells was similar to baseline (0.04±0.03 versus 0.01±0.01,
P
=.12). Hirudin had no effect on the
3
H-thymidine labeling indexes at any of the time points studied despite the fact that hirudin treatment in group 3 rabbits resulted in less cross-sectional area narrowing by plaque at both 7 and 28 days after angioplasty (41±16 versus 24±12 at 7 days and 60±21 versus 44±17 at 28 days, heparin versus hirudin;
P
<.03).

Conclusions
Balloon angioplasty resulted in a marked increase in cellular proliferation that peaked at 72 hours. A 2-hour infusion of hirudin failed to reduce early
3
H-thymidine labeling, suggesting that inhibition of cell proliferation within the first 7 days after angioplasty is not the predominant mechanism by which hirudin exerts its effect on limiting luminal narrowing by plaque 28 days after balloon angioplasty in this animal model.
Inducible Carboxypeptidase Activity
Authors: Redlitz Alexander , Nicolini Francesca A. , Malycky Janis L. , Topol Eric J. , Plow Edward F.
Published: June 2012

Background
An inducible carboxypeptidase activity in human plasma delays tissue-type plasminogen activator (TPA)–induced clot lysis in vitro. We investigated whether carboxypeptidase activity is induced in vivo during thrombosis and thrombolytic therapy in a canine model of myocardial infarction.

Methods and Results
By use of synthetic substrate assays, dog plasma was shown to contain an inducible carboxypeptidase activity that is efficiently inhibited by potato carboxypeptidase inhibitor. This inhibitor accelerates TPA-mediated clot lysis in vitro by an average of 27% (n=5,
P
=.046). Analysis of the inducible carboxypeptidase activity in plasma samples of dogs with electrically induced thrombosis of the circumflex coronary artery treated with TPA revealed that (1) inducible carboxypeptidase activity is increased during thrombosis (8.7±2.0 U/L,
P
<.013) and thrombolytic therapy (9.9±1.8 U/L,
P
<.024) compared with baseline (3.2±2.0 U/L); (2) thrombosis is a prerequisite of carboxypeptidase induction during and after TPA infusion, since carboxypeptidase levels were lower in dogs without a coronary thrombus; and (3) a significant positive correlation (
r
=.6,
P
<.0069) of carboxypeptidase activity with time to restoration of blood flow was observed.

Conclusions
These data indicate that carboxypeptidase activity is induced in vivo and may influence thrombolysis.
Left Ventricular Diastolic Function in Hypertension and Role of Plasma Glucose and Insulin
Authors: Jain A. , Avendano G. , Dharamsey S. , Dasmahapatra A. , Agarwal R. , Reddi A. , Regan T.
Published: June 2012

Background
Experimental production of glucose intolerance has been associated with increased diastolic stiffness of the left ventricle, accompanied by interstitial fibrosis. Because carbohydrate metabolism is altered in hypertension, we undertook the present study to assess the relation of diastolic dysfunction in hypertension to plasma glucose and insulin concentrations. The latter are also affected by obesity. To facilitate this analysis, we studied moderately obese hypertensives. Elucidation of these relations was then sought in diabetic subjects.

Methods and Results
Subjects undergoing catheterization for chest pain were included in the study when significant coronary disease was not present. In groups 1 (lean), 2 (obese), 3 (lean hypertensive), and 4 (obese hypertensives), intraventricular pressures and volumes were determined. Fasting plasma glucose, insulin, hemoglobin
AIC
, and glucose tolerance were assessed. Basal ejection fraction and end-systolic wall stress were normal in the four groups. Chamber stiffness was significantly elevated in the hypertensives and was higher in group 4 than in group 3 (
P
<.05). Diastolic dysfunction was correlated with fasting blood glucose (
r
=.69,
P
<.006) but not with plasma insulin or left ventricular mass. Chamber stiffness was also increased in diabetics, with a larger effect in the obese.

Conclusions
Hypertension is associated with increased diastolic stiffness of the left ventricle, which is enhanced by moderate obesity, and abnormal carbohydrate metabolism. Experimentally and in humans, hypertension is associated with interstitial fibrosis of mycardium, the presumed basis for the diastolic dysfunction. Chamber stiffness in group 4 hypertensives was similar to that in the lean diabetics but less than that in the obese diabetics. Although the latter exhibited a correlation with plasma hemoglobin
AIC
, the large rise in stiffness suggests a potential role for growth factors in further alteration of myocardial composition.
Biological Response to Bard Clamshell Septal Occluders in the Canine Heart
Authors: Kuhn Micheal A. , Latson Larry A. , Cheatham John P. , McManus Bruce , Anderson James M. , Kilzer Karen L. , Furst Joseph
Published: June 2012

Background
The Clamshell Septal Occluder has been used to close various congenital heart defects. The purpose of this study was to evaluate the long-term biological response to this device after placement in the canine heart. Previous in vivo studies with device placement were limited to 60 days.

Methods and Results
An atrial septal defect was created in dogs by blade septostomy followed by balloon dilation. Both old and new (redesigned) devices were placed. Angiographic follow-up was performed at 1, 3, and 6 months and 1 and 2 years after device placement with groups of dogs euthanitized at the same intervals. Gross and microscopic assessment was done on the explanted devices. The implants were covered at least 50% by neointima at 1 month and covered completely by 3 months. There was no thrombus formation. Areas of focal hemorrhage were evident at 1 month and were not present at 3 months. The fibrous capsule that covered the device became more densely organized and neovascularized by 2 years. A focal foreign body reaction at the device-tissue interface persisted for 2 years. There were no arm fractures with either the old or new devices in these dogs.

Conclusions
The Bard Clamshell Septal Occluder is well tolerated in the canine heart for at least 2 years and elicits a normal healing process.
1
H NMR Spectroscopic Imaging of Myocardial Triglycerides in Excised Dog Hearts Subjected to 24 Hours of Coronary Occlusion
Authors: Straeter-Knowlen Ingrid M. , Evanochko William T. , den Hollander Jan A. , Wolkowicz Paul E. , Balschi James A. , Caulfield James B. , Ku David D. , Pohost Gerald M.
Published: June 2012

Background
Myocardial ischemic insult causes depression of fatty-acid β-oxidation and increased fatty-acid esterification with triglyceride (TG) accumulation. This accumulation has been demonstrated to occur in the territory with diminished blood flow surrounding an infarct, ie, the region at risk. To evaluate whether the extent of TG accumulation in the canine heart after 24 hours of ischemia could be detected, we applied myocardial
1
H nuclear magnetic resonance (NMR) spectroscopic imaging (SI).

Methods and Results
Seven adult mongrel dogs underwent 24 hours of left anterior descending coronary artery occlusion. Postmortem, the hearts were excised and the size and location of the infarct were determined. With a Philips 1.5-T clinical NMR imaging/spectroscopic system, two-dimensional (2D)
1
H NMR SI was performed. TG
1
H NMR chemical shift images were reconstructed from the frequency domain spectra by numerical integration. A statistically significant (
P
<.05) increase in TG signal intensity was demonstrated in the region at risk compared with the nonischemic control region. There was an intermediate quantity of TG in the infarct region. Biochemical determination of tissue TG content (milligrams per gram wet weight) in the control, at-risk, and infarct regions confirmed the
1
H NMR measurements. Histological evaluation with oil red O staining also demonstrated graded TG accumulation in myocytes. The highest TG levels were found in the at-risk region and the lowest levels in the control region.

Conclusions
By use of 2D
1
H NMR SI, the present study confirms and extends previous work that demonstrates preferential accumulation of TG in the reversibly injured myocardium after 24 hours of coronary occlusion. This study provides an important step toward the clinical application of TG imaging. When TG imaging is ultimately possible, resultant data would have diagnostic, prognostic, and therapeutic implications.
Plasma Volume and Its Regulatory Factors in Congestive Heart Failure After Implantation of Long-term Left Ventricular Assist Devices
Authors: James Karen B. , McCarthy Patrick M. , Jaalouk Safwan , Bravo Emmanuel L. , Betkowski Adam , Thomas James D. , Nakatani Satoshi , Fouad-Tarazi Fetnat M.
Published: June 2012

Background
Congestive heart failure is associated with blood volume expansion caused by stimulation of the renin-aldosterone system and arginine vasopressin. The use of left ventricular assist devices as bridges to heart transplantation has improved the survival of patients during this critical period. In studying heart failure physiology on support devices, we hypothesized that improvement of cardiac function by a left ventricular assist device is associated with normalization of volume load secondary to normalization of its regulatory substances.

Methods and Results
We studied 15 patients (13 men, 2 women; age, 51±8 years) with end-stage heart failure who were cardiac transplant candidates eligible for HeartMate implantation. We measured plasma volume and plasma levels of atrial natriuretic peptide, aldosterone, renin, and arginine vasopressin sequentially before HeartMate implantation (baseline), after HeartMate implantation (weeks 4 and 8), and after transplantation. Baseline plasma volume was 123±20% of normal; it was 122±22% at week 4 and decreased to 115±14% at week 8. Atrial natriuretic peptide was 359±380 pg/mL at baseline, 245±175 pg/mL at week 4, and 151±66 pg/mL at week 8. Plasma aldosterone fell from 68±59 ng/dL at baseline to 17±16 ng/dL at week 4 (
P
<.05 versus baseline) and was 32±50 ng/dL at week 8. Plasma renin activity decreased from 80±88 ng/dL at baseline to 11±12 ng/dL at week 4 and was 16±38 ng/dL at week 8 (both
P
<.05 versus baseline). Arginine vasopressin fell from 5.0±4.8 fmol/mL at baseline to 1.1±0.7 fmol/mL at week 4 and 1.2±0.8 fmol/mL at week 8 (both
P
<.05 versus baseline).

Conclusions
The reduction of plasma renin activity, plasma aldosterone, and arginine vasopressin occurred earlier than the reduction of plasma volume and atrial natriuretic peptide after HeartMate implantation, possibly because of decreased pulmonary congestion and improved renal perfusion. The reduction of atrial natriuretic peptide cannot be responsible for the lack of adequate decrease of plasma volume; its reduction can be taken as a marker of improved cardiac pump function and decreased atrial stretch.
Application of Percutaneous Transluminal Coronary Angioplasty to Coronary Arterial Stenosis in Kawasaki Disease
Authors: Ino Toshihiro , Akimoto Katsumi , Ohkubo Mataichi , Nishimoto Kei , Yabuta Keijiro , Takaya Junji , Yamaguchi Hiroshi
Published: June 2012

Background
Percutaneous transluminal coronary angioplasty (PTCA) has rarely been performed on patients with coronary lesions that result from Kawasaki disease. In this study, we retrospectively evaluated the effectiveness of PTCA in five patients with coronary arterial stenosis that resulted from Kawasaki disease and reviewed previous reports for possible indicators of PTCA effectiveness.

Methods and Results
Five patients, ranging in age from 2 to 16 years (median, 8 years), underwent conventional PTCA for localized stenosis. The lesion targeted for PTCA was located in the middle right coronary artery of three patients and in the left anterior descending artery in two patients. In four of the five patients, PTCA was angiographically effective, with stenosis rates improving from 84±10% to 33±11% (
P
<.05). When the previously reported cases of six similar patients were taken into consideration, the only predictor of successful PTCA seemed to be the time elapsed between the onset of Kawasaki disease and performance of this procedure.

Conclusions
In cases in which patients show significant localized stenosis as a result of Kawasaki disease, PTCA should be attempted within 6 to 8 years of the onset of the disease. Additionally, intravascular ultrasound imaging was found to be a useful tool for evaluating internal morphology before and after PTCA. In older patients with coronary calcification, other alternatives to PTCA, such as the use of a rotablator or an atherectomy catheter, should be considered.
Physiological and Biochemical Evidence for Coordinate Increases in Muscarinic Receptors and G
i
During Pacing-Induced Heart Failure
Authors: Vatner Dorothy E. , Sato Naoki , Galper Jonas B. , Vatner Stephen F.
Published: June 2012

Background
It is not clear whether the increase in the myocardial guanylyl nucleotide inhibitory protein (G
i
), frequently observed in heart failure, is associated with any functional effects.

Methods and Results
Eight sham-operated dogs and 10 dogs were studied with pacing-induced heart failure (240 bpm for 4 to 7 weeks), characterized by reduced (
P
<.05) left ventricular dP/dt (from 2926±99 to 1303±126 mm Hg/s). The muscarinic agonist acetylcholine (10 μg/kg IV) in the presence of ganglionic blockade reduced left ventricular dP/dt more (
P
<.05) in heart failure (−23±2%) than before heart failure (−8±2%), despite lesser reductions in arterial pressure. G
i
α
2
was increased by 55% in heart failure. Dose-response curves for carbachol (10
−
8
to 10
−
3
mol/L) inhibition of isoproterenol-stimulated adenylyl cyclase demonstrated significantly greater (
P
<.05) inhibition in heart failure compared with sham-operated dogs. These changes were associated with a coordinate increase in muscarinic receptor density, determined by antagonist binding with
3
H-quinuclidinyl benzilate, in heart failure (153±6.2 fmol/mg protein) compared with sham-operated dogs (124±7.4 fmol/mg protein). Agonist binding with carbachol also revealed an increase in total muscarinic receptors in heart failure without a change in fraction of high- and low-affinity receptors.

Conclusions
These data, in the aggregate, provide physiological and biochemical evidence to support the concept that the coordinate increases in muscarinic receptor number and G
i
levels in heart failure are coupled to increased inhibition of adenylyl cyclase activity and an increased inhibition of myocardial contractility.
Anti–Endothelial Cell Antibodies in Takayasu Arteritis
Authors: Eichhorn Jens , Sima Dagmar , Thiele Bernhard , Lindschau Carsten , Turowski Andreas , Schmidt Heiner , Schneider Wolfgang , Haller Hermann , Luft Friedrich C.
Published: June 2012

Background
Although a specific etiology for Takayasu arteritis has not been found, the bulk of evidence favors an autoimmune mechanism. We examined the sera of 19 patients with Takayasu arteritis for antineutrophil cytoplasmic antibodies (ANCA), antinuclear antibodies (ANA), anti-DNA antibodies, antibodies to extractable nuclear antigens (ENA), anti-Ro antibodies, anticardiolipin antibodies, circulating immune complexes, and anti–endothelial cell antibodies (AECA).

Methods and Results
We used enzyme-linked immunoassays, immunofluorescence, counterimmunoelectrophoresis, fluorescent-activated cell sorter (FACS) analysis, and confocal microscopy. We found that although no patient had positive ANCA, ANA, anti-DNA antibodies, ENA antibodies, anti-Ro antibodies, or anticardiolipin antibodies, 18 of the 19 patients had AECA. The AECA titers of the patients were 2561±1458 compared with 126±15 arbitrary units in a normal group of control subjects (
P
<.001). To verify the specificity of AECA, we performed cytofluorimetry on human endothelial cells with the sera from patients and control subjects. Two entirely separate patterns of fluorescence intensity were identified. We next performed immunocytochemistry and confocal microscopy with human endothelial cells subjected to patients' sera and to sera from normal subjects. The cells subjected to sera from patients with Takayasu arteritis demonstrated specific immunofluorescent staining of their plasma membrane and cytosol.

Conclusions
AECA are frequently present in patients with Takayasu arteritis. They may play a role in the pathogenesis. Furthermore, they may be useful as an additional diagnostic tool.
Homocysteine Increases Cyclin-Dependent Kinase in Aortic Rat Tissue
Authors: Lubec Barbara , Labudova Olga , Hoeger Harald , Muehl Adolf , Fang-Kircher Susanne , Marx Manfred , Mosgoeller Wilhelm , Gialamas J.
Published: June 2012

Background
Hyperhomocyst(e)inemia is strongly associated with occlusive arterial disease. A direct effect of homocysteine on the proliferation of smooth muscle cells was proposed recently. This observation led us to examine the effect of homocysteine on cyclin-dependent kinase, the starter of mitosis and reflecting proliferation.

Methods and Results
Seventy
Him
:OFA rats were divided into seven groups. For 12 weeks, 10 rats were fed homocysteine 25 mg/kg body weight per day, 10 were fed 50 mg/kg body wt per day, and 10 were fed 100 mg/kg body weight per day; 10 were given homocysteic acid 100 mg/kg body weight per day, 10 were administered cysteine 100 mg/kg body weight per day, and 10 were given ascorbic acid 270 mg/kg body weight per day. Ten remained untreated and served as controls. Aortic cyclin-dependent kinase was determined at the transcriptional (mRNA) and protein levels. Phosphokinase C and aortic homocyst(e)ine also were evaluated in aortic tissue. Aortic cyclin-dependent kinase protein was significantly (
P
=.0001) elevated in the three homocysteine-treated groups, and mRNA cyclin-dependent kinase levels were significantly elevated in the rats given the 50 and 100 mg/kg body weight per day protocol. Endothelial damage was shown at higher homocysteine doses as reflected by circulating ACE and von Willebrand factor changes. Proliferation of cells of the aortic wall by bromodeoxyuridine incorporation could be shown in the high-dose homocysteine group only.

Conclusions
Our findings indicate that homocysteine specifically stimulates aortic cyclin-dependent kinase at the transcriptional level, with the possible consequence of proliferation of aortic cells as revealed by incorporation of bromodeoxyuridine in the aortic wall.
Deconvolution: A Novel Signal Processing Approach for Determining Activation Time From Fractionated Electrograms and Detecting Infarcted Tissue
Authors: Ellis Willard S. , Eisenberg Susan J. , Auslander David M. , Dae Michael W. , Zakhor Avideh , Lesh Michael D.
Published: June 2012

Background
Two important signal processing applications in electrophysiology are activation mapping and characterization of the tissue substrate from which electrograms are recorded. We hypothesize that a novel signal-processing method that uses deconvolution is more accurate than amplitude, derivative, and manual activation time estimates. We further hypothesize that deconvolution quantifies changes in morphology that detect electrograms recorded from regions of myocardial infarction.

Methods and Results
To determine the accuracy of activation time estimation, 600 unipolar electrograms were calculated with a detailed computer model using various degrees of coupling heterogeneity to model infarction. Local activation time was defined as the time of peak inward sodium current in the modeled myocyte closest to the electrode. Deconvolution, minimum derivative, and maximum amplitude were calculated. Two experienced electrophysiologists blinded to the computer-determined activation times marked their estimates of activation time. F tests compared the variance of activation time estimation for each method. To evaluate the performance of deconvolution to detect infarction, 380 unipolar electrograms were recorded from 10 dogs with infarcts resulting from ligation of the left anterior descending coronary artery. The amplitude, duration, number of inflections, peak frequency, bandwidth, minimum derivative, and deconvolution were calculated. Metrics were compared by Mann-Whitney rank-sum tests, and receiver operating curves were plotted.

Conclusions
Deconvolution estimated local activation time more accurately than the other metrics (
P
<.0001). Furthermore, the algorithm quantified changes in morphology (
P
<.0001) with superior performance, detecting electrograms recorded from regions of myocardial infarction. Thus, deconvolution, which incorporates a priori knowledge of electrogram morphology, shows promise to improve present clinical metrics.
In Vivo Cardiac Electrophysiology Studies in the Mouse
Authors: Berul Charles I. , Aronovitz Mark J. , Wang Paul J. , Mendelsohn Michael E.
Published: June 2012

Background
This report describes a novel in vivo mouse epicardial cardiac electrophysiology study based on clinical protocols used to evaluate cardiac conduction in human patients. The technique allows extensive electrophysiological evaluation, including the response to pacing, programmed stimulation, and pharmacological agents.

Methods and Results
Surface six-lead ECG data from 18 C57BL/6J mice are presented. Normal cardiac conduction properties for 14 of 18 mice that underwent the procedure are summarized, including determination of sinus node recovery times, AV conduction properties, and atrial, AV, and ventricular effective refractory periods. A subset of six mice was studied after the administration of either procainamide (n=3) or quinidine (n=3). All animals in the procainamide group developed either second-degree or complete AV block spontaneously. The sinus cycle length and refractory periods prolonged on procainamide or quinidine, but no tachyarrhythmias could be induced with atrial or ventricular programmed stimulation.

Conclusions
This mouse electrophysiology method allows rapid assessment of the conduction properties of the murine heart. The ability to analyze cardiac conduction in normal and transgenic mice provides a powerful tool for examining molecular electrophysiological mechanisms in normal physiology and disease states.
Increased Accumulation of Tissue ACE in Human Atherosclerotic Coronary Artery Disease
Authors: Diet Frank , Pratt Richard E. , Berry Gerald J. , Momose Naoko , Gibbons Gary H. , Dzau Victor J.
Published: June 2012

Background
Angiotensin may play a pathophysiological role in experimental and human cardiovascular disease. Clinical studies have shown that ACE inhibitors reduce mortality, recurrent myocardial infarction, and ischemic events in patients with left ventricular dysfunction. Animal studies suggest that tissue ACE, particularly within blood vessels, may be an important target.

Methods and Results
To study tissue ACE in human coronary artery disease and to identify potential mechanisms of ACE inhibitor action, we examined ACE expression immunohistochemically in nonatherosclerotic and diseased human coronary arteries. In nonatherosclerotic arteries, ACE immunoreactivity was found in luminal and adventitial vasa vasorum endothelium. In early- and intermediate-stage atherosclerotic lesions, ACE was detected prominently in regions of fat-laden macrophages and in association with T lymphocytes. In advanced lesions, ACE immunoreactivity was also localized to the endothelium of the microvasculature throughout the plaques. Immunoreactive angiotensin II was also detected in these areas. ACE expression in macrophages was further examined by in vitro experiments with a monocytoid cell line. ACE activity was induced threefold after differentiation of the cells into macrophages and was further increased after stimulation with acetylated LDL.

Conclusions
These observations demonstrate that significant sources of tissue ACE in human atherosclerotic plaques are regions of inflammatory cells, especially areas of clustered macrophages as well as microvessel endothelial cells. These results suggest that ACE accumulation within the plaque may contribute to an increased production of local angiotensin that may participate in the pathobiology of coronary artery disease. Plaque ACE probably is an important target of drug action.