bluuebunny/crossref_metadata_2025 huggingface dataset:
Gender-Specific Criteria and Performance of the Exercise Electrocardiogram
Authors: Okin Peter M. , Kligfield Paul
Published: June 2012

Background
Significant gender differences have been found in performance of the exercise ECG for the identification of coronary artery disease. However, identical exercise ECG ST segment criteria have been used in men and women, which might contribute to the lower accuracy of these methods in women than in men.

Methods and Results
To assess the effect of gender-specific test partitions on relative performance of standard and heart rate–adjusted ST segment depression criteria in men and women, the exercise ECGs of 143 women and 477 men were examined. Non–gender-specific test partitions, selected to have matched specificities of 96% for each test method, were determined in all 283 normal subjects, and gender-specific test partitions with identical specificity were determined separately in the 52 normal women and 231 normal men; sensitivity of these criteria was then examined in the 91 women and 246 men with coronary disease. Standard ST segment depression criteria (0.1 mV of additional horizontal or downsloping ST segment depression at end exercise) with identical 96% specificity in the entire group of normal subjects and separately in women and men had a significantly lower sensitivity of 51% in women compared with 67% in men (
P
<.01). Among women, performance of the ST segment/heart rate (ST/HR) slope was more improved than that of the ST/HR index by the use of gender-specific criteria. Compared with the performance of non–gender-specific criteria, application of gender-specific ST/HR slope partitions with matched specificity of 96% resulted in a significant increase in sensitivity in women from 84% to 91% (
P
<.01), with no significant change in sensitivity in men (89% to 88%) and with no residual difference in sensitivity between men and women. Although the use of gender-specific ST/HR slope criteria significantly improved sensitivity in both men and women with respect to standard criteria (each
P
<.0001), the relative increase in sensitivity provided by heart rate adjustment was significantly greater in women than in men (40% versus 21%,
P
<.001). Similar gender differences in improvement in performance using gender-specific criteria for the ST/HR slope were observed when analysis of test performance was restricted to the detection of three-vessel coronary disease (50% versus 9%,
P
=.002).

Conclusions
At high specificity, gender-specific test partitions improve sensitivity of the ST/HR slope for the identification of coronary disease in women, with no decrease in sensitivity in men. In contrast, gender-specific partitions do not change performance of standard test criteria, which is lower in women than in men. Accordingly, the relative benefit of heart rate adjustment by the ST/HR slope method is greater in women than in men. These findings support use of the ST/HR slope with use of gender-specific partitions for the identification and quantification of coronary artery disease in both men and women.
Nifedipine
Authors: Furberg Curt D. , Psaty Bruce M. , Meyer Jeffrey V.
Published: June 2012

Background
The purpose of this study was to assess the effect of the dose of nifedipine, a dihydropyridine calcium antagonist, on the increased risk of mortality seen in the randomized secondary-prevention trials and to review the mechanisms by which this adverse effect might occur.

Methods and Results
We restricted the dose-response meta-analysis to the 16 randomized secondary-prevention trials of nifedipine for which mortality data were available. Recent trials of any calcium antagonist and formulation were also reviewed for information about the possible mechanisms of action that might increase mortality. Overall, the use of nifedipine was associated with a significant adverse effect on total mortality (risk ratio, 1.16, with a 95% CI of 1.01 to 1.33). This summary estimate fails to draw attention to an important dose-response relationship. For daily doses of 30 to 50, 60, and 80 mg, the risk ratios for total mortality were 1.06 (95% CI, 0.89 to 1.27), 1.18 (95% CI, 0.93 to 1.50), and 2.83 (95% CI, 1.35 to 5.93), respectively. In a formal test of dose response, the high doses of nifedipine were significantly associated with increased mortality (
P
=.01). While the mechanism of this adverse effect is not known, there are several plausible explanations, including the established proischemic effect, negative inotropic effects, marked hypotension, recently reported prohemorrhagic effects attributed to antiplatelet and vasodilatory actions of calcium antagonists, and possibly proarrhythmic effects.

Conclusions
In patients with coronary disease, the use of short-acting nifedipine in moderate to high doses causes an increase in total mortality. Other calcium antagonists may have similar adverse effects, in particular those of the dihydropyridine type. Long-term safety data are lacking for most calcium antagonists.
Angiotensin-Converting Enzyme in the Human Heart
Authors: Danser A.H. Jan , Schalekamp Maarten A.D.H. , Bax Willem A. , van den Brink Antoinette Maassen , Saxena Pramod R. , Riegger Günter A.J. , Schunkert Heribert
Published: June 2012

Background
An insertion (I)/deletion (D) polymorphism of the angiotensin-converting enzyme (ACE) gene has been associated with differences in the plasma levels of ACE as well as with myocardial infarction, cardiomyopathy, left ventricular hypertrophy, and coronary artery disease.

Methods and Results
We determined the cardiac ACE activity and the ACE genotype in 71 subjects who died of noncardiac disorders. Cardiac ACE activity was significantly higher (
P
<.01) in subjects with the ACE DD genotype (12.7±1.9 mU/g wet wt) compared with subjects with the ID (8.7±0.8 mU/g) and the II (9.1±1.0 mU/g) genotypes. This difference was independent of sex, age, and the time required for tissue collection.

Conclusions
Cardiac ACE activity is highest in subjects with the DD genotype. Elevated cardiac ACE activity in these subjects may result in increased cardiac angiotensin II levels, and this may be a mechanism underlying the reported association between the ACE deletion polymorphism and the increased risk for several cardiovascular disorders.
Radiofrequency Catheter Ablation of Type 1 Atrial Flutter
Authors: Poty Herve , Saoudi Nadir , Aziz Ahmed Abdel , Nair Mohan , Letac Brice
Published: June 2012

Background
Radiofrequency energy has demonstrated its efficacy in catheter ablation of atrial flutter (AFl). However, long-term recurrences of AFl have been reported frequently after initial, apparently successful ablation. To date, criteria for prediction of late recurrences are lacking.

Methods and Results
Twelve patients (10 men; mean age, 53.6 years; range, 26 to 69 years) were referred for AFl ablation. Duodecapolar and decapolar catheters were used for detailed mapping of the tricuspid ring, the inferior vena cava–tricuspid annulus (IVC-TA) isthmus, and the coronary sinus ostium (CSOs) area. Additional multipolar catheters were used for recording activation of the coronary sinus and the CSOs-TA isthmus. AFl was present at baseline in 9 patients and was induced by proximal coronary sinus (PCS) pacing in 3. Counterclockwise right atrial activation was recorded in all patients. Primary success of ablation was defined as when AFl was no longer inducible even during isoproterenol infusion. AFl was successfully ablated in all 12 patients, with a median of 4 pulses delivered at the IVC-TA isthmus. In the 3 patients in whom AFl was induced, during PCS pacing in sinus rhythm before ablation, a collision of descending and ascending wave fronts was observed at the middle lateral right atrium (LRA). This activation pattern of the LRA also was noted after unsuccessful radiofrequency applications. Noninducibility of AFl after radiofrequency applications was associated with a change of activation pattern at the LRA and with an inversion of the activation sequence of the IVC-TA isthmus (from clockwise to counterclockwise) in 9 patients when pacing from the PCS. In 2 of 3 patients, despite noninducibility of atrial flutter, ablation was pursued to obtain evidence of permanent block of conduction at the IVC-TA isthmus. Finally, a completely descending LRA wave front was observed when pacing from the PCS in all patients except one. Low LRA pacing was also performed in 4 patients and showed evidence for block in the counterclockwise direction at the isthmus. During a follow-up of 9±3 months, AFl recurred in 1 patient; this was the only patient who showed no conduction block at the isthmus after the procedure.

Conclusions
Direction of impulse propagation at LRA and block of propagation at the IVC-TA isthmus during PCS and low LRA pacing appear to be of interest in predicting long-term success of AFl ablation.
Combined Effects of HDL Cholesterol, Triglyceride, and Total Cholesterol Concentrations on 18-Year Risk of Atherosclerotic Disease
Authors: Burchfiel Cecil M. , Laws Ami , Benfante Richard , Goldberg Robert J. , Hwang Lie-Ju , Chiu Darryl , Rodriguez Beatriz L. , Curb J. David , Sharp Dan S.
Published: June 2012

Background
Whether the combination of a low level of HDL cholesterol (HDL-C) and high level of triglyceride (TG) confers increased risk of cardiovascular disease and whether risk varies across levels of total cholesterol (TC) are not well established. Combined effects of HDL-C, TG, and TC on the incidence of atherosclerotic disease were examined prospectively in Japanese-American men from the Honolulu Heart Program.

Methods and Results
Among 1646 men aged 51 to 72 years who were free of coronary heart disease (CHD), stroke, and cancer and were not taking lipid-lowering medication, 318 developed atherosclerotic events (angina, coronary insufficiency, aortic aneurysm, definite CHD, or thromboembolic stroke) and 170 developed definite CHD between 1970 and 1988. Subjects were stratified by TC level (desirable, <200 mg/dL; borderline high, 200 to 239 mg/dL; high, ≥240 mg/dL), HDL-C level (<35 and ≥35 mg/dL), and TG level (<200 and ≥200 mg/dL). With Cox regression with high HDL-C and low TG as reference, age-adjusted relative risks (RR) of atherosclerotic events were significantly elevated in men with low HDL-C and high TG at borderline-high (RR, 2.46; 95% CI, 1.48 to 4.09) and high (RR, 2.21; 95% CI, 1.34 to 3.66) TC levels but not in men with desirable TC levels (RR, 0.89; 95% CI, 0.38 to 2.09). Elevated risks were independent of blood pressure, obesity, fat distribution, diabetes, smoking, and alcohol. Results were not materially altered by exclusion of subjects with angina alone and were similar but somewhat weaker for CHD.

Conclusions
Risk of atherosclerotic disease appears elevated in subjects with low HDL-C and high TG levels when TC is borderline high or high, independent of other cardiovascular risk factors. These findings support recent cholesterol screening recommendations and suggest that joint effects of HDL-C and TG may be important to consider.
Tumor Necrosis Factor Soluble Receptors in Patients With Various Degrees of Congestive Heart Failure
Authors: Ferrari Roberto , Bachetti Tiziana , Confortini Roberta , Opasich Cristina , Febo Oreste , Corti Angelo , Cassani Giovanni , Visioli Odoardo
Published: June 2012

Background
Tumor necrosis factor alpha (TNF-α) increases in patients with severe congestive heart failure (CHF) and cachexia. Two naturally occurring modulators of TNF-α activity have been identified in human serum. These two soluble proteins are the extracellular domains of the TNF receptors (sTNF-RI and sTNF-RII, respectively). The determination of circulating sTNF-Rs could provide us with some additional information about the activation of this cytokine in CHF.

Methods and Results
This study was undertaken to examine the concentration of sTNF-Rs and of bioactive and antigenic TNF-α in 37 consecutive patients with various degrees of CHF compared with that of 26 age-matched healthy subjects. Antigenic TNF-α increased (from 14.3±7.08 to 33.5±13.1 pg/mL,
P
<.001) in preterminal patients with severe CHF (New York Heart Association [NYHA] class IV). In these patients, sTNF-Rs were also increased (sTNF-RI from 1.17±0.43 to 4.43±2.14 ng/mL and sTNF-RII from 2.2±0.44 to 7.55±2.28 ng/mL,
P
<.001). When measured by cytolytic bioassay, TNF-α was undetectable (<100 pg/mL). Addition of 625 pg/mL recombinant human TNF-α (rhTNF-α), corresponding in the bioassay to 60% of the lethal dose, to the serum of healthy subjects resulted in a significant increase of the expected cytotoxicity (from 625 to 1290±411 pg/mL,
P
<.001). Addition of the same dose of rhTNF-α to the serum of patients with mild to moderate CHF (NYHA classes II and III) increased the cytotoxicity from 625 to 877±132 pg/mL,
P
<.001. In 4 patients with severe CHF (class IV), the expected cytotoxicity was completely inhibited, whereas it was reduced from 625 to 263±198 pg/mL,
P
<.001, in the remaining 8 patients. Ten patients died within 1 month of entry into the study. They had the highest level of sTNF-RII (8.18±1.92 ng/mL). sTNF-RII was a more powerful independent indicator of mortality than TNF-α, sTNF-RI, NYHA class, norepinephrine, and atrial natriuretic peptide.

Conclusions
Measurement of sTNF-Rs, in addition to antigenic and bioactive TNF-α, is essential for evaluation of the activation of this cytokine in CHF. Both sTNF-Rs increase in preterminal patients with severe CHF and might inhibit the in vitro cytotoxicity of TNF-α. Antigenic TNF-α also increases in severe CHF. The increased levels of sTNF-RII independently correlate with poor short-term prognosis.
Expression and Functional Significance of Tumor Necrosis Factor Receptors in Human Myocardium
Authors: Torre-Amione Guillermo , Kapadia Samir , Lee Joseph , Bies Roger D. , Lebovitz Russel , Mann Douglas L.
Published: June 2012

Background
Tumor necrosis factor–α (TNF-α), a proinflammatory cytokine with potent negative inotropic properties, is elaborated in septic shock, acute myocarditis, reperfusion injury, and congestive heart failure. TNF-α acts by binding to two specific receptors: TNFR1 and TNFR2. However, neither the presence nor the significance of TNF receptors has been studied in the adult mammalian heart.

Methods and Results
In the present study, we showed that the adult heart expresses mRNA and receptor proteins for TNFR1 and TNFR2. Moreover, immunohistochemical staining studies localized TNFR1 and TNFR2 to the cardiac myocyte, providing a potential signaling pathway for the deleterious effects of TNF-α. The functional significance of the expression of TNFR1 and TNFR2 was explored with the use of a simple cell motion assay in which we assessed the effect(s) of TNF-α mutants known to bind selectively to human TNFR1 and TNFR2. We showed that the negative inotropic effect of wild-type TNF-α in isolated feline cardiac myocytes was mimicked by the TNF mutant that binds to TNFR1, whereas the TNF mutant that binds to TNFR2 had no significant effect on cell motion.

Conclusions
Results of the present study show that the adult human heart expresses both mRNA and receptor proteins for TNFR1 and TNFR2; moreover, the negative inotropic effects of TNF-α in adult cardiac myocytes appear to be initiated by activation of TNFR1.
Left Heart Obstructive Lesions and Left Ventricular Growth in the Midtrimester Fetus
Authors: Hornberger Lisa K. , Sanders Stephen P. , Rein Azaria J.J.T. , Spevak Philip J. , Parness Ira A. , Colan Steven D.
Published: June 2012

Background
Isolated case reports that suggest the potential for development of left heart hypoplasia late in gestation provide the only information about the in utero natural history of left heart obstructive lesions.

Methods and Results
We reviewed the prenatal and postnatal echocardiograms of 21 fetuses with left heart obstructive lesions, including 15 with serial antenatal study, to elucidate the antenatal natural history of this spectrum of disease and to identify features indicative of postnatal disease severity. Ventricular, atrioventricular valve, and great artery dimensions were measured and growth curves were developed with comparisons to data from 47 normal fetuses. Fetuses were divided into groups according to whether postnatally the left heart was capable (group 1, n=10) or incapable (group 2, n=7) of supporting the systemic circulation in the presence of a patent aortic valve. Group 3 (n=4) included fetuses with aortic atresia. At the initial examination (21.7±3.4 weeks’ gestation), left heart dimensions were normal or reduced, with the most diminutive measurements in group 3. Three fetuses in group 2 and most in group 1 had normal initial left heart dimensions. Subsequent growth of left heart structures either paralleled normal growth or was reduced, the latter resulting in the development or progression of left heart hypoplasia. All left heart dimensions grew more slowly in group 2 and group 3 than in group 1 (
P
<.05). Other prenatal features observed only in groups 2 and 3 included reversed (n=10) or bidirectional (n=1) foramen ovale flow and retrograde distal arch flow (n=9). Initial midtrimester mitral valve and ascending aorta
z
scores and the growth rates of all left heart structures correlated strongly with postnatal left ventricular end-diastolic dimension (
P
=.0007 to .03,
r
=.57 to .82) and could be additional indicators of postnatal disease severity. One group 1 fetus developed severe aortic stenosis late in gestation.

Conclusions
The potential for the in utero development or progression in severity of left heart obstruction and hypoplasia in left heart obstructive lesions necessitates serial prenatal study in affected fetuses carried to term.
Rapid Ventricular Induction of Brain Natriuretic Peptide Gene Expression in Experimental Acute Myocardial Infarction
Authors: Hama Norio , Itoh Hiroshi , Shirakami Gotaro , Nakagawa Osamu , Suga Shin-ichi , Ogawa Yoshihiro , Masuda Izuru , Nakanishi Kuniaki , Yoshimasa Takaaki , Hashimoto Yukiya , Yamaguchi Masayuki , Hori Ryouhei , Yasue Hirofumi , Nakao Kazuwa
Published: June 2012

Background
We have demonstrated that brain natriuretic peptide (BNP) is a cardiac hormone predominantly synthesized in and secreted from the ventricle. We have also reported that, compared with atrial natriuretic peptide (ANP), the plasma concentration of BNP is increased to a greater degree in patients with congestive heart failure and more rapidly in patients with acute myocardial infarction (AMI).

Methods and Results
To investigate ventricular gene expression of BNP in AMI, we analyzed plasma and ventricular BNP concentrations along with ventricular BNP mRNA in rats with AMI produced by coronary artery ligation. The BNP concentration in the left ventricle increased about 2-fold as early as 12 hours postinfarction and 5-fold 1 day postinfarction compared with sham-operated rats, whereas left ventricular ANP concentration remained unchanged within 1 day. The tissue concentration of BNP increased in the noninfarcted region as well as in the infarcted region. The surviving myocytes in and around the necrotic tissues in the infarcted region were intensely stained with the anti-BNP antiserum, indicating augmented production in the remaining myocytes in the infarcts. The BNP concentration in the right ventricle also increased about 10-fold 12 hours postinfarction, whereas the ANP concentration remained unchanged within 12 hours. Northern blot analysis revealed that BNP mRNA expression was augmented 3-fold in the left ventricle as early as 4 hours postinfarction. In contrast, ANP mRNA expression was unchanged. Reflecting the rapid induction of ventricular BNP production, the plasma BNP concentration rose to about 100 pg/mL 12 hours postinfarction (sham-operated rats, <70 pg/mL).

Conclusions
These results demonstrate the rapid induction of ventricular BNP gene expression in rats with AMI compared with ANP and suggest that BNP gene expression in the ventricle is regulated distinctively from ANP gene expression against acute ventricular overload. They also suggest that the BNP gene can be one of the acutely responsive cardiac genes for the ventricular overload and suggest a possible pathophysiological role of BNP distinct from ANP in AMI.
Impairment of Endothelium-Dependent Dilation in Rabbit Renal Arteries by Oxidized Lipoprotein(a)
Authors: Galle Jan , Bengen Jens , Schollmeyer Peter , Wanner Christoph
Published: June 2012

Background
Hyperlipoproteinemia is associated with impairment of nitric oxide (NO)–mediated, endothelium-dependent dilation in renal arteries. In the present study, we assessed and compared the effects of human lipoprotein(a) and LDL on endothelium-dependent and -independent dilation in vitro.

Methods and Results
Dilator responses were detected in isolated, saline-perfused, preconstricted arterial segments by a photoelectric device. Acetylcholine-induced, endothelium-dependent dilator responses of rabbit renal arteries were not significantly attenuated after 150 minutes of incubation with native lipoprotein(a) (30 and 100 μg/mL). However, exposure to in vitro oxidized lipoprotein(a) (150 minutes, 30 and 100 μg/mL) suppressed acetylcholine-induced dilator responses in a dose-dependent manner. At similar concentrations, native and oxidized LDL had no effect. Endothelium-independent dilations induced by the NO-donor sodium nitroprusside were also impaired by oxidized lipoprotein(a), whereas forskolin-induced dilator responses were unaffected, indicating that smooth muscle dilator capacity was not impaired. Attenuation of dilator responses by oxidized lipoprotein(a) was potentiated in the presence of superoxide dismutase (SOD). The SOD effect was completely blunted by coincubation with catalase (100 U/mL) or deferoxamine. In the absence of SOD, catalase or deferoxamine had no effect on dilator responses. Using a chemiluminescence assay, we could detect increased O
2
−
production by arteries pretreated with oxidized lipoprotein(a), which suggested that enhanced NO inactivation by O
2
−
could be the underlying mechanism for impairment of endothelium-dependent dilations.

Conclusions
These data indicate that oxidized lipoprotein(a) impairs endothelium-dependent dilation and is more potent than oxidized LDL in this effect. The mechanism of the impairment may involve formation of O
2
−
and inactivation of NO.
Increased Soluble Form of P-Selectin in Patients With Unstable Angina
Authors: Ikeda Hisao , Takajo Yoshinori , Ichiki Kazuya , Ueno Takafumi , Maki Sanae , Noda Takehiko , Sugi Kenzo , Imaizumi Tsutomu
Published: June 2012

Background
P-selectin in platelets and endothelial cells mediates adhesive interaction with leukocytes to form thrombi. The purpose of the present study was to investigate the plasma levels of P-selectin in patients with unstable angina and in those with stable effort angina of different pathophysiologies.

Methods and Results
Plasma P-selectin levels were determined by a monoclonal antibody–based enzyme immunoassay on plasma samples taken from 12 patients with unstable angina, 11 patients with stable effort angina, and 15 healthy volunteers. Patients with unstable angina had angina at rest associated with ECG changes. In patients with unstable angina, plasma P-selectin levels within 1 hour (361±90 ng/mL) and at 3 hours (282±56 ng/mL) after angina were significantly (
P
<.05) higher than those in volunteers (177±31 ng/mL). Plasma P-selectin levels at 5 hours after attack (242±46 ng/mL) did not differ from those in volunteers. Although patients with stable effort angina developed angina with ST-segment depressions by treadmill exercise, their plasma P-selectin levels did not change (before, 178±45; immediately after, 186±36; and 1 hour after the exercise, 179±34 ng/mL).

Conclusions
Plasma P-selectin levels after angina increased significantly in patients with unstable angina but did not in patients with stable effort angina. These findings may contribute to understanding of the pathophysiology of the acute coronary syndrome of unstable angina.
Prospective Study of Small LDLs as a Risk Factor for Non–Insulin Dependent Diabetes Mellitus in Elderly Men and Women
Authors: Austin Melissa A. , Mykkänen Leena , Kuusisto Johanna , Edwards Karen L. , Nelson Carrie , Haffner Steven M. , Pyörälä Kalevi , Laakso Markku
Published: June 2012

Background
The excess risk of atherosclerosis among patients with non–insulin dependent diabetes mellitus (NIDDM) is well documented. However, the presence of conventional risk factors cannot fully account for this excess risk, and the underlying mechanism remains to be elucidated. The present study prospectively evaluated the role of small LDL, a known risk factor for coronary heart disease, as a risk factor for the development of NIDDM.

Methods and Results
The study was based on a nested case-control sample of 204 elderly men and women from Kuopio, Finland. LDL subclasses were characterized by size with 2% to 14% polyacrylamide gels produced by recently developed methods. Logistic regression analysis showed that subjects with a predominance of small LDL (LDL subclass phenotype B) had a greater than twofold increased risk for developing NIDDM over the 3.5-year follow-up period. This association was independent of age, sex, glucose intolerance, and body mass index but was not independent of fasting triglyceride or insulin levels. Further, an increase of 5Å in LDL diameter was associated with a 16% decrease in risk of NIDDM, and a composite variable of LDL diameter and triglyceride and HDL cholesterol concentrations, identified by principal-components analysis, was also associated with NIDDM. These associations may be attributable to the role of small LDL as a marker for insulin resistance.

Conclusions
This study is the first to demonstrate that a predominance of small LDL particles is a risk factor for the future development of NIDDM, and it implies that small LDL contributes to risk of coronary heart disease in prediabetics.
Increased Central Nervous System Monoamine Neurotransmitter Turnover and Its Association With Sympathetic Nervous Activity in Treated Heart Failure Patients
Authors: Lambert Gavin W. , Kaye David M. , Lefkovits Jeffrey , Jennings Garry L. , Turner Andrea G. , Cox Helen S. , Esler Murray D.
Published: June 2012

Background
Congestive heart failure is a debilitating disease characterized by impaired cardiac function with accompanying activation of a variety of neural and hormonal counterregulatory systems. Abnormal activity of the sympathetic nervous system and renin-angiotensin-aldosterone axis and a predisposition to the generation of fatal ventricular arrhythmias are often associated with the development of the disease. Although the underlying cause of sudden death in these patients remains to be unequivocally elucidated, abnormally increased cardiac sympathetic nervous activity may be involved.

Methods and Results
Twenty-two patients with severe congestive heart failure (New York Heart Association functional class III or IV with left ventricular ejection fraction of 18±1%) and 29 healthy male volunteers participated in this study. By combining direct sampling of internal jugular venous blood via a percutaneously placed catheter with a norepinephrine and epinephrine isotope dilution method for examining neuronal transmitter release, we were able to quantify the release of central nervous system monoamine and indoleamine neurotransmitters and investigate their association with the increased efferent sympathetic ouflow that is variably present in treated patients with this condition. Mean cardiac norepinephrine spillover was 145% higher in treated heart failure patients than in healthy subjects (
P
<.05), with norepinephrine release from the heart in 6 of 22 patients being more than the highest control value. Raised internal jugular venous spillover of epinephrine (26±12 versus 2±4 pmol/min,
P
<.05) and of norepinephrine and its metabolites (2740±480 versus 875±338 pmol/min,
P
<.05), indicative of increased central nervous system turnover of both catecholamines, occurred in cardiac failure and was quantitatively linked to the degree of activation of the cardiac sympathetic nervous outflow, as was the jugular overflow of the principal serotonin metabolite, 5-hydroxyindoleacetic acid.

Conclusions
An association between the degree of activation of central monoaminergic neurons and the level of sympathetic nervous tone in the heart was identified in treated patients with heart failure. Epinephrine neurons in the brain may contribute to the sympathoexcitation that is seen in this condition, with the activation of sympathoexcitatory noradrenergic neurons, most likely those of the forebrain, playing an accessory role.
In Vivo Spin Trapping of Glyceryl Trinitrate–Derived Nitric Oxide in Rabbit Blood Vessels and Organs
Authors: Mülsch Alexander , Mordvintcev Peter , Bassenge Eberhard , Jung Frank , Clement Bernd , Busse Rudi
Published: June 2012

Background
The objectives of this study were (1) to assess glyceryl trinitrate (GTN)–derived nitric oxide (NO) formation in vascular tissues and organs of anesthetized rabbits in vivo, (2) to establish a correlation between tissue NO levels and a biological response, and (3) to verify biotransformation of GTN to NO by cytochrome P-450.

Methods and Results
NO was trapped in tissues in vivo as a stable paramagnetic mononitrosyl-iron-diethyldithiocarbamate complex [NOFe(DETC)
2
]. After removal of the tissues, NO was determined by cryogenic electron spin resonance spectroscopy. NO formation in vitro was assessed by spin trapping and by activation of soluble guanylyl cyclase. The GTN-elicited decrease in coronary perfusion pressure was monitored in isolated, constant-flow perfused rabbit hearts. NO was not detected in control tissues. In GTN-treated rabbits, NO formation was higher in organs than in vascular tissues and higher in venous than in arterial vessels. In isolated hearts, ventricular NO levels and decreases in coronary perfusion pressure achieved by GTN were closely correlated. Purified cytochrome P-450 catalyzed NO formation from GTN in a P-450–NADPH reductase– and NADPH–dependent fashion.

Conclusions
Since GTN-derived NO formation in myocardial tissue correlates to the GTN-elicited vasodilator response, we conclude that GTN-derived NO detected in vivo correlates with the systemic effects of GTN. Therefore, the higher rate of NO formation detected in veins compared with arteries explains the preferential venodilator activity of GTN. High NO formation in cytochrome P-450–rich organs in vivo and efficient NO formation from GTN by cytochrome P-450 in vitro highlights the importance of this pathway for NO formation from GTN in the intact organism.
Healing of Myocardial Infarcts in Dogs
Authors: Richard Vincent , Murry Charles E. , Reimer Keith A.
Published: June 2012

Background
Early reperfusion salvages ischemic myocardium and limits myocardial infarct size. However, the effects of late reperfusion, after the possibility for limitation of infarct size has passed, have not been completely elucidated. The purpose of this study was to ascertain the effect of reperfusion after 6 hours of ischemia on the rate of infarct healing and on the size and geometry of the resulting scars, as determined by gross and microscopic quantification.

Methods and Results
Myocardial infarcts were produced in anesthetized, open-chest dogs by occlusion of the circumflex coronary artery. They either were reperfused by removal of the occluding snare or were nonreperfused. The animals were allowed to recover for either 4 days, 2 weeks, or 6 weeks. At these times, infarct size, infarct dimensions (wall thickness and circumferential extent), and the proportion of infarct occupied by necrotic myocardium versus granulation tissue (evolving scar) were measured. At 4 days, infarcts were swollen in both nonreperfused and reperfused groups (increased thickness and circumferential extent of the area at risk). Conversely, at 6 weeks, the size, thickness, and circumferential extent of the scar all were decreased. Two common anatomic complications of human infarction, cardiac rupture and chronic infarct expansion (aneurysm), did not occur in this experimental model. Reperfusion at 6 hours did not affect initial infarct size (4 days) or scar size (6 weeks). At 2 weeks, reperfused infarcts were smaller and were composed of proportionately more granulation tissue and less nonresorbed necrosis than nonreperfused infarcts.

Conclusions
Thus, reperfusion accelerated the rate of infarct repair, ie, the replacement of necrotic myocardium by scar. Acceleration of infarct repair may be a beneficial effect of late reperfusion even after the opportunity for limitation of infarct size has passed.
Physiological Basis of Myocardial Contrast Enhancement in Fast Magnetic Resonance Images of 2-Day-Old Reperfused Canine Infarcts
Authors: Judd Robert M. , Lugo-Olivieri Carlos H. , Arai Masazumi , Kondo Takeshi , Croisille Pierre , Lima Joao A.C. , Mohan Vivek , Becker Lewis C. , Zerhouni Elias A.
Published: June 2012

Background
Contrast-enhanced fast magnetic resonance (MR) images of acute, reperfused human infarcts demonstrate regions of hypoenhancement and hyperenhancement. The relations between the spatial extent and time course of these enhancement patterns to myocardial risk, infarct, and no-reflow regions have not been well characterized.

Methods and Results
The proximal left anterior descending coronary artery was occluded in 11 closed-chest dogs for 90 minutes followed by 2 days of reperfusion. Regional blood flow was determined by use of radioactive microspheres. The animals were studied at the 2-day time point with contrast-enhanced fast MRI (Signa 1.5 T, General Electric). Thioflavin-S was administered to demarcate no-reflow regions. The hearts were then excised, sectioned into five base-to-apex slices, stained with 2,3,5-triphenyltetrazolium chloride (TTC), and photographed under room light (for TTC) and ultraviolet light (for thioflavin). The spatial extents of thioflavin-negative, TTC-negative, and risk regions were compared planimetrically with MRI hypoenhanced and hyperenhanced regions. The spatial locations of subendocardial hypoenhancement in MR images correlated closely with those of thioflavin-negative regions. Microsphere blood flow in these regions was significantly reduced compared with remote regions (0.37±0.09 versus 0.88±0.10 mL/min per gram, respectively,
P
<.001) and with baseline (0.37±0.09 versus 0.87±0.15 mL/min per gram,
P
<.01). The spatial extent of hyperenhancement was smaller than the risk region (
r
=.64, slope=0.48,
P
<.001) but highly correlated with TTC-negative regions and were, on average, 12% larger (
r
=.93, slope=1.12,
P
=.035).

Conclusions
In contrast-enhanced MR images of 2-day-old reperfused canine infarcts, myocardial regions of hypoenhancement are related to the no-reflow phenomenon. Approximately 90% of the myocardium within hyperenhanced regions is nonviable.
Protection Against Ischemic Injury by Nonvasoactive Concentrations of Nitric Oxide Synthase Inhibitors in the Perfused Rabbit Heart
Authors: Depré Christophe , Vanoverschelde Jean-Louis , Goudemant Jean-François , Mottet Isabelle , Hue Louis
Published: June 2012

Background
The functional and metabolic effects of inhibitors of nitric oxide (NO) synthase on ischemic hearts have not been investigated. This work was designed to perform such a study in isolated perfused rabbit hearts submitted to low-flow ischemia.

Methods and Results
After a 30-minute equilibration period, the hearts were submitted to low-flow ischemia for 60 minutes followed by reperfusion for 30 minutes. Functional and metabolic parameters were followed in hearts perfused with or without inhibitors of NO synthase or NO precursors, which were added 15 minutes before ischemia but were absent during reperfusion. Ischemic contracture was delayed and reduced in hearts perfused with 1 μmol/L
l
-
N
-monomethylarginine (L-NMMA) or 1 μmol/L
l
-
N
-arginine methylester, two inhibitors of NO synthase, but not with
d
-
N
-monomethylarginine, the inactive enantiomer of L-NMMA. The protection was suppressed by addition to the perfusate containing L-NMMA of 1 mmol/L
l
-arginine or 0.1 mmol/L sodium nitroprusside but not by addition of 10 μmol/L 8-bromo cGMP, a cGMP analogue. The functional protection by 1 μmol/L L-NMMA was related to a stimulation of glycolysis from exogenous glucose and a preservation of the glycogen stores. This resulted in a better maintenance of high-energy phosphates and a lower acidosis as measured by
31
P nuclear magnetic resonance spectroscopy. During reperfusion, functional recovery was more than doubled, and enzyme release was halved in L-NMMA–treated hearts compared with controls. The functional and metabolic protection was maximal at 1 nmol/L to 1 μmol/L L-NMMA, ie, below the vasoactive concentrations of the inhibitor.

Conclusions
Nonvasoactive concentrations of NO synthase inhibitors protect the heart against ischemic damage; this relates to a stimulation of glycolysis from exogenous glucose.
Endothelial Release of Nitric Oxide Contributes to the Vasodilator Effect of Adenosine in Humans
Authors: Smits Paul , Williams Stephen B. , Lipson Deborah E. , Banitt Peter , Rongen Gerard A. , Creager Mark A.
Published: June 2012

Background
The endogenous nucleoside adenosine plays an important role in the regulation of vascular tone, especially during ischemia. Experimental data derived from animal models suggest that nitric oxide (NO) contributes to the vasodilator effect of adenosine. The primary purpose of this investigation was to determine whether the endothelial release of NO contributes to adenosine-induced vasodilation in humans.

Methods and Results
Venous occlusion plethysmography was used to assess the forearm blood flow (FBF) responses to graded intra-arterial infusions of adenosine (1.5 to 500 μg/min). Dose-response curves were constructed before and during intra-arterial infusion of the NO synthase inhibitor
N
G
-monomethyl-
l
-arginine (L-NMMA) (2 mg/min, n=6) or vehicle (n=6). Before infusion of L-NMMA, adenosine caused a dose-dependent increase in FBF from 2.3 to 15.9 mL · min
−1
· dL
−1
. During concurrent infusion of L-NMMA, adenosine increased FBF from 1.7 to 10.0 mL · min
−1
· dL
−1
, and this change from baseline was significantly reduced compared with that before L-NMMA (
P
<.05). L-NMMA also attenuated the FBF response to adenosine when the basal constrictor effect of L-NMMA was prevented by coinfusion of the NO donor sodium nitroprusside (n=6,
P
<.01). In contrast, L-NMMA did not affect the FBF response to intra-arterial infusion of the endothelium-independent vasodilator verapamil (from 2.0 to 13.9 mL · min
−1
· dL
−1
before L-NMMA and from 1.3 to 13.6 mL · min
−1
· dL
−1
during L-NMMA; n=6,
P
=NS). The second objective of this study was to determine whether the adenosine-induced release of NO is mediated by activation of endothelial potassium channels, putatively coupled to adenosine receptors. Thus, the FBF response to adenosine was measured before and during infusion of the ATP-dependent potassium channel blocker tolbutamide (1 mg/min, n=6), or the potassium channel blocker quinidine (0.5 mg/min, n=6). The adenosine-mediated increments in FBF were not attenuated by either potassium channel blocker.

Conclusions
Adenosine-induced vasodilation in humans is mediated, at least in part, by endothelial release of NO. The transducing mechanism of this phenomenon is not known, but it does not appear to involve the activation of either ATP-dependent or quinidine-sensitive potassium channels.
Coronary Artery Calcium Area by Electron-Beam Computed Tomography and Coronary Atherosclerotic Plaque Area
Authors: Rumberger John A. , Simons D. Brent , Fitzpatrick Lorraine A. , Sheedy Patrick F. , Schwartz Robert S.
Published: June 2012

Background
Coronary calcium identified by electron-beam computed tomography (EBCT) correlates poorly with luminal atherosclerotic narrowing, but calcium, an intimate part of coronary plaque, may be more directly related to atheromatous plaque area.

Methods and Results
Thirty-eight coronary arteries from 13 autopsy hearts were dissected, straightened, and scanned with EBCT in 3-mm contiguous increments. Coronary calcium area was defined as one or more pixels with a density >130 Hounsfield units (0.18 mm
2
/pixel). Each artery was divided into corresponding 3-mm segments, representative histological sections were stained, and atherosclerotic plaque area per segment (mm
2
) was quantified. Coronary artery calcium and coronary artery plaque areas were correlated for the hearts as a whole, for individual coronary arteries, and for individual coronary artery segments. The sums of histological plaque areas versus the sums of calcium areas were highly correlated for each heart and for each coronary artery. However, coronary plaque area was on the order of five times greater than calcium area. Furthermore, minimal diffuse segmental coronary plaque could be present despite the absence of coronary calcium detectable by EBCT.

Conclusions
This histopathologic study confirms an intimate relation between whole heart, coronary artery, and segmental coronary atherosclerotic plaque area and EBCT coronary calcium area but suggests that there is a threshold value for plaque area below which coronary calcium is either absent or not detectable by this methodology.
Silent Cerebral Infarction in Patients With Nonrheumatic Atrial Fibrillation
Authors: Ezekowitz Michael D. , James Kenneth E. , Nazarian Sarkis M. , Davenport John , Broderick Joseph P. , Gupta Sudha R. , Thadani Vijay , Meyer Mark L. , Bridgers Samuel L.
Published: June 2012

Background
Cerebral infarction in patients with atrial fibrillation may vary from being clinically silent to catastrophic. The prevalence of silent cerebral infarction and its effect as a risk factor for symptomatic stroke are important considerations for the evaluation of patients with atrial fibrillation.

Methods and Results
This Veterans Affairs cooperative study was a double-blind controlled trial designed primarily to determine the efficacy of warfarin for the prevention of stroke in neurologically normal patients with nonrheumatic atrial fibrillation. It also was designed to evaluate patients with silent cerebral infarction. Computed tomography scans of the head were performed at entry, at the time of any subsequent stroke, and at termination of follow-up on all patients who completed the study without a neurological event. Of 516 evaluable scans performed at entry, 76 (14.7%) had evidence of one or more silent cerebral infarcts. Age (
P
=.011), a history of hypertension (
P
=.003), active angina (
P
=.012), and elevated mean systolic blood pressure (
P
<.001) were associated with the presence of this finding. Silent cerebral infarction occurred during the study at rates of 1.01% and 1.57% per year for the placebo and warfarin treatment groups, respectively (NS). Silent cerebral infarction at entry was not an independent predictor of later symptomatic stroke, but active angina was a significant predictor; 15% of the placebo-assigned patients with angina developed a stroke compared with 5% of the placebo-assigned patients without angina.

Conclusions
Silent cerebral infarction is frequently seen in asymptomatic patients with atrial fibrillation. Age, history of hypertension, active angina, and elevated mean systolic blood pressure were associated with silent infarction at entry. The sample size was too small to determine whether warfarin had an effect on the incidence of silent infarction during the trial. Active angina at baseline was the only significant independent predictor for the later development of symptomatic stroke.
Cardiac β-Adrenergic Neuroeffector Systems in Acute Myocardial Dysfunction Related to Brain Injury
Authors: White Michel , Wiechmann Robert J. , Roden Robert L. , Hagan Mary Beth , Wollmering Mary M. , Port J. David , Hammond Elizabeth , Abraham William T. , Wolfel Eugene E. , Lindenfeld JoAnn , Fullerton David , Bristow Michael R.
Published: June 2012

Background
Ten percent to 20% of potential cardiac donors with brain injury and no previous cardiac history have myocardial dysfunction. We assessed components of the β-receptor–G-protein–adenylyl cyclase complex as well as the contractile response in 10 explanted acutely failing human hearts (donor heart dysfunction [DHD]) and compared the results with 13 age-matched nonfailing (NF) organ donor controls.

Methods and Results
As measured by echocardiography, all DHD hearts exhibited a decreased shortening fraction (16±2%, mean±SEM). Although total and subpopulation β-receptor densities measured by [
125
I]iodocyanopindolol (ICYP) were similar in the DHD and NF groups, DHD hearts exhibited a 30% decrease in maximum isoproterenol-stimulated adenylyl cyclase activity and a 50% decrease in the maximal response to zinterol. DHD hearts also exhibited decreases in adenylyl cyclase maximal stimulation by forskolin (211±25 [DHD] versus 295±23 [NF] pmol cAMP · min
−1
· mg
−1
,
P
<.05) and 5′-guanylylimidodiphosphate (12.5±1.8 [DHD] versus 19.6±3.2 [NF] pmol cAMP · min
−1
· mg
−1
,
P
<.05), but there was no significant decrease in adenylyl cyclase stimulation by Mn
2+
, a direct activator of adenylyl cyclase. Right ventricular trabeculae removed from DHD hearts exhibited a profound decrease in the contractile response to isoproterenol (8.7±1 [DHD] versus 22±2 [NF] mN,
P
<.001) as well as reduced calcium responses (7.2±1.6 [DHD] versus 14±3 [NF] mN,
P
=.03). Morphological examination of two hearts revealed some ultrastructural evidence suggestive of catecholamine-mediated injury, but there was no difference in tissue creatine kinase activity between the two groups.

Conclusions
Compared with NF hearts, DHD hearts exhibit marked uncoupling of β
1
- and β
2
-adrenergic receptors from adenylyl cyclase and contractile response stimulation as well as decreased intrinsic systolic function. Thus, acute myocardial dysfunction accompanying brain injury is characterized by marked alterations in β-adrenergic signal transduction as well as changes in the contractile apparatus, and this profile is markedly different from what occurs in the chronically failing human heart.