bluuebunny/crossref_metadata_2025 huggingface dataset:
Nitroglycerin Tolerance in Human Vessels
Authors: Sage Peter R. , de la Lande Ivan S. , Stafford Irene , Bennett Catherine L. , Phillipov George , Stubberfield John , Horowitz John D.
Published: June 2012

Background
—The basis for progressive attenuation of the effects of organic nitrates during long-term therapy (nitrate tolerance) remains controversial; proposed mechanisms include impaired nitrate bioconversion resulting in decreased release of nitric oxide (NO) from nitrates and/or increased NO clearance through a reaction with incrementally generated superoxide (O
2
–
).

Methods and Results
—Patients undergoing elective coronary artery bypass were randomized to receive 24 hours of intravenously infused nitroglycerin (NTG; nitrate group) or no nitrate therapy (control group). Discarded segments of the internal mammary artery and saphenous vein were used to examine (1) vascular responsiveness to NTG, sodium nitroprusside, and the calcium ionophore A23187; (2) bioconversion of NTG to 1,2- and 1,3-glyceryl dinitrate; and (3) the generation of O
2
–
. Responses to NTG were reduced 3- to 5-fold in vessels from the nitrate group compared with control vessels (
P
<0.01 for both types of segments), whereas responses to sodium nitroprusside and A23187 were unchanged. Tissue content of 1,2-glyceryl dinitrate was lower (
P
=0.012) in the saphenous veins from the nitrate group than in those from the control group. O
2
–
generation was greater (
P
<0.01) in internal mammary artery samples from the nitrate group than in those from the control group. However, incremental O
2
–
generation induced by an inhibitor of superoxide dismutase did not affect NTG responses.

Conclusions
—NTG tolerance in patients with coronary artery disease is nitrate-specific and is associated with evidence of impaired NTG bioconversion. Tolerance was associated with incremental O
2
–
generation, but short-term elevation of O
2
–
did not affect NTG responsiveness, suggesting increased NO clearance by O
2
–
has a minimal contribution to tolerance.
Comparison of Novel Hemostatic Factors and Conventional Risk Factors for Prediction of Coronary Heart Disease
Authors: Cooper Jacqueline A. , Miller George J. , Bauer Kenneth A. , Morrissey James H. , Meade Thomas W. , Howarth David J. , Barzegar Samad , Mitchell Jacqueline P. , Rosenberg Robert D.
Published: June 2012

Background
—This study sought to assess whether novel markers of hemostatic activity are predictive of coronary heart disease (CHD) and improve risk assessment.

Methods and Results
—Conventional CHD risk factors, the activation peptides of factor IX and factor X, factor VII activity and antigen, activated factor XII, prothrombin fragment 1+2, fibrinopeptide A, and fibrinogen were measured in 1153 men aged 50 to 61 years who were free of myocardial infarction at recruitment. Activated factor VII (VIIa) was measured in 829 men. During 7.8 years of follow-up, 104 had a CHD event. Baseline status was related to outcome by logistic regression by using a modified nested case-control design. Screening performance was judged from receiver operating characteristic curves. A high activated factor XII was associated with increased CHD risk, but low levels were not protective. Plasma VIIa and factor X activation peptide were independently and inversely related to risk. Plasma factor IX activation peptide and fibrinogen were positively associated with risk, but the relations were no longer statistically significant after adjustment for other factors, including VIIa and apoA-I. Other hemostatic markers were not associated with CHD risk.

Conclusions
—Hemostatic status did not add significant predictive power to that provided by conventional CHD risk factors yet was able to substitute effectively for these factors.
Noninvasive Coronary Angiography by Retrospectively ECG-Gated Multislice Spiral CT
Authors: Achenbach Stephan , Ulzheimer Stefan , Baum Ulrich , Kachelrieß Marc , Ropers Dieter , Giesler Tom , Bautz Werner , Daniel Werner G. , Kalender Willi A. , Moshage Werner
Published: June 2012

Background
—We investigated the applicability and image quality of contrast-enhanced coronary artery visualization by multislice spiral CT using retrospective ECG gating.

Methods and Results
—Twenty-five patients in sinus rhythm (significant coronary artery stenoses ruled out by invasive angiography) were studied with a multislice spiral CT (Siemens SOMATOM Volume Zoom). In inspiration (mean breathhold, 37 seconds), a volume data set of the heart was acquired (intravenous contrast agent; 4×1-mm slice thickness; 500-ms rotation; table feed, 1.5 mm/360°). Simultaneous recording of the ECG permitted retrospective reconstruction of contiguous cross sections in intervals of 1 mm at any desired interval of the cardiac cycle. The mean duration of the image reconstruction window was 185 ms. Next to 3-dimensional reconstructions of the heart and coronary arteries, multiplanar reconstructions were rendered to determine the visualized length of the coronary arteries, the contrast-to-noise ratio, and the correlation of coronary artery diameters to quantitative coronary angiography.

Conclusions
—The coronary arteries could be visualized over long segments (left main, 9±4 mm; left anterior descending, 112±34 mm; left circumflex, 80±29 mm; right coronary artery, 116±33 mm). On average, 78±16% of these distances were visualized free of motion artifacts. The mean contrast-to-noise ratio was 9.3±3.3. Coronary artery diameters in multislice spiral CT showed close correlation to quantitative coronary angiography (CT, 3.3±1.0 mm; angiography, 3.2±0.9 mm; mean difference, 0.38 mm;
r
=0.86). Contrast-enhanced multislice spiral CT permits visualization of the coronary artery lumen. Further studies are necessary to determine whether image quality is sufficient to reliably detect coronary artery stenoses.
Predictors of Disease Course in Patients With Acute Myocarditis
Authors: Fuse Koichi , Kodama Makoto , Okura Yuji , Ito Masahiro , Hirono Satoru , Kato Kiminori , Hanawa Haruo , Aizawa Yoshifusa
Published: June 2012

Background
—Clinical manifestations of acute myocarditis, with distinct onset, vary from asymptomatic to fatal. The predictors of the course of the disease in patients with acute myocarditis at initial presentation have not yet been established. In this study, we examined the predictive values of various parameters in the disease course of patients with myocarditis.

Methods and Results
—Twenty-one consecutive patients who had been diagnosed as having acute myocarditis by histological examinations were analyzed. The patients with myocarditis were divided into the survival group (n=13) and the fatal group (n=8). We examined the parameters of the clinical state, hemodynamic variables, required therapies, biochemical laboratory data, and cytokines. The control groups were composed of 23 patients with old myocardial infarction and 20 healthy volunteers. The fatal group had lower blood pressure and higher pulmonary capillary wedge pressure compared with those values in the survival group. Mechanical ventilation support was more frequently required in the fatal group. Serum levels of soluble Fas (sFas) and soluble Fas ligand (sFasL) were significantly higher in the myocarditis group than in the 2 control groups. Furthermore, levels were significantly higher in the fatal group than in the survival group for sFas (13.93±4.77 versus 3.77±0.52 ng/mL, respectively;
P
<0.001) and sFasL (611.4±127.7 versus 269.5±37.3 pg/mL, respectively;
P
<0.05). Other clinical states, hemodynamic variables, required therapies, and biochemical laboratory parameters were not different between the 2 groups.

Conclusions
—Elevation of sFas and sFasL levels at initial presentation appear to be a good serological marker to predict the prognosis of acute myocarditis.
Spectrum of ST-T–Wave Patterns and Repolarization Parameters in Congenital Long-QT Syndrome
Authors: Zhang Li , Timothy Katherine W. , Vincent G. Michael , Lehmann Michael H. , Fox Jolene , Giuli Lisa C. , Shen Jiaxiang , Splawski Igor , Priori Silvia G. , Compton Steven J. , Yanowitz Frank , Benhorin Jesaia , Moss Arthur J. , Schwartz Peter J. , Robinson Jennifer L. , Wang Qing , Zareba Wojciech , Keating Mark T. , Towbin Jeffrey A. , Napolitano Carlo , Medina Aharon
Published: June 2012

Background
—Congenital long-QT syndrome (LQTS) is caused by mutations of genes encoding the slow component of the delayed rectifier current (LQT1, LQT5), the rapid component of the delayed rectifier current (LQT2, LQT6), or the Na
+
current (LQT3), resulting in ST-T–wave abnormalities on the ECG. This study evaluated the spectrum of ST-T–wave patterns and repolarization parameters by genotype and determined whether genotype could be identified by ECG.

Methods and Results
—ECGs of 284 gene carriers were studied to determine ST-T–wave patterns, and repolarization parameters were quantified. Genotypes were identified by individual ECG versus family-grouped ECG analysis in separate studies using ECGs of 146 gene carriers from 29 families and 233 members of 127 families undergoing molecular genotyping, respectively. Ten typical ST-T patterns (4 LQT1, 4 LQT2, and 2 LQT3) were present in 88% of LQT1 and LQT2 carriers and in 65% of LQT3 carriers. Repolarization parameters also differed by genotype. A combination of quantified repolarization parameters identified genotype with sensitivity/specificity of 85%/70% for LQT1, 83%/94% for LQT2, and 47%/63% for LQT3. Typical patterns in family-grouped ECGs best identified the genotype, being correct in 56 of 56 (21 LQT1, 33 LQT2, and 2 LQT3) families with mutation results.

Conclusions
—Typical ST-T–wave patterns are present in the majority of genotyped LQTS patients and can be used to identify LQT1, LQT2, and possibly LQT3 genotypes. Family-grouped ECG analysis improves genotype identification accuracy. This approach can simplify genetic screening by targeting the gene for initial study. The multiple ST-T patterns in each genotype raise questions regarding the pathophysiology and regulation of repolarization in LQTS.
Aerosol Gene Transfer With Inducible Nitric Oxide Synthase Reduces Hypoxic Pulmonary Hypertension and Pulmonary Vascular Remodeling in Rats
Authors: Budts Werner , Pokreisz Peter , Nong Zengxuan , Van Pelt Natascha , Gillijns Hilde , Gerard Robert , Lyons Rick , Collen Desire , Bloch Kenneth D. , Janssens Stefan
Published: June 2012

Background
—Nitric oxide (NO) is a potent vasodilator with an important role in the regulation of pulmonary vascular tone. The effects of NO synthase
(NOS)
gene transfer on pulmonary vascular remodeling associated with hypoxic pulmonary hypertension are unknown.

Methods and Results
—We aerosolized 3×10
9
pfu of an adenoviral vector containing inducible
NOS
gene (AdNOS2), constitutive
NOS3
gene (AdNOS3), or no transgene (AdRR5) into rat lungs. Exhaled NO levels, monitored with chemiluminescence, were higher in AdNOS2-infected rats than in AdNOS3- and AdRR5-infected rats (at 3 days, 33±6 ppb, n=9, versus 17±4, n=9, and 6±2 ppb, n=3,
P
<0.05 for both). Exposure to F
io
2
0.10 for 7 days increased pulmonary artery pressure from 19±4 mm Hg (baseline) to 27±1 and 26±2 mm Hg in AdNOS3- and AdRR5-infected rats, respectively, but only to 21±1 mm Hg in AdNOS2-infected animals (
P
<0.05). After 7 days of hypoxia, total pulmonary resistance in AdRR5- and AdNOS3-infected rats was significantly higher than in AdNOS2-infected animals (0.41±0.05 and 0.39±0.07 versus 0.35±0.03 mm Hg · mL
−
1
· min
−
1
, respectively,
P
<0.05). Right ventricular hypertrophy was reduced in AdNOS2-infected rats [right ventricular/(left ventricular+septal) weight, 0.19±0.10 versus 0.28±0.10 and 0.32±0.10 in AdRR5- and AdNOS3-infected rats, respectively,
P
<0.05]. The percentage of muscularized precapillary pulmonary resistance vessels was also significantly decreased (18±4% versus 25±8% and 30±5% in AdRR5- and AdNOS3-infected rats,
P
<0.05).

Conclusions
—Aerosol
NOS2
gene transfer increases pulmonary NO production and significantly reduces hypoxic pulmonary hypertension and pulmonary vascular remodeling. Aerosol
NOS2
gene transfer may be a promising strategy to target pulmonary vascular disorders.
Trypanosoma cruzi
–Infected Cardiomyocytes Produce Chemokines and Cytokines That Trigger Potent Nitric Oxide–Dependent Trypanocidal Activity
Authors: Machado Fabiana S. , Martins Gislâine A. , Aliberti Júlio C. S. , Mestriner Fabiola L. A. C. , Cunha Fernando Q. , Silva João S.
Published: June 2012

Background
—The pathogenesis of myocarditis that occurs in
Trypanosoma cruzi
–infected mice is still poorly understood. Therefore, it is important to know the mediators that trigger leukocyte migration to the heart as well as the cellular source of these possible mediators. In this study, we investigated (1) NO synthase (NOS) induction, (2) NO synthesis, (3) trypanocidal activity, and (4) chemokine and cytokine mRNA expression by isolated cardiomyocytes infected with
T cruzi
.

Methods and Results
—Mouse cardiomyocytes were isolated, infected with
T cruzi
, and evaluated for induction of inducible NOS (iNOS), nitrite production, trypanocidal activity, and cytokine and chemokine mRNA expression. We found that
T cruzi
–infected murine embryonic cardiomyocytes produced nitrite and expressed mRNAs for the chemokines chemokine growth-related oncogene, monokine induced by interferon-γ, macrophage inflammatory protein-2, interferon-γ–inducible protein, RANTES, and monocyte chemotactic protein, for iNOS, and for the cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-1β. Separate addition of IL-1β, interferon-γ, TNF-α or monocyte chemotactic protein, macrophage inflammatory protein-2, and interferon-γ–inducible protein, to cultured cardiomyocytes resulted in NO production but low trypanocidal activity. However, simultaneous addition of IL-1β, interferon-γ, and TNF-α or the chemokines to cultures resulted in the induction of iNOS, high levels of nitrite, and a marked trypanocidal activity. The iNOS/
l
-arginine pathway mediated the latter activity, inasmuch as it was inhibited by treatment with
N
G
-monomethyl-
l
-arginine.

Conclusions
—These results indicate that iNOS activation and the proinflammatory cytokines and chemokines produced by cardiomyocytes are likely to control parasite growth and cell influx, thus contributing to the pathogenesis of chagasic cardiomyopathy seen in
T cruzi
–infected mice.
Endotoxin-Induced Mortality Is Related to Increased Oxidative Stress and End-Organ Dysfunction, Not Refractory Hypotension, in Heme Oxygenase-1–Deficient Mice
Authors: Wiesel Philippe , Patel Anand P. , DiFonzo Nicole , Marria Pooja B. , Sim Chäng U. , Pellacani Andrea , Maemura Koji , LeBlanc Brian W. , Marino Kathryn , Doerschuk Claire M. , Yet Shaw-Fang , Lee Mu-En , Perrella Mark A.
Published: June 2012

Background
—Heme oxygenase (HO)-1 is an enzyme that degrades heme to generate CO (a vasodilatory gas), iron, and the potent antioxidant bilirubin. A disease process characterized by decreases in vascular tone and increases in oxidative stress is endotoxic shock. Moreover, HO-1 is markedly induced in multiple organs after the administration of endotoxin (lipopolysaccharide [LPS]) to mice.

Methods and Results
—To determine the role of HO-1 in endotoxemia, we administered LPS to mice that were wild-type (+/+), heterozygous (±), or homozygous null (−/−) for targeted disruption of HO-1. LPS produced a similar induction of HO-1 mRNA and protein in HO-1
+/+
and HO-1
+/−
mice, whereas HO-1
−
/−
mice showed no HO-1 expression. Four hours after LPS, systolic blood pressure (SBP) decreased in all the groups. However, SBP was significantly higher in HO-1
−
/−
mice (121±5 mm Hg) after 24 hours, compared with HO-1
+/+
(96±7 mm Hg) and HO-1
+/−
(89±13 mm Hg) mice. A sustained increase in endothelin-1 contributed to this SBP response. Even though SBP was higher, mortality was increased in HO-1
−
/−
mice, and they exhibited hepatic and renal dysfunction that was not present in HO-1
+/+
and HO-1
+/−
mice. The end-organ damage and death in HO-1
−
/−
mice was related to increased oxidative stress.

Conclusions
—These data suggest that the increased mortality during endotoxemia in HO-1
−
/−
mice is related to increased oxidative stress and end-organ (renal and hepatic) damage, not to refractory hypotension.
Alcohol Consumption and Risk of Intermittent Claudication in the Framingham Heart Study
Authors: Djoussé Luc , Levy Daniel , Murabito Joanne M. , Cupples L. Adrienne , Ellison R. Curtis
Published: June 2012

Background
—Intermittent claudication (IC) is associated with an increased risk of cardiovascular disease morbidity and mortality. The relation of alcohol consumption to the risk of IC remains controversial. The purpose of this study was to assess the relation of alcohol consumption and type of beverage to the development of IC among participants in the Framingham Heart Study.

Methods and Results
—Alcohol consumption was categorized as 0, 1 to 6, 7 to 12, 13 to 24, and ≥25 g/d. During a mean follow-up of 6.8 years, 414 subjects developed IC. From the lowest to the highest category of alcohol intake, the age-standardized incidence rates of IC were 5.3, 4.1, 4.2, 3.2, and 4.6 cases/1000 person-years for men and 3.4, 2.5, 1.5, 1.9, and 2.5, respectively, for women. A multivariate Cox regression model demonstrated an inverse relation, with the lowest IC risk at levels of 13 to 24 g/d for men and 7 to 12 g/d for women compared with nondrinkers; the hazard ratio (95% CI) was 0.67 (0.42 to 0.99) for men and 0.44 (0.23 to 0.80) for women. This protective effect was seen mostly with wine and beer consumption.

Conclusions
—Our data are consistent with a protective effect of moderate alcohol consumption on IC risk, with lowest risk observed in men consuming 13 to 24 g/d (1 to 2 drinks/d) and in women consuming 7 to 12 g/d (0.5 to 1 drink/d).
Effects of β
–
-Emitting
188
Re Balloon in Stented Porcine Coronary Arteries
Authors: Makkar Raj , Whiting James , Li Alex , Honda Hidehiko , Fishbein Michael C. , Knapp F.F. (Russ) , Hausleiter Jörg , Litvack Frank , Eigler Neal L.
Published: June 2012

Background
—Restenosis within stents may be prevented by ionizing radiation from an intravascular source.

Methods and Results
—A liquid β
−
radiation (
188
Re) balloon was evaluated in a randomized and blinded porcine coronary model of stent restenosis. Group A pigs (n=17) received 0,16, 22, or 29 Gy at 0.5-mm depth, followed by stenting. Restenosis was quantified by angiography, ultrasound, and histomorphometry at 30 days. Group B (n=7) was stented first and then treated with 0 or 29 Gy with follow-up at 60 days. There was a measurable effect at 16 Gy, which improved with increasing doses. At 29 Gy, the histological stenotic area was reduced by 67% (22% versus 66% in controls,
P
<0.001). Radiation after stenting was equally effective; the stenotic area was reduced (21% versus 65%,
P
<0.001). At 16 Gy, the vessel just distal to the stent was significantly smaller than control vessels because of intimal thickening (
P
=0.003). Radiated vessels had distinctive histology consisting of neointimal fibrin and reduced smooth muscle cells and matrix (
P
<0.0001).

Conclusions
—
188
Re balloon brachytherapy in porcine coronary arteries results in dose-dependent and injury-independent inhibition of stent restenosis for up to 60 days. Restenosis at the borders of the irradiated zone is a potential limitation and may be related to underdosing. Brachytherapy with the
188
Re balloon appears to be safe and feasible for clinical studies.
Dose and Time Effects of Caffeine Intake on Human Platelet Adenosine A
2A
Receptors
Authors: Varani Katia , Portaluppi Francesco , Gessi Stefania , Merighi Stefania , Ongini Ennio , Belardinelli Luiz , Borea Pier Andrea
Published: June 2012

Background
—We determined whether repeated caffeine administration at different dosages and for different periods of time (400 or 600 mg/d for 1 week or 400 mg/d for 2 weeks) upregulates human platelet adenosine A
2A
receptors and is accompanied by increases in cAMP accumulation and decreases in aggregation and calcium levels after stimulation of A
2A
receptors by the selective agonist 2-hexynyl-5′-
N
-ethylcarboxamidoadenosine (HE-NECA).

Methods and Results
—Platelets were obtained from peripheral venous blood of 45 healthy human volunteers at the end of 2 weeks of caffeine abstinence and at 12, 60, and 108 hours after the last dose of caffeine. The lowest dose of caffeine, when given for only 7 days, had no effect. Increasing the total dose, either by giving 400 mg/d for 14 days or giving 600 mg/d, resulted in binding assays performed with the adenosine A
2A
receptor radioligand [
3
H]SCH 58261 [5-amino-7(phenylethyl)-2-(2-furyl)-pyrazolo[4,3-
e
]-1,2,4-triazolo[1,5-
c
]pyrimidine], in the upregulation of A
2A
receptors. Moreover, the potency of HE-NECA to produce antiaggregatory effects, a rise in cAMP accumulation, and a decrease in calcium levels was significantly increased.

Conclusions
—Chronic caffeine intake can lead to upregulation of adenosine A
2A
receptors, which is accompanied by sensitization, in a time- and dose-dependent manner, to the actions of the agonist HE-NECA.
Two-Year Changes in Blood Pressure and Subsequent Risk of Cardiovascular Disease in Men
Authors: Sesso Howard D. , Stampfer Meir J. , Rosner Bernard , Gaziano J. Michael , Hennekens Charles H.
Published: June 2012

Background
—It is unclear whether, given a current blood pressure level, the previous 2-year change in blood pressure adds important predictive information for cardiovascular disease (CVD).

Methods and Results
—We conducted a prospective cohort study of 11 150 middle-aged and older men reporting blood pressure in the Physicians’ Health Study. These men had no history of CVD or antihypertensive medication use through the time of the 2-year follow-up questionnaire; after this time, follow-up for the current study began. A total of 905 incident cases of CVD (705 cases of coronary heart disease and 200 cases of stroke) occurred during a median follow-up of 10.8 years. After controlling for current blood pressure and other coronary risk factors, we found that previous 2-year changes in systolic blood pressure were not associated with the risk of CVD. A similar lack of association was found for individual end points of coronary heart disease and stroke. However, previous 2-year changes in diastolic blood pressure (DBP) may be inversely associated with the risk of CVD (linear trend,
P
=0.049) independent of coronary risk factors and current DBP. In subgroup analyses, previous 2-year blood pressure changes only added information in leaner men (body mass index <24.39 kg/m
2
).

Conclusions
—In this normotensive population of men, the prior 2-year change in DBP, but not systolic blood pressure, may add information to current levels in relation to the risk of CVD. Clinicians may need to consider the previous pattern of DBP change when considering the risk associated with the current DBP level. These data require confirmation in other studies in which blood pressure is measured.
Plasma Disappearance of Albumin and Impact of Capillary Thickness in Idiopathic Dilated Cardiomyopathy and After Heart Transplantation
Authors: Galatius Søren , Bent-Hansen Lasse , Wroblewski Henrik , Sørensen Vibeke B. , Nørgaard Tove , Kastrup Jens
Published: June 2012

Background
—The increased plasma disappearance of albumin has previously been described in decompensated congestive heart failure (CHF); this disappearance normalized after diuretic treatment. Cardiac transplantation (HTX) and current medical treatment affect microvascular structure and function. We investigated the plasma disappearance of albumin and the impact of microvascular thickness and electrostatic properties in patients with compensated CHF and after HTX.

Methods and Results
—The fraction of intravascular albumin that passes to the extravascular space per unit time, as determined from the plasma disappearance of intravenously injected
131
I-labeled albumin, was increased to 7.8±1.7% in 16 patients with CHF compared with 18 controls (6.5±1.9%,
P
<0.05); these levels normalized after HTX (5.8±2.6%,
P
<0.01, n=17). The change in ratio between
131
I-albumin and simultaneously injected negatively charged glycosylated
125
I-albumin (selectivity index, >1/hour in controls) was lower in patients with HTX (0.993±0.022/hour) than in controls (1.008±0.019/hour;
P
<0.05), which indicated a relatively increased plasma disappearance of negatively charged albumin in HTX patients. Capillary basement membrane thickness was evaluated semiquantitatively from skin biopsies and showed no difference in the 3 groups (control, CHF, and HTX patients). However, in all 3 study groups, subjects with thicker capillary basement membranes had lower albumin escape rates (6.1±1.8%, n=32, versus 7.6±2.6% in subjects without thickening of capillary basement membranes, n=19;
P
<0.05).

Conclusions
—The plasma disappearance of albumin increased in patients with compensated CHF and it normalized after HTX. The present normalized capillary basement thicknesses in patients with CHF and the direct association between this parameter and plasma albumin disappearance indicate that previous compensatory microvascular basement membrane growth results in restricted permeability. Microvascular electrostatic properties did not relate to plasma albumin disappearance.
Mechanical Unloading Versus Neurohumoral Stimulation on Myocardial Structure and Endocrine Function In Vivo
Authors: Lisy Ondrej , Redfield Margaret M. , Jovanovic Sofija , Jougasaki Michihisa , Jovanovic Aleksandar , Leskinen Hanna , Terzic Andre , Burnett John C.
Published: June 2012

Background
—Mechanical load and humoral stimuli such as endothelin (ET) and angiotensin II (Ang II) are potent modulators of cardiac structure and endocrine function, specifically gene expression and production and release of atrial natriuretic peptide (ANP). We define the contribution of mechanical load compared with neurohumoral stimulation in vivo with specific focus on myocardial and circulating ANP during chronic myocardial unloading produced by thoracic inferior vena caval constriction (TIVCC).

Methods and Results
—TIVCC was produced by banding the IVC for 10 days in 7 dogs, whereas in the 6 control dogs, the band was not constricted. TIVCC was characterized by a decrease in cardiac output, right atrial pressure, and left ventricular (LV) end-diastolic diameter and marked activation of ET and Ang II in plasma and atrial and ventricular myocardium. Despite neurohumoral stimulation, LV mass index and myocyte diameters in unloaded hearts decreased, reflecting myocyte atrophy. The total number of myocytes in the LV remained unchanged. Atrial stores of ANP increased, but plasma ANP did not change, in association with a trend toward ANP gene expression to decrease in unloaded hearts.

Conclusions
—Chronic mechanical unloading of the heart results in myocardial atrophy and lack of activation of ANP synthesis despite marked neurohumoral stimulation by the growth promoters ET and Ang II.
β-Adrenergic Receptor Subtypes Differentially Affect Apoptosis in Adult Rat Ventricular Myocytes
Authors: Zaugg Michael , Xu Weimin , Lucchinetti Eliana , Shafiq Saiyid A. , Jamali Nasir Z. , Siddiqui M. A. Q.
Published: June 2012

Background
—Catecholamine-induced apoptosis is mediated by activation of the β-adrenergic signaling pathway. We tested the hypothesis that β
1
- and β
2
-adrenergic receptor (AR) subtypes differentially affect apoptosis in adult rat ventricular myocytes in vitro.

Methods and Results
—Myocytes were first exposed to norepinephrine (NE) alone (10 μmol/L) or NE+atenolol (AT) (10 μmol/L) for 12 hours. AT, a β
1
-selective AR antagonist, abolished the NE-induced increase in nick end-labeling (TUNEL)–positive cells compared with control (NE, 33±3% versus control, 3±1%,
P
<0.0001; NE+AT, 4±2% versus control, 3±1%,
P
=0.98). Annexin V staining, DNA laddering, and caspase activity determinations corroborated these results. Subsequent experiments under prazosin treatment established the apoptosis dose-response curves for the increasingly β
2
-selective AR agonists isoproterenol (ISO) (β
1
≈β
2
) and albuterol (ALB) (β
2
>β
1
). ISO and ALB induced significantly less apoptosis than NE (β
1
>β
2
) at equimolar concentrations as assessed by TUNEL staining [1 μmol/L: NE (8±2%)≈ISO (7±1%)>ALB (2±1%); 10 μmol/L: NE (35±2%)>ISO (23±1%)>ALB (3±1%); 100 μmol/L: NE (50±2%)>ISO (29±2%)>ALB (14±1%),
P
<0.0001 except for NE versus ISO at 1 μmol/L with
P
=0.62]. ALB-induced apoptosis at 100 μmol/L was abolished by AT (10 μmol/L), indicating a β
1
AR-mediated effect. Importantly, ICI 118551 (0.1 μmol/L), a highly selective β
2
AR antagonist, did not decrease the percentage of NE-, ISO-, and ALB-induced apoptosis. Reverse transcription–polymerase chain reaction studies revealed that AT completely reversed the β-adrenergic signaling–induced changes in the Bcl-2–to-Bax ratio.

Conclusions
—These observations provide evidence that βAR-mediated apoptotic death signaling is largely dissociated from β
2
ARs and selectively mediated by β
1
ARs in adult rat ventricular myocytes.
Probabilistic Model for Prediction of Angiographically Defined Obstructive Coronary Artery Disease Using Electron Beam Computed Tomography Calcium Score Strata
Authors: Bielak Lawrence F. , Rumberger John A. , Sheedy Patrick F. , Schwartz Robert S. , Peyser Patricia A.
Published: June 2012

Background
—Electron beam CT (EBCT) is an accurate, noninvasive method to detect and quantify coronary artery calcification, a marker of coronary artery disease (CAD). This investigation examined the accuracy of EBCT to detect obstructive CAD (≥50% stenosis) and determined the optimal strata for quantity of coronary artery calcification to facilitate clinical decision-making.

Methods and Results
—Clinical research patients (n=213) were examined with coronary angiography and EBCT (angiography group), and 765 research participants were examined with only EBCT (nonangiography group). Of the angiography group, 53% had obstructive CAD. After adjustment for verification bias, the estimated sensitivity and specificity for calcium score ≥1 were 97.0% and 72.4%, respectively. Likelihood ratios for strata of calcium score associated with obstructive CAD were calculated in each sex and 2 age groups. Among those ≥50 years old, the same 4 strata of EBCT calcium scores were identified in each sex; likelihood ratios ranged from 0.03 (calcium score 0) to 12.85 (calcium score ≥200). The same 3 strata of EBCT calcium scores were identified in each sex among those <50 years old; likelihood ratios ranged from 0.13 (calcium score 0) to 190 (calcium score ≥100).

Conclusions
—A calcium score ≥200 among those ≥50 years old and calcium score ≥100 among those <50 years old provided strong evidence that patients of either sex had obstructive CAD. A calcium score of 0 provided strong evidence that patients ≥50 years old did not have obstructive CAD.
Smoking Increases Tissue Factor Expression in Atherosclerotic Plaques
Authors: Matetzky Shlomo , Tani Shigemasa , Kangavari Simon , Dimayuga Paul , Yano Juliana , Xu Helen , Chyu Kuang-Yuh , Fishbein Michael C. , Shah Prediman K. , Cercek Bojan
Published: June 2012

Background
—Smoking increases the risk of atherothrombotic events. To determine whether smoking influences plaque thrombogenicity, we examined the effect of cigarette smoking and aspirin use on tissue factor (TF) expression in atherosclerotic plaques.

Methods and Results
—A total of 23 apoE−/− mice were exposed to cigarette smoke with (n=9) or without (n=14) aspirin treatment. Eleven mice who were exposed to filtered room air served as controls. Aortic root plaques of mice exposed to smoke had higher immunoreactivity for TF (14±4% versus 6.4±3%;
P
=0.0005), vascular cell adhesion molecule-1 (15±4% versus 5±2%;
P
=0.002), and macrophages (16±5% versus 6±2%;
P
=0.002) compared with nonsmoking controls. Aspirin treatment attenuated smoking-induced changes in plaque composition. In human plaques obtained by carotid endarterectomy, TF immunoreactivity (8±5% versus 2±2%;
P
=0.0002) and activity (
P
=0.03) were higher in the plaques from smokers (n=28) than those from nonsmokers (n=28). Aspirin use was associated with reduced TF expression in smokers (9±8% versus 3±4%;
P
=0.0017).

Conclusions
—Our results suggest increased plaque TF expression and thrombogenicity as a novel mechanism for the increased risk of atherothrombotic events in smokers. Treatment with aspirin may reduce TF expression.
Treating Electrical Storm
Authors: Nademanee Koonlawee , Taylor Richard , Bailey William E. , Rieders Daniel E. , Kosar Erol M.
Published: June 2012

Background
—Electrical storm (ES), defined as recurrent multiple ventricular fibrillation (VF) episodes, often occurs in patients with recent myocardial infarction. Because treating ES according to the Advanced Cardiac Life Support (ACLS) guidelines yields a poor outcome, we evaluated the efficacy of sympathetic blockade in treating ES patients and compared their outcome with that of patients treated according to the ACLS guidelines.

Methods and Results
—Forty-nine patients (36 men, 13 women, mean age 57±10 years) who had ES associated with a recent myocardial infarction were separated into 2 groups. Patients in group 1 (n=27) received sympathetic blockade treatment: 6 left stellate ganglionic blockade, 7 esmolol, and 14 propranolol. Patients in group 2 (n=22) received antiarrhythmic medication as recommended by the ACLS guidelines. Patient characteristics were similar in the 2 groups. The 1-week mortality rate was higher in group 2: 18 (82%) of the 22 patients died, all of refractory VF; 6 (22%) of the 27 group 1 patients died, 3 of refractory VF (
P
<0.0001). Patients who survived the initial ES event did well over the 1-year follow-up period: Overall survival in group 1 was 67%, compared with 5% in group 2 (
P
<0.0001).

Conclusions
—Sympathetic blockade is superior to the antiarrhythmic therapy recommended by the ACLS guidelines in treating ES patients. Our study emphasizes the role of increased sympathetic activity in the genesis of ES. Sympathetic blockade−not class 1 antiarrhythmic drugs−should be the treatment of choice for ES.
Spatial Heterogeneity in Fasting and Insulin-Stimulated
18
F-2-Deoxyglucose Uptake in Pigs With Hibernating Myocardium
Authors: Fallavollita James A.
Published: June 2012

Background
—Previous studies of hibernating myocardium in the fasting state have shown regionally increased
18
F-2-deoxyglucose (FDG) uptake with a marked transmural gradient. We hypothesized that this adaptation to chronic ischemia might be associated with altered maximal FDG uptake.

Methods and Results
—Pigs were instrumented with a 1.5-mm proximal left anterior descending artery (LAD) stenosis. Studies were conducted 106±4 days later on anesthetized animals with complete LAD occlusion and anteroapical dysfunction. In fasting animals (n=9), FDG uptake in dysfunctional LAD regions was 2-fold higher than in normally perfused myocardium (7.9±1.2 versus 4.0±0.5μmol · min
−
1
· 100 g
−
1
,
P
<0.05), with a pronounced transmural gradient (endocardial/epicardial ratio 2.56±0.19 versus 1.25±0.03,
P
<0.05). Euglycemic, hyperinsulinemic clamp (insulin clamp, n=8) produced a 5- to 9-fold increase in FDG uptake, but there was no longer a regional difference in accumulation (LAD, 37.8±4.2 versus normal, 36.4±5.1 μmol · min
−
1
· 100 g
−
1
,
P
=NS) and the transmural distribution was uniform. FDG uptake in the fasting state varied inversely with coronary flow during vasodilation. In contrast, during insulin clamp there was no relation between FDG uptake and vasodilated flow, resulting in a reduced spatial heterogeneity in individual samples (relative dispersion=SD/mean; fasting, 52±5% versus insulin, 24±2%,
P
<0.05).

Conclusions
—In the fasting state, FDG uptake in pigs with hibernating myocardium was heterogeneous and was increased in dysfunctional regions with a marked transmural gradient and high spatial heterogeneity. In contrast, FDG uptake was more homogeneously distributed during insulin clamp with (1) uptake in dysfunctional myocardium similar to remote normal regions, (2) uniform transmural distribution, and (3) reduced spatial heterogeneity.
Quo Vadis?
Authors: Hill Joseph A. , Kerber Richard E.
Published: June 2012

Background
—Cardiovascular medicine is weathering challenges on multiple fronts, and the paradigm of cardiovascular fellowship training has changed as a result.

Methods and Results
—On the basis of a review of the literature and surveys of former trainees, we have evaluated our Cardiovascular Fellowship Program at the University of Iowa. We have identified principles fundamental to the training of fellows. We extend these principles to propose practical ideas for responding to the challenges we face in the rapidly changing landscape of medicine in a new millennium.

Conclusions
—We have proposed a few principles and numerous concrete, practical suggestions that will guide our Cardiovascular Fellowship in the future. These ideas may prove useful to other training programs.
The Power-Velocity Integral at the Vena Contracta
Authors: Buck Thomas , Mucci Ronald A. , Guerrero J. Luis , Holmvang Godtfred , Handschumacher Mark D. , Levine Robert A.
Published: June 2012

Background
—Noninvasive quantification of regurgitation is limited because Doppler measures velocity, not flow. Because backscattered Doppler power is proportional to sonified blood volume, power times velocity should be proportional to flow rate. Early studies, however, suggested that this held only for laminar flow, not for regurgitant jets, in which turbulence and fluid entrainment augment scatter. We therefore hypothesized that this Doppler power principle can be applied at the proximal vena contracta, where flow is laminar before entrainment, so that the power-times-velocity integral should vary linearly with flow rate and its time integral with stroke volume (SV).

Methods and Results
—This was tested in vitro with steady and pulsatile flow through 0.07- to 0.8-cm
2
orifices and in 36 hemodynamic stages in vivo, replacing the left atrium with a rigid chamber and column for direct visual recording of mitral regurgitant SV (MRSV). In 12 patients, MRSV was compared with MRI mitral inflow minus aortic outflow and in 11 patients with 3D echo left ventricular ejection volume–Doppler aortic forward SV. Vena contracta power in the narrow high-velocity spectrum from a broad measuring beam was calibrated against that from a narrow reference beam of known area. Calculated and actual flow rates and SV correlated well in vitro (
r
=0.99, 0.99; error=−1.6±2.5 mL/s, −2.4±2.9 mL), in vivo (MRSV:
r
=0.98, error=0.04±0.87 mL), and in patients (MRSV:
r
=0.98, error=−2.8±4.5 mL).

Conclusions
—The power-velocity integral at the vena contracta provides an accurate direct measurement of regurgitant flow, overcoming the limitations of existing Doppler techniques.
Lewis A. Conner
Authors: Fisher Jeffrey
Published: June 2012

Abstract
—Lewis A. Conner, MD (1867 to 1950), was a pioneer in public health cardiology, cardiac rehabilitation, and cardiac psychology. He helped establish the Burke Rehabilitation Hospital and was the founding president of the New York and American Heart Associations (AHA). Dr Conner was the founder of the
American Heart Journal
, America’s first medical subspecialty journal, and the official publication of the American Heart Association until 1950, when
Circulation
was created. Conner spent more than a half-century on the staff of the New York Hospital and Cornell University Medical College and was Chairman of Medicine from 1916 to 1932. During this time, he created the innovative Cornell Pay Clinic and united the “old” New York Hospital with the new and scientifically-oriented Cornell University Medical College on a modern and inspiring urban campus. An extraordinary clinician and a humanist with great equanimity, Conner devoted his career to the Oslerian tradition of scholarship, leadership, and organization in the quest for improved patient care. This article contains newly discovered biographic material on Dr Conner and explores his professional and personal connection to Sir William Osler.
Acute Systemic Inflammation Impairs Endothelium-Dependent Dilatation in Humans
Authors: Hingorani Aroon D. , Cross Jenny , Kharbanda Rajesh K. , Mullen Michael J. , Bhagat Kiran , Taylor Mia , Donald Ann E. , Palacios Miriam , Griffin George E. , Deanfield John E. , MacAllister Raymond J. , Vallance Patrick
Published: June 2012

Background
—We tested the hypothesis that endothelial dysfunction underlies the association between an acute inflammatory episode and the transiently increased risk of a cardiovascular event by examining the effects of an experimental inflammatory stimulus on endothelium-dependent vasodilation.

Methods and Results
—
Salmonella typhi
vaccine was used to generate a systemic inflammatory response in healthy volunteers. In 12 subjects, dilatation of the brachial artery to flow and to sublingual nitroglycerin (NTG) was recorded (conduit vessel response), and in 6 subjects, venous occlusion plethysmography was used to measure forearm blood flow during intrabrachial infusion of the endothelium-dependent dilators acetylcholine (ACh) and bradykinin (BK) and the endothelium-independent dilators NTG and verapamil (resistance vessel response). Responses were assessed 16 hours before and 8 and 32 hours after vaccination. Vaccination resulted in elevations in white cell count and serum levels of interleukin-6 and interleukin-1 receptor antagonist. Eight hours after vaccination, resistance vessel responses to BK (
P
=0.0099) and ACh (
P
=0.0414) were markedly attenuated, and brachial artery flow-mediated dilatation was depressed. Resistance vessel responses to verapamil and NTG were unchanged, as was the conduit vessel response to NTG. Thirty-two hours after vaccination, resistance vessel responses to BK and ACh had returned to normal.

Conclusions
—
S typhi
vaccine generates a mild inflammatory reaction associated with temporary but profound dysfunction of the arterial endothelium in both resistance and conduit vessels to both physical and pharmacological dilator stimuli. This finding might explain the association between infection and inflammation and the enhanced risk of an acute cardiovascular event.
Reduction in Myocardial Collagen Cross-Linking Parallels Left Ventricular Dilatation in Rat Models of Systolic Chamber Dysfunction
Authors: Woodiwiss A. J. , Tsotetsi O. J. , Sprott S. , Lancaster E. J. , Mela T. , Chung E. S. , Meyer T. E. , Norton G. R.
Published: June 2012

Background
—The transition from compensated left ventricular hypertrophy (LVH) to heart failure is associated with alterations in the myocardial interstitium. We hypothesized that LV dilatation is associated with modifications in collagen cross-linking.

Methods and Results
—We studied 2 rat models of LV dilatation: (1) pressure-overload hypertrophy with heart failure (POH-F) induced by suprarenal abdominal aortic banding and (2) LVH induced by 7 months of isoproterenol (ISO, 0.04 mg · kg
−1
· d
−1
) administration. In POH-F rats and in rats receiving ISO, LV dilatation and a reduced systolic chamber performance were noted. Myocardial hydroxyproline concentrations ([HPRO]) were increased in the POH-F rats, whereas in rats receiving ISO, [HPRO] was decreased. In POH-F rats, the ratio of myocardial collagen type I to type III was increased, but in rats receiving ISO, myocardial collagen I/III was unchanged. In contrast to the diverse changes in myocardial collagen concentrations and phenotypes observed in the 2 models of LV dilatation, the ratio of myocardial insoluble to soluble (relationship between cross-linked and non–cross-linked) collagen was decreased in both the POH-F and ISO groups. Moreover, administration of captopril (0.22 mmol · kg
−1
· d
−1
), which inhibited the ISO-induced reduction in myocardial insoluble/soluble collagen but not the reduction in [HPRO], prevented the ISO-induced alterations in LV dimensions and performance.

Conclusions
—Because decreases in the ratio of myocardial insoluble to soluble collagen parallel LV dilatation in rats, reductions in myocardial collagen cross-linking may be an important mechanism contributing to LV dilatation in heart disease.
Lethal Autoimmune Myocarditis in Interferon-γ Receptor–Deficient Mice
Authors: Eriksson U. , Kurrer M. O. , Bingisser R. , Eugster H. P. , Saremaslani P. , Follath F. , Marsch S. , Widmer U.
Published: June 2012

Background
—Interferon-γ (IFN-γ) is an essential cytokine in the regulation of inflammatory responses in autoimmune diseases. Little is known about its role in inflammatory heart disease.

Methods and Results
—We showed that IFN-γ receptor–deficient mice (IFN-γR
–/–
) on a BALB/c background immunized with a peptide derived from cardiac α-myosin heavy chain develop severe myocarditis with high mortality. Although myocarditis subsided in wild-type mice after 3 weeks, IFN-γR
–/–
mice showed persistent disease. The persistent inflammation was accompanied by vigorous in vitro CD4 T-cell responses and impaired inducible nitric oxide synthase expression, together with evidence of impaired nitric oxide production in IFN-γR
–/–
hearts. Treatment of wild-type mice with the nitric oxide synthetase inhibitor
N
-nitro-l-arginine-methyl-ester enhanced in vitro CD4 T-cell proliferation and prevented healing of myocarditis.

Conclusions
—Our data provide evidence that IFN-γ protects mice from lethal autoimmune myocarditis by inducing the expression of inducible nitric oxide synthase followed by the downregulation of T-cell responses.
Blood Donations and Risk of Coronary Heart Disease in Men
Authors: Ascherio Alberto , Rimm Eric B. , Giovannucci Edward , Willett Walter C. , Stampfer Meir J.
Published: June 2012

Background
—In experimental animals, iron overload appears to promote atherosclerosis and ischemic myocardial damage, but the results of epidemiological studies that relate iron stores to risk of coronary heart disease (CHD) have been inconsistent.

Methods and Results
—We prospectively studied blood donations, which effectively reduce body iron stores, in relation to the risk of CHD among participants in the Health Professionals Follow-up Study. The lifetime history of blood donation was assessed with a questionnaire in 1992. The 38 244 men who were free of diagnosed cardiovascular disease at that time were included in the analyses. During 4 years of follow-up, we documented 328 nonfatal myocardial infarctions and 131 coronary deaths. Although the number of lifetime blood donations was strongly associated with lower plasma ferritin levels in a subsample, the blood donation was not associated with risk of myocardial infarction or fatal CHD. The age-adjusted relative risk (RR) of myocardial infarction for men in the highest category of blood donations (≥30) compared with never donors was 1.2 (95% CI 0.8 to 1.8), and this RR was not materially changed after adjustment for several coronary risk factors. No significant associations were found between blood donation and the risk of myocardial infarction in analyses restricted to men with hypercholesterolemia or those who never used antioxidant supplements or aspirin.

Conclusions
—The study results do not support the hypothesis that reduced body iron stores lower CHD risk.