bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Body Size, Ponderosity, and Blood Pressure on Left Ventricular Growth in Children and Young Adults in the Bogalusa Heart Study
Authors: Urbina Elaine M. , Gidding Samuel S. , Bao Weihang , Pickoff Arthur S. , Berdusis Kaliope , Berenson Gerald S.
Published: June 2012

Background
The measurement of left ventricular mass (LVM) is important because individuals with increased LVM are at increased risk for cardiovascular diseases, including myocardial infarction and congestive heart failure. There are limited longitudinal data on the acquisition of LVM in children and young adults and the relative importance of sex, growth, excess body weight, and blood pressure (BP) on change in LVM.

Methods and Results
The study cohort consisted of a cross section of 160 healthy children and young adults 9 to 22 years of age at first exam in the biracial community of Bogalusa, La. All had stable BP levels recorded over a 2- to 3-year period. Repeated examinations were performed 4 to 5 years apart. At each exam, 6 BPs were obtained with a mercury sphygmomanometer by trained examiners. The mean of the observations was used, with the fourth Korotkoff phase serving as the measure of diastolic BP. Anthropometric data, including height (HT), weight (WT), and triceps skin fold thickness (TSF), were also obtained, and M-mode echocardiograms were performed. Ponderal index (PI=WT/HT
3
) was used as a measure of weight-for-height. Tracking of HT (
r
=.68 to .76), WT (
r
=.73 to .82), PI (
r
=.77 to .89), TSF (
r
=.70 to .80), BP (
r
=.47 to .60), and LVM (
r
=.40 to .70) was strong in both sexes (
P
<.0001). LVM indexed for linear growth (LVM/HT
2.7
) tracked in females (
r
=.56,
P
<.0001) but not in males. In univariate cross-sectional analyses, LVM/HT
2.7
correlated with WT, PI, and TSF in both sexes (
r
=.21 to .60,
P
<.05) and with systolic BP (SBP) in females (
r
=.23,
P
<.05). WT was the only independent correlate of LVM/HT
2.7
in both sexes in multivariate cross-sectional analysis in a model containing age, SBP, WT, and TSF as independent variables (
r
2
=.08 to .28,
P
<.02). In longitudinal univariate analyses, initial measurements of WT, PI, and TSF predicted final LVM/HT
2.7
in both sexes (
r
=.28 to .56,
P
<.01), and SBP was significant for females (
r
=.27,
P
<.05). In multivariate analyses, initial WT was associated with final LVM and LVM/HT
2.7
in both sexes (
r
2
=.27 to .54,
P
<.01). Finally, baseline LVM correlated with final SBP in both sexes (
r
=.21 to .27,
P
<.05), and initial LVM/HT
2.7
correlated with final SBP in females (
r
=.26,
P
<.05) with a trend for males (
r
=.17).

Conclusions
These data indicate that linear growth is the major determinant of cardiac growth in children and that excess weight may lead to the acquisition of LVM beyond that expected from normal growth. Increased mass may also precede the development of increased BP. The development of obesity may therefore be a significant, and possibly modifiable, risk factor for developing left ventricular hypertrophy and hypertension, risk factors for cardiovascular morbidity and mortality.
Dissociation Between Exertional Symptoms and Circulatory Function in Patients With Heart Failure
Authors: Wilson John R. , Rayos Glenn , Yeoh T. K. , Gothard Patricia , Bak Karen
Published: June 2012

Background
Patients with heart failure frequently report exertional dyspnea and fatigue. These symptoms are usually attributed to circulatory dysfunction and therefore are typically treated with cardiovascular medications. Serial assessment of exertional symptoms has also become the principal method used to assess drug efficacy in heart failure. Nevertheless, the relation between exertional symptoms in heart failure and circulatory dysfunction remains uncertain.

Methods and Results
This study was undertaken to investigate the relation between exertional symptoms, ventilatory and skeletal muscle dysfunction, and circulatory function in patients with heart failure. To this end, 52 ambulatory patients with heart failure underwent hemodynamic monitoring during maximal treadmill exercise testing. During exercise, the severity of dyspnea and fatigue was evaluated on a scale of 6 to 20 (Borg scale). The level of perceived exercise intolerance during daily activities was evaluated with the Minnesota Living With Heart Failure Questionnaire and the Yale Dyspnea-Fatigue Index. Maximal treadmill exercise increased the V̇
o
2
to 13.4±2.8 mL · min
−1
· kg
−1
, the dyspnea score to 15.7±2.3, the fatigue score to 14.8±3.4, the pulmonary wedge pressure to 28±11 mm Hg, and the pulmonary artery lactate concentration to 34.5±16.3 mg/dL and decreased the pulmonary artery hemoglobin oxygen saturation to 30±9%. The level of perceived dyspnea had no relation to the pulmonary wedge pressure and correlated only minimally with the level of excessive ventilation (
r
=.39). The level of perceived fatigue correlated only weakly with blood lactate concentration (
r
=.55). Eleven patients (21%) exhibited a normal cardiac output and wedge pressure <20 mm Hg during exercise, 22 (42%) exhibited a normal cardiac output but wedge pressure >20 mm Hg during exercise, and 19 (37%) exhibited reduced cardiac output and wedge pressure >20 mm Hg during exercise. Despite these markedly different hemodynamic responses, all three groups exhibited similar levels of fatigue and dyspnea at comparable workloads and had comparable total scores for the Minnesota Living With Heart Failure Questionnaire and the Yale Dyspnea-Fatigue Index. There was no relation between the Living With Heart Failure Questionnaire and peak exercise V̇
o
2
and only a weak correlation between the Dyspnea-Fatigue Index and peak V̇
o
2
(
r
=.48).

Conclusions
The level of exercise intolerance perceived by patients with heart failure has little or no relation to objective measures of circulatory, ventilatory, or metabolic dysfunction during exercise. In patients who report severe exertional symptoms, it may be desirable to directly measure hemodynamic response to exercise to ensure that these symptoms are due to circulatory dysfunction.
Positive and Negative Inotropic Effects of
dl
-Sotalol and
d
-Sotalol in Failing and Nonfailing Human Myocardium Under Physiological Experimental Conditions
Authors: Holubarsch Christian , Schneider Ralf , Pieske Burkert , Ruf Thorsten , Hasenfuss Gerd , Fraedrich Gustav , Posival Herbert , Just Hanjörg
Published: June 2012

Background
dl
-Sotalol has class III antiarrhythmic activity through prolongation of the repolarization phase of the action potential as well as β-adrenoceptor–blocking properties. Although the former effect was found to exert positive inotropic effects in animal experimental studies, the latter may be detrimental in heart failure due to negative inotropism. In contrast to
dl
-sotalol,
d
-sotalol is suggested to exert only positive inotropic effects, which were never tested in isolated human myocardium.

Methods and Results
Therefore, we investigated the effects of racemic
dl
-sotalol and its enantiomer
d
-sotalol in human right atrial muscle strip preparations and in left ventricular muscle strip preparations from nonfailing and end-stage failing human hearts.
dl
-sotalol and
d
-sotalol significantly (
P
<.01) increased peak developed force in atrial preparations by 14.0±3.4% and 16.7±3.8%, respectively, but had no effect in ventricular myocardium. In nonfailing ventricular myocardium, both
dl
-sotalol and
d
-sotalol shifted the dose-response curve for isoproterenol to higher concentrations (
P
<.01); however,
dl
-sotalol was 100-fold more effective than
d
-sotalol. In nonfailing myocardium, a positive force-frequency relation was found between 30 and 120 beats per minute, but isoproterenol was much more powerful in its inotropic effects. In failing myocardium, reduction in stimulation rate from 120 to 30 beats per minute increased peak developed force more pronounced than did the application of isoproterenol.

Conclusions
(1)
d
-Sotalol has no relevant β-adrenoceptor–blocking activity compared with
dl
-sotalol. (2) Neither
dl
-sotalol nor
d
-sotalol exhibit positive inotropic effects in human left ventricular myocardium. (3) Heart rate reduction increases contractile force in end-stage failing human myocardium due to an inverse force-frequency relation and thereby counteracts the potential negative inotropic properties of β-blockade.
The Circulatory Regulation of TPA and UPA Secretion, Clearance, and Inhibition During Exercise and During the Infusion of Isoproterenol and Phenylephrine
Authors: Chandler Wayne L. , Levy Wayne C. , Stratton John R.
Published: June 2012

Background
Exercise to exhaustion and infusions of isoproterenol and phenylephrine were used to study interactions between plasminogen activator regulation and the control of regional blood flow in 10 healthy males.

Methods and Results
Experimental measurements of cardiac output, heart rate, tissue plasminogen activator (TPA), urokinase plasminogen activator (UPA), plasminogen activator inhibitor (PAI-1), C1-inhibitor, and TPA/C1-inhibitor complex during the infusions and exercise were used to develop a comprehensive fluid-phase model of the circulatory regulation of fibrinolysis. α- and β-adrenergic agonists increased TPA and UPA in plasma by different mechanisms: Phenylephrine decreased hepatic blood flow and thus clearance while isoproterenol stimulated increased secretion of TPA and UPA. Exercise to exhaustion increased TPA and UPA through a combination of increased secretion and decreased clearance. The time course of UPA and TPA release were similar, but the magnitude of their secretion responses differed. In vivo, C1-inhibitor bound to TPA at a rate of 553 mol
−1
· s
−1
. C1-inhibitor contributed equally with PAI-1 to TPA inhibition when active PAI-1 levels were low (20 to 50 pmol/L) but was less important when active PAI-1 levels were high.

Conclusions
We conclude that secretion, inhibition, clearance, and regional blood flow effects must all be taken into account when evaluating changes in plasminogen activator levels.
Dose-Dependent Dissociation of ACE-Inhibitor Effects on Blood Pressure, Cardiac Hypertrophy, and β-Adrenergic Signal Transduction
Authors: Böhm Michael , Castellano Maurizio , Agabiti-Rosei Enrico , Flesch Markus , Paul Martin , Erdmann Erland
Published: June 2012

Background
Dose-dependent effects of ACE inhibitors on blood pressure, cardiac hypertrophy, and β-adrenergic signal transduction were examined in an animal model with β-adrenergic desensitization, which has been identified in failing hearts and in hypertensive cardiac hypertrophy. It is unknown whether beneficial ACE-inhibitor effects are due to an unloading of the failing heart or a reduction of neuroendocrine activation with β-adrenergic resensitization.

Methods and Results
Low-dose (LD, 1 mg/kg) and high-dose (HD, 25 mg/kg) fosinopril treatment was performed in spontaneously hypertensive rats (SHR) and control (WKY) rats. Myocardial norepinephrine concentrations, adenylyl cyclase activity, β-adrenergic receptors (radioligand binding), G
sα
(functional reconstitution), and G
iα
(pertussis toxin labeling) were determined. Ventricular weights and blood pressures were measured. HD but not LD reduced blood pressure and left ventricular weights in SHR. Isoprenaline- and guanylylimidodiphosphate-stimulated adenylyl cyclase activities as well as β
1
-adrenergic receptors were reduced in SHR. The catalyst and G
sα
were unchanged, but G
iα
and norepinephrine concentrations were increased. Both LD and HD treatments restored β-adrenergic alteration.

Conclusions
LD treatment with ACE inhibitors restored β-adrenergic signal transduction defects independently of regression of cardiac hypertrophy. This could contribute to the effects of ACE inhibitors in patients, who are often treated with nonhypotensive doses.
Expression of Renin-Angiotensin System Components in the Heart, Kidneys, and Lungs of Rats With Experimental Heart Failure
Authors: Pieruzzi Federico , Abassi Zaid A. , Keiser Harry R.
Published: June 2012

Background
Chronic activation of the renin-angiotensin system (RAS) plays an important role in the pathogenesis of heart failure. Increasing evidence indicates that other than the circulating RAS, a local RAS exists in several tissues, including the heart. The present study was carried out to quantify cardiac, renal, and pulmonary mRNA levels of renin, angiotensin-converting enzyme (ACE), and types 1 and 2 angiotensin II receptors (AT-1 and AT-2), in rats with different severities of heart failure.

Methods and Results
Heart failure was induced by the creation of an aortocaval fistula below the renal arteries. Rats with aortocaval fistula either compensate and maintain a normal sodium balance or decompensate and develop severe sodium retention. Six days after placement of the aortocaval fistula, heart weight (normalized to body weight) increased 35% (
P
<.05) in compensated and 65% in decompensated rats compared with control rats. Plasma renin activity increased 45% (
P
<.05) in rats in sodium balance and 127% in sodium-retaining rats. Total RNA was extracted from the heart, kidneys, and lungs, followed by reverse transcription–quantitative polymerase chain reaction. Renin mRNA levels in the heart, after 40 cycles, increased 68% (
P
<.01) and 140% in rats with either compensated or decompensated heart failure, respectively. Renal renin-mRNA levels also increased 130% (
P
<.05) in decompensated and only 52% (
P
<.05) in compensated animals. ACE-mRNA increased in a similar pattern in the heart but not in either the kidneys or lungs. Moreover, pulmonary, renal, and cardiac ACE immunoreactivity levels, assessed by Western blot analysis, showed the same trend. AT-1 receptor mRNA levels decreased 54% (
P
<.05) only in the myocardium of decompensated rats, whereas AT-2 receptor mRNA did not change in any tissue studied.

Conclusions
The development of heart failure is associated with a remarkable increase in the expression of a local RAS in the heart, which may contribute to the pathogenesis of this clinical syndrome.
Plasma HDL Cholesterol, Triglycerides, and Adiposity
Authors: Mahaney Michael C. , Blangero John , Comuzzie Anthony G. , VandeBerg John L. , Stern Michael P. , MacCluer Jean W.
Published: June 2012

Background
The conjoint trait hypothesis proposes that combined low HDL cholesterol (HDL-C) and high triglyceride (TG) levels represent a single, inherited phenotype that adiposity may influence in an unspecified manner. We conducted formal statistical genetic tests of the conjoint trait hypothesis and the relation of the conjoint trait to adiposity using data for 569 subjects in 25 pedigrees from the San Antonio Family Heart Study.

Methods and Results
We conducted multivariate genetic analyses to detect the effects of genes and environmental factors on variation in plasma concentrations of HDL-C and TG, fat mass (as percent body weight [FM%], determined by bioelectric impedance), and body mass index (BMI). We used maximum-likelihood methods to simultaneously estimate the phenotypic means and SDs, heritabilities (h
2
), effects of sex, age-by-sex, eight dietary and medical covariates, and genetic and environmental correlations. Likelihood ratio tests disclosed significant heritabilities (
P
<.001) for all traits (h
2
HDL-
C
=0.55, h
2
TG
=0.53, h
2
FM%
=0.37, h
2
BMI
=0.44) but significant genetic correlations (
P
<.001), indicating pleiotropy, between two trait pairs only: HDL-C and TG (ρ
G
=−0.52) and fat mass and BMI (ρ
G
=0.86). We obtained significant environmental correlations between all trait pairs except HDL-C and BMI (
P
>.05).

Conclusions
Both shared genes (pleiotropy) and shared environmental factors contribute to the commonly observed inverse phenotypic association between plasma levels of HDL-C and TG. Rather than low HDL-C and high TG being a single, genetically transmissible entity, it is the inverse relation between these two phenotypes throughout their normal ranges of variation as well as at the extremes that is influenced by shared genes and shared environments. However, common environmental factors, not shared genes, account for reported associations of plasma HDL-C and TG levels with measures of adiposity.
Catalase Inhibition With 3-Amino-1,2,4-Triazole Does Not Abolish Infarct Size Reduction in Heat-Shocked Rats
Authors: Auyeung Yanying , Sievers Richard E. , Weng Daniel , Barbosa Vania , Wolfe Christopher L.
Published: June 2012

Background
Recent studies have shown that improved myocardial salvage after heat-shock pretreatment correlates with the amount of induced cardiac heat-shock protein (HSP)72. However, heat shock also induces myocardial catalase activity, potentially reducing free radical–mediated ischemic injury. The aim of the present study was to determine whether catalase inhibition with 3-amino-1,2,4-triazole (3-AT) abolishes the reduction of infarct size conferred by heat-shock treatment in rats.

Methods and Results
Myocardial catalase activity was measured in both heat-shocked and control rats 60 minutes after either 3-AT (1000 mg/kg IV) or saline infusion. In separate experiments, heat-shocked and control rats were treated with 3-AT or saline 60 minutes before being subjected to 35 minutes of left coronary artery occlusion and 120 minutes of reperfusion. Infarct size was determined by dual perfusion with triphenyltetrazolium chloride and phthalocyanine blue dye. Heat-shock treatment significantly increased myocardial catalase compared with control animals (180.5±4.8, n=6, versus 86.2±14.7, n=5, units/g wet wt;
P
<.05). Treatment with 3-AT significantly reduced myocardial catalase activity in both heat-shocked and control animals (29.6±5.7, n=5, and 36.4±15.3, n=6, respectively). Heat-shock treatment significantly reduced infarct size in rats that were both treated and untreated with 3-AT compared with respective control groups (22.5±3.7%, n=26, 28.2±4.0%, n=22, 52.0±3.0%, n=23, and 48.6±3.2%, n=26, respectively;
P
<.0001 for both heat-shocked groups versus both control groups; infarct mass/risk area mass×100).

Conclusions
Catalase inhibition with 3-AT does not abolish the reduction of infarct size in heat-shocked rats.
Prognostic Importance of Intimal Thickness as Measured by Intracoronary Ultrasound After Cardiac Transplantation
Authors: Rickenbacher Peter R. , Pinto Fausto J. , Lewis Neil P. , Hunt Sharon A. , Alderman Edwin L. , Schroeder John S. , Stinson Edward B. , Brown Byron W. , Valantine Hannah A.
Published: June 2012

Background
Although intracoronary ultrasound (ICUS) has been validated for the early detection of transplant coronary artery disease (TxCAD), the prognostic importance of findings detected by this new imaging technique is unknown.

Methods and Results
This study examined the relation of clinical outcome in 145 heart transplant recipients (mean age, 45.1±11.1 years) with the amount of intimal thickness measured by ICUS during routine annual coronary angiography 1 to 10 years (mean, 3.1±2.2 years) after transplantation. From published autopsy data, a mean intimal thickness of >0.3 mm was considered significant. During a mean follow-up time of 48.2±10.2 months, 23 deaths (12 cardiac) occurred, and 6 patients required retransplantation. Angiographic TxCAD developed in 22 of 125 patients (17.6%) in the subgroup with normal angiograms at the time of ICUS and a follow-up annual angiographic study. In the total population and the subgroup, mean intimal thicknesses of >0.3 and ≤0.3 mm, respectively, were associated with significantly inferior 4-year actuarial overall survival (73% versus 96%,
P
=.005; 72% versus 92%,
P
=.05), cardiac survival (79% versus 96%,
P
=.005; 80% versus 98%,
P
=.04), and freedom from cardiac death and retransplantation (74% versus 98%,
P
<.0001; 70% versus 96%,
P
=.001). In addition, ICUS predicted freedom from development of subsequent angiographic TxCAD in the subgroup that was initially normal (26% versus 72%,
P
=.02). A mean intimal thickness by ICUS of >0.3 mm was associated with inferior clinical outcome regardless of the presence of angiographic TxCAD and predicted the development of subsequent angiographic TxCAD. Despite significantly longer duration after transplantation, higher rejection incidence, and lower average daily cyclosporine dose, none of these covariates were independent risk factors for outcome.

Conclusions
These findings confirm the prognostic importance of mean intimal thickening of >0.3 mm in heart transplant recipients and suggest that these patients should be candidates for early interventional strategies.
In Vivo MRI Visualization of Acute Myocardial Ischemia and Reperfusion in Ferrets by the Persistent Action of the Contrast Agent Gd(BME-DTTA)
Authors: Simor Tamás , Chu Wen-Jang , Johnson Lynne , Safranko Andras , Doyle Mark , Pohost Gerald M. , Elgavish Gabriel A.
Published: June 2012

Background
Contrast agent–enhanced magnetic resonance imaging (MRI) has the potential to visualize myocardial ischemia. To date, however, no agent has been found that has a sustained effect that allows MRI detection for the entire duration of ischemia and reperfusion and thus is useful in conjunction with stress test MRI. In this article, we introduce the gadolinium complex of
N
3
,
N
6
-bis(2′-myristoyloxyethyl)-1,8-dioxo-triethylene-tetraamine-
N
,
N
,
N
′,
N
′-tetraacetic acid [Gd(BME-DTTA)], an agent potentially useful for such a purpose.

Methods and Results
Four protocols were carried out. ECG-triggered, partially T1-weighted, spin-echo MRI was used in protocols A through C. In protocol A, in nonischemic ferrets, 50 μmol/kg Gd(BME-DTTA) induced a 70±5% intensity enhancement lasting 3 hours. In protocol B, the left anterior descending coronary artery was occluded, and a
99m
Tc-sestamibi–induced autoradiographic contrast verified (
r
=.87,
P
<.01) a Gd(BME-DTTA)-induced (n=5) or Gd(DTPA)- induced (n=4) MRI contrast. In the Gd(BME-DTTA) group a sustained contrast and in the Gd(DTPA) group a short-lived contrast were observed. In protocol C (n=11), during ischemia, a 31±3.3% (
P
<.02) contrast was evident between the ischemic and nonischemic myocardial regions. Upon reperfusion, a contrast of 19±3% (
P
<.05) and 13±4.5% (
P
<.05) persisted for 5 and 15 minutes, respectively. Beyond 15 minutes, the contrast continued to diminish gradually. Nonradioactive microspheres verified (
r
=.87,
P
<.05) ischemia and reperfusion in this model. In protocol D (n=4), blood ΔR1 data showed that the blood pool retained Gd(BME-DTTA) for the entire time frame of the experiment at high enough concentration to provide an appropriate wash-in effect during the initial contrast enhancement and during reperfusion.

Conclusions
This study demonstrates that Gd(BME-DTTA) induces a sustained MRI contrast between regions of normal versus ischemic myocardium, showing the potential of this agent for the diagnosis of ischemic heart disease in conjunction with stress tests.
Infarct Size After Acute Myocardial Infarction Measured by Quantitative Tomographic
99m
Tc Sestamibi Imaging Predicts Subsequent Mortality
Authors: Miller Todd D. , Christian Timothy F. , Hopfenspirger Mona R. , Hodge David O. , Gersh Bernard J. , Gibbons Raymond J.
Published: June 2012

Background
99m
Tc sestamibi is a recently developed radioisotope that has been used to measure myocardium at risk and infarct size. The relation between these measurements and subsequent patient outcome has not yet been demonstrated.

Methods and Results
Two hundred seventy-four consecutive patients with acute myocardial infarction underwent tomographic
99m
Tc sestamibi imaging on arrival at the hospital (to measure myocardium at risk before reperfusion therapy) and at hospital discharge (to measure the amount of salvaged myocardium and final infarct size). Defect size on the sestamibi images was quantified using a threshold value of 60% of peak counts from the circumferential count profile curves generated for five representative slices of the left ventricle. Patients were followed after hospital discharge to evaluate the association between final infarct size and subsequent mortality. The median defect size measured was 27% of the left ventricle at presentation to the hospital (range, 0% to 77%) and was 12% of the left ventricle at hospital discharge (range, 0% to 68%). Almost one half of the patients had a final infarct size of ≤10%. The median amount of myocardium salvaged was 9% (range, −31% to 75%). During a median duration of follow-up of 12 months, there were 10 deaths (7 cardiac and 3 noncardiac) and 1 resuscitated out-of-hospital cardiac arrest. There was a significant association between infarct size and overall mortality (χ
2
=8.66,
P
=.003) and cardiac mortality (χ
2
=11.89,
P
<.001). Two-year mortality was 7% for patients whose infarct size was ≥12% versus 0% for patients whose infarct size was <12%. There also was a significant association between myocardium at risk and cardiac mortality (χ
2
=6.87,
P
=.009). There was no association between myocardium at risk and overall mortality or between amount of myocardium salvaged and either overall mortality or cardiac mortality.

Conclusions
Larger infarct size measured by
99m
Tc sestamibi imaging after acute myocardial infarction is associated with increased mortality risk during short-term follow-up.
Endothelin ET
A
and ET
B
Receptors Cause Vasoconstriction of Human Resistance and Capacitance Vessels In Vivo
Authors: Haynes William G. , Strachan Fiona E. , Webb David J.
Published: June 2012

Background
The role of endothelin ET
B
receptors in mediating vasoconstriction in humans is unclear. As yet, there have been no in vivo studies in resistance vessels, and in vitro data have been contradictory. We therefore investigated the function of ET
B
receptors in vivo in human forearm resistance and hand capacitance vessels using endothelin-1 as a nonselective agonist at ET
A
and ET
B
receptors and endothelin-3 and sarafotoxin S6c as selective agonists at the ET
B
receptor.

Methods and Results
A series of single-blind studies were performed, each in six healthy men. Brachial artery infusion of endothelin-1 and endothelin-3 caused slow-onset dose-dependent forearm vasoconstriction. Although endothelin-3 caused significantly less forearm vasoconstriction than endothelin-1 at low doses, vasoconstriction was similar to the two isopeptides at the highest dose (60 pmol/min). Endothelin-3 caused transient forearm vasodilatation at this dose, whereas endothelin-1 showed only a nonsignificant trend toward causing early vasodilatation. Intra-arterial sarafotoxin S6c caused a progressive reduction in forearm blood flow, although less than that to endothelin-1 (
P
=.04). Dorsal hand vein infusion of sarafotoxin S6c caused local venoconstriction that was also less than that to endothelin-1 (
P
=.002).

Conclusions
Selective ET
B
receptor agonists cause constriction of forearm resistance and hand capacitance vessels in vivo in humans, suggesting that both ET
A
and ET
B
receptors mediate vasoconstriction. Hence, antagonists at both ET
A
and ET
B
receptors, or inhibitors of the generation of endothelin-1, may be necessary to completely prevent vasoconstriction to endogenously generated endothelin-1.
HDLs Containing Apolipoproteins A-I and A-II (LpA-I:A-II) as Markers of Coronary Artery Disease in Men With Non–Insulin- Dependent Diabetes Mellitus
Authors: Syvänne Mikko , Kahri Juhani , Virtanen Kari S. , Taskinen Marja-Riitta
Published: June 2012

Background
Abnormalities in HDL and an increased risk of coronary artery disease (CAD) coexist in non–insulin-dependent diabetes mellitus (NIDDM). HDLs can be separated by their apolipoprotein (apo) content into particles containing apoA-I but not apoA-II (LpA-I) and those containing both apoA-I and apoA-II (LpA-I:A-II). The LpA-I particles have been suggested to be more effective in conferring protection against CAD than the LpA-I:A-II particles. However, data are sparse, and no studies have defined the role of these two classes of particles in NIDDM.

Methods and Results
LpA-I and LpA-I:A-II particles were quantified by a differential electroimmunoassay in four groups of men with similar age and body mass index (BMI) distributions. Group 1 consisted of 50 patients with NIDDM and angiographically verified CAD; group 2, 50 men with CAD but no diabetes; group 3, 50 men with NIDDM but no CAD; and group 4, 31 healthy men. Serum apoA-I and apoA-II concentrations were measured by immunoturbidimetry, and HDL
2
and HDL
3
were separated by ultracentrifugation. Concentrations of LpA-I:A-II particles in group 1 were 13.8%, 18.3%, and 26.9% lower than in groups 2 through 4, respectively. In a two-by-two factorial ANOVA, adjusted for age and BMI, the differences were significant for both CAD (
P
<.001) and NIDDM (
P
<.001), with no interaction between the factors. These results were confirmed by comparable differences in the serum concentrations of apoA-I and apoA-II. LpA-I particles were related to the presence or absence of CAD (
P
=.013), but the difference was lost in a multivariate analysis. A low HDL
3
cholesterol concentration characterized both CAD (
P
=.002) and NIDDM (
P
=.024). HDL
2
cholesterol differed significantly with regard to the presence of NIDDM (
P
=.033) but only borderline with respect to CAD (
P
=.073).

Conclusions
ApoA-II–containing lipoproteins and HDL
3
cholesterol are powerful markers of CAD in men with NIDDM.
Adjunctive Selectin Blockade Successfully Reduces Infarct Size Beyond Thrombolysis in the Electrolytic Canine Coronary Artery Model
Authors: Silver Mitchell J. , Sutton Joseph M. , Hook Sharon , Lee Philmo , Malycky Janis L. , Phillips M. Laurie , Ellis Stephen G. , Topol Eric J. , Nicolini Francesca A.
Published: June 2012

Background
An adjunctive pharmacological strategy to thrombolytic therapy that is tailored to limit reperfusion injury after thrombolysis could further maximize the unquestioned benefit of restoring flow to ischemic myocardium. Ischemia–reperfusion injury exhibits features characteristic of an acute inflammatory response, including the rapid activation and infiltration of neutrophils. The initial process of neutrophil migration from the circulation to injured tissue is modulated by a group of adhesion molecules called selectins. The purpose of the present study was to assess the efficacy of a selectin blocker (CY 1503) given as an adjunct to thrombolytic therapy to interfere with the inflammatory response after ischemia–reperfusion and subsequently reduce myocardial infarct size in the electrolytic canine model.

Methods and Results
A fully occlusive thrombus was formed in the left circumflex coronary artery by electrolytic injury in 20 anesthetized open-chest dogs. After occlusion, an infusion of 1 mg/kg recombinant tissue-type plasminogen activator (rTPA) was administered over 20 minutes with either a bolus of placebo or the selectin blocker CY 1503 (40 mg/kg). At the onset of reperfusion, 20 μg/kg per minute rTPA was administered for 1 hour to prevent reocclusion. After 1 hour of reperfusion, infarct size, myocardial myeloperoxidase activity, and reperfusion arrhythmias were measured. In CY 1503–treated dogs, there was a significant 69% reduction in infarct size when expressed as a percentage of the area at risk (6.7±8.4% versus 21.8±13.6%;
P
=.008) and a marked reduction in myeloperoxidase activity (0.014±0.009 versus 0.0370±0.025 U/min per gram;
P
=.02) compared with the placebo group. There was no difference between the groups in the occurrence of reperfusion arrhythmias.

Conclusions
Selectin blockade as an adjunct to rTPA-mediated thrombolysis significantly reduces infarct size and myocardial neutrophil infiltration well beyond thrombolysis alone in the electrolytic canine model. These data suggest that selectin blockade is extremely effective at reducing ischemia–reperfusion injury and myocardial infarct size in this model and that the neutrophil is a potent mediator of ischemia–reperfusion injury.
Dynamics of Early Postischemic Myocardial Functional Recovery
Authors: Manché A. , Edmondson S.J. , Hearse D.J.
Published: June 2012

Background
The present study was designed to explore the relation between the duration of ischemia and the rate and extent of myocardial functional recovery after reperfusion.

Methods and Results
Isolated rat hearts were perfused with blood from a support animal for 15 minutes (flow rate, 2.5 mL/min; perfusion pressure, 60.1±1.3 mm Hg). Control left ventricular developed pressure (LVDP) was measured, and the hearts (six per group) were subjected to 10, 20, 30, 40, 50, 60, 70, or 80 minutes of global ischemia (37°C) and 60 minutes of reperfusion. Pacing (320 beats per minute) was instituted before and after ischemia. In all groups, transient arrhythmias occurred at the onset of reperfusion, to be followed by an early phase of recovery that peaked after 2 to 3 minutes of reperfusion. The relation between the extent of this initial recovery and the duration of preceding ischemia was described by a bell-shaped curve. Thus, the maximum initial mean recovery after 10, 20, 30, 40, 50, 60, 70, or 80 minutes of ischemia was 97%, 108%, 145%, 154%, 118%, 34%, 41%, and 24%, respectively, of preischemic LVDP. Possibly indicative of reperfusion-induced injury, LVDP then declined in all groups so that after 20 minutes of reperfusion, the mean recovery was 63%, 53%, 48%, 50%, 56%, 12%, 9%, and 5%, respectively. In the 10-, 20-, 30-, and 40-minute ischemia groups, there then was a secondary increase in LVDP, possibly indicating the start of recovery from stunning. After 60 minutes of reperfusion, the mean recovery of LVDP was 82%, 65%, 59%, 54%, 47%, 9%, 7%, and 4%, respectively; this second phase of recovery was inversely proportional to the duration of ischemia. To define the early phase of recovery that had been obscured by reperfusion-induced arrhythmias, we repeated the experiments with the inclusion of a cardioplegic infusion (St Thomas’ solution for 2 minutes before ischemia). This significantly reduced the incidence of ventricular fibrillation during early reperfusion. The extent of the initial postischemic recovery of LVDP was similar to that observed without cardioplegia; however, the mean secondary recovery was greater in all groups. Again, the relation of early transient (2 to 5 minutes) recovery to the duration of ischemia was represented by a bell-shaped curve, whereas the secondary recovery was inversely related.

Conclusions
Although the results of the present study confirm the protective properties of cardioplegia, they also shed some light on the nature of reperfusion-induced injury and myocardial stunning and their complex relation to the severity of the preceding ischemia.
Early Left Ventricular Dysfunction Elicits Activation of Sympathetic Drive and Attenuation of Parasympathetic Tone in the Paced Canine Model of Congestive Heart Failure
Authors: Eaton Gregory M. , Cody Robert J. , Nunziata Enrico , Binkley Philip F.
Published: June 2012

Background
Although autonomic imbalance is known to be characteristic of patients with clinically overt symptomatic congestive heart failure, it is currently unknown whether this autonomic response arises early in the course of left ventricular dysfunction or is restricted to the later stages of circulatory failure.

Methods and Results
This investigation utilized the technique of spectral analysis of heart rate variability in a paced canine model of congestive heart failure that permits an examination of autonomic activity at the earliest stages of ventricular dysfunction to determine whether early systolic dysfunction in congestive heart failure is characterized by autonomic imbalance, which may contribute to subsequent myocardial and vascular dysfunction. The results indicate that autonomic imbalance as reflected in an abnormal pattern of heart rate variability evolves early in the course of ventricular systolic dysfunction consisting of both a significant increase in sympathetically influenced low-frequency heart rate variability and a significant reduction of parasympathetically mediated high-frequency variability. This was quantified by a marked and significant increase in the area under the low-frequency region from 0.053±0.037 (beats per minute)
2
at baseline to 0.182±0.143 (beats per minute)
2
at 48 hours to 0.253± 0.202 (beats per minute)
2
after 7 days of pacing (ANOVA,
P
<.04). The area under the high-frequency region of the curve showed a decrease from a baseline value of 0.945±0.037 (beats per minute)
2
to 0.811±0.152 (beats per minute)
2
at 48 hours to 0.733±0.197 (beats per minute)
2
after 7 days of pacing (ANOVA,
P
<.03). This resulted in a shift in autonomic balance away from parasympathetic tone and toward augmented sympathetic drive as reflected by the ratio of high- to low-frequency areas from a baseline value of 15.2±9.6 to 10.1±6.89 at 48 hours and 0.004±0.001 at 7 days (ANOVA,
P
<.01).

Conclusions
The results indicate that autonomic imbalance as reflected in an abnormal pattern of heart rate variability evolves early in the course of ventricular systolic dysfunction consisting of both a significant increase in sympathetically influenced low-frequency heart rate variability and a significant reduction of parasympathetically mediated high-frequency variability. The early appearance of these autonomic abnormalities suggests that autonomic imbalance plays a significant role in promoting the progression of circulatory failure.
Angiotensin II Augments Reflex Activity of the Sympathetic Nervous System During Cardiopulmonary Resuscitation in Pigs
Authors: Lindner Karl H. , Prengel Andreas W. , Pfenninger Ernst G. , Lindner Ingrid M.
Published: June 2012

Background
During hypotensive states, angiotensin II augments reflex activity of the sympathetic nervous system. The purpose of the present study was to assess the effects of this vasoconstrictor on myocardial blood flow and plasma catecholamine concentrations during and after CPR.

Methods and Results
After 4 minutes of ventricular fibrillation and 3 minutes of open-chest CPR, 14 pigs (24 to 26 kg) were randomized into two groups receiving either saline (n=7) or 0.05 mg/kg angiotensin II (n=7). Arterial plasma catecholamine concentration was measured with high-pressure liquid chromatography. Organ blood flow was measured with radiolabeled microspheres. During CPR, after drug administration, left ventricular myocardial blood flow was significantly higher in the angiotensin II–treated group than in the control group. During CPR, median epinephrine concentrations before and 90 seconds and 5 minutes after drug administration were 63.0, 35.2, and 22.5 ng/mL, respectively, in the control group and 63.2, 139.8, and 154.2 ng/mL, respectively, in the angiotensin II group (
P
<.001 at 90 seconds and
P
<.01 at 5 minutes). At the same times, median norepinephrine concentrations were 52.6, 59.8, and 33.9 ng/mL, respectively, in the control group and 42.5, 98.7, and 111.3 ng/mL, respectively, in the angiotensin II group (
P
<.01 at 5 minutes). Restoration of spontaneous circulation was possible in all of the angiotensin II–treated pigs, whereas only 3 of the 7 saline-treated pigs could be resuscitated. At 5 minutes after successful resuscitation, epinephrine was 6.8 ng/mL in the control group and 16.1 ng/mL in the angiotensin II group (
P
<.05).

Conclusions
During CPR, angiotensin II appears to increase coronary perfusion pressure and myocardial blood flow, not only by direct peripheral arteriolar vasoconstriction via angiotensin II receptors but also by inducing a massive catecholamine release with adrenergic peripheral vasoconstriction.
Hirulog in the Treatment of Unstable Angina
Authors: Fuchs Joanna , Cannon Christopher P.
Published: June 2012

Background
Direct thrombin inhibitors are a new class of drugs that may offer a more effective and potentially simpler alternative to heparin. Hirulog is a synthetic peptide based on the leech-derived compound hirudin and, like hirudin, is a highly specific, direct inhibitor of free and clot-bound thrombin.

Methods and Results
TIMI 7 was a randomized, double-blind study of Hirulog, given with 325 mg/d aspirin to 410 patients with unstable angina. Patients received a constant infusion of Hirulog for 72 hours at one of four doses: 0.02 (n=160), 0.25 (n=81), 0.5 (n=88), and 1.0 (n=81) mg · kg
−1
· h
−1
. The primary efficacy end point was “unsatisfactory outcome,” defined as death, nonfatal myocardial infarction (MI), rapid clinical deterioration, or recurrent ischemic pain at rest with ECG changes by 72 hours. Unsatisfactory outcome was not different among the four dose groups: 8.1%, 6.2%, 11.4%, and 6.2% (
P
=NS). However, the secondary end point of death or nonfatal MI through hospital discharge occurred in 10.0% of patients treated with 0.02 mg · kg
−1
· h
−1
compared with 3.2% of patients treated with the three higher doses of Hirulog (0.25, 0.5, and 1.0 mg · kg
−1
· h
−1
,
P
=.008). Only 2 of 410 patients (0.5%) experienced a major hemorrhage attributed to Hirulog.

Conclusions
The direct thrombin inhibitor Hirulog is a promising new antithrombotic agent that deserves further study. The results of TIMI 7 lend support to the use of an antithrombin agent with aspirin in patients with unstable angina.
In-Hospital Cost of Percutaneous Coronary Revascularization
Authors: Ellis Stephen G. , Miller Dave P. , Brown Kimberly J. , Omoigui Nowa , Howell Georgiana L. , Kutner Michael , Topol Eric J.
Published: June 2012

Background
Hospital charges associated with percutaneous transluminal coronary revascularization (PTCR) in the United States exceeded $6 billion in 1994 and are likely to be constrained in some manner in the near future. Despite this high cost to the public, little is known about the major determinants and sources of variability of PTCR.

Methods and Results
From a consecutive series of 1258 procedures with attempted PTCR at a single tertiary referral center, we analyzed 65 clinical, angiographic, physician, and outcome variables as potential correlates of total (hospital and physician) cost. Direct and indirect costs, both hospital and physician, were determined on the basis of resource utilization using “top-down” methodology and were available for 1237 procedures (1086 patients) (98.3%). Mean (±SD) patient age was 62±11 years, 76% were male, 3% had acute myocardial infarction, 71% had unstable angina, 58% had multivessel disease, left ventricular ejection fraction was 54±12%, 26% had use of at least one nonballoon revascularization device, and median length of stay was 4.4 days. Procedural success was obtained in 89%, and major complications (death, bypass surgery, or Q-wave myocardial infarction) occurred in 3.8%. The median cost was $9176, but it was asymmetrically distributed, and the interquartile and total ranges were wide ($7333 to $13 845 and $3422 to $193 474, respectively). Analyses of independent correlates of cost and log

e

(cost) were performed using multivariate linear regression in training and test populations. Modeling found 15 independent preprocedural correlates of log

e

(cost) (
R
2
=.37) and 23 overall correlates (
R
2
=.65), excluding length of stay per se. Addition of length of stay to the model increased the explanatory power of the model to
R
2
=.82. Preprocedural variables most predictive of log

e

(cost) included presentation with acute myocardial infarction, decision delay (>48 hours between admission and diagnostic angiography and/or >24 hours between angiography and intervention), weekend delay, use of intra-aortic balloon counterpulsation, intention to stent, creatinine ≥2.0 mg%, and lesion complexity (modified American College of Cardiology/American Heart Association score) (all
P
<.001). In the model that included postprocedural variables as well, length of stay, noncardiac death, urgent bypass surgery, use of the Rotablator, Q-wave myocardial infarction, rise in creatinine ≥1.0%, and blood product transfusion were all strong independent correlates of log

e

(cost) (
P
<.001).

Conclusions
The range of total hospital costs associated with percutaneous intervention is extraordinarily wide. Baseline patient characteristics account for nearly half of the explained variance, but procedural complications and system delays account for much of the remainder. Quantification of the determinants of cost may promote more economically efficient care in the future.
Carcinoid Heart Disease
Authors: Robiolio Paul A. , Rigolin Vera H. , Wilson John S. , Harrison J. Kevin , Sanders Linda L. , Bashore Thomas M. , Feldman Jerome M.
Published: June 2012

Background
Although serotonin has been postulated as an etiologic agent in the development of carcinoid heart disease, no direct evidence for different ambient serotonin levels in cardiac and noncardiac patients has been reported to date.

Methods and Results
The present study reviews our experience with 604 patients in the Duke Carcinoid Database. Nineteen patients with proven carcinoid heart disease (by cardiac catheterization and/or echocardiogram) were compared with the remaining 585 noncardiac patients in the database with regard to circulating serotonin and its principal metabolite, 5-hydroxyindole acetic acid (5-HIAA). No significant demographic differences existed between the cardiac and noncardiac groups; however, typical carcinoid syndrome symptoms (ie, flushing and diarrhea) were almost threefold more common in the cardiac group (
P
<.001). Compared with the noncardiac group, heart disease patients demonstrated strikingly higher (
P
<.0001) mean serum serotonin (9750 versus 4350 pmol/mL), plasma serotonin (1130 versus 426 pmol/mL), platelet serotonin (6240 versus 2700 pmol/mg protein), and urine 5-HIAA (219 versus 55.3 mg/24 h) levels. The spectrum of heart disease among the 19 patients showed a strong right-sided valvular predominance, with tricuspid regurgitation being the most common valvular dysfunction (92% by cardiac catheterization; 100% by echocardiogram).

Conclusions
These data suggest that serotonin plays a major role in the pathogenesis of the cardiac plaque formation observed in carcinoid patients.
Impact of Left Ventricular Unloading After Late Reperfusion of Canine Anterior Myocardial Infarction on Remodeling and Function Using Isosorbide-5-Mononitrate
Authors: Jugdutt Bodh I. , Khan Mohammad I. , Jugdutt S. Joanne , Blinston Gordon E.
Published: June 2012

Background
Late reperfusion during acute myocardial infarction results in delayed recovery of ventricular function and less remodeling, whereas ventricular unloading with nitrates improves function and attenuates remodeling. Whether late reperfusion combined with prolonged unloading with isosorbide-5-mononitrate (ISMN) might produce greater functional recovery and less remodeling than late reperfusion alone is not known.

Methods and Results
In vivo left ventricular function and topography (echocardiograms), postmortem topography (planimetry), and collagen (hydroxyproline) were measured in dogs that were randomized to reperfusion 2 hours after left anterior descending coronary artery ligation, and ISMN (n=12) or placebo (n=12) was given as 25 mg IV over 4 hours followed by 50 mg PO QID for 6 weeks. Compared with placebo, the ISMN group had similar heart rate but lower left atrial pressure, mean arterial pressure, and rate-pressure products. Although in vivo baseline remodeling and functional parameters were similar in the two groups, by 6 weeks the ISMN group had smaller (
P
≤.05) infarct and noninfarct segment lengths, ventricular volumes, and mass; less (
P
<.001) asynergy; and greater (
P
<.001) ejection fraction. More important, by 2 days, ejection fraction was 18% greater (
P
<.025) and asynergy 26% less (
P
<.05) with ISMN. At 6 weeks, ISMN showed less (
P
≤.05) scar size, scar collagen, cavity dilation, noninfarct wall thickness, and apical bulging than placebo. In another 4 dogs, acute ISMN produced less improvement in function and remodeling than prolonged ISMN.

Conclusions
Late reperfusion of acute anterior myocardial infarction combined with prolonged ISMN unloading results in greater and earlier recovery of ventricular function and less remodeling than late reperfusion alone.