bluuebunny/crossref_metadata_2025 huggingface dataset:
Cholesterol Management in Theory and Practice
Authors: Gotto Antonio M.
Published: June 2012

Abstract
The preponderance of evidence confirms the importance of aggressive lipid modification in patients at risk for coronary heart disease (CHD). However, data suggest that this information is underimplemented in the clinical setting, even in patients with existing CHD, in whom the greatest benefit of such treatment has been shown. The fact that many practitioners do not pursue a proven treatment strategy in patients who qualify must be redressed through education and reinforcement of existing recommendations. In the present review, the current clinical and mechanistic understanding of the benefit of aggressive lipid management is summarized, with a focus on the clinical implications of recent findings. These include growing public awareness of cholesterol as a modifiable CHD risk factor, recommendations for earlier and more aggressive intervention in patients with existing disease, and discussion of the cost-effectiveness of lipid-regulating therapy. Despite the secular trend of declining CHD morbidity and mortality rates in recent years, CHD remains the leading cause of death in both men and women in the United States. It is imperative to prevent any reduction in public focus on primary and secondary prevention.
Hemodynamic Effects of Chronic Prenatal Ventricular Pacing for the Treatment of Complete Atrioventricular Block
Authors: Liddicoat John R. , Klein Judith R. , Reddy V. Mohan , Klautz Robert J. M. , Teitel David F. , Hanley Frank L.
Published: June 2012

Background
Increasing the heart rate of the fetus with cardiac failure caused by complete AV block (CAVB) may allow delivery of a full-term, stable neonate with preserved ventricular function. Direct fetal pacing may be a feasible method to achieve this, but the effect of pacing on the structure and function of the rapidly developing fetal heart is unknown.

Methods and Results
CAVB was created in fetal lambs at 80% gestation by cryoablating the AV node. Epicardial ventricular pacing at 130 bpm was achieved by use of a pacemaker placed under the pectoral muscles. The fetus was returned to the uterus and allowed to continue to term. Ventricular function was assessed 1 week after birth in 7 lambs with CAVB and 10 control lambs. By use of the conductance catheter technique, the end-systolic pressure-volume relationship was determined at different heart rates, pacing conditions, and inotropic states. The contractility was not different between the two groups at their baseline heart rates and rhythms or when they were paced synchronously compared with asynchronously. Also, both groups responded significantly and similarly to inotropic manipulation, indicating preserved contractile reserve. Finally, in both groups, increased heart rates were associated with increased contractility, indicating an intact force-frequency relationship.

Conclusions
We conclude that chronic epicardial ventricular pacing is well tolerated by the fetus, can be successfully applied as a treatment for CAVB, and does not adversely affect myocardial function in the rapidly developing, immature heart.
Prostacyclin Receptor Desensitization Is a Reversible Phenomenon in Human Platelets
Authors: Fisch Andreas , Tobusch Karen , Veit Kerstin , Meyer Jürgen , Darius Harald
Published: June 2012

Background
Long-term exposure of platelets to endogenous or exogenous prostacyclin or its analogues might result in desensitization of the platelet prostacyclin receptor in vitro and in vivo accompanied by a loss in receptor density on the platelet surface and a reduced sensitivity toward the inhibitory effects of prostacyclins. However, the reversibility of this process in platelets has not yet been investigated.

Methods and Results
Human platelets desensitized by the chemically stable prostacyclin analogue iloprost showed a significant reduction in [
3
H]-iloprost binding sites that was reversed by saponin permeabilization. This indicates functionally active internalized prostacyclin receptors. To assess whether the internalized prostacyclin receptors recycle to the cell surface after withdrawal of the agonist, iloprost sensitivity and prostacyclin receptor binding properties of iloprost (30 nmol/L, 2 hours) desensitized platelets incubated in iloprost-free autologous plasma were investigated. While desensitized platelets showed a significant increase in IC
50
for iloprost inhibition of thrombin-induced platelet aggregation, serotonin release, and
p
-selectin expression and a reduced iloprost-stimulated cAMP formation, platelet iloprost sensitivity was restored 3 hours after iloprost withdrawal. In addition, the significant reduction in B
max
and the increase in
K
D
of prostacyclin receptors in desensitized platelets as revealed by [
3
H]-iloprost binding studies also returned to the initial values.

Conclusions
These results indicate that prostacyclin receptors internalized during short-term desensitization are not degraded but can be recycled rapidly to the platelet surface in a functionally active form after withdrawal of the agonist.
Postextrasystolic Potentiation and Dobutamine Echocardiography in Predicting Recovery of Myocardial Function After Coronary Bypass Revascularization
Authors: Scognamiglio Roldano , Fasoli Giuseppe , Casarotto Dino , Miorelli Manuela , Nistri Stefano , Palisi Monica , Marin Marco , Volta Sergio Dalla
Published: June 2012

Background
Identification of viable but hibernating myocardium remains a relevant issue in the current era of myocardial revascularization. Echocardiography can be helpful in detecting reversible contractile dysfunction and optimizing the selection of patients for coronary bypass surgery.

Methods and Results
Eighty-four consecutive candidates for bypass surgery with chronic multivessel coronary artery disease were screened, and 60 were included in this prospective study. Preoperative evaluation of a reversible contractile dysfunction in asynergic myocardial regions was performed by dobutamine infusion at 5 (low dose) and 10 (intermediate dose) μg·kg
−1
·min
−1
with each stage lasting at least 5 minutes; postextrasystolic potentiation (PESP), with a coupling interval ranging from 500 to 300 ms with a progressive 10-ms decrease; or a combination of both dobutamine infusion and PESP. Sensitivity (92% versus 86%) and predictive accuracy (89% versus 84%) were higher with PESP than dobutamine (
P
=.009 and
P
=.001, respectively), but the combination did not improve sensitivity or accuracy. Dobutamine induced ischemic dysfunction in 15% of patients at the intermediate dose; however, the low dose resulted in loss of sensitivity.

Conclusions
PESP echocardiography is a useful and cost-effective method to identify viable myocardium in patients with multivessel coronary disease undergoing revascularization and is more sensitive and accurate than dobutamine infusion.
ACE Inhibition
Authors: Lyons Declan , Roy Suzanne , O’Byrne Sharon , Swift Cameron G.
Published: June 2012

Background
The mechanisms by which ACE inhibitors produce a sustained clinical benefit are not entirely clear but may involve the sympathetic nervous system. We compared the effect of local brachial artery infusions of an ACE inhibitor (perindoprilat) with the effect of placebo (0.9% NaCl) on endogenously mediated (lower body negative pressure [LBNP]) and exogenously mediated (brachial artery infusions of norepinephrine) sympathetic vasoconstriction.

Methods and Results
Eight healthy, normotensive male volunteers (20 to 32 years) were studied on one occasion. Forearm blood flow (FABF; mL · dL forearm
−1
· min
−1
) responses to LBNP (−20 cm H
2
O) and increasing increments of norepinephrine (60, 120, and 240 pmol/min) were compared when coinfused with placebo and perindoprilat (5 nmol/mL). FABF was measured simultaneously in both arms by venous occlusion plethysmography with mercury-in-Silastic strain gauges with drugs infused locally at the left brachial artery. The right arm served as a control. Baseline FABFs did not differ between the infused and control arms (3.04±0.52 versus 3.05±0.42 mL · dL forearm
−1
· min
−1
;
P
=.98). Perindoprilat did not alter FABF when infused alone, but the FABF response to LBNP in the infused arm was attenuated during the perindoprilat infusion compared with placebo (−17.8±4.3% versus −33.8±3.1%, respectively;
P
=.015). The FABF response to the maximum dose of norepinephrine was also attenuated during the perindoprilat infusion compared with placebo (−28.3±1.4% versus −36.9±2.8%, respectively;
P
=.015). The mean slope of the FABF (log transformed) versus norepinephrine dose-response curve was significantly attenuated by perindoprilat compared with placebo (−0.11±0.019 versus −0.02±0.02;
P
=.001).

Conclusions
We conclude that ACE inhibition has a significant postsynaptic sympatholytic effect in the forearm circulation of men.
Both Dietary Fish-Oil Supplementation and Aspirin Fail to Inhibit Atherosclerosis in Long-term Vein Bypass Grafts in Moderately Hypercholesterolemic Nonhuman Primates
Authors: Boerboom Lawrence E. , Olinger Gordon N. , Almassi G. Hossein , Skrinska Victor A.
Published: June 2012

Background
Aortocoronary vein bypass grafts are vulnerable to late atherosclerotic occlusion. Conventional platelet inhibitor therapy provides early but not persistent protection against graft failure. Evidence suggests that consumption of marine foods may reduce cardiovascular disease, possibly because of the unique long-chain unsaturated ω-3 fatty acids present in these foods. We hypothesized that dietary fish-oil supplementation would protect against atherosclerosis in vein bypass grafts.

Methods and Results
Thirty-three moderately hypercholesterolemic cynomolgus macaques were divided into four groups: control, control+aspirin, fish oil, and fish oil+aspirin. Each control group received olive oil as placebo to equalize calorie and fat consumption with that of the fish-oil groups. Both oils were in ethyl ester form, with the fish oil providing 0.88 g/d eicosapentaenoic acid. The aspirin dose was 40 mg/d. Cephalic vein grafts were interposed bilaterally in the carotid arteries and excised for analysis at 4 years. Bleeding time was significantly prolonged in all groups receiving fish oil or aspirin (
P
<.05). Plasma cholesterol levels were similar among groups, averaging 6.9±2.4 mmol/L (267±94 mg/dL). The extent of atherosclerosis in vein grafts did not differ among groups as evaluated both by Sudan IV staining of intimal lipid lesions (27±21% of total surface area,
P
=.89) and analysis of cholesterol content (236±203 nmol/mg, 9.1±7.8 μg/mg,
P
=.85). Vein graft connective tissue composition was also unaffected by treatment.

Conclusions
Our findings do not support the use of concentrated dietary fish-oil supplements or aspirin for the prevention of atherosclerosis in long-term vein bypass grafts. Consumption of fish flesh or less refined oil preparations could have effects different from those of the purified fish-oil ethyl esters we used.
Evidence for Primary Genetic Determination of Heart Rate Regulation
Authors: Kreutz Reinhold , Struk Berthold , Stock Phillippe , Hübner Norbert , Ganten Detlev , Lindpaintner Klaus
Published: June 2012

Background
We investigated whether an accelerated heart rate (HR), observed in the stroke-prone spontaneously hypertensive rat (SHRSP
HD
), is a primary, genetically determined trait and whether it contributes to blood pressure (BP) regulation in this model of polygenic hypertension.

Methods and Results
We measured BP and HR in SHRSP
HD
and normotensive Wistar-Kyoto rats (WKY), as well as in F
2
hybrids bred from crossing the two strains, at baseline and after 12 days of dietary NaCl loading. Random marker genome screening and cosegregation analysis were performed on F
2
hybrids derived from SHRSP
HD
/WKY-0
HD
(n=115) and SHRSP
HD
/WKY-1
HD
(n=139) crosses (WKY-0
HD
and WKY-1
HD
are two congenic WKY strains). HR in SHRSP
HD
was significantly higher than in WKY-0
HD
both at baseline (404±30 versus 375±46 bpm;
P
=.0034) and after NaCl (437±23 versus 364±40 bpm;
P
=10
−9
). BP in F
2
hybrids showed no significant correlation with HR either at baseline or after NaCl loading. HR after NaCl loading but not at baseline was significantly linked in a recessive fashion to a locus on chromosome 3: in animals homozygous for the SHRSP
HD
allele, HR was 414±49 compared with 383±44 bpm in heterozygotes and WKY homozygotes (F
210,1
=19.7,
P
=1.4×10
−5
, lod score=5.9). The putative BP-relevant gene at this locus, termed
HR-SP1
, showed no evidence of linkage to any of the BP parameters measured.

Conclusions
Our results demonstrate that a genetic locus on rat chromosome 3,
HR-SP1
, contributes directly to the regulation of HR in SHRSP
HD
but exhibits no effect on BP. Thus, in addition to its modulation by reflex-mediated neurohumoral mechanisms, HR is also under the direct influence of primary genetic factors.
Sustained Platelet Glycoprotein IIb/IIIa Blockade With Oral Xemilofiban in 170 Patients After Coronary Stent Deployment
Authors: Kereiakes Dean J. , Kleiman Neal , Ferguson James J. , Runyon John Paul , Broderick Thomas M. , Higby Nancy A. , Martin Linda H. , Hantsbarger Gary , McDonald Shawn , Anders Robert J.
Published: June 2012

Background
Inhibition of platelet aggregation with parenteral glycoprotein (GP) IIb/IIIa receptor blockers can reduce the ischemic complications of angioplasty. Sustained efficacy and safety of protracted GP IIb/IIIa blockade with an orally administered agent have not previously been determined. This study is the first randomized, dose-ranging, single-blind, placebo-controlled trial of xemilofiban, an oral platelet GP IIb/IIIa receptor antagonist, administered to patients after intracoronary stent deployment. The pharmacodynamic efficacy of xemilofiban-induced platelet inhibition and clinical safety of this agent was evaluated during chronic therapy.

Methods and Results
After elective intracoronary stent deployment, patients were randomized to receive placebo (250 mg ticlopidine PO BID) or xemilofiban in doses of 5, 10, 15, or 20 mg PO BID. All patients received 325 mg aspirin PO QD. Inhibition of ex vivo platelet aggregation in response to 20 μmol/L ADP and 4 μg/mL collagen was measured over time after the initial dose of study drug and at 1 and 2 weeks of chronic therapy. Study drug was discontinued after 2 weeks, and all patients were followed clinically for ≥30 days. Oral xemilofiban resulted in a dose-dependent inhibition of platelet aggregation in response to both agonists that was sustained through 2 weeks of chronic therapy. Doses of xemilofiban required to achieve ≥50% inhibition of platelet aggregation were ≥10 mg, and the duration of inhibition was 8 to 10 hours. No significant hemorrhagic episodes or blood transfusions were observed in this trial.

Conclusions
Oral xemilofiban in doses of ≥10 mg produced ≥50% inhibition of platelet aggregation in response to ADP and collagen for 8 to 10 hours after dosing. Platelet inhibition was sustained through 2 weeks of chronic therapy. The optimal duration of oral GP IIb/IIIa blockade to effectively suppress recurrent ischemic events after coronary intervention remains to be determined.
Heterogeneous Sympathetic Innervation in German Shepherd Dogs With Inherited Ventricular Arrhythmia and Sudden Cardiac Death
Authors: Dae Michael W. , Lee Randall J. , Ursell Philip C. , Chin Michael C. , Stillson Carol A. , Moise N. Sydney
Published: June 2012

Background
Recently, a colony of German shepherd dogs with inherited spontaneous cardiac arrhythmias and associated sudden death has been developed and characterized. Due to the median age of onset of the arrhythmia (4.5 months), the tendency for the arrhythmia to occur during REM sleep or after exercise, and the absence of structural heart disease, we hypothesized a developmental abnormality of the sympathetic innervation to the heart.

Methods and Results
We studied 11 dogs from this colony, ranging in age from 6 months to 6 years, and four 7-month-old German shepherd dogs unrelated to the colony as controls. We imaged the distribution of functional myocardial sympathetic innervation and perfusion with [
123
I]metaiodobenzylguanidine (MIBG) and
201
Tl, respectively. Sympathetic nerve distribution was evaluated morphologically by immunocytochemical localization of tyrosine hydroxylase. All of the hearts showed evidence of a regional decrease in MIBG uptake, ranging from 5.3% to 53.4% of the myocardium, whereas control dogs showed homogeneous MIBG uptake. Immunocytochemical studies on sections from regions with decreased MIBG uptake showed a striking paucity of nerves compared with regions with normal MIBG uptake, confirming denervation. When the dogs were grouped into those with (n=6) and without (n=5) evidence of ventricular tachycardia on ambulatory ECG, the group with ventricular tachycardia showed 35±16.5% denervation, whereas the group without ventricular tachycardia showed 12±5.6% denervation (
P
<.02).

Conclusions
Abnormal heterogeneous sympathetic innervation exists in these dogs with inherited ventricular arrhythmia and sudden cardiac death. Mechanisms relating the presence and extent of regional denervation to the incidence of ventricular arrhythmia remain to be defined.
Serum Cholesterol and Mortality Rates in a Native American Population With Low Cholesterol Concentrations
Authors: Fagot-Campagna Anne , Hanson Robert L. , Narayan K. M. Venkat , Sievers Maurice L. , Pettitt David J. , Nelson Robert G. , Knowler William C.
Published: June 2012

Background
Low serum cholesterol concentrations are associated with high death rates from cancer, trauma, and infectious diseases, but the meaning of these associations remains controversial. The present report evaluates whether low cholesterol is likely to be a causal factor for mortality from all causes or from specific causes.

Methods and Results
Among 4553 Pima Indians ≥20 years old, a population with low serum cholesterol (median, 4.50 mmol/L), 1077 deaths occurred during a mean follow-up of 12.8 years. Trauma was the most common cause. The relationship between serum cholesterol measured at 2-year intervals and age- and sex-standardized mortality rates was U-shaped. Cholesterol was related positively to mortality from cardiovascular diseases and diabetes (including nephropathy) and negatively to mortality from cancer and alcohol-related diseases. The relationship was U-shaped for mortality from infectious diseases, and cholesterol was not related to mortality from trauma. Change in cholesterol from one examination to the next was positively related to mortality from diabetes. In proportional-hazards models adjusted for potential confounders, the relationship between baseline cholesterol and mortality was U-shaped for all causes and diabetes and positive for cardiovascular diseases. Other relationships were nonsignificant. Among 3358 subjects followed ≥5 years, the relationship was significant and positive only for mortality from cardiovascular diseases.

Conclusions
Despite a high exposure risk for Pima Indians, if low cholesterol level is a causal factor, the relationships between low serum cholesterol and high mortality rates probably result from diseases lowering cholesterol rather than from a low cholesterol causing the diseases.
Circadian Variation of Paroxysmal Atrial Fibrillation
Authors: Yamashita Takeshi , Murakawa Yuji , Sezaki Kazunori , Inoue Masashi , Hayami Noriyuki , Shuzui Yutaka , Omata Masao
Published: June 2012

Background
Circadian variation in the incidence of acute cardiovascular events is well known but has not been extensively investigated in paroxysmal atrial fibrillation, although the significance of this arrhythmia is growing in our society with the increasing number of aged people.

Methods and Results
We detected 150 patients with paroxysmal atrial fibrillation in a drug-free state from among 25 500 consecutive Holter recordings. To determine whether the onset, maintenance, and termination of paroxysmal atrial fibrillation were random events, we analyzed the total recorded duration of arrhythmia and the incidence of and number of patients with the onset, maintenance, and termination of this arrhythmia as hourly data and as hourly probabilities. A prominent circadian rhythm of the total duration of atrial fibrillation, ≈90% of which was well explained by a single cosinusoidal function, was detected with a nadir around 11
am
. Because the onset of the arrhythmia had little or no circadian rhythm, this finding was due to a diurnal pattern of maintenance and termination, both of which were well expressed by a double-harmonic density function. Maintenance showed a trough at 11
am,
and termination showed a peak at the same time, leading to the nonuniform duration of single episodes of atrial fibrillation throughout the 24-hour day.

Conclusions
Paroxysmal atrial fibrillation showed a unique circadian variation that differed from the well-known pattern for acute cardiovascular events, a point that should be kept in mind when antiarrhythmic therapy is evaluated. Identification of factors that regulate the circadian pattern of the maintenance and termination of paroxysmal atrial fibrillation may lead to better chronotherapy for preventing perpetuation of this arrhythmia.
Beat-to-Beat QT Interval Variability
Authors: Berger Ronald D. , Kasper Edward K. , Baughman Kenneth L. , Marban Eduardo , Calkins Hugh , Tomaselli Gordon F.
Published: June 2012

Background
Dilated cardiomyopathy (DCM) is associated with a high incidence of malignant ventricular arrhythmias and sudden death. Abnormalities in repolarization of ventricular myocardium have been implicated in the development of these arrhythmias. Spatial heterogeneity in repolarization has been studied in DCM, but temporal fluctuations in repolarization in this setting have been largely ignored. We sought to test the hypothesis that beat-to-beat QT interval variability is increased in DCM patients compared with control subjects.

Methods and Results
Eighty-three patients with ischemic and nonischemic DCM and 60 control subjects served as the study population. Beat-to-beat QT interval variability was measured by automated analysis on the basis of 256-second records of the surface ECG. A QT variability index (QTVI) was calculated for each subject as the logarithm of the ratio of normalized QT variance to heart rate variance. The coherence between heart rate and QT interval fluctuations was determined by spectral analysis. In patients, ejection fractions were assessed by echocardiography or ventriculography, and spatial QT dispersion was determined from the standard 12-lead ECG. DCM patients had greater QT variance than control subjects (60.4±63.1 versus 25.7±24.8 ms
2
,
P
<.0001) despite reduced heart rate variance (6.7±7.8 versus 10.5±10.4 bpm
2
,
P
=.01). The QTVI was higher in DCM patients than in control subjects, with a high degree of significance (−0.43±0.71 versus −1.29±0.51,
P
<10
−12
). QTVI did not correlate with ejection fraction or spatial QT dispersion but did depend on New York Heart Association functional class. QTVI did not differ between DCM patients with ischemic and those with nonischemic origin. Coherence between heart rate and QT interval fluctuations at physiological frequencies was lower in DCM patients compared with control subjects (0.28±0.14 versus 0.39±0.18,
P
<.0001).

Conclusions
DCM is associated with beat-to-beat fluctuations in QT interval that are larger than normal and uncoupled from variations in heart rate. QT interval variability increases with worsening functional class but is independent of ejection fraction. These data indicate that DCM leads to temporal lability in ventricular repolarization.
Angiotensin II Increases Tissue Endothelin and Induces Vascular Hypertrophy
Authors: Moreau Pierre , d’Uscio Livius V. , Shaw Sidney , Takase Hiroyuki , Barton Matthias , Lüscher Thomas F.
Published: June 2012

Background
In vitro studies on vascular smooth muscle cells suggest that endothelin has a stimulating effect on cellular proliferation. This study was designed to determine the endogenous effect of endothelin on angiotensin II–induced hypertrophy of small arteries in vivo.

Methods and Results
Two weeks of angiotensin II administration (200 ng·kg
−1
·min
−1
) increased media thickness, media/lumen ratio, and cross-sectional area of basilar and small mesenteric arteries, confirming the proliferative properties of angiotensin II. The tissue levels of endothelin-1 were elevated in mesenteric arteries after angiotensin II administration. The administration of the selective and specific ET
A
-receptor antagonist
LU135252
(50 mg·kg
−1
·d
−1
) in combination with angiotensin II prevented the changes of vascular geometry and partially reduced the increase in blood pressure induced by angiotensin II. Indeed, part of the effect on the vascular structure of the endothelin-receptor antagonist seemed pressure-independent.

Conclusions
Our results therefore demonstrate that angiotensin II increases the production of endothelin in the blood vessel wall that, via ET
A
receptors, mediates changes in vascular structure of the cerebral and mesenteric circulation. Endothelin antagonists may therefore be of value to reduce blood pressure and to prevent vascular structural changes in conditions of increased activity of the renin-angiotensin system.
Major Histocompatibility Complex Class II Antigen Expression in Rejecting Cardiac Allografts
Authors: McGhie A. Iain , Radovancevic Branislav , Capek Pavel , Moore Warren H. , Kasi Leela , Lamki Lamk , Clubb Fred J. , Frazier O. Howard , Willerson James T.
Published: June 2012

Background
Increased expression of major histocompatibility complex class II (MHC-II) antigen occurs during cardiac allograft rejection. We tested the hypotheses that (1) radiolabeled antibody to MHC-II antigen allows detection of cardiac allograft rejection using nuclear imaging techniques and (2) uptake of radiolabeled antibody to MHC-II antigen correlates with severity of rejection.

Methods and Results
Thirteen beagles with cervical cardiac allografts were studied for 64±23 days by use of myocardial biopsy and in vivo imaging. Uptake of radiolabeled (
131
I [n=2],
123
I [n=1], or
111
In [n=10]) antibody to MHC-II increased over baseline in 7 animals that developed histological evidence of progressively worsening allograft rejection (group A), from 72.2±46.1 to 176.8±102.0 counts/pixel/mCi (
P
<.009). In 4 beagles without progressively worsening allograft rejection (group B), uptake was unchanged during follow-up (74.4±43.8 and 60.2±37.4 counts/pixel/mCi;
P
=NS). In animals studied with
111
In-labeled antibody, uptake increased from 102.9±23.1 at baseline to 233.2±82.7 counts/pixel/mCi at follow-up in group A animals (
P
=.036), with no significant change in group B (91.1±34.9 and 75.9±24.9 counts/pixel/mCi;
P
=NS). Uptake of
111
In-labeled antibody was 107.5±35.7, 135.9±70.8, and 307.8±90.1 counts/pixel/mCi in biopsy samples showing evidence of mild, moderate, and severe rejection, respectively (
P
=.001). Biopsy samples showing mild, moderate, and intense MHC-II expression antibody uptake had uptakes of 92.6±36.3, 158.5±54.7, and 307.8±90.1 counts/pixel/mCi, respectively (
P
=.00004).

Conclusions
Radiolabeled monoclonal antibodies to MHC-II antigen can detect cardiac allograft rejection in this large mammal model of cardiac allograft transplantation, and this technique may have a potential role in the detection of rejection in patients after cardiac transplantation.
Blockade of Brain ‘Ouabain’ Prevents the Impairment of Baroreflexes in Rats After Myocardial Infarction
Authors: Huang Bing S. , Yuan Baoxue , Leenen Frans H. H.
Published: June 2012

Background
The purpose of this study was to test whether increased brain “ouabain” contributes to impairment of both arterial and cardiopulmonary baroreceptor reflexes in congestive heart failure (CHF).

Methods and Results
Two to 5 days after coronary artery ligation (MI) or sham surgery in male Wistar rats, chronic intracerebroventricular (ICV) infusion was started with either antibody Fab fragments, which bind ouabain and related steroids with high affinity, or γ-globulins as control (200 μg · 12 μL
−1
· d
−1
for both) with osmotic minipumps implanted subcutaneously. After 8 weeks of infusion, in conscious rats, mean arterial pressure (MAP), heart rate (HR), central venous pressure (CVP), and renal sympathetic nerve activity (RSNA) were recorded at rest and in response to ramp changes in blood pressure (BP) induced by intravenous phenylephrine and nitroprusside and to changes in CVP elicited by acute volume expansion with 5% dextrose. Compared with sham rats, in MI rats with ICV γ-globulins, resting MAP was significantly lower and CVP increased, and both arterial and cardiopulmonary baroreflex control of RSNA and HR were attenuated. ICV Fab fragments prevented the decrease in resting BP and largely prevented impairment of arterial and cardiopulmonary baroreflex control of both RSNA and HR.

Conclusions
These data indicate that increased brain ouabain plays a major role in the impairment of baroreflexes in rats with CHF after myocardial infarction.
Complex Causes of Fatal Myocardial Infarction
Authors: James Thomas N.
Published: June 2012

Abstract
It is too often deduced that myocardial infarction is due to coronary occlusion and that subsequent death needs no other explanation. But the great majority of myocardial infarctions are not fatal, whether treated or untreated. There is, of course, some relation to the size of the infarct and the presence or absence of complicating conditions such as diabetes mellitus or hypertension, but little attention has been directed at the myriad of other events and processes influencing the clinical course. Examples include the exact anatomic territory infarcted and whether it includes the sinus node or AV node or important neuroreceptors; whether many small arteries are occluded (especially downstream of narrowed main coronary branches); whether the heart is hypertrophied, dilated, infected, or infiltrated; and whether there may be intracardiac, extracardiac, or intracranial neuropathological conditions that could destabilize cardiac electrical activity. It is now known that apoptosis plays a major role in myocardial infarction or ischemia, but it also occurs within the heart completely independently of infarction. There is also the vexing dilemma that an effective coronary collateral circulation, which is determined primarily by transanastomotic pressure gradient, is made less effective by exactly those treatments that reestablish flow in an occluded coronary artery. Since thrombolysis and angioplasty are automatically considered urgent treatment for an occluded coronary artery, it is prudent to remember the complex causes that determine whether the patient lives or dies.
Influence of Diabetes on 5-Year Mortality and Morbidity in a Randomized Trial Comparing CABG and PTCA in Patients With Multivessel Disease
Authors: Investigators The BARI
Published: June 2012

Background
Patients with diabetes mellitus have increased morbidity and mortality after coronary revascularization. The Bypass Angioplasty Revascularization Investigation (BARI), a trial of percutaneous transluminal coronary angioplasty (PTCA) versus coronary artery bypass graft surgery (CABG) in patients with multivessel disease, reported a 5-year survival advantage of CABG over PTCA in patients with treated diabetes mellitus (TDM). This report examines these findings in more detail.

Methods and Results
Eighteen clinical centers randomly assigned 1829 patients with multivessel coronary disease to undergo initial CABG or PTCA. Patients were followed an average of 5.4 years. TDM was defined as a history of diabetes with use of oral hypoglycemic agents or insulin at study entry. Nineteen percent of the randomized population (353 patients) met these criteria. TDM patients had more unfavorable baseline characteristics than other patients, but among TDM patients, these characteristics were similar between the CABG and PTCA groups. Better average 5.4-year survival with CABG was due to reduced cardiac mortality (5.8% versus 20.6%,
P
=.0003), which was confined to those receiving at least one internal mammary artery graft.

Conclusions
Patients with TDM assigned to an initial strategy of CABG have a striking reduction in cardiac mortality compared with PTCA. Long-term internal mammary artery graft patency may contribute to this improved outcome by reducing the fatality of follow-up myocardial infarction.
Aortic Function in Arterial Hypertension Determined by Pressure-Diameter Relation
Authors: Stefanadis Christodoulos , Dernellis John , Vlachopoulos Charalambos , Tsioufis Costas , Tsiamis Eleftherios , Toutouzas Konstantinos , Pitsavos Christos , Toutouzas Pavlos
Published: June 2012

Background
Aortic elastic properties, important determinants of left ventricular function and coronary blood flow, are compromised in hypertension. The aim of this study was to determine aortic function in hypertensive patients and in normal subjects before and after administration of diltiazem, a calcium antagonist widely used in the treatment of essential hypertension.

Methods and Results
The aortic pressure-diameter relation was obtained before and after diltiazem administration in 15 hypertensives and 15 control normotensives. Instantaneous diameter of the thoracic aorta was acquired with a high-fidelity intravascular catheter developed in our institution and previously validated. Instantaneous aortic pressure was measured simultaneously and at the same aortic level with a catheter-tip micromanometer. Energy loss due to the viscosity of aortic wall was measured from the area of the loop. Aortic distensibility was calculated using the formula 2×(pulsatile change in aortic diameter)/([diastolic aortic diameter]×[aortic pulse pressure]). At baseline, aortic distensibility was lower and energy loss was greater in hypertensives than in normotensives (distensibility: 1.4±0.3 versus 3.5±0.7 cm
2
· dyne
−1
· 10
−6
, respectively,
P
<.001; energy loss: 14.1±3.3 versus 8.2±2.2 mm · mm Hg, respectively,
P
<.001). After diltiazem administration, aortic distensibility was increased, whereas energy loss was decreased in both hypertensives (peak response: distensibility, 2.0±0.4 cm
2
· dyne
−1
· 10
−6
,
P
<.001; energy loss, 9.3±1.6 mm · mm Hg,
P
<.001) and normotensives (peak response: distensibility, 5.2±0.5 cm
2
· dyne
−1
· 10
−6
,
P
<.001; energy loss, 5.0±1.2 mm · mm Hg,
P
<.001).

Conclusions
Aortic elastic properties are compromised and energy loss due to aortic wall viscosity is increased in hypertensives compared with normotensives. Function of the aorta is improved in both hypertensive and normotensive subjects after the administration of diltiazem.
Contrasting Effects of Conjugated Estrogens and Tamoxifen on Dilator Responses of Atherosclerotic Epicardial Coronary Arteries in Nonhuman Primates
Authors: Williams J. Koudy , Honoré Erika K. , Adams Michael R.
Published: June 2012

Background
Estrogens have been shown to improve dilator responses of atherosclerotic coronary arteries. Tamoxifen is a mixed estrogen agonist/antagonist with as yet unexplored effects on vascular function. Therefore, the goal of this study was to compare the effects of conjugated equine estrogens (CEEs) with those of tamoxifen on epicardial coronary artery dilator responses in atherosclerotic, ovariectomized monkeys.

Methods and Results
Fifty ovariectomized cynomolgus monkeys were fed an atherogenic diet for 34 months. During this time, monkeys were assigned to one of three treatment groups: (1) control, no hormone replacement (n=15); (2) CEEs mixed in the diet at a dose of 0.043 mg · kg
−1
· d
−1
(n=14); or (3) tamoxifen mixed in the diet at a dose of 1.3 mg · kg
−1
· d
−1
(n=21). Quantitative angiography was used to measure coronary artery dilator responses to intracoronary infusions of acetylcholine (10
−8
, 10
−7
, and 10
−6
mol/L) and nitroglycerin (15 μg/min). Coronary arteries of the tamoxifen-treated group constricted in response to high-dose acetylcholine (−5.4± 2.3%,
P
<.05 versus control), whereas those of the CEE group did not (
P
>.05 versus control). Conversely, arteries from the CEE group dilated in response to nitroglycerin (9.1±2.1%,
P
<.05 versus control), whereas those from the tamoxifen group did not (
P
>.05 versus control). Statistical adjustments for variations in plaque extent (determined subsequently after necropsy) and plasma lipoproteins did not alter the results.

Conclusions
Tamoxifen has primarily estrogen-antagonistic effects on epicardial coronary artery dilator responses in atherosclerotic monkeys. Results implicate the estrogen receptor as a modulator of coronary artery dilator responses in ovariectomized, atherosclerotic monkeys.
Pharmacological Modulation of Pressure-Overload Cardiac Hypertrophy
Authors: Wong Kit , Boheler Kenneth R. , Petrou Mario , Yacoub Magdi H.
Published: June 2012

Background
Appropriate cardiac hypertrophy (CH) is necessary in several clinical settings, such as pulmonary artery banding in the two-stage arterial switch operation for transposition of the great arteries. Pressure-overload CH, however, produces ventricular dysfunction due to structural and molecular changes. The β
2
-adrenergic receptor agonist clenbuterol has been shown to induce CH without such adverse effects to the rat heart. This study was performed to determine its effects on left ventricular (LV) function, structure, and gene expression in pressure-overload CH.

Methods and Results
Sprague-Dawley rats were assigned to one of four groups: 1, sham-operated (n=15); 2, banding of ascending aorta (n=22); 3, banding+clenbuterol (n=18); and 4, banding+thyroxine (n=17). At the end of 3 weeks, groups 2, 3, and 4 showed an increase in LV mass index of 49.7±5.1%, 66.1±3.8%, and 47.6±4.6%, respectively, relative to group 1. A subgroup with severe CH (>50%) in group 2 was found to have significantly impaired developed pressure and diastolic relaxation and an increase in passive stiffness, with significantly reduced LV expression of sarcoplasmic reticulum Ca
2+
-ATPase2a (SERCA2a) mRNA and increased LV collagen concentration. In comparison, similarly hypertrophied animals in groups 3 and 4 demonstrated improved developed pressure, normal relaxation and diastolic stiffness with normal collagen concentration, and a greater abundance of SERCA2a mRNA.

Conclusions
Clenbuterol administration in conjunction with pressure overload produces a specific type of CH with preserved LV function. In addition, an increase in LV mass was associated with less fibrosis and greater expression of SERCA2a mRNA than banding alone.
Local Expression of C-Type Natriuretic Peptide Markedly Suppresses Neointimal Formation in Rat Injured Arteries Through an Autocrine/Paracrine Loop
Authors: Ueno Hikaru , Haruno Akihiro , Morisaki Nobuhiro , Furuya Mayumi , Kangawa Kenji , Takeshita Akira , Saito Yasushi
Published: June 2012

Background
In vivo gene transfer into injured arteries may provide a new means to facilitate molecular understanding of and to treat the intractable fibroproliferative arterial diseases. Selection of an optimal molecule to be transferred will be a key to successful gene therapy in the future. We tested the hypothesis that a secreted multifactorial molecule should act more efficiently through an autocrine/paracrine loop to suppress neointimal formation elicited in injured arteries than a simple growth-inhibiting molecule that might be expressed inside cells.

Methods and Results
We constructed an adenoviral vector (AdCACNP) expressing C-type natriuretic peptide (CNP), a secreted stimulator of membrane-bound guanyl cyclase. AdCACNP directs cells to secrete large quantities of biologically active CNP. Serum-stimulated DNA synthesis and cell proliferation were only moderately suppressed in arterial smooth muscle cells infected with AdCACNP in vitro. However, when AdCACNP was applied to balloon-injured rat carotid arteries in vivo, neointimal formation was markedly reduced (90% reduction) in an infection-site–specific manner without an increase in plasma CNP level.

Conclusions
Our results showed that CNP, a secreted multifactorial molecule, was indeed effective in suppressing fibroproliferative response in injured arteries and suggest that the potent antiproliferation effect may not be the most critical factor for the effective suppression of neointimal formation. An adenovirus-mediated expression of CNP could be an effective and site-specific form of molecular intervention in proliferative arterial diseases.
Delayed Coronary Endothelial Protection 24 Hours After Preconditioning
Authors: Kaeffer Nathalie , Richard Vincent , Thuillez Christian
Published: June 2012

Background
Preconditioning (PC) induces delayed protection against myocardial ischemia/reperfusion (I/R) injury. Whether a similar late protective effect exists in coronary endothelial cells is not known. Thus, we assessed whether PC also induces late protection against endothelial injury after I/R and the potential role of reactive oxygen species as triggers for late PC in this setting.

Methods and Results
Rats were subjected to sham surgery or to PC with 1 cycle of 2 minutes I/5 minutes R and 2 cycles of 5 minutes I/5 minutes R in the absence or presence of the free radical scavenger
N
-2-mercaptopropionyl glycine (MPG). Twenty-four hours later, rats were subjected to 20 minutes I/60 minutes R in the absence or presence of MPG. At the end of R, coronary segments (diameter, 200 to 300 μm) were removed distal to the site of occlusion and mounted in wire myographs. I/R reduced the relaxations to acetylcholine (maximal relaxations: sham, 72±6%; I/R, 31±6%), and this impairment was prevented by MPG (64±7%). PC improved the response to acetylcholine (48±6%), but this beneficial effect was abolished by MPG (23±5%).

Conclusions
PC induces late protection against reperfusion-induced coronary endothelial injury. Moreover, in addition to being mediators of endothelial injury during reperfusion after prolonged ischemia, reactive oxygen species produced during PC also protect the coronary endothelium from reperfusion injury 24 hours later.
Decrease in Forces Responsible for Diastolic Suction During Acute Coronary Occlusion
Authors: Bell Stephen P. , Fabian Judit , Watkins Matthew W. , LeWinter Martin M.
Published: June 2012

Background
The production of left ventricular (LV) restoring forces generated during contraction, which are responsible for diastolic suction, is dependent on end-systolic volume (ESV) and systolic transmural and 3D deformation. We tested the hypothesis that acute coronary occlusion would result in loss of forces that cause suction.

Methods and Results
Ten open-chest dogs were subjected to a 10-minute acute coronary occlusion (proximal left anterior descending coronary artery). A servomotor connected to the left atrium (LA) was used to rapidly clamp LA pressure during systole below the level of the succeeding LV diastolic pressure, resulting in nonfilling diastoles during which the LV fully relaxed at its ESV. LA clamps at multiple ESVs (conductance catheter) allowed delineation of positive and negative portions of the fully relaxed LV pressure-volume relation (FRPVR). A negative fully relaxed pressure (FRP) indicates the presence of restoring forces. After 10 minutes of acute coronary occlusion, there was an upward shift of the FRPVR. Thus, for example, at matched ESVs before and during coronary occlusion, FRP was −1.1±1.1 (±SD) mm Hg before versus 0.2±1.2 mm Hg after 10 minutes of coronary occlusion (
P
<.05).

Conclusions
Acute coronary occlusion results in a rapid decrease in forces responsible for suction. This phenomenon is independent of the level of ESV and may contribute to ischemic diastolic dysfunction.
Modulation of the Renin-Angiotensin Pathway Through Enzyme Inhibition and Specific Receptor Blockade in Pacing-Induced Heart Failure
Authors: Spinale Francis G. , de Gasparo Marc , Whitebread Steve , Hebbar Latha , Clair Mark J. , Melton D. Mark , Krombach R. Stephen , Mukherjee Rupak , Iannini Julie P. , O Seung-Jun
Published: June 2012

Background
The goal of this study was to determine the effects of ACE inhibition (ACEI) alone, AT
1
angiotensin (Ang) II receptor blockade alone, and combined ACEI and AT
1
Ang II receptor blockade on LV function, systemic hemodynamics, and neurohormonal system activity in a model of congestive heart failure (CHF).

Methods and Results
Pigs were randomly assigned to each of 5 groups: (1) rapid atrial pacing (240 bpm) for 3 weeks (n=9), (2) ACEI (benazeprilat, 0.187 mg · kg
−1
· d
−1
) and rapid pacing (n=9), (3) AT
1
Ang II receptor blockade (valsartan, 3 mg · kg
−1
· d
−1
) and rapid pacing (n=9), (4) ACEI and AT
1
Ang II receptor blockade (benazeprilat/valsartan, 0.05/3 mg · kg
−1
· d
−1
) and rapid pacing (n=9), and (5) sham controls (n=10). In the pacing group, LV fractional shortening (LVFS) fell (13.4±1.4% versus 39.1±1.0%) and end-diastolic dimension (LVEDD) increased (5.61±0.11 versus 3.45±0.07 cm) compared with control (
P
<.05). With AT
1
Ang II blockade and rapid pacing, LVEDD and LVFS were unchanged from pacing-only values. ACEI reduced LVEDD (4.95±0.11 cm) and increased LVFS (20.9±1.9%) from pacing-only values (
P
<.05). ACEI and AT
1
Ang II blockade reduced LVEDD (4.68±0.07 cm) and increased LVFS (25.2±0.9%) from pacing only (
P
<.05). Plasma norepinephrine and endothelin increased by more than fivefold with chronic pacing and remained elevated with AT
1
Ang II blockade. Plasma norepinephrine was reduced from pacing-only values by more than twofold in the ACEI group and the combination group. ACEI and AT
1
Ang II receptor blockade reduced plasma endothelin levels by >50% from rapid-pacing values.

Conclusions
These findings suggest that the effects of ACEI in the setting of CHF are not solely due to modulation of Ang II levels but rather to alternative enzymatic pathways and that combined ACEI and AT
1
Ang II receptor blockade may provide unique benefits for LV pump function and neurohormonal systems in the setting of CHF.
Applicability of Cardiac Troponin T and I for Early Risk Stratification in Unstable Coronary Artery Disease
Authors: Lüscher Michael S. , Thygesen Kristian , Ravkilde Jan , Heickendorff Lene
Published: June 2012

Background
Studies have demonstrated that troponin T is a strong independent indicator of a poor prognosis in patients with unstable coronary artery disease. Up to the present, no study has compared the prognostic value of troponin T with that of troponin I in the same cohort of patients.

Methods and Results
Patients (n=516) suspected of having unstable coronary artery disease were investigated. Follow-up was done after 30 days, and the occurrences of cardiac death, acute myocardial infarction, refractory angina pectoris, and recurrent angina pectoris were registered. Elevated levels of troponin T (≥0.10 μg/L) were associated with an increased risk of cardiac death at 30 days compared with patients with normal levels, 3.2% versus 0.4% (
P
=.014). Troponin I values above the chosen cutoff (2.0 μg/L) were similarly found to be an indicator of increased risk of cardiac death, 3.2% versus 0.7% (
P
=.026). With regard to the composite end point of cardiac death/acute myocardial infarction, the troponins were strong independent indicators of adverse outcome.

Conclusions
In patients suspected of having unstable coronary artery disease, both troponin T and troponin I provide independent prognostic information with regard to cardiac death and acute myocardial infarction.