bluuebunny/crossref_metadata_2025 huggingface dataset:
Adipocyte-Derived Plasma Protein, Adiponectin, Suppresses Lipid Accumulation and Class A Scavenger Receptor Expression in Human Monocyte-Derived Macrophages
Authors: Ouchi Noriyuki , Kihara Shinji , Arita Yukio , Nishida Makoto , Matsuyama Akifumi , Okamoto Yoshihisa , Ishigami Masato , Kuriyama Hiroshi , Kishida Ken , Nishizawa Hitoshi , Hotta Kikuko , Muraguchi Masahiro , Ohmoto Yasukazu , Yamashita Shizuya , Funahashi Tohru , Matsuzawa Yuji
Published: June 2012

Background
—Excessive lipid accumulation in macrophages plays an important role in the development of atherosclerosis. Recently, we discovered an adipocyte-specific plasma protein, adiponectin, that is decreased in patients with coronary artery disease. We previously demonstrated that adiponectin acts as a modulator for proinflammatory stimuli and inhibits monocyte adhesion to endothelial cells. The present study investigated the effects of adiponectin on lipid accumulation in human monocyte-derived macrophages.

Methods and Results
—Human monocytes were differentiated into macrophages by incubation in human type AB serum for 7 days, and the effects of adiponectin were investigated at different time intervals. Treatment with physiological concentrations of adiponectin reduced intracellular cholesteryl ester content, as determined using the enzymatic, fluorometric method. The adiponectin-treated macrophages contained fewer lipid droplets stained by oil red O. Adiponectin suppressed the expression of the class A macrophage scavenger receptor (MSR) at both mRNA and protein levels by Northern and immunoblot analyses, respectively, without affecting the expression of CD36, which was quantified by flow cytometry. Adiponectin reduced the class A MSR promoter activity, as measured by luciferase reporter assay. Adiponectin treatment dose-dependently decreased class A MSR ligand binding and uptake activities. The mRNA level of lipoprotein lipase as a marker of macrophage differentiation was decreased by adiponectin treatment, but that of apolipoprotein E was not altered. Adiponectin was detected around macrophages in the human injured aorta by immunohistochemistry.

Conclusions
—The adipocyte-derived plasma protein adiponectin suppressed macrophage-to-foam cell transformation, suggesting that adiponectin may act as a modulator for macrophage-to-foam cell transformation.
Antibodies to Human Heat-Shock Protein 60 Are Associated With the Presence and Severity of Coronary Artery Disease
Authors: Zhu Jianhui , Quyyumi Arshed A. , Rott David , Csako Gyorgy , Wu Hongsheng , Halcox Julian , Epstein Stephen E.
Published: June 2012

Background
—Antibodies to mycobacterial heat-shock protein (HSP) 65 have been reported to be associated with carotid artery thickening. We examined whether antibodies to human HSP60 are associated with the risk of coronary artery disease (CAD).

Methods and Results
—Blood samples from 391 patients (62% men, mean age 57 years) being evaluated for CAD by coronary angiography were tested for IgG antibodies to human HSP60 by ELISA. We found that 75% of the study subjects had anti-HSP60 antibodies. The prevalence of CAD was increased in seropositive compared with seronegative patients (68% versus 49%,
P
=0.0009). Mean titers of HSP60 antibodies were higher in CAD patients than in non-CAD patients (
P
=0.008). No association between HSP60 antibodies and infection or inflammation was found. Importantly, HSP60 antibodies were related to disease severity. The prevalence of HSP60 antibodies was 76%, 80%, and 85% in patients with 1-, 2-, and 3-vessel disease, compared with 64% in patients without CAD (
P
for trend=0.003). A similar association between increasing antibody titers and number of diseased vessels was also found (
P
=0.03). Significant associations between antibodies to HSP60 and CAD severity persisted after adjustment for traditional risk factors by age, race, sex, smoking, diabetes, hypercholesterolemia, hypertension, and C-reactive protein levels. Adjusted OR for number of vessels diseased was 1.86 (95% CI 1.13 to 3.04).

Conclusions
—This is the first study demonstrating a significant association between human HSP60 antibodies and both the presence and severity of CAD.
Notched T Waves on Holter Recordings Enhance Detection of Patients With LQT2 (
HERG
) Mutations
Authors: Lupoglazoff J. M. , Denjoy I. , Berthet M. , Neyroud N. , Demay L. , Richard P. , Hainque B. , Vaksmann G. , Klug D. , Leenhardt A. , Maillard G. , Coumel P. , Guicheney P.
Published: June 2012

Background
—The 2 genes
KCNQ1
(LQT1) and
HERG
(LQT2), encoding cardiac potassium channels, are the most common cause of the dominant long-QT syndrome (LQTS). In addition to QT-interval prolongation, notched T waves have been proposed as a phenotypic marker of LQTS patients.

Methods and Results
—The T-wave morphology of carriers of mutations in
KCNQ1
(n=133) or
HERG
(n=57) and of 100 control subjects was analyzed from Holter ECG recordings. Averaged T-wave templates were obtained at different cycle lengths, and potential notched T waves were classified as grade 1 (G1) in case of a bulge at or below the horizontal, whatever the amplitude, and as grade 2 (G2) in case of a protuberance above the horizontal. The highest grade obtained from a template defined the notch category of the subject. T-wave morphology was normal in the majority of LQT1 and control subjects compared with LQT2 (92%, 96%, and 19%, respectively,
P
<0.001). G1 notches were relatively more frequent in LQT2 (18% versus 8% [LQT1] and 4% [control],
P
<0.01), and G2 notches were seen exclusively in LQT2 (63%). Predictors for G2 were young age, missense mutations, and core domain mutations in
HERG
.

Conclusions
—This study provides novel evidence that Holter recording analysis is superior to the 12-lead ECG in detecting G1 and G2 T-wave notches. These repolarization abnormalities are more indicative of LQT2 versus LQT1, with G2 notches being most specific and often reflecting
HERG
core domain missense mutations.
Pulmonary Veins and Ligament of Marshall as Sources of Rapid Activations in a Canine Model of Sustained Atrial Fibrillation
Authors: Wu Tsu-Juey , Ong James J. C. , Chang Che-Ming , Doshi Rahul N. , Yashima Masaaki , Huang Hsun-Lun A. , Fishbein Michael C. , Ting Chih-Tai , Karagueuzian Hrayr S. , Chen Peng-Sheng
Published: June 2012

Background
—In dogs, chronic rapid pacing may result in sustained atrial fibrillation (AF). However, activation patterns in pacing-induced sustained AF are unclear.

Methods and Results
—We induced sustained AF (>48 hours) in 6 dogs by rapid pacing for 139±84 days. We then performed computerized atrial epicardial mappings and recorded the activations in the ligament of Marshall (LOM) and the pulmonary veins (PVs). During AF, mean activation cycle length in the right atrial free wall (126±17 ms) was significantly longer than that in the left atrial free wall (96±5 ms,
P
=0.006). In addition, mean activation cycle length in the left atrial free wall was significantly longer than that in the LOM (84±5 ms,
P
<0.001), the left inferior PV (81±4 ms,
P
=0.001), and the left superior PV (85±7 ms,
P
=0.003). Similarly, the dominant frequency was highest in the LOM and the PVs (range 11.2 to 13.3 Hz), followed by the left and right atria (
P
<0.001). In all dogs studied, rapid and complicated electrograms were consistently observed at the LOM and the PVs. During AF, both wandering wavelets and organized reentry were present. There were more wave fronts in the left atrium than in the right atrium (
P
<0.001).

Conclusions
—In chronic pacing-induced sustained AF, the LOM and the PVs are the sources of rapid activations. The mechanism by which the left atrium activates faster and has more wave fronts than the right atrium may relate to the fact that the left atrium is closer to the sources of rapid activations.
Induction of Rapid Atherogenesis by Perivascular Carotid Collar Placement in Apolipoprotein E–Deficient and Low-Density Lipoprotein Receptor–Deficient Mice
Authors: von der Thüsen Jan H. , van Berkel Theo J.C. , Biessen Erik A.L.
Published: June 2012

Background
—Perivascular collar placement has been used as a means for localized atherosclerosis induction in a variety of experimental animal species. In mice, however, atherosclerosis-like lesions have thus far not been obtained by this method. The aim of this study was the development of a mouse model of rapid, site-controlled atherogenesis.

Methods and Results
—Silastic collars were placed around the carotid arteries of apolipoprotein E–deficient (apoE−/−) and LDL receptor–deficient (LDLr−/−) mice. The development of collar-induced lesions was found to occur predominantly in the area proximal to the collar and to be dependent on a high-cholesterol diet. Lesions were evident in apoE−/− mice after 3 weeks and in LDLr−/− mice after 6 weeks and were overtly atherosclerotic in appearance. Lumen stenosis reached 85% in apoE−/− mice and 61% in LDLr−/− mice 6 weeks after collar insertion. Expression levels of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were increased both proximal and distal to the collar, whereas endothelial nitric oxide synthase expression was downregulated at the proximal site.

Conclusions
—We propose that this model of collar-induced acceleration of carotid atherogenesis is of hemodynamic cause. It may serve as a substrate for sequential mechanistic studies concerned with the underlying cause and pathogenesis of atherosclerosis. The rapidity of lesion development will also aid the efficient screening of new potentially antiatherogenic chemical entities and the evaluation of therapies with limited duration of effectiveness, such as adenoviral gene therapy.
Deceleration Time in Ischemic Cardiomyopathy
Authors: Yong Yongqi , Nagueh Sherif F. , Shimoni Sarah , Shan Kesavan , He Zuo-Xiang , Reardon Michael J. , Letsou George V. , Howell Jimmy F. , Verani Mario S. , Quiñones Miguel A. , Zoghbi William A.
Published: June 2012

Background
—In patients with heart failure secondary to left ventricular (LV) systolic dysfunction, a short deceleration time (DT) successfully predicts clinical outcome. The impact of myocardial viability and revascularization on the mitral inflow velocities, however, is unknown.

Methods and Results
—Forty patients with ischemic cardiomyopathy underwent
201
Tl scintigraphy (SPECT) and 2D, Doppler, and dobutamine echocardiography (DE, to 40 μg · kg
−1
· min
−1
) 2 days before CABG. Echocardiography was repeated 3 months after revascularization to determine recovery of function. Significant correlations were present between DT and LV contractile reserve by DE (
r
=0.72), scar perfusion defect by SPECT (
r
=−0.69), and the change in ejection fraction (ΔEF) after surgery (
r
=0.77) (all
P
<0.01). DT >150 ms effectively identified (sensitivity 79%, specificity 81%) patients with ΔEF ≥5%. The population was divided into 2 groups according to DT: group 1 (DT >150 ms, n=21) and group 2 (DT ≤150 ms, n=19). At baseline, NYHA class, LV EF, age, and use of cardiovascular drugs were similar between the 2 groups. The number of viable segments by both DE and SPECT, however, was higher in group 1 (both
P
<0.01), and only patients in group 1 had an increase in EF (29±4.8% to 40±8%,
P
<0.01) after surgery. Death and heart transplantation occurred in 7 patients from group 2 and 1 patient from group 1 (
P
=0.017).

Conclusions
—In patients with ischemic cardiomyopathy, the reduced amount of viable myocardium results in a restrictive mitral inflow pattern, which in turn predicts poor survival.
Improved Surgical Outcome After Fetal Diagnosis of Hypoplastic Left Heart Syndrome
Authors: Tworetzky Wayne , McElhinney Doff B. , Reddy V. Mohan , Brook Michael M. , Hanley Frank L. , Silverman Norman H.
Published: June 2012

Background
—Hypoplastic left heart syndrome (HLHS) is frequently diagnosed prenatally, but this has not been shown to improve surgical outcome.

Methods and Results
—We reviewed patients with HLHS between July 1992 and March 1999 to determine the influence of prenatal diagnosis on preoperative clinical status, outcomes of stage 1 surgery, and parental decisions regarding care. Of 88 patients, 33 were diagnosed prenatally and 55 after birth. Of 33 prenatally diagnosed patients, 22 were live-born, and pregnancy was terminated in 11. Of 22 prenatally diagnosed patients who were live-born, 14 underwent surgery, and parents elected to forego treatment in 8. Of 55 patients diagnosed postnatally, 38 underwent surgery, and 17 did not because of parental decisions or clinical considerations. Prenatally diagnosed patients were less likely to undergo surgery than patients diagnosed after birth (
P
=0.008). Among live-born infants, there was a similar rate of nonintervention. Among patients who underwent surgery, survival was 75% (39/52). All patients who had a prenatal diagnosis and underwent surgery survived, whereas only 25 of 38 postnatally diagnosed patients survived (
P
=0.009). Patients diagnosed prenatally had a lower incidence of preoperative acidosis (
P
=0.02), tricuspid regurgitation (
P
=0.001), and ventricular dysfunction (
P
=0.004). They were also less likely to need preoperative inotropic medications or bicarbonate (
P
=0.005). Preoperative factors correlating with early mortality included postnatal diagnosis (
P
=0.009), more severe acidosis (
P
=0.03), need for bicarbonate or inotropes (
P
=0.008 and 0.04), and ventricular dysfunction (
P
=0.05).

Conclusions
—Prenatal diagnosis of HLHS was associated with improved preoperative clinical status and with improved survival after first-stage palliation in comparison with patients diagnosed after birth.
In Vivo Ventricular Gene Delivery of a β-Adrenergic Receptor Kinase Inhibitor to the Failing Heart Reverses Cardiac Dysfunction
Authors: Shah Ashish S. , White David C. , Emani Sitaram , Kypson Alan P. , Lilly R. Eric , Wilson Katrina , Glower Donald D. , Lefkowitz Robert J. , Koch Walter J.
Published: June 2012

Background
—Genetic manipulation to reverse molecular abnormalities associated with dysfunctional myocardium may provide novel treatment. This study aimed to determine the feasibility and functional consequences of in vivo β-adrenergic receptor kinase (βARK1) inhibition in a model of chronic left ventricular (LV) dysfunction after myocardial infarction (MI).

Methods and Results
—Rabbits underwent ligation of the left circumflex (LCx) marginal artery and implantation of sonomicrometric crystals. Baseline cardiac physiology was studied 3 weeks after MI; 5×10
11
viral particles of adenovirus was percutaneously delivered through the LCx. Animals received transgenes encoding a peptide inhibitor of βARK1 (Adeno-βARKct) or an empty virus (EV) as control. One week after gene delivery, global LV and regional systolic function were measured again to assess gene treatment. Adeno-βARKct delivery to the failing heart through the LCx resulted in chamber-specific expression of the βARKct. Baseline in vivo LV systolic performance was improved in Adeno-βARKct–treated animals compared with their individual pre–gene delivery values and compared with EV-treated rabbits. Total β-AR density and βARK1 levels were unchanged between treatment groups; however, β-AR–stimulated adenylyl cyclase activity in the LV was significantly higher in Adeno-βARKct–treated rabbits compared with EV-treated animals.

Conclusions
—In vivo delivery of Adeno-βARKct is feasible in the infarcted/failing heart by coronary catheterization; expression of βARKct results in marked reversal of ventricular dysfunction. Thus, inhibition of βARK1 provides a novel treatment strategy for improving the cardiac performance of the post-MI heart.
Short- and Long-Term Effects of Amiodarone on the Two Components of Cardiac Delayed Rectifier K
+
Current
Authors: Kamiya Kaichiro , Nishiyama Atsushi , Yasui Kenji , Hojo Mayumi , Sanguinetti Michael C. , Kodama Itsuo
Published: June 2012

Background
—Amiodarone is the most promising drug for the treatment of life-threatening tachyarrhythmias in patients with structural heart disease. The pharmacological effects of amiodarone on cardiac ion channels are complex and may differ for short-term and long-term administration.

Methods and Results
—The delayed rectifier K
+
current (I
K
) of ventricular myocytes isolated from rabbit hearts was recorded with the whole-cell voltage-clamp technique. I
K
was separated into 2 components by use of specific blockers for either I
Ks
(chromanol 293B, 30 μmol/L) or I
Kr
(E-4031, 10 μmol/L). Short-term application of amiodarone caused a concentration-dependent decrease in I
Kr
with an IC
50
of 2.8 μmol/L (n=8) but only a minimal reduction in I
Ks
. The short-term effects of amiodarone were also determined in
Xenopus
oocytes expressing the cloned human channels that conduct I
Kr
and I
Ks
(HERG and KvLQT1/minK). HERG current in oocytes was reduced by amiodarone (IC
50
=38 μmol/L), whereas KvLQT1/minK current was unaffected by 300 μmol/L amiodarone. To study the effects of long-term drug administration, rabbits were treated for 4 weeks with oral amiodarone (100 mg · kg
−1
· d
−1
) before cell isolation. Long-term administration of amiodarone decreased I
K
to 55% (n=10) in control rabbits and altered the relative density of I
Kr
and I
Ks
. The majority (92%) of current was I
Kr
. mRNA levels of rabbit
ERG
,
KVLQT1
, and
minK
in left ventricular myocardium did not differ between control and long-term amiodarone.

Conclusions
—Amiodarone has differential effects on the 2 components of I
K
, depending on the application period; short-term treatment inhibits primarily I
Kr
, whereas long-term treatment reduces I
Ks
.
Randomized Assessment of Syncope Trial
Authors: Krahn Andrew D. , Klein George J. , Yee Raymond , Skanes Allan C.
Published: June 2012

Background
—Establishing a diagnosis in patients with unexplained syncope is complicated by infrequent and unpredictable events. Prolonged monitoring may be an alternative strategy to conventional testing with short-term monitoring and provocative tilt and electrophysiological testing.

Methods and Results
—Sixty patients (aged 66±14 years, 33 male) with unexplained syncope were randomized to “conventional” testing with an external loop recorder and tilt and electrophysiological testing or to prolonged monitoring with an implantable loop recorder with 1 year of monitoring. If patients remained undiagnosed after their assigned strategy, they were offered crossover to the alternate strategy. A diagnosis was obtained in 14 of 27 patients randomized to prolonged monitoring compared with 6 of 30 patients undergoing conventional testing (52% versus 20%,
P
=0.012). Crossover was associated with a diagnosis in 1 of 6 patients undergoing conventional testing compared with 8 of 13 patients who completed monitoring (17% versus 62%,
P
=0.069). Overall, prolonged monitoring was more likely to result in a diagnosis than was conventional testing (55% versus 19%,
P
=0.0014). Bradycardia was detected in 14 patients undergoing monitoring compared with 3 patients undergoing conventional testing (40% versus 8%,
P
=0.005).

Conclusions
—A prolonged monitoring strategy is more likely to provide a diagnosis than conventional testing in patients with unexplained syncope. Consideration should be given to earlier implementation of a monitoring strategy.
Calcineurin Plays a Critical Role in the Development of Pressure Overload–Induced Cardiac Hypertrophy
Authors: Zou Yunzeng , Hiroi Yukio , Uozumi Hiroki , Takimoto Eiki , Toko Haruhiro , Zhu Weidong , Kudoh Sumiyo , Mizukami Miho , Shimoyama Masaki , Shibasaki Futoshi , Nagai Ryozo , Yazaki Yoshio , Komuro Issei
Published: June 2012

Background
—Although activation of the Ca
2+
-dependent phosphatase calcineurin has been reported to induce cardiomyocyte hypertrophy, whether calcineurin is involved in pressure overload–induced cardiac hypertrophy remains controversial.

Methods and Results
—We examined in the present study the role of calcineurin in pressure overload–induced cardiac hypertrophy using transgenic mice that overexpress the dominant negative mutant of calcineurin specifically in the heart. There were no significant differences in body weight, blood pressure, heart rate, heart weight, and the cardiac calcineurin activity between the transgenic mice and their littermate wild-type mice at basal state. The activity of calcineurin was markedly increased by pressure overload produced by constriction of the abdominal aorta in the heart of wild-type mice but less increased in the heart of the transgenic mice. Pressure overload induced increases in heart weight, wall thickness of the left ventricle, and diameter of cardiomyocytes; reprogramming of expressions of immediate early response genes and fetal-type genes; activation of extracellular signal–regulated protein kinases; and fibrosis. All these hypertrophic responses were more prominent in the wild-type mice than in the transgenic mice.

Conclusions
—These results suggest that calcineurin plays a critical role in the development of pressure overload–induced cardiac hypertrophy.
Cardiac Gene Delivery With Cardiopulmonary Bypass
Authors: Davidson Michael J. , Jones J.Mark , Emani Sitaram M. , Wilson Katrina H. , Jaggers James , Koch Walter J. , Milano Carmelo A.
Published: June 2012

Background

—

Cardiac gene therapy offers the possibility of enhancing myocardial performance in the compromised heart. However, current gene delivery techniques have limited myocardial transgene expression and pose the risk of extracardiac expression. Isolation of the coronary circulation during cardiac surgery may allow for more efficient and cardiac-selective gene delivery in a clinically relevant model.

Methods and Results

—

Neonatal piglets (3 kg) underwent a median sternotomy and cardiopulmonary bypass, followed by aortic cross-clamping with 30 minutes of cardioplegic arrest. Adenoviral vectors containing transgenes for either β-galactosidase (adeno-β-gal, n=11) or the human β
2
-adrenergic receptor (adeno-β
2
-AR, n=15) were administered through the cardioplegia cannula immediately after arrest and were allowed to dwell in the coronary circulation during the cross-clamp period. After 1 week, the animals were killed, and their heart, lungs, and liver were excised and examined for gene expression. Analysis of β-galactosidase staining revealed transmural myocardial gene expression among animals receiving adeno-β-gal. No marker gene expression was detected in liver or lung tissue. β-AR density in the left ventricle after adeno-β
2
-AR delivery was 396±85% of levels in control animals (
P
<0.01). Animals receiving adeno-β
2
-AR and control animals demonstrated similar β-AR density in both the liver (114±8% versus 100±9%,
P
=NS) and lung (114±7% versus 100±9%,
P
=NS). There was no evidence of cardiac inflammation.

Conclusions

—

By using cardiopulmonary bypass and cardioplegic arrest, intracoronary delivery of adenoviral vectors resulted in efficient myocardial uptake and expression. Undetectable transgene expression in liver or lung tissue suggests cardiac-selective expression.
C-Reactive Protein, Insulin Resistance, Central Obesity, and Coronary Heart Disease Risk in Indian Asians From the United Kingdom Compared With European Whites
Authors: Chambers John C. , Eda Shinichi , Bassett Paul , Karim Yusuf , Thompson Simon G. , Gallimore J.Ruth , Pepys Mark B. , Kooner Jaspal S.
Published: June 2012

Background

—

Indian Asians in the United Kingdom have increased coronary heart disease (CHD) mortality compared with European whites, but the causes are not well understood. Increased circulating concentrations of C-reactive protein (CRP) are an independent risk factor for CHD. Therefore, we investigated this marker of inflammation in healthy UK Indian Asian and European white men.

Methods and Results

—

We measured serum CRP concentrations and conventional CHD risk factors in 1025 healthy male subjects (518 Indian Asians and 507 European whites) aged 35 to 60 years who were recruited at random from general practitioner lists. The geometric mean CRP concentration was 17% higher (95% confidence interval, 3% to 33%) in Indian Asians compared with European whites. CRP values were strongly associated with conventional CHD risk factors, measures of obesity, and metabolic disturbances associated with insulin resistance in both racial groups. The difference in CRP concentrations between Indian Asians and European whites remained after adjustment for conventional CHD risk factors but was eliminated by an adjustment for central obesity and insulin resistance score in Asians. On the basis of these results, we estimate that the processes underlying elevated CRP and/or increased CRP production itself are associated with an ≈14% increase in population CHD risk among Indian Asians compared with European whites.

Conclusions

—

CRP concentrations are higher in healthy Indian Asians than in European whites and are accounted for by greater central obesity and insulin resistance in Indian Asians. Our results suggest that inflammation or other mechanisms underlying elevated CRP values may contribute to the increased CHD risk among Indian Asians.
Exercise Training Attenuates Age-Associated Diastolic Dysfunction in Rats
Authors: Brenner Daniel A. , Apstein Carl S. , Saupe Kurt W.
Published: June 2012

Background

—

In contrast to systolic function, which is relatively well preserved with advancing age, diastolic function declines steadily after age 30. Our goal was to determine whether changes in diastolic function that occur with aging could be reversed with exercise training.

Methods and Results

—

Adult (6-month-old) and old (24-month-old) Fischer 344/BNF1 rats were studied after either 12 weeks of treadmill training or normal sedentary cage life. Three aspects of diastolic function were studied: (1) left ventricular (LV) filling in vivo via Doppler echocardiograph, (2) LV passive compliance, and (3) the degree of ischemia-induced LV stiffening. Maximal exercise capacity was lower in the old rats (18±1 minutes to exhaustion on a standard treadmill) than in the adult rats (25±1 minutes). Training increased exercise capacity by 43% in the old rats and 46% in the adults (to 26±1 and 37±1 minutes, respectively). Echocardiographic indices of LV relaxation were significantly lower in the old rats, but with training, they increased back to the levels seen in the adults. LV stiffness measured in the isolated, perfused hearts was not affected by age or training. Also in the isolated hearts, the LV stiffened more rapidly during low-flow ischemia in the old hearts than in the adults, but training eliminated this age-associated difference in the response to ischemia.

Conclusions

—

Our findings indicate that in rats, some age-associated changes in diastolic function are reversible and thus may not be intrinsic to aging but instead secondary to other processes, such as deconditioning.
Effects of Lipid-Lowering by Simvastatin on Human Atherosclerotic Lesions
Authors: Corti Roberto , Fayad Zahi A. , Fuster Valentin , Worthley Stephen G. , Helft Gerard , Chesebro James , Mercuri Michele , Badimon Juan J.
Published: June 2012

Background

This study was designed to investigate the effects of lipid-lowering by simvastatin on human atherosclerotic lesions.

Methods and Results

Eighteen asymptomatic hypercholesterolemic patients with documented aortic and/or carotid atherosclerotic plaques were selected for the study. A total of 35 aortic and 25 carotid artery plaques were detected. Serial black-blood MRI of the aorta and carotid artery of the patients was performed at baseline and 6 and 12 months after lipid-lowering therapy with simvastatin. The effects of the treatment on atherosclerotic lesions were measured as changes in lumen area, vessel wall thickness, and vessel wall area, a surrogate of atherosclerotic burden. Simvastatin induced a significant (
P
<0.01) reduction in total and LDL cholesterol levels at 6 weeks that was maintained thereafter. At 6 months, no changes in lumen area, vessel wall thickness, or vessel wall area were observed. However, at 12 months, significant reductions in vessel wall thickness and vessel wall area, without changes in lumen area, were observed in both aortic and carotid arteries (
P
<0.001).

Conclusions

This in vivo human study demonstrates that effective and maintained lipid-lowering therapy by simvastatin is associated with a significant regression of atherosclerotic lesions. Our observation suggests that statins induce vascular remodeling, as manifested by reduced atherosclerotic burden without changes in the lumen.
Efficacy of Dofetilide in the Treatment of Atrial Fibrillation-Flutter in Patients With Reduced Left Ventricular Function
Authors: Pedersen Ole D. , Bagger Henning , Keller Niels , Marchant Bradley , Køber Lars , Torp-Pedersen Christian
Published: June 2012

Background

In patients with left ventricular dysfunction, atrial fibrillation and flutter (AF and AFl, respectively) are common arrhythmias associated with increased morbidity and mortality. The present study investigated the potential of dofetilide in AF-AFl patients with left ventricular dysfunction to restore and maintain sinus rhythm, which might reduce mortality and hospitalizations.

Methods and Results

In the Danish Investigations of Arrhythmia and Mortality ON Dofetilide (DIAMOND) studies, 506 patients were in AF-AFl at baseline. Over the course of study, cardioversion occurred in 148 (59%) dofetilide- and 86 (34%) placebo-treated patients. In these patients, the probability of maintaining sinus rhythm for 1 year was 79% with dofetilide versus 42% with placebo (
P
<0.001). Dofetilide had no effect on all-cause mortality, but restoration and maintenance of sinus rhythm was associated with significant reduction in mortality (risk ratio [RR], 0.44; 95% CI, 0.30 to 0.64;
P
<0.0001). In addition, dofetilide therapy was associated with a significantly lower risk ratio versus placebo for either all-cause (RR, 0.70; 95% CI, 0.56 to 0.89;
P
≤0.005) or congestive heart failure (RR, 0.69; 95% CI, 0.51 to 0.93;
P
≤0.02) rehospitalization.

Conclusions

Dofetilide is safe and increases the probability of obtaining and maintaining sinus rhythm in patients with structural heart disease. The present study suggests that restoration of sinus rhythm is associated with improved survival.
JAK/STAT Signaling Is Associated With Cardiac Dysfunction During Ischemia and Reperfusion
Authors: Mascareno Eduardo , El-Shafei Mohammed , Maulik Nilanjana , Sato M. , Guo Yueling , Das Dipak K. , Siddiqui M.A.Q.
Published: June 2012

Background

Activation of the heart renin-angiotensin system (RAS) under pathophysiological conditions has been correlated with the development of ischemic injury. The binding of angiotensin II to its receptors triggers induction of several, perhaps multifunctional, intracellular signaling pathways, notable among them the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. In this study, we investigated whether the JAK/STAT signaling is involved in the ischemia/reperfusion injury in adult rat myocardium.

Methods and Results

We report here that 2 components of the JAK/STAT signaling pathway, namely STAT 5A and STAT 6, are selectively activated in the rat heart subjected to ischemia/reperfusion. The activated STATs bind to a conserved nucleotide sequence (St domain) in the promoter of the angiotensinogen (ANG) gene and consequently upregulate the level of ANG mRNA. Treatment of the hearts with losartan (4.5 μmol/L), an AT
1
blocker, or with tyrphostin AG490 (5 μmol/L), an inhibitor of JAK 2 phosphorylation, results in loss of the STAT/ANG promoter binding activity and an upregulated level of ANG mRNA. Hearts treated with the JAK 2 inhibitor tyrphostin AG490 showed a reduction in myocardial infarct size and in number of cardiomyocytes undergoing apoptosis. The treated hearts also showed a recovery in functional hemodynamics of the myocardium.

Conclusions

These findings suggest that activation of the JAK/STAT signaling pathway is a significant contributing factor to the pathogenesis of myocardial ischemia and that interference in activation of the pathway potentiates recovery in cardiac function.
Akt Activation Preserves Cardiac Function and Prevents Injury After Transient Cardiac Ischemia In Vivo
Authors: Matsui Takashi , Tao Jingzang , del Monte Federica , Lee Kyung-Han , Li Ling , Picard Michael , Force Thomas L. , Franke Thomas F. , Hajjar Roger J. , Rosenzweig Anthony
Published: June 2012

Background

The serine-threonine kinase Akt is activated by several ligand-receptor systems previously shown to be cardioprotective. Akt activation reduces cardiomyocyte apoptosis in models of transient ischemia. Its role in cardiac dysfunction or infarction, however, remains unclear.

Methods and Results

We examined the effects of a constitutively active Akt mutant (myr-Akt) in a rat model of cardiac ischemia-reperfusion injury. In vivo gene transfer of myr-Akt reduced infarct size by 64% and the number of apoptotic cells by 84% (
P
<0.005 for each). Ischemia-reperfusion injury decreased regional cardiac wall thickening as well as the maximal rate of left ventricular pressure rise and fall (+dP/dt and −dP/dt). Akt activation restored regional wall thickening and +dP/dt and −dP/dt to levels seen in sham-operated rats. To better understand this benefit, we examined the effects of myr-Akt on hypoxic cardiomyocyte dysfunction in vitro. myr-Akt prevented hypoxia-induced abnormalities in cardiomyocyte calcium transients and shortening. Akt activation also enhanced sarcolemmal expression of Glut-4 in vivo and increased glucose uptake in vitro to the level seen with insulin treatment.

Conclusions

Akt activation exerts a powerful cardioprotective effect after transient ischemia that probably reflects its ability to both inhibit cardiomyocyte death and improve function of surviving cardiomyocytes. Akt may represent an important nodal target for therapy in ischemic and other heart disease.
Flecainide acetate prevents recurrence of symptomatic paroxysmal supraventricular tachycardia. The Flecainide Supraventricular Tachycardia Study Group.
Authors: Henthorn R W , Waldo A L , Anderson J L , Gilbert E M , Alpert B L , Bhandari A K , Hawkinson R W , Pritchett E L
Published: June 2012

Oral flecainide acetate was administered to 34 patients with documented symptomatic paroxysmal supraventricular tachycardia (PSVT) with a double-blind, placebo-controlled, 8-week crossover trial design. PSVT was defined as a regular tachycardia of at least 120 beats/min without evidence of atrioventricular dissociation. The study required considerable patient cooperation. Patients first entered a 4-week qualifying phase followed by a 3-week, open label, flecainide dose-ranging phase. They were then randomized in a blind fashion to receive either placebo or tolerated flecainide dose for an 8-week treatment period and then crossed over after four symptomatic documented episodes of PSVT or at the end of the treatment period. By all efficacy parameters analyzed, flecainide was superior to placebo. Flecainide was associated with an actuarial 79% freedom from symptomatic PSVT events compared with only 15% on placebo at 60 days (p less than 0.001). Of the 34 patients, 29 had recurrence of symptomatic PSVT at least once during the placebo phase; only eight patients had a recurrence during the flecainide phase (p less than 0.001). The median time to the first symptomatic PSVT event was 11 days in the placebo group and greater than 55 days in the flecainide group (p less than 0.001). Likewise, the interval between attacks was a median of 12 days on placebo compared with more than 55 days on flecainide (p less than 0.001). Finally, the flecainide slowed symptomatic PSVT heart rates to 143 +/- 12 beats/min from 178 +/- 12 on placebo (p less than 0.02) in the seven patients who had events in the placebo and flecainide treatment phases.(ABSTRACT TRUNCATED AT 250 WORDS)
Clinical experience with the Palmaz-Schatz coronary stent. Initial results of a multicenter study.
Authors: Schatz R A , Baim D S , Leon M , Ellis S G , Goldberg S , Hirshfeld J W , Cleman M W , Cabin H S , Walker C , Stagg J
Published: June 2012

Stenting of native coronary arteries with a balloon-expandable stent was attempted in 226 patients after elective angioplasty. Delivery of the device was successful in 213 (94%) of the patients. Of these, 39 received aspirin and dipyridamole only (group 1) and 174 received aspirin, dipyridamole, and warfarin for 1-3 months (group 2). There was no abrupt closure (less than or equal to 1 day) or perioperative death in either group. In-hospital or perioperative complications in group 1 compared with group 2 were as follows: subacute closure (1-14 days), seven (18%) patients versus one (0.6%) patient, respectively, p less than 0.0001; myocardial infarction, five (13%) patients versus one (0.6%) patient, respectively; condition requiring urgent bypass surgery, one (2.5%) patient versus no patients, respectively. Thus, the incidence of major complications such as death, myocardial infarction, or a condition requiring urgent bypass surgery was 15% in group 1 and 0.6% in group 2. Clinical follow-up revealed that 92% of the patients were asymptomatic at 3 months after stenting compared with 6% before stenting (p less than 0.0001). Of the 13 patients who were symptomatic, nine underwent cardiac catheterization and, ultimately, successful elective coronary angioplasty or bypass surgery. We conclude that a high delivery success rate can be expected with this device and that clinical thrombosis is less frequent in anticoagulated patients than in nonanticoagulated patients. Furthermore, in this selected patient population, coronary stenting results in a low incidence of in-hospital and perioperative complications. Clinical success, defined by absence of symptoms, appears to be sustained at 3 months.
Racial differences in responses to thrombolytic therapy with recombinant tissue-type plasminogen activator. Increased fibrin(ogen)olysis in blacks. The Thrombolysis and Angioplasty in Myocardial Infarction Study Group.
Authors: Sane D C , Stump D C , Topol E J , Sigmon K N , Clair W K , Kereiakes D J , George B S , Stoddard M F , Bates E R , Stack R S
Published: June 2012

To determine whether there are differences in responses to thrombolytic therapy in certain populations, the data for the Thrombolysis and Angioplasty in Myocardial Infarction (phase 1) study were analyzed for black and white patients. Baseline variables including risk factors and extent of coronary artery disease were similar in the 352 white and 24 black patients. The time from onset of chest pain to recombinant tissue-type plasminogen activator (rt-PA) therapy and rt-PA dosing regimens were the same in the two groups. The patency rate of the infarct-related artery at 90 minutes was 91% for blacks and was 72% for whites (p = 0.051). Blacks displayed significantly lower nadir fibrinogen levels (0.57 +/- 0.62 versus 1.3 +/- 0.76 g/l, p less than 0.0001), greater delta fibrinogen (baseline-nadir) (2.7 +/- 1.1 versus 1.7 +/- 1.1 g/l, p less than 0.0001), and increased peak levels of fibrin(ogen) degradation products (837 +/- 865 versus 245 +/- 475 micrograms/ml, p less than 0.0001). rt-PA antigen levels tended to be higher in blacks than in whites (2.8 +/- 2.2 versus 2.2 +/- 3.2 micrograms/ml [p = 0.10] at the peak and 1.6 +/- 1.3 versus 0.99 +/- 1.4 micrograms/ml [p = 0.06] at the end of the maintenance infusion). Major clinical outcomes including survival until time of hospital discharge (92% black versus 93% white, p = 0.68) were not significantly different. However, despite undergoing fewer angioplasty procedures (25% versus 46.3%, p = 0.047), blacks received more transfusions (58.8% versus 19.5% were administered greater than or equal to 2 units packed erythrocytes, p = 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Sex differences in high density lipoprotein cholesterol among low-level alcohol consumers.
Authors: Weidner G , Connor S L , Chesney M A , Burns J W , Connor W E , Matarazzo J D , Mendell N R
Published: June 2012

The purpose of this study was to examine high density lipoprotein cholesterol (HDL-C) levels in a sample of community-living women and men who consumed 1 drink of alcohol/day or less. Self-reports of alcohol consumption and clinical assessments of plasma lipid and lipoprotein levels were obtained twice, at 12 months apart. Among men, consumption of 1 drink/day or less was unrelated to levels in HDL-C. In contrast, among women alcohol consumption throughout this relatively low consumption range was positively associated with HDL-C levels. These findings indicate that the association of alcohol and higher levels of HDL-C may occur at lower intakes of alcohol in women than in men.
Regurgitant jet size by transesophageal compared with transthoracic Doppler color flow imaging.
Authors: Smith M D , Harrison M R , Pinton R , Kandil H , Kwan O L , DeMaria A N
Published: June 2012

Combined echocardiography and Doppler color flow mapping from transthoracic imaging windows has become the standard method for the noninvasive assessment of valvular regurgitation. This study compared regurgitant jet areas by Doppler color flow imaging derived from the newer transesophageal approach with measurements obtained from conventional transthoracic apical views. Maximal regurgitant jet area determinations and an overall visual estimate of lesion severity were obtained from 42 patients who underwent color flow examination by both techniques. Seventy-three regurgitant lesions were visualized by transesophageal flow imaging: 34 mitral, 22 aortic, and 17 tricuspid jets. Transthoracic studies in the same patients revealed fewer regurgitant lesions for each valve; 20 mitral, 16 aortic, and 12 tricuspid (p = 0.0009). A comparison of maximal jet areas determined by transesophageal and transthoracic studies showed a good overall correlation (r = 0.85, SEE = 2.8 cm2) and a systematic overestimation by the transesophageal technique (TEE = 0.96 TTX + 2.7). For the subgroup with mitral insufficiency, valve lesions visualized by both techniques were larger by the transesophageal approach (n = 18, 6.0 versus 3.6 cm2, p = 0.008). Semiquantitative visual grading of individual valve lesions by two independent observers revealed a higher grade of regurgitation with more jets classified as mild (38 versus 25), moderate (18 versus 13), and severe (17 versus 10) by esophageal imaging than by transthoracic imaging. Thus, transesophageal color flow mapping techniques yield a higher prevalence of valvular regurgitation than do transthoracic techniques in the same patients. Jet area and the overall estimate of regurgitant lesion severity were also greater by transesophageal color Doppler imaging compared with standard transthoracic imaging.(ABSTRACT TRUNCATED AT 250 WORDS)
Secular trends in Q wave and non-Q wave acute myocardial infarction. The Minnesota Heart Survey.
Authors: Edlavitch S A , Crow R , Burke G L , Baxter J
Published: June 2012

The Minnesota Heart Survey examined trends of Q wave and non-Q wave acute myocardial infarction (AMI) using a 50% random sample of all hospital discharges of patients with AMI or another acute coronary disease from 35 of 36 hospitals in 1970 and 30 of 31 hospitals in 1980 in the Minneapolis-St. Paul metropolitan area. A total of 1,901 and 1,864 potential AMI cases were abstracted in 1970 and 1980, respectively. Electrocardiograms were coded according to the Minnesota code. AMIs were validated by computerized algorithm based on chest pain, enzymes, electrocardiograms, and autopsy. This study shows that with the use of a consistent, standard diagnostic algorithm, attack rates for Q wave AMI did not change significantly between 1970 and 1980 and that attack rates for non-Q wave AMI decreased significantly during the same decade. However, when the more sensitive cardiac enzymes creatine phosphokinase and creatine phosphokinase-MB were considered, attack rates of both Q wave and non-Q wave AMIs increased. This research documents four important trends for community AMI rates that are at variance with those reported by others. There was a decline in non-Q wave AMI attack rates from 1970 to 1980; women had outcomes equal to or worse than those for men for both case-fatality and 7-year survival rates; patients with non-Q wave AMIs had worse in-hospital prognoses than those with Q wave AMIs; and 7-year survival rates were worse for Q wave AMI in 1980. These findings demonstrate the need for standard diagnostic criteria for Q wave and non-Q wave AMI if trends are to be monitored. In the future, as new trials of operative and nonoperative therapies of AMI are undertaken, these considerations will increase in importance.
Intravital detection of skin capillary aneurysms by videomicroscopy with indocyanine green in patients with progressive systemic sclerosis and related disorders.
Authors: Bollinger A , Saesseli B , Hoffmann U , Franzeck U K
Published: June 2012

Conventional capillaroscopy and infrared fluorescence videomicroscopy with indocyanine green were performed at the nailfold in 12 healthy controls and 38 patients with microangiopathy due to systemic sclerosis or related disorders. Saccular aneurysms featuring head and neck (type 1) and aneurysmatic enlargements (type 2) were defined. Microaneurysms were located at the apex or near the apex of capillary loops and were significantly more common in patients than in controls (p less than 0.02 for type 1 and p less than 0.001 for type 2). Combination of the two lesions was found only in patients and appears to be a valuable new diagnostic sign for the presence of microangiopathy. In comparison with conventional capillaroscopy, about twice as many microaneurysms were detected by videomicroscopy with indocyanine green coupling almost completely to plasma proteins. The new technique allows visualization of capillary aneurysms even when filled only by plasma.
Effect of weight reduction in moderately overweight patients on recorded ambulatory blood pressure and free cytosolic platelet calcium.
Authors: Scherrer U , Nussberger J , Torriani S , Waeber B , Darioli R , Hofstetter J R , Brunner H R
Published: June 2012

Although platelet cytosolic calcium has been shown to decrease during pharmacological treatment of hypertension, there is no evidence that cytosolic calcium also falls during a nonpharmacological reduction in blood pressure. To provide such evidence, we examined prospectively the relation between platelet cytosolic calcium and ambulatory blood pressure during weight reduction in moderately overweight (body mass index [BMI] greater than 25), mildly hypertensive individuals. The experimental group (responders: BMI reduction greater than 5%) consisted of 19 patients who lost 8.5 +/- 2.9 kg (mean +/- SD, p less than 0.05) during a 10-week hypocaloric diet, whereas the control group (nonresponders: BMI reduction less than 5%) consisted of 12 patients who showed no relevant change in body weight (-2.0 +/- 1.3 kg) during the same period of time. The moderate weight loss of the responders decreased blood pressure by 14/5 mm Hg (p less than 0.05), as measured by ambulatory monitoring, which renders a placebo effect unlikely. This nonpharmacological reduction in blood pressure was accompanied by a proportional 11% decrease (p less than 0.05) in platelet cytosolic calcium and also by significant (p less than 0.05) decreases in plasma catecholamines and serum cholesterol. These findings establish the concept of a nonpharmacological reduction in free cytosolic platelet calcium in humans and add further evidence suggesting a link between intracellular calcium homeostasis and blood pressure regulation.