bluuebunny/crossref_metadata_2025 huggingface dataset:
Decreased Expression of the Cardiac LIM Domain Protein MLP in Chronic Human Heart Failure
Authors: Zolk Oliver , Caroni Pico , Böhm Michael
Published: June 2012

Background
—The cardiac LIM domain protein MLP, a member of the cysteine-rich protein family, is an essential regulator of cardiac muscle development. Mice with a disruption of the MLP gene resemble the morphological and clinical picture of dilated cardiomyopathy and heart failure in humans. We investigated whether altered MLP expression is significant for the pathogenesis of human heart failure.

Methods and Results
—Immunohistochemistry and in situ hybridization confirmed the expression of MLP protein and mRNA in human cardiomyocytes. Western blot analysis revealed that the MLP peptide was present in the contractile protein fraction but not in the cytosolic or membrane fraction and that the binding of MLP to myofibrils required functional zinc finger domains. MLP immunoreactivity was decreased ≈50% (
P
<0.05) in the left ventricular myocardium of patients with chronic heart failure due to dilated or ischemic cardiomyopathy compared with non-failing donor hearts. MLP mRNA expression, as assessed by Northern blot experiments, was not significantly different between failing and non-failing control hearts, which suggests that decreased MLP synthesis or increased MLP protein turnover, rather than a decreased number of RNA transcripts, may play a role.

Conclusions
—Because MLP may promote myofibril assembly, the down-regulation of this adapter protein might play an essential role in myofibril derangement or impaired myofibril rearrangement in the failing human myocardium.
Attenuation of Myocardial Ischemia/Reperfusion Injury by Superinduction of Inducible Nitric Oxide Synthase
Authors: Kanno Shinichi , Lee Paul C. , Zhang Yuqing , Ho Chien , Griffith Bartley P. , Shears Larry L. , Billiar Timothy R.
Published: June 2012

Background
—Nitric oxide (NO) has been implicated as a mediator in myocardial ischemia/reperfusion (I/R) injury, but its functional properties have been conflicting. We investigated whether NO has a protective role against I/R injury.

Methods and Results
—Using endothelial NO synthase knockout (eNOS KO) mice, inducible NOS KO mice, the NO donor
S
-nitroso-
N
-acetylpenicillamine (SNAP), and the NOS inhibitor
N
-iminoethyl-
l
-ornithine (L-NIO), we performed studies of isolated perfused hearts subjected to 30 minutes of global ischemia followed by reperfusion. After 60 minutes of reperfusion, nitrite levels in the coronary effluent in the SNAP and eNOS KO groups were significantly elevated compared with other groups. Immunoblot and immunohistochemistry showed that iNOS was markedly induced in the eNOS KO hearts. Under spontaneous beating conditions during reperfusion, increased NO activity was correlated with a prevention of the hyperdynamic contractile response and enhanced myocardial protection, as evidenced by a reduction in myocardial injury and infarct size. During prolonged reperfusion, SNAP-treated hearts were able to preserve contractile functions for 180 minutes, whereas L-NIO–treated hearts showed a sustained deterioration in contractility.

Conclusions
—NO protects against I/R injury by preventing the hyperdynamic response of isolated perfused hearts during early reperfusion. In the eNOS KO hearts, a paradoxical increase in NO production was seen, accompanied by a superinduction of iNOS, possibly due to an adaptive mechanism.
Adenosine A
1
Receptor Activation Induces Delayed Preconditioning in Rats Mediated by Manganese Superoxide Dismutase
Authors: Dana Ali , Jonassen Anne K. , Yamashita Nobushige , Yellon Derek M.
Published: June 2012

Background
—We have previously described a second window of protection against infarction in rabbits 24 to 72 hours after adenosine A
1
receptor (A
1
R) activation. In this study, we examined the potential role of the mitochondrial antioxidant manganese superoxide dismutase (Mn-SOD) as a potential end effector in mediating this protection.

Methods and Results
—Rats were treated with an intravenous bolus of the A
1
R agonist 2-chloro-
N
6
-cyclopentyladenosine (CCPA, 75 μg/kg) or saline vehicle. They were also given a 5 mg/kg IV infusion of a 22-mer phosphorothioate oligodeoxynucleotide (ODN) with sequence antisense to the initiation site of rat Mn-SOD mRNA. Sense ODN and scrambled ODN were used as controls. Twenty-four hours later, hearts were isolated and perfused with buffer at constant pressure and subjected to 35 minutes of regional ischemia and 2 hours of reperfusion. Treatment with CCPA compared with saline vehicle (control) significantly reduced infarct size, expressed as percentage of myocardium at risk (22.3±3.3% versus 42.1±3.8%, respectively;
P
=0.001). This protection was completely abolished by prior treatment with antisense ODN, which had no effect on its own. Neither sense ODN nor scrambled ODN had an effect on the CCPA-induced delayed cardioprotection. In separate animals, 24 hours after the same treatment, hearts were assayed for Mn-SOD content and activity. CCPA treatment induced a significant increase in myocardial Mn-SOD content and activity compared with the control condition; this increase was abolished by pretreatment with antisense ODN.

Conclusions
—This is the first study to show that transient A
1
R activation induces delayed cardioprotection in the rat. These results strongly suggest an important role for mitochondrial Mn-SOD as a potential end effector of this protection.
Long-Term Endothelin Receptor Antagonist Administration Improves Alterations in Expression of Various Cardiac Genes in Failing Myocardium of Rats With Heart Failure
Authors: Sakai Satoshi , Miyauchi Takashi , Yamaguchi Iwao
Published: June 2012

Background
—We reported that long-term (3-month) treatment with the endothelin (ET) type A (ET
A
) receptor antagonist BQ-123 markedly improved survival in rats with chronic heart failure (CHF). However, it is not known whether long-term treatment with an ET receptor antagonist improves alterations in the expression of cardiac genes in failing hearts.

Methods and Results
—CHF rats and control sham-operated rats were treated with BQ-123, SB209670 (ET
A/B
dual receptor antagonist), or saline (vehicle) for 3 months. The survival of CHF rats was markedly higher in the BQ-123 or SB209670 treatment group than in the saline treatment group. The changes in the gene expression of classic molecular markers for failing hearts (mRNA levels of atrial natriuretic peptide and β-myosin heavy chain) were greatly inhibited by BQ-123 or SB209670 treatment in CHF rats. Long-term BQ-123 treatment also normalized the alterations in the expression of functional molecular markers in failing hearts (eg, mRNA levels of ryanodine receptor, sarcoplasmic reticulum Ca
2+
-ATPase, angiotensin-converting enzyme, angiotensin II type 1 receptor, and prepro-ET-1).

Conclusions
—We demonstrated for the first time that long-term (3-month) treatment with an ET receptor antagonist improves the alterations in the expression of various cardiac genes of classic molecular markers (eg, mRNA in atrial natriuretic peptide and β-myosin heavy chain) and of functional molecular markers (eg, mRNA levels of ryanodine receptor, sarcoplasmic reticulum Ca
2+
-ATPase, angiotensin-converting enzyme, angiotensin II type 1 receptor, and prepro-ET-1) in the failing hearts of CHF rats, suggesting that the great improvement of survival in CHF rats by an ET blocker is partly attributed to the prevention of molecular changes in failing hearts.
Flavone-8-Acetic Acid (Flavonoid) Profoundly Reduces Platelet-Dependent Thrombosis and Vasoconstriction After Deep Arterial Injury In Vivo
Authors: Mruk Jozef S. , Webster Mark W. I. , Heras Magda , Reid Joel M. , Grill Diane E. , Chesebro James H.
Published: June 2012

Background
—Flavone-8-acetic acid (FAA; [Flavonoid]), an adjuvant antitumor drug, inhibits ristocetin-induced aggregation of human platelets. The effect of FAA on platelet-dependent thrombosis was studied in vivo in the porcine carotid artery after deep arterial injury by balloon angioplasty.

Methods and Results
—
111
In-labeled autologous platelet and
125
I-labeled porcine fibrin(ogen) deposition, and the incidence of macroscopic mural thrombosis onto deeply injured artery (tunica media) were compared in 20 pigs (40±1 kg [mean±SEM], body surface area=1.0±0.1 m
2
), randomized to FAA bolus (n=10) of 5.5g/m
2
, followed by an infusion at 0.14g · m
−2
· min
−1
or placebo (n=10). Vasoconstriction was measured immediately beyond the dilated segment using quantitative angiography. Platelet deposition (×10
6
/cm
2
of carotid artery) was reduced over 12-fold in pigs treated with FAA (13±3 versus 164±51,
P
=0.001) compared with placebo. Fibrin(ogen) deposition (×10
12
molecules/cm
2
of carotid artery) did not significantly differ in FAA-treated pigs versus placebo (40±8 versus 140±69,
P
=0.08). Large mural thrombi were present in 100% of placebo-treated pigs versus very small thrombi in 40% of FAA-treated pigs (
P
=0.005). Vasoconstriction was reduced from 46±6% in the placebo group to 15±3% in the FAA group (
P
<0.001). Plasma level of FAA before angioplasty was 515±23 μg/mL. The activated partial thromboplastin time was unchanged. The bleeding time was >2SD above the normal mean in 4 of 5 treated pigs (increased from 157±29 to 522±123 s).

Conclusions
—FAA markedly reduced platelet deposition, mural thrombi, and injury-induced vasoconstriction after deep arterial injury, suggesting that a major inhibition of platelet glycoprotein Ibα may be beneficial therapy.
The Athlete’s Heart
Authors: Pluim Babette M. , Zwinderman Aeilko H. , van der Laarse Arnoud , van der Wall Ernst E.
Published: June 2012

Background
—It has been postulated that depending on the type of exercise performed, 2 different morphological forms of athlete’s heart may be distinguished: a strength-trained heart and an endurance-trained heart. Individual studies have not tested this hypothesis satisfactorily.

Methods and Results
—The hypothesis of divergent cardiac adaptations in endurance-trained and strength-trained athletes was tested by applying meta-analytical techniques with the assumption of a random study effects model incorporating all published echocardiographic data on structure and function of male athletes engaged in purely dynamic (running) or static (weight lifting, power lifting, bodybuilding, throwing, wrestling) sports and combined dynamic and static sports (cycling and rowing). The analysis encompassed 59 studies and 1451 athletes. The overall mean relative left ventricular wall thickness of control subjects (0.36 mm) was significantly smaller than that of endurance-trained athletes (0.39 mm,
P
=0.001), combined endurance- and strength-trained athletes (0.40 mm,
P
=0.001), or strength-trained athletes (0.44 mm,
P
<0.001). There was a significant difference between the 3 groups of athletes and control subjects with respect to left ventricular internal diameter (
P
<0.001), posterior wall thickness (
P
<0.001), and interventricular septum thickness (
P
<0.001). In addition, endurance-trained athletes and strength-trained athletes differed significantly with respect to mean relative wall thickness (0.39 versus 0.44,
P
=0.006) and interventricular septum thickness (10.5 versus 11.8 mm,
P
=0.005) and showed a trend toward a difference with respect to posterior wall thickness (10.3 versus 11.0 mm,
P
=0.078) and left ventricular internal diameter (53.7 versus 52.1 mm,
P
=0.055). With respect to cardiac function, there were no significant differences between athletes and control subjects in left ventricular ejection fraction, fractional shortening, and E/A ratio.

Conclusions
—Results of this meta-analysis regarding athlete’s heart confirm the hypothesis of divergent cardiac adaptations in dynamic and static sports. Overall, athlete’s heart demonstrated normal systolic and diastolic cardiac functions.
N-Type Calcium Channels Control Sympathetic Neurotransmission in Human Heart Atrium
Authors: Molderings G. J. , Likungu J. , Göthert M.
Published: June 2012

Background
—Because knowledge about the type of calcium channels involved in action potential–induced norepinephrine release from the human peripheral sympathetic nervous system is sparse, we investigated which types of calcium channels are functionally important in the sympathetic nerves of human cardiac tissue.

Methods and Results
—In superfused segments of human right atrial appendages, the type of calcium channels that control [
3
H]norepinephrine release evoked by transmural electrical stimulation was determined. [
3
H]norepinephrine release was almost abolished by 0.2 μmol/L ω-conotoxin GVIA (a selective blocker of N-type channels) but was not modified by 0.1 μmol/L ω-agatoxin IVA (a selective blocker of P- and Q-type channels). Mibefradil (a T-type and N-type calcium channel blocker) at concentrations of 0.3 to 3 μmol/L reduced the evoked tritium overflow in a frequency- and calcium-dependent manner, whereas 0.1 to 10 μmol/L amlodipine, diltiazem, and verapamil (selective blockers of L-type channels) were ineffective.

Conclusions
—Norepinephrine release from cardiac sympathetic nerves is triggered by Ca
2+
influx via N-type but not L- and P/Q-type calcium channels. The inhibitory effect of mibefradil on norepinephrine release at clinically relevant concentrations is probably due to its blocking action on N-type Ca
2+
channels. This property of mibefradil is unique among the calcium channel blockers that have been or still are therapeutically applied and may considerably contribute to its slight negative chronotropic effect in vivo.
Noninvasive ECG Imaging of Electrophysiologically Abnormal Substrates in Infarcted Hearts
Authors: Burnes John E. , Taccardi Bruno , MacLeod Robert S. , Rudy Yoram
Published: June 2012

Background
—Myocardial infarction and subsequent remodeling create substrates with altered electrophysiological (EP) properties that are highly arrhythmogenic. Existing ECG methods cannot always detect the existence of such substrates nor provide any detailed information about their EP characteristics. A noninvasive method with such capabilities is greatly needed for identifying patients at risk of arrhythmias and for guidance and evaluation of therapy. Recently, we developed a noninvasive ECG imaging modality that can reconstruct epicardial EP information from body surface potentials. We extended its application to hearts with structural disease and examined its ability to detect and characterize abnormal EP substrates.

Methods and Results
—Epicardial potentials were recorded with a 490-electrode sock from an open-chest dog. Recordings were obtained from a normal heart and from the same heart 2 hours after left anterior descending coronary artery occlusion and ethanol injection to create an infarct. Body surface potentials were generated from these epicardial potentials in a human torso model. Realistic geometry errors and measurement noise were added to the torso data, which were then used to noninvasively reconstruct epicardial potentials and electrograms (EGMs), with excellent accuracy. EP characteristics associated with the infarct substrate were reconstructed, including (1) a negative region over the infarct, (2) EGMs with large predominant negative deflections (eg, Q-wave EGMs), (3) Q-wave EGMs with superimposed RS deflections reflecting local activation of surviving myocardium within the infarct border zone, (4) reduced magnitudes of EGM negative derivatives, and (5) negative QRS integrals of EGMs over the infarct.

Conclusions
—ECG imaging can noninvasively detect and map abnormal EP substrates associated with infarction and structural heart disease.
Serial In Vivo MRI Documents Arterial Remodeling in Experimental Atherosclerosis
Authors: Worthley Stephen G. , Helft Gérard , Fuster Valentin , Zaman Azfar G. , Fayad Zahi A. , Fallon John T. , Badimon Juan J.
Published: June 2012

Background
—Arterial remodeling in response to atherosclerosis may be outward (positive) or inward (negative) and is an important mechanism in the clinical manifestations of atherosclerosis and restenosis after percutaneous coronary interventions. Postmortem and intravascular ultrasound studies of arterial remodeling do not allow serial and noninvasive data to be obtained. In a rabbit model of atherosclerosis, we sought to validate MRI as a new tool for documentation of arterial remodeling.

Methods and Results
—Watanabe heritable hyperlipidemic rabbits underwent serial MRI at baseline and 6 months after aortic balloon denudation. The lumen area had a small but significant (
P
=0.006) increase, from 4.36±0.16 to 4.89±0.12 mm
2
. There was a large, significant (
P
<0.0001) increase in the outer wall area, from 7.96±0.19 to 10.46±0.19 mm
2
. The vessel wall area (a marker of atherosclerotic burden) increased significantly (
P
<0.0001), from 3.61±0.07 to 5.57±0.09 mm
2
. Thus, the increase in atherosclerotic burden over time was completely accounted for by positive arterial remodeling. The subgroup used for histopathological validation confirmed a significant (
P
<0.0001) agreement between histopathology and MRI for assessment of all 3 parameters.

Conclusions
—MRI can provide serial and noninvasive data about the arterial wall, allowing assessment of arterial remodeling in this rabbit model. Thus, MRI appears to be a useful tool for the investigation of arterial remodeling both in native atherosclerosis and after percutaneous coronary intervention.
Dual-Loop Intra-Atrial Reentry in Humans
Authors: Shah Dipen , Jaïs Pierre , Takahashi Atsushi , Hocini Meleze , Peng Jing Tian , Clementy Jacques , Haïssaguerre Michel
Published: June 2012

Background
—Dual-loop atrial reentrant tachycardias have not been clinically described.

Methods and Results
—Five patients (3 men, 2 women; mean age, 48±16 years) were studied 24±15 years after surgical closure of an ostium secundum atrial septal defect for drug-resistant atrial tachycardia. Complete tachycardia mapping was performed in the right atrium with multipolar catheters and a 3-dimensional electroanatomic mapping system (Biosense), followed by linear radiofrequency ablation of the narrowest part of each complete loop. Six tachycardias with a typical flutter morphology, a cycle length of 262±40 ms, and a superior f-wave axis (−77±11°) were mapped, 4 with a Biosense map including 106±32 points. Five figure-8 tachycardias had a counterclockwise loop around the tricuspid valve sharing a common anterior channel with a clockwise loop around the lateral atriotomy scar. One tachycardia was thought to have 2 counterclockwise loops around the same obstacles. Radiofrequency delivery in the cavotricuspid isthmus in each case transformed the tachycardia without any pause in a different morphology tachycardia with an inferior P-wave axis (50±42°) and nearly the same cycle length (272±39 ms) but with the periatriotomy loop alone. This arrhythmia required ablation of a second isthmus: between the lower end of the atriotomy and the inferior vena cava in 4 and the superior tricuspid annulus in 1. After a follow-up of 19±6 months, there were no recurrences.

Conclusions
—Figure-8 double-loop tachycardias mimicking the ECG pattern of a common atrial flutter occur in some patients after a surgical atriotomy. Ablation of 1 loop produces a sudden transformation to a new reentrant tachycardia formed of the remaining loop that requires ablation at a second isthmus.
Hyperfibrinogenemia Is Associated With Specific Histocytological Composition and Complications of Atherosclerotic Carotid Plaques in Patients Affected by Transient Ischemic Attacks
Authors: Mauriello Alessandro , Sangiorgi Giuseppe , Palmieri Giampiero , Virmani Renu , Holmes David R. , Schwartz Robert S. , Pistolese Raimondo , Ippoliti Arnaldo , Spagnoli Luigi Giusto
Published: June 2012

Background
—Epidemiological studies have demonstrated that hyperfibrinogenemia is an independent risk factor for cerebrovascular atherosclerosis. However, the underlying mechanisms are poorly understood. We studied whether hyperfibrinogenemia could modify the histological composition of atherosclerotic plaque and precipitate carotid thrombosis resulting from rupture of the plaque.

Methods and Results
—We studied the histological composition of 71 carotid atherosclerotic plaques from patients who had undergone surgical endarterectomy after a first episode of transient ischemic attack. Patients were divided into 3 groups corresponding to the tertiles of plasma fibrinogen values. Hypercholesterolemia, hypertriglyceridemia, hypertension, diabetes, and smoking habit were also assessed. At the histological analysis, plaques of patients in the highest tertile of fibrinogen (>407 mg/dL) were characterized by a high incidence of thrombosis (66.7% of cases) compared with plaques of subjects in the lower (21.7%) (
P
=0.002) and middle (29.2%) (
P
=0.009) tertiles. Plaque rupture was significantly associated with high fibrinogen levels (54.2%,
P
=0.003). Multivariate logistic regression indicated that hyperfibrinogenemia was an independent risk factor for a decrease in cap thickness (
P
=0.0005), macrophage foam cell infiltration of the cap (
P
=0.003), and thrombosis (
P
=0.003). When the presence of other risk factors was accounted for, hyperfibrinogenemia remained an independent predictor of carotid thrombosis with an odds ratio of 5.83, compared with other risk factors.

Conclusions
—The results of the present study add to the evidence that hyperfibrinogenemia, independently of other risk factors, is associated with a specific histological composition of carotid atherosclerotic plaques that predisposes them to rupture and thrombosis.
Maximally Recommended Doses of Angiotensin-Converting Enzyme (ACE) Inhibitors Do Not Completely Prevent ACE-Mediated Formation of Angiotensin II in Chronic Heart Failure
Authors: Jorde Ulrich P. , Ennezat Pierre V. , Lisker Jay , Suryadevara Vanarani , Infeld Jason , Cukon Sonja , Hammer Adam , Sonnenblick Edmund H. , Le Jemtel Thierry H.
Published: June 2012

Background
—The added benefits of angiotensin II type I receptor (AT
1
) blockers (ARBs) to ACE inhibition suggests that recommended doses of ACE inhibitors provide only partial inhibition of ACE in chronic heart failure (CHF). Accordingly, the level of ACE inhibition was assessed by the pressor response to angiotensin (Ang) I in patients who had been treated with recommended doses of ACE inhibitors.

Methods and Results
—Forty-two patients with CHF receiving 40 mg/d of a long-acting ACE inhibitor or 150 mg of captopril were studied. Radial artery systolic pressure (RASP, mm Hg) was monitored noninvasively. The pressor response to ascending doses of Ang I was evaluated in all patients before and after administration of the ARB valsartan. The pressor response to Ang I before and after valsartan was also reevaluated in 11 patients after the dose of ACE inhibitor was doubled for 1 week. RASP increased linearly with significantly ascending doses of Ang I despite treatment with ACE inhibitors. The pressor response to Ang I was blunted significantly by valsartan. Ang I–induced increase in RASP did not correlate with duration of ACE inhibitor therapy. After the dose of ACE inhibitors was doubled, the pressor response to Ang I was no longer different from that noted after valsartan.

Conclusions
—Recommended doses of ACE inhibitors do not fully inhibit ACE in CHF. The level of ACE inhibition achieved is not related to duration of ACE inhibitor therapy. Greater ACE inhibition is also achieved at twice the recommended doses of ACE inhibitors.
In Vivo Gene Transfer of Prepro-Calcitonin Gene–Related Peptide to the Lung Attenuates Chronic Hypoxia-Induced Pulmonary Hypertension in the Mouse
Authors: Champion Hunter C. , Bivalacqua Trinity J. , Toyoda Kazunori , Heistad Donald D. , Hyman Albert L. , Kadowitz Philip J.
Published: June 2012

Background
—Calcitonin gene–related peptide (CGRP) is believed to play an important role in maintaining low pulmonary vascular resistance (PVR) and in modulating pulmonary vascular responses to chronic hypoxia; however, the effects of adenovirally mediated gene transfer of CGRP on the response to hypoxia are unknown.

Methods and Results
—In the present study, an adenoviral vector encoding prepro-CGRP (AdRSVCGRP) was used to examine the effects of in vivo gene transfer of CGRP on increases in PVR, right ventricular mass (RVM), and pulmonary vascular remodeling that occur in chronic hypoxia in the mouse. Intratracheal administration of AdRSVCGRP, followed by 16 days of chronic hypoxia (F
io
2
0.10), increased lung CGRP and cAMP levels. The increase in pulmonary arterial pressure (PAP), PVR, RVM, and pulmonary vascular remodeling in response to chronic hypoxia was attenuated in animals overexpressing prepro-CGRP, whereas systemic pressure was not altered while in chronically hypoxic mice, angiotensin II and endothelin-1–induced increases in PAP were reduced, whereas decreases in PAP in response to CGRP and adrenomedullin were not changed and decreases in PAP in response to a cAMP phosphodiesterase inhibitor were enhanced by AdRSVCGRP.

Conclusions
—In vivo CGRP lung gene transfer attenuates the increase in PVR and RVM, pulmonary vascular remodeling, and pressor responses in chronically hypoxic mice, suggesting that CGRP gene transfer alone and with a cAMP phosphodiesterase inhibitor may be useful for the treatment of pulmonary hypertensive disorders.
Gene Transfer of Endothelial Nitric Oxide Synthase Improves Relaxation of Carotid Arteries From Diabetic Rabbits
Authors: Lund D. D. , Faraci F. M. , Miller F. J. , Heistad D. D.
Published: June 2012

Background
—Diabetes mellitus is associated with impairment of NO-mediated vascular relaxation. The purpose of this study was to determine whether adenovirus-mediated gene transfer of endothelial NO synthase (eNOS) or Cu/Zn superoxide dismutase (SOD1) improves responsiveness to acetylcholine in alloxan-induced diabetic rabbits.

Methods and Results
—After 8 weeks, plasma glucose was greater in diabetic rabbits (418±35 mg/dL) (mean±SEM) than in normal rabbits (105±4 mg/dL). Carotid arteries were removed and cut into ring segments. Arteries were incubated for 2 hours with adenoviral vectors driven by a CMV promoter expressing β-galactosidase (β-gal), eNOS, SOD1, or vehicle. After incubation with virus, arteries were incubated for an additional 24 hours to allow transgene expression. Vascular reactivity was examined by recording isometric tension. After precontraction with phenylephrine, responses to the endothelium-independent vasodilator sodium nitroprusside were similar in diabetic and normal arteries. Endothelium-dependent relaxation to acetylcholine (3×10
−6
mol/L) was significantly less in arteries from diabetic animals (68±5%) than in normal vessels (90±3%). Adenoviral transfection of arteries with eNOS improved relaxation in response to acetylcholine in diabetic (EC
50
eNOS=0.64±0.12×10
−7
mol/L versus vehicle =1.70±0.43×10
−7
mol/L) but not normal arteries. Vasorelaxation in response to acetylcholine was inhibited by
N
ω
-nitro-
l
-arginine (100 μmol/L) in all groups. Responses to acetylcholine were unchanged after gene transfection of SOD1 or β-gal in arteries from diabetic or normal rabbits.

Conclusions
—Adenovirus-mediated gene transfer of eNOS, but not SOD, improves impaired NO-mediated relaxation in vessels from diabetic rabbits.
Assessment of Myocardial Perfusion by Harmonic Power Doppler Imaging at Rest and During Adenosine Stress
Authors: Heinle Sheila K. , Noblin Jennifer , Goree-Best Pam , Mello Ana , Ravad Guy , Mull Stephanie , Mammen Pradeep , Grayburn Paul A.
Published: June 2012

Background
—Harmonic power Doppler imaging (HPDI) is a novel technique for assessing myocardial perfusion by contrast echocardiography in humans. The purpose of this study was to compare myocardial perfusion by HPDI with that obtained by
99m
Tc-sestamibi single photon emission computed tomography (SPECT) during rest and pharmacological stress.

Methods and Results
—HPDI was performed on 123 patients who were referred for SPECT imaging for known or suspected coronary artery disease. Images were obtained at baseline and during adenosine infusion (0.14 mg · kg
−
1
· min
−
1
×6 minutes) in 3 apical views. Myocardial perfusion by HPDI was graded for each coronary territory as absent, patchy, or full. The persistence of absent or patchy myocardial perfusion by HPDI between rest and adenosine was interpreted as a fixed defect, whereas any decrease in perfusion grade was interpreted as a reversible defect. Overall concordance between HPDI and SPECT was 83 (81%) of 103 for normal versus abnormal perfusion. Agreement between the 2 methods for each of the 3 coronary territories was 81% (κ=0.57) for the left anterior descending artery, 76% (κ=0.52) for the right coronary artery, and 72% (κ=0.40) for the left circumflex artery. Discrepancies between the 2 techniques were most notable in the circumflex territory, where fixed defects were observed in 33% by HPDI but in only 14% by SPECT (χ
2
=15.8,
P
=0.0001).

Conclusions
—This study demonstrates that HPDI can reliably detect myocardial perfusion during pharmacological stress, although there was a significantly higher number of falsely abnormal results in the circumflex territory.
Coronary Artery Fly-Through Using Electron Beam Computed Tomography
Authors: van Ooijen Peter M. A. , Oudkerk Matthijs , van Geuns Robert J. M. , Rensing Benno J. , de Feyter Pim J.
Published: June 2012

Background
—Virtual reality techniques have recently been introduced into clinical medicine. This study examines the possibility of coronary artery fly-through using a dataset obtained by noninvasive coronary angiography with contrast-enhanced electron-beam computed tomography.

Methods and Results
—Ten patients were examined, and 40 to 60 transaxial tomograms (thickness, 1.5 mm; in-plane pixel dimensions, ≈0.5×0.5 mm) were obtained after intravenous contrast injection. The datasets were processed on a graphics workstation using volume-rendering software. For fly-throughs, the contrast-enhanced lumen was made transparent and other tissue was made opaque. Then, key frames were selected in a path through the vessel, with software interpolation of frames between key frames. A typical movie contained 150 to 300 frames (10 to 15 key frames). Fly-throughs of coronary bypass grafts (n=3), left anterior descending arteries (LAD; n=6), and the intermediate branch (n=1) were reconstructed. Coronary calcifications were seen in 3 patients. The fly-through of the intermediate branch, the bypass grafts, and one of the LADs did not show any irregularities. In 2 cases, a stenosis was visible in the LAD; its presence was confirmed by conventional coronary angiography.

Conclusions
—Recent developments in fast-volume rendering using special-purpose hardware in combination with noninvasive coronary angiography with electron beam computed tomography have provided the possibility of performing coronary artery fly-throughs.
Reduced Cytosolic Ca
2+
Loading and Improved Cardiac Function After Cardioplegic Cold Storage of Guinea Pig Isolated Hearts
Authors: Stowe David F. , Varadarajan Srinivasan G. , An Jianzhong , Smart Steven C.
Published: June 2012

Background
—Hypothermia is cardioprotective, but it causes Ca
2+
loading and reduced function on rewarming. The aim was to associate changes in cytosolic Ca
2+
with function in intact hearts before, during, and after cold storage with or without cardioplegia (CP).

Methods and Results
—Guinea pig hearts were initially perfused at 37°C with Krebs-Ringer’s (KR) solution (in mmol/L: Ca
2+
2.5, K
+
5, Mg
2+
2.4). One group was perfused with CP solution (Ca
2+
2.5, K
+
18, Mg
2+
7.2) during cooling and storage at 3°C for 4 hours; another was perfused with KR. LV pressure (LVP), dP/dt, O
2
consumption, and cardiac efficiency were monitored. Cytosolic phasic [Ca
2+
] was calculated from indo 1 fluorescence signals obtained at the LV free wall. Cooling with KR increased diastolic and phasic [Ca
2+
], whereas cooling with CP suppressed phasic [Ca
2+
] and reduced the rise in diastolic [Ca
2+
]. Reperfusion with warm KR increased phasic [Ca
2+
] 86% more after CP at 20 minutes and did not increase diastolic [Ca
2+
] at 60 minutes, compared with a 20% increase in phasic [Ca
2+
] after KR. During early and later reperfusion after CP, there was a 126% and 50% better return of LVP than after KR; during later reperfusion, O
2
consumption was 23% higher and cardiac efficiency was 38% higher after CP than after KR.

Conclusions
—CP decreases the rise in cardiac diastolic [Ca
2+
] observed during cold storage in KR. Decreased diastolic [Ca
2+
] and increased systolic [Ca
2+
] after CP improves function on reperfusion because of reduced Ca
2+
loading during and immediately after cold CP storage.
Randomized Controlled Study Investigating the Effect of Biatrial Pacing in Prevention of Atrial Fibrillation After Coronary Artery Bypass Grafting
Authors: Levy T. , Fotopoulos G. , Walker S. , Rex S. , Octave M. , Paul V. , Amrani M.
Published: June 2012

Background
—Atrial fibrillation (AF) is a common problem after CABG. Prevention with prophylactic drug therapy has had limited success, therefore alternative approaches are required. This study investigated the role of biatrial pacing compared with no pacing on AF incidence after isolated first-time CABG.

Methods and Results
—During surgery, temporary pacing leads were placed in the lateral wall of the right atrium and at the roof of the left atrium in Bachmann’s bundle to allow bipolar pacing and sensing at each site. After surgery, all patients were connected to an external pacemaker (Chorum ELA) that also acted as a Holter monitor. Patients were consecutively randomized to either 4 days of biatrial pacing at a base rate of 80 bpm or to no pacing (control group, base rate 30 bpm). End points included an episode of AF lasting >1 hour on pacemaker Holter, clinically detected AF, intensive care unit (ICU) and hospital stay, and postoperative complications. One hundred thirty patients were randomized. Biatrial pacing significantly reduced both monitored (13.8% versus 38.5%,
P
=0.001) and clinical (10.8% versus 33.8%,
P
=0.002) episodes of AF. Median ICU (19 versus 24 hours,
P
=NS) and mean hospital stay (7.7±6.9 versus 9.7±10,
P
=NS) did not significantly change. The number of postoperative complications was lower in the biatrial group (13 versus 35,
P
=0.001).

Conclusions
—Biatrial pacing after CABG significantly decreases the incidence of AF. This is associated with reduced postoperative complications and a trend toward reduced ICU and hospital stay.
Prospective, Randomized, Infancy-Onset Trial of the Effects of a Low-Saturated-Fat, Low-Cholesterol Diet on Serum Lipids and Lipoproteins Before School Age
Authors: Rask-Nissilä Leena , Jokinen Eero , Rönnemaa Tapani , Viikari Jorma , Tammi Anne , Niinikoski Harri , Seppänen Ritva , Tuominen Juhani , Simell Olli
Published: June 2012

Background
—We showed previously that repeated dietary counseling during the first 3 years of life reduces the concentration of serum nonfasting cholesterol. We have now extended the study to children 5 years of age and analyzed fasting blood samples, enabling LDL cholesterol calculations for the first time.

Methods and Results
—Families of 7-month-old infants (n=1062) were randomized to a control group (n=522) or an intervention group (n=540) that received individualized dietary counseling with the aims of a fat intake of 30% to 35% of daily energy, a saturated/monounsaturated/polyunsaturated fatty acid ratio of 1:1:1, and a cholesterol intake of <200 mg/d. Nutrient intakes were studied biannually, nonfasting serum lipid values were studied annually, and fasting values were studied at 5 years of age. The intervention children always had lower intakes of saturated fat and cholesterol than the control children. The intervention boys had 0.39 mmol/L (
P
<0.0001) lower mean serum cholesterol values than the control boys between 13 and 60 months of age, but among girls, the difference was of marginal significance (0.15 mmol/L,
P
=0.052). Five-year-old intervention boys had 9% lower mean serum LDL cholesterol concentrations than the control boys (
P
=0.0002; 95% CI, −0.39 to −0.12 mmol/L), whereas no difference was observed in girls. In both sexes, serum triglyceride concentrations were similar in the 2 groups.

Conclusions
—The restriction of saturated fat and cholesterol intake by repeated, individualized dietary counseling since infancy resulted in lower serum total and LDL cholesterol concentrations at 5 years of age. However, the effect was significant only in boys.
The Unclampable Ascending Aorta in Coronary Artery Bypass Patients
Authors: Gaudino Mario , Glieca Franco , Alessandrini Francesco , Luciani Nicola , Cellini Carlo , Pragliola Claudio , Possati Gianfederico
Published: June 2012

Background
—The unclampable ascending aorta (UAA) is a condition increasingly encountered during CABG procedures. We report our experience with CABG patients with UAA and place particular emphasis on the preoperative diagnosis and surgical management.

Methods and Results
—UAA was diagnosed in 211 of 4812 consecutive CABG patients (4.3%). On the basis of the chest radiograph, echocardiogram, and coronary angiograph, a preoperative diagnosis was achieved in only 58 patients (27.4%). An age of >70 years, diabetes, smoking, unstable angina, diffuse coronaropathy, and peripheral vasculopathy were all predictors of UAA. Patients were treated with hypothermic ventricular fibrillation (no-touch technique n=129) or beating heart revascularization (no-pump technique n=82) depending on the possibility of founding an arterial cannulation site. The overall in-hospital mortality rate was 2.8% (6 of 211) with no differences between the 2 surgical strategies. The no-touch technique was associated with a greater incidence of neurological complications (stroke and transient ischemic attack), renal insufficiency, and stay in the intensive care unit and hospital. However, at midterm follow-up, more patients of the no-pump group had ischemia recurrence.

Conclusions
—A preoperative diagnosis of UAA is achievable only in a minority of patients, which highlights the necessity revising the current diagnostic protocols. The use of the no-touch technique is associated with an high perioperative risk but a superior possibility of complete revascularization, whereas adoption of the no-pump strategy ensures a smoother postoperative course at the expense of an higher incidence of ischemia recurrence.
Cardiorespiratory Fitness and Coronary Heart Disease Risk Factors
Authors: LaMonte Michael J. , Eisenman Patricia A. , Adams Ted D. , Shultz Barry B. , Ainsworth Barbara E. , Yanowitz Frank G.
Published: June 2012

Background
—Cardiorespiratory fitness is favorably associated with most modifiable coronary heart disease (CHD) risk factors. Findings are limited, however, by few data for women, persons with existing CHD, and low-risk populations. In the present study, we described cross-sectional associations between cardiorespiratory fitness and CHD risk factors in a large cohort of middle-aged men and women, of whom the majority were LDS Church members (Mormons), with and without existing CHD.

Methods and Results
—Comprehensive health examinations were performed on 3232 men (age 45.9±10.8 years) and 1128 women (age 43.8±12.8 years) between 1975 and 1997. Maximal treadmill exercise testing was used to categorize those with (12% of the men and 10% of the women) and those without CHD into age- and sex-specific cardiorespiratory fitness quintiles. After adjustments for age, body fat, smoking status, and family history of CHD, favorable associations were observed between fitness and most CHD risk factors among men and women, regardless of CHD status.

Conclusions
—These data indicate that enhanced levels of cardiorespiratory fitness may confer resistance to elevations in CHD risk factors even in a low-risk sample of middle-aged men and women. Furthermore, these findings reinforce current public health recommendations that advocate increased national levels of physical activity and cardiorespiratory fitness for primary and secondary CHD prevention.
Time to Presentation With Acute Myocardial Infarction in the Elderly
Authors: Sheifer Stuart E. , Rathore Saif S. , Gersh Bernard J. , Weinfurt Kevin P. , Oetgen William J. , Breall Jeffrey A. , Schulman Kevin A.
Published: June 2012

Background
—Although prompt treatment is a cornerstone of the management of acute myocardial infarction (AMI), prior studies have shown that one fourth of AMI patients arrive at the hospital >6 hours after symptom onset. It would be valuable to identify individuals at highest risk for late arrival, but predisposing factors have yet to be fully characterized.

Methods and Results
—Data from the Cooperative Cardiovascular Project, involving Medicare beneficiaries aged >65 years hospitalized between January 1994 and February 1996 with confirmed AMI, were used to identify patients who presented “late” (≥6 hours after symptom onset). Patient characteristics were tested for associations with late presentation by use of backward stepwise logistic regression. Among 102 339 subjects, 29.4% arrived late. Significant predictors of late arrival (odds ratio, 95% CI) included diabetes (1.11, 1.07 to 1.14) and a history of angina (1.32, 1.28 to 1.35), whereas prior MI (0.82, 0.79 to 0.85), prior angioplasty (0.80, 0.75 to 0.85), prior bypass surgery (0.93, 0.89 to 0.98), and cardiac arrest (0.52, 0.46 to 0.58) predicted early presentation. Additionally, initial evaluation at an outpatient clinic (2.63, 2.51 to 2.75) and daytime presentation (1.67, 1.59 to 1.72) predicted late arrival. Finally, female sex, black race, and poverty, which were evaluated with an 8-level race–sex–socioeconomic status interaction term, were also risk factors for delay.

Conclusions
—Delayed hospital presentation is a common problem among Medicare beneficiaries with AMI. Factors associated with delay include not only clinical and logistical issues but also race, sex, and socioeconomic characteristics. Education efforts designed to hasten AMI treatment should be directed at individuals with risk factors for late arrival.
Feasibility of a Novel Blood Noise Reduction Algorithm to Enhance Reproducibility of Ultra–High-Frequency Intravascular Ultrasound Images
Authors: Hibi Kiyoshi , Takagi Atsushi , Zhang Xiangmin , Teo Tat-Jin , Bonneau Heidi N. , Yock Paul G. , Fitzgerald Peter J.
Published: June 2012

Background
—Ultra–high-frequency (40- to 50-MHz) intravascular ultrasound (IVUS) improves image quality compared with conventional 20- to 30-MHz IVUS. However, as the frequency of IVUS increases, high-intensity backscatter from blood components may cause visual difficulties in discrimination between the lumen and arterial wall structure. The purpose of this study was to evaluate the effect of a novel blood noise reduction algorithm (BNR) on quantitative coronary ultrasound measurements.

Methods and Results
—IVUS studies using a 40-MHz transducer were performed in 35 patients with coronary artery disease. A total of 620 gray-scale images (310 pairs) were processed with and without the BNR, and lumen cross-sectional area (CSA) was determined by 2 independent observers. With the BNR, the intraobserver and interobserver correlation coefficients for lumen CSA were significantly improved (0.85 to 0.99 and 0.80 to 0.98, respectively). In the 270 images (135 pairs) in which vessel wall measurements were possible, the BNR significantly improved the intraobserver and interobserver correlation coefficients for plaque plus media CSA (0.83 to 0.99 and 0.76 to 0.97, respectively), whereas no influence was observed for external elastic membrane CSA (1.00 to 1.00 and 0.99 to 0.99, respectively).

Conclusions
—This study demonstrates the feasibility of this novel algorithm to reduce blood noise, thereby enabling accurate lumen border delineation and providing reproducible measurements of both the lumen and plaque plus media CSAs. Incorporating a digital BNR may serve as an important adjunct to ultra–high-frequency IVUS imaging for improving accurate quantitative evaluation of vessel dimensions.
Randomized Secondary Prevention Trial of Azithromycin in Patients With Coronary Artery Disease
Authors: Muhlestein Joseph B. , Anderson Jeffrey L. , Carlquist John F. , Salunkhe Kirti , Horne Benjamin D. , Pearson Robert R. , Bunch T. Jared , Allen Ann , Trehan Sanjeev , Nielson Cindy
Published: June 2012

Background
—
Chlamydia pneumoniae
is associated with coronary artery disease (CAD), although its causal role is uncertain. A small preliminary study reported a >50% reduction in ischemic events by azithromycin, an antibiotic effective against
C pneumoniae
, in seropositive CAD patients. We tested this prospectively in a larger, randomized, double-blind study.

Methods and Results
—CAD patients (n=302) seropositive to
C pneumoniae
(IgG titers ≥1:16) were randomized to placebo or azithromycin 500 mg/d for 3 days and then 500 mg/wk for 3 months. The primary clinical end point included cardiovascular death, resuscitated cardiac arrest, nonfatal myocardial infarction (MI), stroke, unstable angina, and unplanned coronary revascularization at 2 years. Treatment groups were balanced, and azithromycin was generally well tolerated. During the trial, 47 first primary events occurred (cardiovascular death, 9; resuscitated cardiac arrest, 1; MI, 11; stroke, 3; unstable angina, 4; and unplanned coronary revascularization, 19), with 22 events in the azithromycin group and 25 in the placebo group. There was no significant difference in the 1 primary end point between the 2 groups (hazard ratio for azithromycin, 0.89; 95% CI, 0.51 to 1.61;
P
=0.74). Events included 9 versus 7 occurring within 6 months and 13 versus 18 between 6 and 24 months in the azithromycin and placebo groups, respectively.

Conclusions
—This study suggests that antibiotic therapy with azithromycin is not associated with marked early reductions (≥50%) in ischemic events as suggested by an initial published report. However, a clinically worthwhile benefit (ie, 20% to 30%) is still possible, although it may be delayed. Larger (several thousand patient), longer-term (≥3 to 5 years) antibiotic studies are therefore indicated.
First Human Experience With Pulmonary Vein Isolation Using a Through-the-Balloon Circumferential Ultrasound Ablation System for Recurrent Atrial Fibrillation
Authors: Natale Andrea , Pisano Ennio , Shewchik Jeannie , Bash Dianna , Fanelli Raffaele , Potenza Domenico , Santarelli Pietro , Schweikert Robert , White Richard , Saliba Walid , Kanagaratnam Logan , Tchou Patrick , Lesh Michael
Published: June 2012

Background
—Standard mapping and ablation of focal sources of atrial fibrillation are associated with very long procedure times and low efficacy. An anatomic approach to complete pulmonary vein isolation could overcome these limitations.

Methods and Results
—Fifteen patients with atrial fibrillation refractory to medication underwent circumferential isolation of the pulmonary veins by using a novel catheter, with an ultrasound transducer (8-MHz) mounted near the tip, in a saline-filled balloon. Twelve atrial foci and/or atrial fibrillation triggers were identified in 9 patients (pulmonary vein locations: left upper, 3; right upper, 6; right middle, 1; right lower, 1; and left inferior, 1). In 5 patients, lesions were placed in the absence of any mapped triggers. Irrespective of trigger mapping, circumferential isolation of both upper pulmonary veins was attempted in all patients. The lower pulmonary veins were ablated when sinus rhythm activation mapping revealed evidence of a sleeve of atrial muscle in the vein. The median number of lesions per patient required to isolate 1 pulmonary vein was 4 (range, 1 to 29). After ablation, no evidence of narrowing was seen with repeat venography or follow-up computed tomography scan. After a mean follow-up of 35±6 weeks, 5 patients had recurrence of atrial fibrillation. Three responded to drugs that were previously ineffective, and 2 remained in atrial fibrillation.

Conclusions
—This novel ultrasound ablation system can successfully isolate multiple pulmonary veins. At early follow-up, this approach seems to be effective in preventing recurrent atrial fibrillation in a significant number of patients.