bluuebunny/crossref_metadata_2025 huggingface dataset:
Akt Promotes Survival of Cardiomyocytes In Vitro and Protects Against Ischemia-Reperfusion Injury in Mouse Heart
Authors: Fujio Yasushi , Nguyen Thao , Wencker Detlef , Kitsis Richard N. , Walsh Kenneth
Published: June 2012

Background
—IGF-1 has been shown to protect myocardium against death in animal models of infarct and ischemia-reperfusion injury. In the present study, we investigated the role of the IGF-1–regulated protein kinase Akt in cardiac myocyte survival in vitro and in vivo.

Methods and Results
—IGF-1 promoted survival of cultured cardiomyocytes under conditions of serum deprivation in a dose-dependent manner but had no effect on cardiac fibroblast survival. The cytoprotective effect of IGF-1 on cardiomyocytes was abrogated by the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor wortmannin. Wortmannin had no effect on cardiomyocyte viability in the absence of IGF-1. IGF-1–mediated cytoprotection correlated with the wortmannin-sensitive induction of Akt protein kinase activity. To examine the functional consequences of Akt activation in cardiomyocyte survival, replication-defective adenoviral constructs expressing wild-type, dominant-negative, and constitutively active
Akt
genes were constructed. Transduction of dominant-negative
Akt
blocked IGF-1–induced survival but had no effect on cardiomyocyte survival in the absence of IGF-1. In contrast, transduction of wild-type
Akt
enhanced cardiomyocyte survival at subsaturating levels of IGF-1, whereas constitutively active
Akt
protected cardiomyocytes from apoptosis in the absence of IGF-1. After transduction into the mouse heart in vivo, constitutively active
Akt
protected against myocyte apoptosis in response to ischemia-reperfusion injury.

Conclusions
—These data are the first documentation that Akt functions to promote cellular survival in vivo, and they indicate that the activation of this pathway may be useful in promoting myocyte survival in the diseased heart.
Microbubble Persistence in the Microcirculation During Ischemia/Reperfusion and Inflammation Is Caused by Integrin- and Complement-Mediated Adherence to Activated Leukocytes
Authors: Lindner Jonathan R. , Coggins Matthew P. , Kaul Sanjiv , Klibanov Alexander L. , Brandenburger Gary H. , Ley Klaus
Published: June 2012

Background
—Albumin microbubbles that are used for contrast echocardiography persist within the myocardial microcirculation after ischemia/reperfusion (I-R). The mechanism responsible for this phenomenon is unknown.

Methods and Results
—Intravital microscopy of the microcirculation of exteriorized cremaster muscle was performed in 12 wild-type mice during intravenous injections of fluorescein-labeled microbubbles composed of albumin, anionic lipids, or cationic lipids. Injections were performed at baseline and after 30 to 90 minutes of I-R in 8 mice and 2 hours after intrascrotal tumor necrosis factor-α (TNF-α) in 4 mice. Microbubble adherence at baseline was uncommon (<2/50 high-power fields). After I-R, adherence increased (
P
<0.05) to 9±5 and 5±4 per 50 high-power fields for albumin and anionic lipid microbubbles, respectively, due to their attachment to leukocytes adherent to the venular endothelium. TNF-α produced even greater microbubble binding, regardless of the microbubble shell composition. The degree of microbubble attachment correlated (
r
=0.84 to 0.91) with the number of adhered leukocytes. Flow cytometry revealed that microbubbles preferentially attached to activated leukocytes. Albumin microbubble attachment was inhibited by blocking the leukocyte β
2
-integrin Mac-1, whereas lipid microbubble binding was inhibited when incubations were performed in complement-depleted or heat-inactivated serum rather than control serum.

Conclusions
—Microvascular attachment of albumin and lipid microbubbles in the setting of I-R and TNF-α–induced inflammation is due to their β
2
-integrin– and complement-mediated binding to activated leukocytes adherent to the venular wall. Thus, microbubble persistence on contrast ultrasonography may be useful for the detection and monitoring of leukocyte adhesion in inflammatory diseases.
Regulation of Endothelial Constitutive Nitric Oxide Synthase Gene Expression in Endothelial Cells and In Vivo
Authors: Kuboki Koji , Jiang Zhen Y. , Takahara Noriko , Ha Sung Woo , Igarashi Masahiko , Yamauchi Teruaki , Feener Edward P. , Herbert Terrance P. , Rhodes Christopher J. , King George L.
Published: June 2012

Background
—The vasodilatory effect of insulin can be acute or increase with time from 1 to 7 hours, suggesting that insulin may enhance the expression of endothelial nitric oxide synthase (eNOS) in endothelial cells. The objective of the present study was to characterize the extent and signaling pathways by which insulin regulates the expression of eNOS in endothelial cells and vascular tissues.

Methods and Results
—Physiological concentrations of insulin (10
−10
to 10
−7
mmol/L) increased the levels of eNOS mRNA, protein, and activity by 2-fold after 2 to 8 hours of incubation in cultured bovine aortic endothelial cells. Insulin enhanced eNOS gene expression in microvessels isolated from Zucker lean rats but not from insulin-resistant Zucker fatty rats. Inhibitors of phosphatidylinositol-3 kinase (PI-3 kinase) decreased the effect of insulin on eNOS gene expression, but a general protein kinase C (PKC) inhibitor, GF109203X or PKCβ isoform inhibitor, LY333531 enhanced eNOS expression. In contrast, PKC activators inhibited both the activation by insulin of PI-3 kinase and eNOS mRNA levels. Overexpression of PKCβ isoform in endothelial cells inhibited the stimulation by insulin of eNOS expression and PI-3 kinase activities in parallel.

Conclusions
—Insulin can regulate the expression of eNOS gene, mediated by the activation of PI-3 kinase, in endothelial cells and microvessels. Thus, insulin may chronically modulate vascular tone. The activation of PKC in the vascular tissues as in insulin resistance and diabetes may inhibit PI-3 kinase activity and eNOS expression and may lead to endothelial dysfunctions in these pathological states.
Antisense Inhibition of β
1
-Adrenergic Receptor mRNA in a Single Dose Produces a Profound and Prolonged Reduction in High Blood Pressure in Spontaneously Hypertensive Rats
Authors: Zhang Yuan Clare , Bui Jonathan D. , Shen Leping , Phillips M. Ian
Published: June 2012

Background
—β-Blockers are the first line of therapy for hypertension. However, they are associated with side effects because of central nervous system (CNS) effects and β
2
-adrenergic antagonism. To overcome these problems and provide a long-term β
1
-blockade, antisense oligonucleotides against rat β
1
-adrenergic receptor (β
1
-AR) mRNA (β
1
-AS-ODN) were designed and tested for the ability to inhibit cardiac β
1
-ARs as well as lower blood pressure in spontaneously hypertensive rats (SHRs).

Methods and Results
—Radioligand binding assay showed that a single intravenous injection of β
1
-AS-ODN delivered in cationic liposomes significantly decreased cardiac β
1
-AR density by 30% to 50% for 18 days (
P
<0.01), with no effect on β
2
-ARs. This was accompanied by marked attenuation of β
1
-AR–mediated positive inotropic response in isolated perfused hearts in vitro (
P
<0.02) and in conscious SHRs monitored by telemetry in vivo (
P
<0.02). Furthermore, the blood pressure of SHRs was reduced for 20 days, with a 38 mm Hg maximum drop. Heart rate was not significantly decreased. Quantitative autoradiography was performed to assess β
1
-AS-ODN effects on the CNS, which demonstrated no changes in β
1
-ARs in brain, in contrast to a significant reduction in heart and kidney (
P
<0.05). For comparison with β-blockers, the effects of atenolol on cardiovascular hemodynamics were examined, which lowered blood pressure for only 10 hours and elicited appreciable bradycardia in SHRs.

Conclusions
—These results indicate that β
1
-AS-ODN, a novel approach to specific β
1
-blockade, has advantages over currently used β-blockers in providing a profound and prolonged reduction in blood pressure without affecting heart rate, β
2
-ARs, and the CNS. Diminished cardiac contractility resulting from less β
1
-AR expression contributes to the antihypertensive effect.
Prospective Randomized Comparison of Irrigated-Tip Versus Conventional-Tip Catheters for Ablation of Common Flutter
Authors: Jaïs Pierre , Shah Dipen C. , Haïssaguerre Michel , Hocini Mélèze , Garrigue Stéphane , Le Metayer Philippe , Clémenty Jacques
Published: June 2012

Background
—Radiofrequency (RF) ablation of common flutter requires the creation of a complete ablation line to produce bidirectional conduction block in the cavotricuspid isthmus. An irrigated-tip ablation catheter has been shown to be effective in patients in whom conventional ablation has failed. This randomized study compares the efficacy and safety of this catheter with those of a conventional catheter for de novo flutter ablation.

Methods and Results
—Cavotricuspid ablation was performed with a conventional (n=26) or an irrigated-tip catheter (n=24). RF was applied for 60 minutes with a temperature-controlled mode: 65°C to 70°C up to 70 W with a conventional catheter or 50°C up to 50 W (with a 17-mL/min saline flow rate) with the irrigated-tip catheter. The end point was the achievement of bidirectional isthmus block, and a crossover was performed after 21 unsuccessful applications. Procedural ablation parameters as well as number of applications, x-ray exposure, procedure duration, impedance rise, and clot formation were compared for each group. A coronary angiogram was performed before and after each ablation for the first 30 patients. Complete bidirectional isthmus block was achieved for all patients. Four patients crossed over from conventional to irrigated-tip catheters. The number of applications, procedure duration, and x-ray exposure were significantly higher with the conventional than with the irrigated-tip catheter: 13±10 versus 5±3 pulses, 53±41 versus 27±16 minutes, and 18±14 versus 9±6 minutes, respectively. No significant side effects occurred, and the coronary angiograms of the first 30 patients after ablation were unchanged.

Conclusions
—Irrigated-tip catheters were found to be more effective than and as safe as conventional catheters for flutter ablation, facilitating the rapid achievement of bidirectional isthmus block.
Anti-Ischemic Effect of a Novel Cardioprotective Agent, JTV519, Is Mediated Through Specific Activation of δ-Isoform of Protein Kinase C in Rat Ventricular Myocardium
Authors: Inagaki Koichi , Kihara Yasuki , Hayashida Wataru , Izumi Toshiaki , Iwanaga Yoshitaka , Yoneda Takeshi , Takeuchi Yuzo , Suyama Katsuo , Muso Eri , Sasayama Shigetake
Published: June 2012

Background
—A new 1,4-benzothiazepine derivative, JTV519, has a strong protective effect against Ca
2+
overload–induced myocardial injury. We investigated the effect of JTV519 on ischemia/reperfusion injury in isolated rat hearts.

Methods and Results
—At 30 minutes of reperfusion after 30-minute global ischemia, the percent recovery of left ventricular developed pressure was improved, and the creatine phosphokinase and lactate dehydrogenase leakage was reduced in a concentration-dependent manner when JTV519 was administered in the coronary perfusate both at 5 minutes before the induction of ischemia and at the time of reperfusion. The myocardial protective effect of JTV519 was completely blocked by pretreatment of the heart with GF109203X, a specific protein kinase C (PKC) inhibitor. In contrast, the effect of JTV519 was not affected by α
1
-, A
1
-, and B
2
-receptor blockers that couple with PKC in the cardiomyocyte. Both immunofluorescence images and immunoblots of JTV519-treated left ventricular myocardium and isolated ventricular myocytes demonstrated that this agent induced concentration-dependent translocation of the δ-isoform but not the other isoforms of PKC to the plasma membrane.

Conclusions
—The mechanism of cardioprotection by JTV519 against ischemia/reperfusion injury involves isozyme-specific PKC activation through a receptor-independent mechanism. This agent may provide a novel pharmacological approach for the treatment of patients with acute coronary diseases via a subcellular mechanism mimicking ischemic preconditioning.
Stent and Artery Geometry Determine Intimal Thickening Independent of Arterial Injury
Authors: Garasic Joseph M. , Edelman Elazer R. , Squire James C. , Seifert Philip , Williams Michael S. , Rogers Campbell
Published: June 2012

Background
—Clinical trials show that larger immediate postdeployment stent diameters provide greater ultimate luminal size, whereas animal data show that arterial injury and stent design determine late neointimal thickening. At deployment, a stent stretches a vessel, imposing a cross-sectional polygonal luminal shape that depends on the stent design, with each strut serving as a vertex. We asked whether this design-dependent postdeployment luminal geometry affects late neointimal thickening independently of the extent of strut-induced injury.

Methods and Results
—Stainless steel stents of 3 different configurations were implanted in rabbit iliac arteries for 3 or 28 days. Stents designed with 12 struts per cross section had 50% to 60% less mural thrombus and 2-fold less neointimal area than identical stents with only 8 struts per cross section. Sequential histological sectioning of individual stents showed that immediate postdeployment luminal geometry and subsequent neointimal area varied along the course of each stent subunit. Mathematical modeling of the shape imposed by the stent on the artery predicted late neointimal area, based on the re-creation of a circular vessel lumen within the confines of the initial stent-imposed polygonal luminal shape.

Conclusions
—Immediate postdeployment luminal geometry, dictated by stent design, determines neointimal thickness independently of arterial injury and may be useful for predicting patterns of intimal growth for novel stent designs.
Permanent, Direct His-Bundle Pacing
Authors: Deshmukh Pramod , Casavant David A. , Romanyshyn Mary , Anderson Kathleen
Published: June 2012

Background
—Direct His-bundle pacing (DHBP) produces synchronous ventricular depolarization and improved cardiac function relative to apical pacing. Although it has been performed transiently in the electrophysiology laboratory and persistently in open-chested canines, permanent DHBP in humans has not been achieved.

Methods and Results
—A total of 18 patients aged 69±10 years who had a history of chronic atrial fibrillation, dilated cardiomyopathy, and normal activation (ie, QRS≤120 ms) were screened for permanent DHBP using an electrophysiology catheter. In 14 patients, the His bundle could be reliably stimulated. Of these 14, permanent DHBP using a fixed screw-in lead was successful in 12 patients. Radiofrequency atrioventricular node ablation was performed in patients exhibiting a fast ventricular response. All patients received single-chamber rate-responsive pacemakers. Acute pacing thresholds were 2.4±1.0 V at a pulse duration of 0.5 ms. Lead complications included exit block requiring reoperative adjustment and gross lead dislodgment. Echocardiographic improvement in heart function was shown by reductions in the left ventricular end-diastolic dimension from 59±8 to 52±6 mm (
P
≤0.01) and in the end-systolic dimension from 51±10 to 43±8 mm (
P
<0.01), with an accompanying increase in fractional shortening from 14±7% to 20±10% (
P
=0.05). The left ventricular ejection fraction improved from 20±9% to 31±11% (
P
<0.01), and the cardiothoracic ratio decreased from 0.61±0.06 to 0.57±0.07 (
P
<0.01). Despite DHBP, 2 patients died at 8 and 36 months.

Conclusions
—Permanent DHBP is feasible in select patients who have chronic atrial fibrillation and dilated cardiomyopathy. Long-term, DHBP results in a reduction of left ventricular dimensions and improved cardiac function.
Oscillatory Patterns in Sympathetic Neural Discharge and Cardiovascular Variables During Orthostatic Stimulus
Authors: Furlan Raffaello , Porta Alberto , Costa Fernando , Tank Jens , Baker Lemont , Schiavi Richard , Robertson David , Malliani Alberto , Mosqueda-Garcia Rogelio
Published: June 2012

Background
—We tested the hypothesis that a common oscillatory pattern might characterize the rhythmic discharge of muscle sympathetic nerve activity (MSNA) and the spontaneous variability of heart rate and systolic arterial pressure (SAP) during a physiological increase of sympathetic activity induced by the head-up tilt maneuver.

Methods and Results
—Ten healthy subjects underwent continuous recordings of ECG, intra-arterial pressure, respiratory activity, central venous pressure, and MSNA, both in the recumbent position and during 75° head-up tilt. Venous samplings for catecholamine assessment were obtained at rest and during the fifth minute of tilt. Spectrum and cross-spectrum analyses of R-R interval, SAP, and MSNA variabilities and of respiratory activity provided the low (LF, 0.1 Hz) and high frequency (HF, 0.27 Hz) rhythmic components of each signal and assessed their linear relationships. Compared with the recumbent position, tilt reduced central venous pressure, but blood pressure was unchanged. Heart rate, MSNA, and plasma epinephrine and norepinephrine levels increased, suggesting a marked enhancement of overall sympathetic activity. During tilt, LF
MSNA
increased compared with the level in the supine position; this mirrored similar changes observed in the LF components of R-R interval and SAP variabilities. The increase of LF
MSNA
was proportional to the amount of the sympathetic discharge. The coupling between LF components of MSNA and R-R interval and SAP variabilities was enhanced during tilt compared with rest.

Conclusions
—During the sympathetic activation induced by tilt, a similar oscillatory pattern based on an increased LF rhythmicity characterized the spontaneous variability of neural sympathetic discharge, R-R interval, and arterial pressure.
Improved Mechanoenergetics and Cardiac Rest and Reserve Function of In Vivo Failing Heart by Calcium Sensitizer EMD-57033
Authors: Senzaki Hideaki , Isoda Takayoshi , Paolocci Nazareno , Ekelund Ulf , Hare Joshua M. , Kass David A.
Published: June 2012

Background
—Myofilament Ca
2+
sensitizers enhance contractility but can adversely alter diastolic function through sensitization to low intracellular Ca
2+
concentration. Concomitant phosphodiesterase III inhibition (PDE3I) may offset diastolic changes but limit the mechanoenergetic benefits. We tested whether selective Ca
2+
sensitization in vivo with the use of EMD-57033 enhances both systolic and diastolic function in failing hearts at minimal energetic cost.

Methods and Results
—Pressure-dimension data were measured with sonomicrometry/micromanometry in conscious dogs before (CON, n=9) and after tachycardia-induced heart failure (HF, n=11). In contrast to blunted dobutamine (DOB) responses in HF, low-dose EMD-57033 (0.4 mg · kg
−1
· min
−1
for 20 minutes) markedly enhanced contractility, doubling end-systolic elastance and raising fractional shortening similarly in CON-treated and HF hearts. EMD-57033 effects were achieved at a reduced heart rate, without vasodilation. EMD-57033 augmented blunted heart rate-dependent contractility responses in HF at a rate of twice that of DOB, despite matched basal inotropic responses. EMD-57033 also improved diastolic function, lowering left ventricular end-diastolic pressure and increasing the filling rate. At equipotent inotropic doses and matched preload, EMD-57033 lowered the oxygen cost of contractility by −11.4±5.8%, whereas it rose 64±18% with DOB (
P
=0.001) and 28±11% with milrinone. Doubling EMD-57033 dose further augmented positive inotropy in CON and HF, accompanied by vasodilation, increased heart rate, and other changes consistent with PDE3I coactivity, but the oxygen cost of contractility remained improved compared with the use of DOB.

Conclusions
—Selective Ca
2+
sensitization with minimal PDE3I in vivo is achieved with the use of EMD-57033, improving basal and rate-stimulated contractility and mechanoenergetics of HF without compromising diastolic function. Despite PDE3I activity at higher doses, energetic benefits persist.
Long-Term Follow-Up of Patients With Mild Coronary Artery Disease and Endothelial Dysfunction
Authors: Suwaidi Jassim Al , Hamasaki Shuichi , Higano Stuart T. , Nishimura Rick A. , Holmes David R. , Lerman Amir
Published: June 2012

Background
—Coronary endothelial dysfunction is characterized by vasoconstrictive response to the endothelium-dependent vasodilator acetylcholine. Although endothelial dysfunction is considered an early phase of coronary atherosclerosis, there is a paucity of information regarding the outcome of these patients. Thus, this study was designed to evaluate the outcome of patients with mild coronary artery disease on the basis of their endothelial function.

Methods and Results
—Follow-up was obtained in 157 patients with mildly diseased coronary arteries who had undergone coronary vascular reactivity evaluation by graded administration of intracoronary acetylcholine, adenosine, and nitroglycerin and intracoronary ultrasound at the time of diagnostic study. Patients were divided on the basis of their response to acetylcholine into 3 groups: group 1 (n=83), patients with normal endothelial function; group 2 (n=32), patients with mild endothelial dysfunction; and group 3 (n=42), patients with severe endothelial dysfunction. Over an average 28-month follow-up (range, 11 to 52 months), none of the patients from group 1 or 2 had cardiac events. However, 6 (14%) with severe endothelial dysfunction had 10 cardiac events (
P
<0.05 versus groups 1 and 2). Cardiac events included myocardial infarction, percutaneous or surgical coronary revascularization, and/or cardiac death.

Conclusions
—Severe endothelial dysfunction in the absence of obstructive coronary artery disease is associated with increased cardiac events. This study supports the concept that coronary endothelial dysfunction may play a role in the progression of coronary atherosclerosis.
Inspiratory Impedance During Active Compression-Decompression Cardiopulmonary Resuscitation
Authors: Plaisance Patrick , Lurie Keith G. , Payen Didier
Published: June 2012

Background
—Blood pressure is severely reduced in patients in cardiac arrest receiving standard cardiopulmonary resuscitation (CPR). Although active compression-decompression (ACD) CPR improves acute hemodynamic parameters, arterial pressures remain suboptimal with this technique. We performed ACD CPR in patients with a new inspiratory threshold valve (ITV) to determine whether lowering intrathoracic pressures during the “relaxation” phase of ACD CPR would enhance venous blood return and overall CPR efficiency.

Methods and Results
—This prospective, randomized, blinded trial was performed in prehospital mobile intensive care units in Paris, France. Patients in nontraumatic cardiac arrest received ACD CPR plus the ITV or ACD CPR alone for 30 minutes during advanced cardiac life support. End tidal CO
2
(ETCO
2
), diastolic blood pressure (DAP) and coronary perfusion pressure, and time to return of spontaneous circulation (ROSC) were measured. Groups were similar with respect to age, gender, and initial rhythm. Mean maximal ETCO
2
, coronary perfusion pressure, and DAP values, respectively (in mm Hg), were 13.1±0.9, 25.0±1.4, and 36.5±1.5 with ACD CPR alone versus 19.1±1.0, 43.3±1.6, and 56.4±1.7 with ACD plus valve (
P
<0.001 between groups). ROSC was observed in 2 of 10 patients with ACD CPR alone after 26.5±0.7 minutes versus 4 of 11 patients with ACD CPR plus ITV after 19.8±2.8 minutes (
P
<0.05 for time from intubation to ROSC).

Conclusions
—Use of an inspiratory resistance valve in patients in cardiac arrest receiving ACD CPR increases the efficiency of CPR, leading to diastolic arterial pressures of >50 mm Hg. The long-term benefits of this new CPR technology are under investigation.
Insertion-Deletion Polymorphism of the
ACE
Gene Modulates Reversibility of Endothelial Dysfunction With ACE Inhibition
Authors: Prasad Abhiram , Narayanan Suresh , Husain Syed , Padder Feroz , Waclawiw Myron , Epstein Neil , Quyyumi Arshed A.
Published: June 2012

Background
—The aim of this study was to examine whether angiotensin-converting enzyme (ACE) inhibition improves coronary endothelial dysfunction in patients with atherosclerosis and its risk factors and whether this was related to the
ACE
insertion-deletion
(I/D)
polymorphism.

Methods and Results
—In 56 patients with atherosclerosis or its risk factors, we studied endothelium-dependent responses with acetylcholine and endothelium-independent function with sodium nitroprusside, before and after ACE inhibition with enalaprilat. Enalaprilat did not alter either resting coronary tone or vasodilation with sodium nitroprusside. However, it potentiated the coronary microvascular and epicardial responses with acetylcholine; coronary blood flow increased from 82±7 to 90±8 mL/min (
P
=0.05) after enalaprilat. Patients with depressed endothelial function (
P
<0.001) and those with
ACE DD
or
ID
genotypes (
P
=0.002) but not those homozygous for the
I
allele had the greatest improvement by multivariate analysis. Similarly, acetylcholine-mediated epicardial vasomotion improved in segments that initially constricted (endothelial dysfunction): from −10.1±1% to −1.4±2% (
P
<0.001) after enalaprilat. No augmentation was observed in segments that dilated (normal endothelial dysfunction) with acetylcholine. Patients with the
D
allele, hypercholesterolemia, and smokers (all
P
<0.05) had greater improvement.

Conclusions
—Acute ACE inhibition improves coronary epicardial and microvascular endothelium-dependent vasomotion in patients with atherosclerosis or its risk factors who have endothelial dysfunction and presence of the
D
allele.
Initiation of Atrial Fibrillation by Ectopic Beats Originating From the Superior Vena Cava
Authors: Tsai Chin-Feng , Tai Ching-Tai , Hsieh Ming-Hsiung , Lin Wei-Shiang , Yu Wen-Chung , Ueng Kwo-Chang , Ding Yu-An , Chang Mau-Song , Chen Shih-Ann
Published: June 2012

Background
—The superior vena cava (SVC) has cardiac musculature extending from the right atrium. However, no previous study in humans has given details regarding the ectopic foci that initiate paroxysmal atrial fibrillation (PAF), which may originate from the SVC.

Methods and Results
—A total of 130 patients with frequent attacks of PAF initiated by ectopic beats were included. Eight patients (6%) had spontaneous AF initiated by a burst of rapid ectopic beats from the SVC (located 19±7 mm above the junction of the SVC and right atrium), which was confirmed by multiplane angiographic and intracardiac echocardiographic visualization and was marked by a sharp SVC potential preceding atrial activity. During initial repetitive discharges, the group with SVC ectopy had a higher incidence of intravenous conduction block than the group with pulmonary vein ectopy (75% versus 37%;
P
=0.03). The activation time of the earliest intracardiac ectopic activities relative to ectopic P wave onset was significantly shorter in the SVC ectopy than the pulmonary vein ectopy group (37±15 versus 84±32 ms;
P
<0.001). After 5±3 applications of radiofrequency energy, AF was eliminated. SVC angiography after ablation revealed a local indentation of the venous wall in one patient. Two patients manifested coexisting sinus rhythm and a “focal” fibrillating activity confined inside the SVC after radiofrequency ablation. During a follow-up period of 9±3 months, all 8 patients were free of antiarrhythmic drugs, without tachycardia recurrence or symptoms of SVC obstruction.

Conclusions
—Ectopic beats initiating PAF can originate from the SVC. A radiofrequency current delivered to eliminate these ectopies is a highly effective and safe way to prevent PAF.
Mechanism of Lumen Enlargement During Intracoronary Stent Implantation
Authors: Ahmed Javed M. , Mintz Gary S. , Weissman Neil J. , Lansky Alexandra J. , Pichard Augusto D. , Satler Lowell F. , Kent Kenneth M.
Published: June 2012

Background
—Intravascular ultrasound analysis has assessed mechanisms of lumen enlargement after nonstent interventions, but not after stenting.

Methods and Results
—Preintervention and postintervention intravascular ultrasound was used to study 25 de novo native coronary lesions treated with single MultiLink stents without preatheroablation. External elastic membrane, lumen, and plaque and media (P&M) areas were measured every 1 mm to include the lesion and reference segments that were 5 mm proximal and distal to it. Lesion mean lumen area increased from 4.0±1.0 mm
2
before the intervention to 8.8±2.0 mm
2
after the intervention (
P
<0.0001) as a result of an increase in mean external elastic membrane area (14.2±2.7 to 16.1±3.0 mm
2
,
P
<0.0001) and a decrease in mean P&M area (10.2±2.2 to 7.2±1.8 mm
2
,
P
<0.0001). The decrease in lesion P&M was accompanied by an increase in both proximal reference mean P&M (7.0±1.9 to 8.4±2.0 mm
2
,
P
<0.0001) and distal reference mean P&M (5.8±2.1 to 7.2±2.1 mm
2
,
P
<0.0001). Volumetric analysis showed an axial redistribution of plaque away from the center of the lesion toward the reference segments to increase the plaque burden in both the proximal and distal reference segments. Total (lesion plus reference) mean P&M decreased from 8.6±2.1 to 7.5±1.8 mm
2
(
P
<0.0001).

Conclusions
—The mechanisms of lumen enlargement after stenting involved (1) significant axial redistribution of plaque from the lesion into the reference segments, (2) vessel expansion, and (3) either plaque embolization or compression.
Lipoprotein(a) and Coronary Heart Disease
Authors: Danesh John , Collins Rory , Peto Richard
Published: June 2012

Background
—Studies of the association between the plasma concentration of lipoprotein(a) [Lp(a)] and coronary heart disease (CHD) have reported apparently conflicting findings. We report a meta-analysis of the prospective studies with at least 1 year of follow-up published before 2000.

Methods and Results
—The following information was abstracted for each study: geographical location of study, size, type of cohort (population-based or selected because of previous disease), mean age, follow-up duration, blood storage temperature and duration, assay methods, degree of adjustment for potential confounders, and relationship of baseline Lp(a) measurement with subsequent CHD risk. There were 5436 deaths from CHD or nonfatal myocardial infarctions during a weighted mean follow-up of 10 years in the 27 eligible studies. Comparison of individuals in the top third of baseline plasma Lp(a) measurements with those in the bottom third in each study yielded a combined risk ratio of 1.6 (95% CI 1.4 to 1.8, 2
P
<0.00001), with similar findings when the analyses were restricted to the 18 studies of general populations (combined risk ratio 1.7, 95% CI 1.4 to 1.9; 2
P
<0.00001). Despite differences among studies in blood storage techniques and assay methods, there was no significant heterogeneity among the results from the 18 population-based studies or among those from the 9 studies of patients with previous disease. Lp(a) was only weakly correlated with classical vascular risk factors, and adjustment for those that had been recorded made little difference to the reported risk ratios.

Conclusions
—These prospective studies demonstrate a clear association between Lp(a) and CHD, but further studies are needed to determine the extent to which this is causal.
Extensive Troponin I and T Modification Detected in Serum From Patients With Acute Myocardial Infarction
Authors: Labugger Ralf , Organ Lenny , Collier Christine , Atar Dan , Van Eyk Jennifer E.
Published: June 2012

Background
—Cardiac troponin I and T (cTnI and cTnT) are specific biochemical serum markers for acute myocardial infarction (AMI). However, cTnI diagnostic assays are plagued by difficulties, resulting in ≥20-fold differences in measured values. These discrepancies may result from the release of the numerous cTnI modification products that are present in ischemic myocardium. The resolution of these discrepancies requires an investigation of the exact forms of cTnI present in the bloodstream of patients after myocardial injury.

Methods and Results
—A western blot–direct serum analysis protocol was developed that allowed us to detect intact cTnI and a spectrum of up to 11 modified products in the serum from patients with AMI. For the first time, we document both a cTnI degradation pattern and the existence of phosphorylated cTnI in serum. The number and extent of these modifications reflect patterns similar to the time profiles of the routine clinical serum markers of total creatine kinase, creatine kinase-MB, and cTnI (determined by ELISA). Data from in vitro experiments, which were undertaken to study the degradation of human recombinant cTnI and cTnT when spiked in serum, indicate that some modification products present in patient serum existed in the myocardium and that recombinant cTnI alteration dramatically reduces the detectability of cTnI by the Immuno1 assay over time (our assay was unaffected).

Conclusions
—This pilot study defines, for the first time, what forms of cTnI and cTnT appear in the bloodstream of AMI patients, and it clarifies the lack of standardization between different cTnI diagnostic assays.
Coronary Heart Disease in Smokers
Authors: Kaufmann Philipp A. , Gnecchi-Ruscone Tomaso , di Terlizzi Marco , Schäfers Klaus P. , Lüscher Thomas F. , Camici Paolo G.
Published: June 2012

Background
—Coronary endothelial function and vasomotion are impaired in smokers without coronary disease, and this is thought to be due to increased oxidative stress.

Methods and Results
—We used positron emission tomography to measure the coronary flow reserve, an integrated measure of coronary flow, through both the large epicardial coronary arteries and the microcirculation in 11 smokers and 8 control subjects before and after administration of the antioxidant vitamin C. At baseline, coronary flow reserve was reduced by 21% in smokers compared with control subjects (
P
<0.05) but was normalized after vitamin C, whereas the drug had no effect in control subjects.

Conclusions
—The present study is the first to demonstrate that the noxious prooxidant effects of smoking extend beyond the epicardial arteries to the coronary microcirculation and affect the regulation of myocardial blood flow. Vitamin C restores coronary microcirculatory responsiveness and impaired coronary flow reserve in smokers, which provides evidence that the damaging effect of smoking is at least in part accounted for by an increased oxidative stress.
Importance of Atrial Flutter Isthmus in Postoperative Intra-Atrial Reentrant Tachycardia
Authors: Chan David P. , Van Hare George F. , Mackall Judith A. , Carlson MD Mark D. , Waldo Albert L.
Published: June 2012

Background
—In survivors of congenital heart surgery, intra-atrial reentrant tachycardia (IART) often develops. Previous reports have emphasized the atriotomy scar as the central barrier around which a reentrant circuit may rotate but have not systematically evaluated the atrial flutter isthmus in such patients. We sought to determine the role of the atrial flutter isthmus in supporting IART in a group of postoperative patients with congenital heart disease.

Methods and Results
—Nineteen postoperative patients with IART underwent electrophysiological studies with entrainment mapping of the atrial flutter isthmus for determining postpacing intervals. Radiofrequency ablation was performed at the identified isthmus in an effort to create a complete line of block. Twenty-one IARTs were identified in 19 patients, with a mean tachycardia cycle length of 293±73 ms. The atrial flutter isthmus was part of the circuit in 15 of 21 (71.4%). In the remaining 6 of 21, the ablation target zone was at sites near atrial incisions or suture lines. Ablation was successful in 19 of 21 (90.4%) IARTs and in 14 of 15 (93.3%) cases at the atrial flutter isthmus.

Conclusions
—In most of our postoperative patients, the atrial flutter isthmus was part of the reentrant circuit. The fact that the atrial flutter isthmus is vulnerable to ablation suggests that whenever IART occurs late after repair of a congenital heart defect, the atrial flutter isthmus should be evaluated. These data support the theory that some form of conduction block between the vena cava is essential for the establishment of a stable substrate for the atrial flutter reentrant circuit.
Proteolysis of von Willebrand Factor and Shear Stress–Induced Platelet Aggregation in Patients With Aortic Valve Stenosis
Authors: Pareti F. I. , Lattuada A. , Bressi C. , Zanobini M. , Sala A. , Steffan A. , Ruggeri Z. M.
Published: June 2012

Background
—Excessive bleeding may complicate congenital cardiac defects. To explain the pathogenesis of this abnormality, we evaluated selected parameters of primary hemostasis in patients with aortic valve stenosis before and after corrective surgery.

Methods and Results
—We examined shear-induced platelet aggregation with the filter aggregometer test and von Willebrand factor (vWF) structure by evaluating the multimeric distribution and extent of subunit proteolysis. The platelet count was reduced before corrective surgery, and shear-induced platelet aggregation was impaired. Moreover, vWF multimers of higher molecular mass were decreased, and proteolytic subunit fragments were increased. After correction of the cardiac defect, all of these parameters returned to normal.

Conclusions
—Alterations of vWF and platelet function may contribute to the bleeding diathesis in patients with aortic valve stenosis. Improvement after corrective surgery suggests that the passage of blood through a stenosed aortic valve may result in shear forces that induce vWF interaction with platelets in the circulation and, in turn, trigger platelet clearance, vWF degradation, and the impairment of primary hemostasis.
Adiponectin, an Adipocyte-Derived Plasma Protein, Inhibits Endothelial NF-κB Signaling Through a cAMP-Dependent Pathway
Authors: Ouchi Noriyuki , Kihara Shinji , Arita Yukio , Okamoto Yoshihisa , Maeda Kazuhisa , Kuriyama Hiroshi , Hotta Kikuko , Nishida Makoto , Takahashi Masahiko , Muraguchi Masahiro , Ohmoto Yasukazu , Nakamura Tadashi , Yamashita Shizuya , Funahashi Tohru , Matsuzawa Yuji
Published: June 2012

Background
—Among the many adipocyte-derived endocrine factors, we found an adipocyte-derived plasma protein, adiponectin, that was decreased in obesity. We recently demonstrated that adiponectin inhibited tumor necrosis factor-α (TNF-α)–induced expression of endothelial adhesion molecules and that plasma adiponectin level was reduced in patients with coronary artery disease (
Circulation
. 1999;100:2473–2476). However, the intracellular signal by which adiponectin suppressed adhesion molecule expression was not elucidated. The present study investigated the mechanism of modulation for endothelial function by adiponectin.

Methods and Results
—The interaction between adiponectin and human aortic endothelial cells (HAECs) was estimated by cell ELISA using biotinylated adiponectin. HAECs were preincubated for 18 hours with 50 μg/mL of adiponectin, then exposed to TNF-α (10 U/mL) or vehicle for the times indicated. NF-κB–DNA binding activity was determined by electrophoretic mobility shift assays. TNF-α–inducible phosphorylation signals were detected by immunoblotting. Adiponectin specifically bound to HAECs in a saturable manner and inhibited TNF-α–induced mRNA expression of monocyte adhesion molecules without affecting the interaction between TNF-α and its receptors. Adiponectin suppressed TNF-α–induced IκB-α phosphorylation and subsequent NF-κB activation without affecting other TNF-α–mediated phosphorylation signals, including Jun N-terminal kinase, p38 kinase, and Akt kinase. This inhibitory effect of adiponectin is accompanied by cAMP accumulation and is blocked by either adenylate cyclase inhibitor or protein kinase A (PKA) inhibitor.

Conclusions
—These observations raise the possibility that adiponectin, which is naturally present in the blood stream, modulates the inflammatory response of endothelial cells through cross talk between cAMP-PKA and NF-κB signaling pathways.
Impact of Smoking on Health-Related Quality of Life After Percutaneous Coronary Revascularization
Authors: Taira Deborah A. , Seto Todd B. , Ho Kalon K. L. , Krumholz Harlan M. , Cutlip Donald E. , Berezin Ronna , Kuntz Richard E. , Cohen David J.
Published: June 2012

Background
—PTCA is performed primarily to improve health-related quality of life (HRQOL) in patients with symptomatic coronary artery disease. In patients undergoing PTCA, smoking has been shown to increase risks of late myocardial infarction and death. Whether smoking also affects HRQOL after PTCA is currently unknown.

Methods and Results
—We examined the relation between smoking status and HRQOL among 1432 patients who underwent PTCA as part of 2 multicenter clinical trials. HRQOL was assessed with the use of the Medical Outcomes Study SF-36 questionnaire. Patients were classified as smokers (n=301), quitters (n=141), or nonsmokers (n=990) on the basis of their smoking status at the time of their index procedure and during the first year of follow-up. For the overall population, HRQOL improved significantly after PTCA for all scales except general health perception, with improvements ranging from 5.5 points for mental health to 23.2 points for role-physical functioning. After adjustment for baseline characteristics and initial HRQOL, nonsmokers had gains at 6 months that were larger than those of smokers for all health domains: physical function (15.4 versus 10.4 points), role-physical (24.5 versus 13.9), pain (18.4 versus 13.3), general health perception (1.7 versus −4.5), vitality (11.0 versus 4.7), social function (12.8 versus 3.5), role-emotional (13.5 versus 6.7), and mental health (6.8 versus 0.8;
P
<0.02 for all comparisons). Quitters had 6-month HRQOL improvements that were greater than those in smokers for all domains as well. Findings were similar at 1 year.

Conclusions
—Quality-of-life benefits of PTCA are diminished by continued smoking. Efforts to promote smoking cessation at the time of PTCA may substantially improve the health outcomes of these procedures.
Effect of Amlodipine on the Progression of Atherosclerosis and the Occurrence of Clinical Events
Authors: Pitt Bertram , Byington Robert P. , Furberg Curt D. , Hunninghake Donald B. , Mancini G. B. John , Miller Michael E. , Riley Ward , (for the PREVENT Investigators)
Published: June 2012

Background
—The results of angiographic studies have suggested that calcium channel–blocking agents may prevent new coronary lesion formation, the progression of minimal lesions, or both.

Methods and Results
—The Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT) was a multicenter, randomized, placebo-controlled, double-masked clinical trial designed to test whether amlodipine would slow the progression of early coronary atherosclerosis in 825 patients with angiographically documented coronary artery disease. The primary outcome was the average 36-month angiographic change in mean minimal diameters of segments with a baseline diameter stenosis of 30%. A secondary hypothesis was whether amlodipine would reduce the rate of atherosclerosis in the carotid arteries as assessed with B-mode ultrasonography, which measured intimal-medial thicknesses (IMT). The rates of clinical events were also monitored. The placebo and amlodipine groups had nearly identical average 36-month reductions in the minimal diameter: 0.084 versus 0.095 mm, respectively (
P
=0.38). In contrast, amlodipine had a significant effect in slowing the 36-month progression of carotid artery atherosclerosis: the placebo group experienced a 0.033-mm increase in IMT, whereas there was a 0.0126-mm decrease in the amlodipine group (
P
=0.007). There was no treatment difference in the rates of all-cause mortality or major cardiovascular events, although amlodipine use was associated with fewer cases of unstable angina and coronary revascularization.

Conclusions
—Amlodipine has no demonstrable effect on angiographic progression of coronary atherosclerosis or the risk of major cardiovascular events but is associated with fewer hospitalizations for unstable angina and revascularization.
Relationship Between Circadian Blood Pressure Patterns and Progression of Early Carotid Atherosclerosis
Authors: Sander Dirk , Kukla Christian , Klingelhöfer Jürgen , Winbeck Kerstin , Conrad Bastian
Published: June 2012

Background
—Arterial hypertension is a major risk factor for cardiovascular damage. The results of several studies suggest that target organ damage is greater in hypertensive persons with high blood pressure variability.

Methods and Results
—During 3.3 years of follow-up, we studied the relationship between circadian blood pressure changes and the progression of early carotid atherosclerosis in 286 patients aged >55 years. Blood pressure patterns were evaluated with a long-term blood pressure monitor, and the extent of atherosclerosis was measured as the intima-media wall thickness (IMT) of the common carotid artery. Patients were subdivided according to blood pressure variability. The progression of IMT was significantly greater in the patients with increased systolic blood pressure variability (0.11 mm/y [95% CI 0.09 to 0.14] versus 0.05 mm/y [0.03 to 0.08];
P
<0.005) even after adjustment for other risk factors. Multivariate regression analysis revealed the daytime systolic blood pressure variability to be the best predictor for the progression of IMT. Raised daytime systolic blood pressure variability (>15 mm Hg) is associated with an increased relative risk of the development of early atherosclerosis (3.9 [1.4 to 11.1];
P
<0.01) and of cardiovascular events (1.87 [1.08 to 3.20];
P
<0.01).

Conclusions
—The daytime systolic blood pressure variability is a strong predictor of early carotid atherosclerosis progression and is useful to define the risk-benefit ratio of therapeutic approaches.
Cardiac Dysfunction and Mortality in HIV-Infected Children
Authors: Lipshultz Steven E. , Easley Kirk A. , Orav E. John , Kaplan Samuel , Starc Thomas J. , Bricker J. Timothy , Lai Wyman W. , Moodie Douglas S. , Sopko George , Colan Steven D. ,   for the Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection (PC HIV) Study Group
Published: June 2012

Background
—Left ventricular (LV) dysfunction is common in children infected with the human immunodeficiency virus (HIV), but its clinical importance is unclear. Our objective was to determine whether abnormalities of LV structure and function independently predict all-cause mortality in HIV-infected children.

Methods and Results
—Baseline echocardiograms were obtained on 193 children with vertically transmitted HIV infection (median age, 2.1 years). Children were followed up for a median of 5 years. Cox regression was used to identify measures of LV structure and function predictive of mortality after adjustment for other important demographic and baseline clinical risk factors. The time course of cardiac variables before mortality was also examined. The 5-year cumulative survival was 64%. Mortality was higher in children who, at baseline, had depressed LV fractional shortening (FS) or contractility; increased LV dimension, thickness, mass, or wall stress; or increased heart rate or blood pressure (
P
≤0.02 for each). Decreased LV FS (
P
<0.001) and increased wall thickness (
P
=0.004) were also predictive of increased mortality after adjustment for CD4 count (
P
<0.001), clinical center (
P
<0.001), and encephalopathy (
P
<0.001). FS showed abnormalities for up to 3 years before death, whereas wall thickness identified a population at risk only 18 to 24 months before death.

Conclusions
—Depressed LV FS and increased wall thickness are risk factors for mortality in HIV-infected children independent of depressed CD4 cell count and neurological disease. FS may be useful as a long-term predictor and wall thickness as a short-term predictor of mortality.