bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of the Human G Protein–Coupled Receptor Kinase 2 (GRK2) Gene Promoter
Authors: Ramos-Ruiz Ricardo , Penela Petronila , Penn Raymond B. , Mayor Federico
Published: June 2012

Background
—Desensitization of G protein–coupled receptors (GPCR) is emerging as an important feature of several cardiovascular diseases. G protein–coupled receptor kinase 2 (GRK2) plays a key role in the regulation of a variety of these receptors, and its cardiac expression levels are altered in pathological situations such as chronic heart failure. However, very little is known about the signals and mechanisms that modulate GRK2 expression in cardiovascular cells.

Methods and Results
—We have studied the transcriptional activity of the 1.6-kb-long proximal genomic region of the human GRK2 gene. In an aortic smooth muscle cell line, agents that lead to physiological vasoconstriction and hypertrophy, such as phorbol esters, increased GRK2 promoter activity. Activation of signaling pathways by cotransfected G
αq
subunits or α
1
-adrenergic receptors also markedly enhanced the expression of the GRK2 promoter constructs. Conversely, proinflammatory cytokines, such as interleukin-1β, tumor necrosis factor-α, or interferon-γ, led to the opposite effect, decreasing the activity of the GRK2 promoter.

Conclusions
—Our results suggest that the expression of GRK2 in vascular cells is tightly controlled at the transcriptional level by the interplay between several extracellular messengers, which may trigger alterations of normal GRK2 levels in some physiopathological circumstances, thus promoting changes in the efficacy of the GPCR signal transduction.
Randomized Trial of Contrast Media Utilization in High-Risk PTCA
Authors: Davidson Charles J. , Laskey Warren K. , Hermiller James B. , Harrison J. Kevin , Matthai William , Vlietstra Ronald E. , Brinker Jeffrey A. , Kereiakes Dean J. , Muhlestein Joseph B. , Lansky Alexandra , Popma Jeffrey J. , Buchbinder Maurice , Hirshfeld John W.
Published: June 2012

Background
—Previous in vitro and in vivo studies have suggested an association between thrombus-related events and type of contrast media. Low osmolar contrast agents appear to improve the safety of diagnostic and coronary artery interventional procedures. However, no data are available on PTCA outcomes with an isosmolar contrast agent.

Methods and Results
—A multicenter prospective randomized double-blind trial was performed in 856 high-risk patients undergoing coronary artery intervention. The objective was to compare the isosmolar nonionic dimer iodixanol (n=405) with the low osmolar ionic agent ioxaglate (n=410). A composite variable of in-hospital major adverse clinical events (MACE) was the primary end point. A secondary objective was to evaluate major angiographic and procedural events during and after PTCA. The composite in-hospital primary end point was less frequent in those receiving iodixanol compared with those receiving ioxaglate (5.4% versus 9.5%, respectively;
P
=0.027). Core laboratory defined angiographic success was more frequent in patients receiving iodixanol (92.2% versus 85.9% for ioxaglate,
P
=0.004). There was a trend toward lower total clinical events at 30 days in patients randomized to iodixanol (9.1% versus 13.2% for ioxaglate,
P
=0.07). Multivariate predictors of in-hospital MACE were use of ioxaglate (
P
=0.01) and treatment of a de novo lesion (
P
=0.03).

Conclusions
—In this contemporary prospective multicenter trial of PTCA in the setting of acute coronary syndromes, there was a low incidence of in-hospital clinical events for both treatment groups. The cohort receiving the nonionic dimer iodixanol experienced a 45% reduction in in-hospital MACE when compared with the cohort receiving ioxaglate.
Right Atrial Angiographic Evaluation of the Posterior Isthmus
Authors: Heidbüchel Hein , Willems Rik , van Rensburg Hennie , Adams Jef , Ector Hugo , Van de Werf Frans
Published: June 2012

Background
—Gaining anatomic information about the posterior isthmus is not generally part of flutter ablation procedures. We postulated that right atrial (RA) angiography could rationalize the ablation approach by revealing the conformation of the isthmus.

Methods and Results
—In 100 consecutive patients, biplane RA angiography was performed before ablation to guide catheter contact with the isthmus along its length. Angiography showed a wide variation in the width of the isthmus (17 to 54 mm; 31.3±7.9), its angle with the inferior vena cava in the right anterior oblique projection (68° to 114°; 90.3±9.0°), and its lateral position relative to the inferior vena cava in the left anterior oblique projection. A deep sub-Eustachian recess was revealed in 47%, with a mean depth of 4.3±2.1 mm (1.5 to 9.4). A Eustachian valve was visualized in 24%. Ablation resulted in bidirectional conduction block (which could be transient) in all, with a median of 2 dragging radiofrequency (RF) applications (2.3±2.5 RF applications; 57°C, ≤99 seconds each). Permanent block was achieved in 99%, with a median of 3 RF applications (3.4±3.0). The presence of a Eustachian valve or concave isthmus was associated with statistically more RF applications; the same trend was seen for patients with deep pouches. The number of RF applications decreased statistically throughout the study, indicating a learning curve. No patient had a recurrence after a follow-up of 13±11 months.

Conclusions
—Right atrial angiography reveals a highly variable isthmus anatomy, often showing particular configurations that can make ablation more laborious. Rational adaptation of the ablation approach to these anatomic findings may contribute to successful ablation.
Heart Rate Dynamics at the Onset of Ventricular Tachyarrhythmias as Retrieved From Implantable Cardioverter-Defibrillators in Patients With Coronary Artery Disease
Authors: Pruvot Etienne , Thonet Gilles , Vesin Jean-Marc , van-Melle Guy , Seidl Karlheinz , Schmidinger Herwig , Brachmann Johannes , Jung Werner , Hoffmann Ellen , Tavernier René , Block Michael , Podczeck Andrea , Fromer Martin
Published: June 2012

Background
—The recent availability of implantable cardioverter-defibrillators (ICDs) that record 1024 R-R intervals preceding a ventricular tachyarrhythmia (VTA) provides a unique opportunity to analyze heart rate variability (HRV) before the onset of VTA.

Methods and Results
—Fifty-eight post–myocardial infarction patients with an implanted ICD for recurrent VTA provided 2 sets of 98 heart rate recordings in sinus rhythm: (1) before a VTA and (2) during control conditions. Three subgroups were considered according to the antiarrhythmic (AA) drug regimen. A state of sympathoexcitation was suggested by the significant reduction in HRV before VTA onset compared with control conditions. β-Blockers and
dl
-sotalol enhanced HRV in control recordings; nevertheless, HRV declined before VTA independent of AA drugs. A gradual increase in heart rate and decrease in sinus arrhythmia at VTA onset were specific findings of patients who received
dl
-sotalol.

Conclusions
—The peculiar heart rate dynamics observed before VTA onset are suggestive of a state of sympathoexcitation that is independent of AA drugs.
Left Ventricular Apex Ablation Decreases the Upper Limit of Vulnerability
Authors: Chattipakorn Nipon , Fotuhi Parwis C. , Zheng Xiangsheng , Ideker Raymond E.
Published: June 2012

Background
—After shocks with an ≈50% probability of success for the upper limit of vulnerability (ULV
50
) of strength, the first few activations appear focally on the epicardium at almost the same site at the left ventricular (LV) apex in both successful and failed induction of ventricular fibrillation (VF). We tested the hypothesis that subendocardial ablation at this early site would decrease the shock strength required for the ULV
50
.

Methods and Results
—Ten S1 stimuli were delivered from the right ventricular apex at a 300-ms coupling interval in 5 pigs. Biphasic shocks were delivered from right ventricular–superior vena cava electrodes after the last S1 stimulus. The ULV
50
was determined using an up/down protocol with T-wave scanning. Radiofrequency ablation was performed endocardially at the apical LV. The ULV
50
was determined again 30 minutes after ablation. To determine the importance of the ablation region, this protocol was repeated in another 5 pigs with ablation at the LV base. Delivered voltage (401±60 versus 323±50 V) and energy (11±3 versus 7±2 J) for the ULV
50
were significantly decreased after LV apex ablation by 19% and 34%, respectively. However, no difference existed in ULV
50
before and after LV base ablation. Lesions at both the LV apex and base were subendocardial and ranged from 0.8 to 1.1 cm in diameter.

Conclusions
—Subendocardial ablation at the apical LV markedly decreases ULV
50
, which suggests that the activation originating from this postshock early site is responsible for VF initiation and that interventions to electrically silence this site can influence the outcome of VF induction by ULV shocks.
Time Course and Mechanism of Myocardial Catecholamine Release During Transient Ischemia In Vivo
Authors: Lameris Thomas W. , de Zeeuw Sandra , Alberts Gooitzen , Boomsma Frans , Duncker Dirk J. , Verdouw Pieter D. , Veld Arie J. Man in ’t , van den Meiracker Anton H.
Published: June 2012

Background
—Elevated concentrations of norepinephrine (NE) have been observed in ischemic myocardium. We investigated the magnitude and mechanism of catecholamine release in the myocardial interstitial fluid (MIF) during ischemia and reperfusion in vivo through the use of microdialysis.

Methods and Results
—In 9 anesthetized pigs, interstitial catecholamine concentrations were measured in the perfusion areas of the left anterior descending coronary artery (LAD) and the left circumflex coronary artery. After stabilization, the LAD was occluded for 60 minutes and reperfused for 150 minutes. During the final 30 minutes, tyramine (154 nmol · kg
−1
· min
−1
) was infused into the LAD. During LAD occlusion, MIF NE concentrations in the ischemic region increased progressively from 1.0±0.1 to 524±125 nmol/L. MIF concentrations of dopamine and epinephrine rose from 0.4±0.1 to 43.9±9.5 nmol/L and from <0.2 (detection limit) to 4.7±0.7 nmol/L, respectively. Local uptake-1 blockade attenuated release of all 3 catecholamines by >50%. During reperfusion, MIF catecholamine concentrations returned to baseline within 120 minutes. At that time, the tyramine-induced NE release was similar to that seen in nonischemic control animals despite massive infarction. Arterial and MIF catecholamine concentrations in the left circumflex coronary artery region remained unchanged.

Conclusions
—Myocardial ischemia is associated with a pronounced increase of MIF catecholamines, which is at least in part mediated by a reversed neuronal reuptake mechanism. The increase of MIF epinephrine implies a (probably neuronal) cardiac source, whereas the preserved catecholamine response to tyramine in postischemic necrotic myocardium indicates functional integrity of sympathetic nerve terminals.
Predictors of Mortality and Mortality From Cardiac Causes in the Bypass Angioplasty Revascularization Investigation (BARI) Randomized Trial and Registry
Authors: Brooks Maria Mori , Jones Robert H. , Bach Richard G. , Chaitman Bernard R. , Kern Morton J. , Orszulak Thomas A. , Follmann Dean , Sopko George , Blackstone Eugene H. , Califf Robert M.
Published: June 2012

Background
—The impact of percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass grafting (CABG) on long-term mortality rates in the presence of various demographic, clinical, and angiographic factors is uncertain in the population of patients suitable for both procedures.

Methods and Results
—In the Bypass Angioplasty Revascularization Investigation (BARI) randomized trial and registry, 3610 patients who were eligible to receive PTCA and CABG were revascularized between 1989 and 1992. Multivariate Cox models were used to identify factors associated with 5-year mortality and cardiac mortality, with particular attention to factors that interact with treatment. Diabetic patients receiving insulin had higher mortality and cardiac mortality rates with PTCA compared with CABG (relative risk [RR] 1.78 and 2.63, respectively,
P
<0.001), and patients with ST elevation had higher cardiac mortality rates with CABG than with PTCA (RR 4.08,
P
<0.001). Factors most strongly associated with high overall mortality rates were insulin-treated diabetes, congestive heart failure, kidney failure, and older age. Black race was also associated with higher mortality rates (RR 1.49,
P
=0.019).

Conclusions
—A set of variables was identified that could be used to help select a revascularization procedure and to evaluate risk of long-term mortality in the population of patients considering revascularization.
Positional Genomic Analysis Identifies the β
2
-Adrenergic Receptor Gene as a Susceptibility Locus for Human Hypertension
Authors: Bray Molly S. , Krushkal Julia , Li Li , Ferrell Robert , Kardia Sharon , Sing Charles F. , Turner Stephen T. , Boerwinkle Eric
Published: June 2012

Background
—After genome-wide linkage analyses of blood pressure levels, we resequenced 5 positional candidate genes in a linkage region on chromosome 5 and genotyped selected variants in several family samples from Rochester, Minn.

Methods and Results
—In a sample of 55 pedigrees containing ≥1 sibling-pair(s) discordant for systolic blood pressure, polymorphisms within the β
2
-adrenergic receptor gene (Arg16Gly,
P
=0.009) and the glutathione peroxidase 3 gene (−302G→A,
P
=0.037; −623A→C,
P
=0.013) were significantly related to blood pressure levels. In a second sample of 298 nuclear families (n=1283 individuals), the Arg16Gly polymorphism was significantly associated with diastolic blood pressure in family-based analyses (
P
=0.016) and with both diastolic (
P
=0.009) and mean arterial blood pressure (
P
=0.038) in analyses of the parental generation only. Neither polymorphism in the glutathione peroxidase 3 gene was associated with blood pressure levels in this sample. An additional 291 families (n=1240 individuals) were added to the nuclear family sample, and the Gln27Glu polymorphism in the β
2
-adrenergic receptor gene was significantly associated with both systolic (
P
=0.034) and mean arterial blood pressure (
P
=0.035) in the parental generation of the combined 589 families. The frequencies of both the Gly16 and Glu27 alleles were higher in hypertensives than in normotensives (0.649 versus 0.604 and 0.490 versus 0.429, respectively), and the odds ratio for the occurrence of hypertension was 1.80 (95% confidence interval, 1.08 to 3.00;
P
=0.023) for the Glu27 allele.

Conclusions
—The results of this study provide support for further detailed investigations of the mechanistic pathways by which variations in the β
2
-adrenergic receptor gene may influence blood pressure levels.
Uncertainty Principle of Signal-Averaged Electrocardiography
Authors: Goldberger Jeffrey J. , Challapalli Sridevi , Waligora Michael , Kadish Alan H. , Johnson David A. , Ahmed Mirza W. , Inbar Shmuel
Published: June 2012

Background
—Signal-averaged ECG (SAECG) reproducibility is reported to have a component that is independent of residual noise.

Methods and Results
—In group 1, multiple paired SAECGs were obtained to noise levels of 0.3±0.1 and 0.5±0.2 μV. For the 0.5- and 0.3-μV noise recordings, QRS duration (QRSd) was 101.2±11.3 and 104.6±9.6 ms, respectively (
P
<0.0001), and the differences in paired QRSd (ΔQRSd) were normally distributed, with variances of 11.4 and 26.2 ms
2
(
P
<0.0001). Paired SAECGs were obtained in group 2 patients without and with late potentials; ΔQRSd variance was 3.3 and 217.9 ms
2
(
P
<0.0001). In group 3, ≥10 SAECGs were acquired at noise levels of 0.2 to 0.8 μV, in 0.1-μV increments. QRSd increased as noise level decreased. The variance was greater in low-noise (0.2 to 0.4 μV) versus higher-noise (0.5 to 0.8 μV) recordings. In group 4, SAECGs were analyzed with bidirectional and Bispec filters, with no difference in QRSd between the 2 filters and a normally distributed ΔQRSd. A computer simulation demonstrated that alterations in the phase relationship of noise to signal results in a normal distribution of signal end points.

Conclusions
—Within the acceptable noise range for SAECG, lower noise results in longer QRSd and larger variance, suggesting that more accurate recordings may have less reproducibility. The random timing of noise relative to signal results in the distribution/variance of repeated measurements. Statistical strategies may be used to reduce some of this variance and may enhance the diagnostic utility of SAECG.
Role of Nitric Oxide and Adenosine in Control of Coronary Blood Flow in Exercising Dogs
Authors: Tune Johnathan D. , Richmond Keith Neu , Gorman Mark W. , Feigl Eric O.
Published: June 2012

Background
—Inhibition of nitric oxide (NO) synthesis results in very little change in coronary blood flow, but this is thought to be because cardiac adenosine concentration increases to compensate for the loss of NO vasodilation. Accordingly, in the present study, adenosine measurements were made before and during NO synthesis inhibition during exercise.

Methods and Results
—Experiments were performed in chronically instrumented dogs at rest and during graded treadmill exercise before and during inhibition of NO synthesis with
N
ω
-nitro-
l
-arginine (L-NNA, 35 mg/kg IV). Before inhibition of NO synthesis, myocardial oxygen consumption increased ≈3.7-fold, and coronary blood flow increased ≈3.2-fold from rest to the highest level of exercise, and this was not changed by NO synthesis inhibition. Coronary venous oxygen tension was modestly reduced by L-NNA at all levels of myocardial oxygen consumption. However, the slope of the relationship between myocardial oxygen consumption and coronary venous oxygen tension was not altered by L-NNA. Inhibition of NO synthesis did not increase coronary venous plasma or estimated interstitial adenosine concentration. During exercise, estimated interstitial adenosine remained well below the threshold concentration necessary for coronary vasodilation before or after L-NNA.

Conclusions
—NO causes a modest coronary vasodilation at rest and during exercise but does not act as a local metabolic vasodilator. Adenosine does not mediate a compensatory local metabolic coronary vasodilation when NO synthesis is inhibited.
Enteroviral Capsid Protein VP1 Is Present in Myocardial Tissues From Some Patients With Myocarditis or Dilated Cardiomyopathy
Authors: Li Yanwen , Bourlet Thomas , Andreoletti Laurent , Mosnier Jean-François , Peng Tianqing , Yang Yingzhen , Archard Leonard C. , Pozzetto Bruno , Zhang Hongyi
Published: June 2012

Background
—There are still discrepancies in the association of enterovirus and myocardial disease, partially due to lack of data on the detection of virus antigens in tissues. It is desirable to localize enteroviral antigens so as to establish a link between the two and to study mechanisms of virus persistence.

Methods and Results
—Nineteen fixed explanted or postmortem myocardial samples were obtained from patients with myocarditis or dilated cardiomyopathy (DCM). Control samples were collected from 11 subjects who had died accidentally or of noncardiovascular disease. Viral antigen was detected by an improved immunohistochemical technique using an enterovirus group–specific antibody to viral capsid protein VP1. Nine of 11 myocarditis cases (81.8%) and 6 of 8 DCM cases (75%) were positive. Signals were localized in the cytoplasm of myocytes. Intense immunostaining was observed in acute myocarditis, whereas VP1 was detected in scattered myocytes in chronic myocarditis or DCM. Enteroviral RNA was detected in 6 of 11 myocarditis samples (54.5%) and 3 of 8 DCM samples (37.5%) by the reverse transcription–nested polymerase chain reaction, correlating with antigen detection (κ=0.6±0.21). Neither viral antigen nor RNA was detected in any controls.

Conclusions
—Our findings demonstrate a direct link between enterovirus infection and some myocarditis or DCM cases. The pattern of VP1 detection may correlate with disease stage and severity. The data suggest that viral protein synthesis may be involved in persistent enterovirus infection in the pathogenesis of DCM.
Chronic
N
G
-Nitro-
l
-Arginine Methyl Ester–Induced Hypertension
Authors: Bartunek Jozef , Weinberg Ellen O. , Tajima Minori , Rohrbach Susanne , Katz Sarah E. , Douglas Pamela S. , Lorell Beverly H.
Published: June 2012

Background
—Chronic
N
G
-nitro-
l
-arginine methyl ester (L-NAME), which inhibits nitric oxide synthesis, causes hypertension and would therefore be expected to induce robust cardiac hypertrophy. However, L-NAME has negative metabolic effects on protein synthesis that suppress the increase in left ventricular (LV) mass in response to sustained pressure overload. In the present study, we used L-NAME–induced hypertension to test the hypothesis that adaptation to pressure overload occurs even when hypertrophy is suppressed.

Methods and Results
—Male rats received L-NAME (50 mg · kg
−1
· d
−1
) or no drug for 6 weeks. Rats with L-NAME–induced hypertension had levels of systolic wall stress similar to those of rats with aortic stenosis (85±19 versus 92±16 kdyne/cm). Rats with aortic stenosis developed a nearly 2-fold increase in LV mass compared with controls. In contrast, in the L-NAME rats, no increase in LV mass (1.00±0.03 versus 1.04±0.04 g) or hypertrophy of isolated myocytes occurred (3586±129 versus 3756±135 μm
2
) compared with controls. Nevertheless, chronic pressure overload was not accompanied by the development of heart failure. LV systolic performance was maintained by mechanisms of concentric remodeling (decrease of in vivo LV chamber dimension relative to wall thickness) and augmented myocardial calcium–dependent contractile reserve associated with preserved expression of α- and β-myosin heavy chain isoforms and sarcoplasmic reticulum Ca
2+
ATPase (SERCA-2).

Conclusions
—When the expected compensatory hypertrophic response is suppressed during L-NAME–induced hypertension, severe chronic pressure overload is associated with a successful adaptation to maintain systolic performance; this adaptation depends on both LV remodeling and enhanced contractility in response to calcium.
Pulsatility of Ascending Aortic Pressure Waveform Is a Powerful Predictor of Restenosis After Percutaneous Transluminal Coronary Angioplasty
Authors: Nakayama Yasunori , Tsumura Kei , Yamashita Naotoshi , Yoshimaru Kiyomichi , Hayashi Tomoshige
Published: June 2012

Background
—Because ascending aortic pressure has a greater effect on coronary perfusion during diastole than systole, we hypothesized that a high coronary diastolic-to-systolic pressure ratio prevents coronary lesions from restenosing after percutaneous transluminal coronary angioplasty (PTCA) and that ascending aortic pulsatility relative to mean pressure is higher in patients with restenosis than in those without restenosis. The purpose of this study was to evaluate prospectively whether the morphology of the ascending aortic pressure wave can be used to predict restenosis after PTCA.

Methods and Results
—We measured the coronary artery diameter and the aortic pressure before PTCA. To quantify the relative magnitude of the pulsatile-to-mean aortic pressure, we normalized the pulse pressure to mean pressure and referred to this value as the fractional pulse pressure (PPf). We prospectively investigated the effect of PPf in relation to subsequent risk of restenosis after PTCA in patients with coronary artery disease. PPf was a powerful predictor of restenosis. Crude cumulative incidence rates of restenosis were 17.6% for the lowest, 33.3% for the middle, and 77.8% for the highest tertile of PPf levels. After adjustments for age, smoking habits, systolic blood pressure, type 2 diabetes, hypercholesterolemia, old myocardial infarction, vessel location, vessel size, and sex, the odds ratio of restenosis was 33.5 (95% confidence interval, 2.04 to 550.6) for the highest tertile of the PPf level compared with the lowest tertile level.

Conclusions
—Pulsatility of the ascending aortic pressure is a predictive factor for restenosis after PTCA.
Sodium Channel Blockers Identify Risk for Sudden Death in Patients With ST-Segment Elevation and Right Bundle Branch Block but Structurally Normal Hearts
Authors: Brugada Ramon , Brugada Josep , Antzelevitch Charles , Kirsch Glenn E. , Potenza Domenico , Towbin Jeffrey A. , Brugada Pedro
Published: June 2012

Background
—A mutation in the cardiac sodium channel gene (SCN5A) has been described in patients with the syndrome of right bundle branch block, ST-segment elevation in leads V1 to V3, and sudden death (Brugada syndrome). These electrocardiographic manifestations are transient in many patients with the syndrome. The present study examined arrhythmic risk in patients with overt and concealed forms of the disease and the effectiveness of sodium channel blockers to unmask the syndrome and, thus, identify patients at risk.

Methods and Results
—The effect of intravenous ajmaline (1 mg/kg), procainamide (10 mg/kg), or flecainide (2 mg/kg) on the ECG was studied in 34 patients with the syndrome and transient normalization of the ECG (group A), 11 members of 3 families in whom a SCN5A mutation was associated with the syndrome and 8 members in whom it was not (group B), and 53 control subjects (group C). Ajmaline, procainamide, or flecainide administration resulted in ST-segment elevation and right bundle branch block in all patients in group A and in all 11 patients with the mutation in group B. A similar pattern could not be elicited in the 8 patients in group B who lacked the mutation or in any person in group C. The follow-up period (37±33 months) revealed no differences in the incidence of arrhythmia between the 34 patients in whom the phenotypic manifestation of the syndrome was transient and the 24 patients in whom it was persistent (log-rank, 0.639).

Conclusions
—The data demonstrated a similar incidence of potentially lethal arrhythmias in patients displaying transient versus persistent ST-segment elevation and right bundle branch block, as well as the effectiveness of sodium channel blockers to unmask the syndrome and, thus, identify patients at risk.
Accelerated Onset and Increased Incidence of Ventricular Arrhythmias Induced by Ischemia in Cx43-Deficient Mice
Authors: Lerner Deborah L. , Yamada Kathryn A. , Schuessler Richard B. , Saffitz Jeffrey E.
Published: June 2012

Background
—Myocardial ischemia causes profound changes in both active membrane currents and passive electrical properties. Because these complex changes develop and progress concomitantly, it has not been possible to elucidate the relative contributions of any one component to arrhythmogenesis induced by acute ischemia. Cx43+/− mice express 50% of the normal level of connexin43 (Cx43), the major ventricular electrical coupling protein, but are otherwise identical to wild-type (Cx43+/+) mice. Comparison of arrhythmogenesis in Cx43+/− and +/+ mice can provide insights into the role of changes in electrical coupling as an independent variable in the complex setting of acute ischemia.

Methods and Results
—Acute ischemia was induced in isolated perfused mouse hearts by occlusion of the left anterior descending coronary artery. Spontaneous ventricular tachyarrhythmias (VT) occurred in more than twice as many Cx43+/− hearts than Cx43+/+ hearts. VT was induced in nearly 3 times as many Cx43+/− hearts. Multiple runs and prolonged runs of spontaneous VT were more frequent in Cx43+/− hearts. Onset of the first run of VT occurred significantly earlier in Cx43+/− hearts. Premature ventricular beats were also more frequent in Cx43+/− hearts. The size of the hypoperfused region was equivalent in both groups.

Conclusions
—Reduced expression of Cx43 accelerates the onset and increases the incidence, frequency, and duration of ventricular tachyarrhythmias after coronary artery occlusion. Thus diminished electrical coupling per se plays a critical role in arrhythmogenesis induced by acute ischemia.
Bradycardia and the Role of β-Blockade in the Amelioration of Left Ventricular Dysfunction
Authors: Nagatsu Masayoshi , Spinale Francis G. , Koide Masaaki , Tagawa Hirofumi , DeFreitas Gilberto , Cooper George , Carabello Blase A.
Published: June 2012

Background
—It is clear that β-blockers are effective for treatment of congestive heart failure, but their mechanism of action remains controversial. Hypothesized mechanisms include normalization of β-receptor function and myocardial protection from the effects of catecholamines, possibly by the institution of bradycardia. We hypothesized that β-blockade–induced bradycardia was an important mechanism by which these agents were effective for correction of LV dysfunction.

Methods and Results
—In 2 groups of dogs with mitral regurgitation and LV dysfunction, β-blockers were instituted. In 1 group that received β-blockers and pacing (group β+P), a pacemaker prevented the natural bradycardia that β-blockers cause. In both groups, substantial LV dysfunction developed. Before β-blockade, the end-systolic stiffness constant decreased from 3.5±0.1 to 2.7±0.2 (
P
<0.01) at 3 months in group β+P. A similar reduction occurred in the group that eventually received only β-blockers (group βB). In group βB, end-systolic stiffness improved after 3 months of β-blockade from 2.9±0.2 to 3.5±0.4 and was not different from baseline. However, in group β+P, end-systolic stiffness failed to improve (2.7±0.2) after 3 months of mitral regurgitation, and was 2.9±0.2 at the end of the studies. The contractile function of cardiocytes isolated from the ventricles at the end of the studies confirmed these in vivo estimates of contractility.

Conclusions
—We conclude that institution of bradycardia is a major mechanism by which β-blockers are effective for restoration of contractile function in a model of LV dysfunction.
Attenuated Cardiac Allograft Vasculopathy in Mice With Targeted Deletion of the Transcription Factor STAT4
Authors: Koglin Jörg , Glysing-Jensen Troels , Gadiraju Silpa , Russell Mary E.
Published: June 2012

Background
—To study transcription factor signaling pathways that mediate cardiac allograft vasculopathy, we used mice with targeted gene deletion of signal transducer and activator of transcription (STAT)4 and STAT6 as recipients in our mouse cardiac transplant model of chronic rejection.

Methods and Results
—At day 55 after transplantation, cardiac grafts placed into STAT4 −/− (n=10) had reduced frequency (24±2%) and severity (9±4%) of vascular occlusion compared with wild-type controls (n=7, frequency 70±12% [
P
<0.001], severity 25±6% [
P
<0.05]). This decrease was associated with reduced intragraft expression (
32
P RT-PCR and immunohistochemistry) of the Th1 signature cytokines interferon-γ (
P
<0.001) and interleukin (IL)-2 (
P
<0.001). Furthermore, cardiac grafts in STAT4 −/− had fewer infiltrating CD45
+
mononuclear cells (99±27 cells/mm
3
compared with 551±168 cells/mm
3
in wild-type controls [
P
<0.05]) and reduced expression of P-selectin (
P
<0.001) and E-selectin (
P
<0.01) ligand, recently shown to regulate Th1 cell recruitment. In contrast, in grafts placed into STAT6 −/− (n=11), the development of cardiac allograft vasculopathy (frequency 62±8%, severity 28±6%) and Th2 cytokine profiles (IL-4, IL-10) were comparable to those in wild-type controls.

Conclusions
—Hence, we show that immune responses mediated by STAT4, but not STAT6, contribute to the development of cardiac allograft vasculopathy. We speculate that when present, STAT4-mediated signaling pathways may promote cardiac allograft vasculopathy by directing Th1-specific lymphocyte recruitment, activation, and effector functions.
Economic Outcomes of Implantable Cardioverter-Defibrillators
Authors: Stanton Marshall S. , Bell Gregory K.
Published: June 2012

Background
—We reviewed the literature pertaining to the cost-effectiveness of implantable cardioverter-defibrillator (ICD) therapy in the management of ventricular fibrillation and tachycardia. Discussed are the methodology, advantages, and limitations of economic-outcomes analyses as related to ICD therapy; the impact of new technology and physician practice patterns; and methodological recommendations for future studies.

Methods and Results
—Articles published between 1990 and 1997 were screened for cost-effectiveness analyses of ICD versus antiarrhythmic drug therapy. Randomized clinical trials, prospective and retrospective studies, and economic models were included. These studies report incremental cost-effectiveness ratios ranging from cost savings of $13 975 per life-year saved (LYS) to an incremental cost of $114 917 per LYS for ICD therapy. Differences were due to study type, cost-reporting methodology, ICD technology used, and length of follow-up. Assuming current technology and physician practice patterns, we find that ICD total therapy costs may break even in 1 to 3 years.

Conclusions
—Recent literature suggests that ICDs are a cost-effective therapy for management of life-threatening ventricular tachyarrhythmias. The advent of new technology and patient management practices should further improve the cost-effectiveness of ICD therapy. Future studies of ICD cost-effectiveness should address the implications of truncated follow-up periods and quality of life.
Acute Myocardial Infarction Complicated by Atrial Fibrillation in the Elderly
Authors: Rathore Saif S. , Berger Alan K. , Weinfurt Kevin P. , Schulman Kevin A. , Oetgen William J. , Gersh Bernard J. , Solomon Allen J.
Published: June 2012

Background
—Although atrial fibrillation (AF) is a common complication of acute myocardial infarction (MI), patient characteristics and association with outcomes remain poorly defined in the elderly.

Methods and Results
—We evaluated 106 780 Medicare beneficiaries ≥65 years of age from the Cooperative Cardiovascular Project treated for acute MI between January 1994 and February 1996 to determine the prevalence and prognostic significance of AF complicating acute MI in elderly patients. Patients were categorized on the basis of the presence of AF, and those with AF were further subdivided by time of AF (present on arrival versus developing during hospitalization). AF and non-AF patients were compared by univariate analysis, and logistic regression modeling was used to identify clinical predictors of AF. The influence of AF on outcomes was evaluated by unadjusted Kaplan-Meier survival curves and logistic regression models. AF was documented in 23 565 patients (22.1%): 11 510 presented with AF and 12 055 developed AF during hospitalization. AF patients were older, had more advanced heart failure, and were more likely to have had a prior MI and undergone coronary revascularization. AF patients had poorer outcomes, including higher in-hospital (25.3% versus 16.0%), 30-day (29.3% versus 19.1%), and 1-year (48.3% versus 32.7%) mortality. AF remained an independent predictor of in-hospital (odds ratio [OR], 1.21), 30-day (OR, 1.20), and 1-year (OR, 1.34) mortality after multivariate adjustment. Patients developing AF during hospitalization had a worse prognosis than patients who presented with AF.

Conclusions
—AF is a common complication of acute MI in elderly patients and independently influences mortality, particularly when it develops during hospitalization.
Implications of Stroke Risk Criteria on the Anticoagulation Decision in Nonvalvular Atrial Fibrillation
Authors: Go Alan S. , Hylek Elaine M. , Phillips Kathleen A. , Borowsky Leila H. , Henault Lori E. , Chang YuChiao , Selby Joe V. , Singer Daniel E.
Published: June 2012

Background
—Warfarin dramatically reduces the risk of stroke in patients with nonvalvular atrial fibrillation (NVAF) but increases the likelihood of bleeding. Accurately identifying patients who need anticoagulation is critical. We assessed the potential impact of prominent stroke risk classification schemes on this decision in a large sample of patients with NVAF.

Methods and Results
—We used clinical and electrocardiographic databases to identify 13 559 ambulatory patients with NVAF from July 1996 through December 1997. We compared the proportion of patients classified as having a low enough stroke risk to receive aspirin using published criteria from the Atrial Fibrillation Investigators (AFI), American College of Chest Physicians (ACCP), and the Stroke Prevention in Atrial Fibrillation Investigators (SPAF). In this cohort, AFI criteria classified 11% as having a low stroke risk, compared with 23% for ACCP and 29% for SPAF (κ range, 0.44 to 0.85). This 2- to-3-fold increase in low stroke risk patients by ACCP and SPAF criteria primarily resulted from the inclusion of many older subjects (65 to 75 years±men >75 years) with no additional clinical stroke risk factors.

Conclusions
—The age threshold for assigning an increased stroke risk has a dramatic impact on whether to recommend warfarin in populations of patients with NVAF. Large, prospective studies with many stroke events are needed to precisely determine the relationship of age to stroke risk in AF and to identify which AF subgroups are at a sufficiently low stroke risk to forego anticoagulation.
A Classification of Unstable Angina Revisited
Authors: Hamm Christian W. , Braunwald Eugene
Published: June 2012

Abstract
—Unstable angina is a critical phase of coronary heart disease with widely variable symptoms and prognosis. A decade ago, a classification of unstable angina based on clinical symptoms was introduced. This system was then validated by prospective clinical studies to correlate with the prognosis and was linked to angiographic and histological findings. It has been used to categorize patients in many large clinical trials. In recent years, the pathophysiological roles of platelet activation and inflammation in unstable angina have been elucidated. Subsequently, improved markers of myocardial injury, acute-phase proteins, and hemostatic markers that may be associated with clinical outcomes have been identified. Particularly, cardiac-specific troponin T and troponin I have been shown to represent the best predictors of early risk in patients with angina at rest. Accordingly, it is suggested that the original classification be extended by subclassifying one large group of unstable angina patients, ie, those with angina at rest within the past 48 hours (class IIIB), into troponin-positive (T
pos
) and troponin-negative (T
neg
) patients. The 30-days risk for death and myocardial infarction is considered to be up to 20% in class IIIB-T
pos
but <2% in class IIIB-T
neg
patients. Initial results suggest that troponins may function as surrogate markers for thrombus formation and can effectively guide therapy with glycoprotein IIb/IIIa antagonists or low-molecular-weight heparins. These observations provide additional impetus for adding the measurement of these markers to the clinical classification and represent a novel concept of treating these high-risk patients.
Alterations by Norepinephrine of Cardiac Sympathetic Nerve Terminal Function and Myocardial β-Adrenergic Receptor Sensitivity in the Ferret
Authors: Liang Chang-seng , Rounds Naomi Kenmotsu , Dong Erdan , Stevens Suzanne Y. , Shite Junya , Qin Fuzhong
Published: June 2012

Background
—Chronic excessive norepinephrine (NE) causes cardiac sympathetic nerve terminal abnormalities, myocardial β-adrenergic receptor downregulation, and β-adrenergic subsensitivity. The present study was carried out to determine whether these changes could be prevented by antioxidants.

Methods and Results
—Ferrets were administered either NE (1.33 mg/d) or vehicle by use of subcutaneous pellets for 4 weeks. Animals were simultaneously assigned to receive either antioxidant vitamins (β-carotene, ascorbic acid, and α-tocopherol) or placebo pellets. NE increased plasma NE 4- to 5-fold but had no effect on heart rate, heart weight, arterial pressure, or left ventricular systolic function. However, myocardial NE uptake activity and NE uptake-1 site density were reduced, as well as cardiac neuronal NE, tyrosine hydroxylase, and neuropeptide Y. In addition, there was a decrease in myocardial β-adrenergic receptor density with a selective decrease of the β
1
-receptor subtype, reduction of the high-affinity site for isoproterenol, decreased basal adenylyl cyclase activity, and the adenylyl cyclase responses to isoproterenol, Gpp(NH)p, and forskolin. All of these changes were prevented by antioxidant vitamins. The effects of NE on myocardial β-adrenergic receptor density, NE uptake-1 carrier site density, and neuronal NE were also prevented by superoxide dismutase or Trolox C.

Conclusions
—The toxic effects of NE on the sympathetic nerve terminals are mediated via the formation of NE-derived oxygen free radicals. Preservation of the neuronal NE reuptake mechanism is functionally important, because the antioxidants also prevented myocardial β-adrenergic receptor downregulation and postreceptor abnormalities. Thus, antioxidant therapy may be beneficial in heart failure, in which cardiac NE release is increased.
Catalytic Life of Activated Factor XIII in Thrombi
Authors: Robinson Brian R. , Houng Aiilyan K. , Reed Guy L.
Published: June 2012

Background
—Because the increased fibrinolytic resistance of older thrombi may be caused by the continuous cross-linking action of fibrin-bound activated factor XIII (FXIIIa), we examined the persistence of FXIIIa catalytic activity in clots of various ages.

Methods and Results
—The time-related changes in FXIIIa activity in clots was measured with (1) α
2
-antiplasmin (α
2
AP), a physiological glutamine substrate; (2) α
2
AP
13–24
, a peptide; and (3) pentylamine, a nonspecific lysine substrate. The cross-linking of α
2
AP, α
2
AP
13–24
, and pentylamine into fibrin by clot-bound FXIIIa declined rapidly with half-lives of 19, 21, and 26 minutes, respectively. Mutational studies showed that glutamine 14 (but not glutamine 3 or 16) and valine 17 of α
2
AP
13–24
were required for efficient cross-linking to fibrin. The loss of activity was not due primarily to FXIIIa proteolysis and was partially restored by reducing agents, suggesting that oxidation contributes to the loss of the enzyme’s activity in clots. In vivo, the ability of thrombus-bound FXIIIa to cross-link an infused α
2
AP
13–24
peptide into existing pulmonary emboli also declined significantly over time.

Conclusions
—FXIIIa cross-links α
2
AP and an α
2
AP peptide, in a sequence-specific manner, into formed clots with a catalytic half-life of ≈20 minutes. This indicates that FXIIIa activity is a hallmark of new thrombi and that the antifibrinolytic cross-linking effects of FXIIIa are achieved more rapidly in thrombi than previously believed.
Plasma Homocysteine Predicts Mortality Independently of Traditional Risk Factors and C-Reactive Protein in Patients With Angiographically Defined Coronary Artery Disease
Authors: Anderson Jeffrey L. , Muhlestein Joseph B. , Horne Benjamin D. , Carlquist John F. , Bair Tami L. , Madsen Troy E. , Pearson Robert R.
Published: June 2012

Background
—Plasma homocysteine (tHCY) has been associated with coronary artery disease (CAD). We tested whether tHCY also increases secondary risk, after initial CAD diagnosis, and whether it is independent of traditional risk factors, C-reactive protein (CRP), and methylenetetrahydrofolate reductase (
MTHFR
) genotype.

Methods and Results
—Blood samples were collected from 1412 patients with severe angiographically defined CAD (stenosis ≥70%). Plasma tHCY was measured by fluorescence polarization immunoassay. The study cohort was evaluated for survival after a mean of 3.0±1.0 years of follow-up (minimum 1.5 years, maximum 5.0 years). The average age of the patients was 65±11 years, 77% were males, and 166 died during follow-up. Mortality was greater in patients with tHCY in tertile 3 than in tertiles 1 and 2 (mortality 15.7% versus 9.6%,
P
=0.001 [log-rank test], hazard ratio [HR] 1.63). The relative hazard increased 16% for each 5-μmol/L increase in tHCY (
P
<0.001). In multivariate Cox regression analysis, controlling for univariate clinical and laboratory predictors, elevated tHCY remained predictive of mortality (HR 1.64,
P
=0.009), together with age (HR 1.72 per 10-year increment,
P
<0.0001), ejection fraction (HR 0.84 per 10% increment,
P
=0.0001), diabetes (HR 1.98,
P
=0.001), CRP (HR 1.42 per tertile,
P
=0.004), and hyperlipidemia. Homozygosity for the
MTHFR
variant was weakly predictive of tHCY levels but not mortality.

Conclusions
—In patients with angiographically defined CAD, tHCY is a significant predictor of mortality, independent of traditional risk factors, CRP, and
MTHFR
genotype. These findings increase interest in tHCY as a secondary risk marker and in secondary prevention trials (ie, with folate/B vitamins) to determine whether reduction in tHCY will reduce risk.
Relationship of Infarct Artery Patency and Left Ventricular Ejection Fraction to Health-Related Quality of Life After Myocardial Infarction
Authors: Coyne Karin S. , Lundergan Conor F. , Boyle Deneane , Greenhouse Samuel W. , Draoui Yasmine C. , Walker Pamela , Ross Allan M. , Investigators for the GUSTO-I Angiographic Study
Published: June 2012

Background
—Post–myocardial infarction global ejection fraction and infarct-related artery patency might be expected to be associated with health-related quality-of-life (HRQOL) outcomes, but this association has not been previously shown. The GUSTO-I Angiographic Study cohort 2-year follow-up afforded an examination of such potential relationships.

Methods and Results
—A total of 1848 patients (87.7% response rate) who were enrolled in the GUSTO-I Angiographic Study were contacted for a telephone interview regarding their current HRQOL (physical function, psychological well-being, perceived health status, and social function) 2 years after MI. In multivariable models, left ventricular ejection fraction (EF) was significantly related to physical (
P
=0.021) and social (
P
=0.014) function, psychological well-being (
P
=0.042), and perceived health status (
P
=0.024). Infarct-related artery patency was not directly related to any HRQOL outcome. A decreasing EF was predictive of poorer outcomes in each HRQOL dimension. Men consistently had better outcomes in all HRQOL dimension with the exception of perceived health status. Increasing age was predictive of poorer outcomes in all dimensions of HRQOL except for psychological well-being where the inverse occurred; younger patients experienced greater depression, anxiety and worry than their older counterparts. The presence of comorbidities increased the likelihood of worse outcomes in all dimensions.

Conclusions
—This is the first study to demonstrate a significant relationship between EF and long-term HRQOL outcomes. This advantage in left ventricular function preservation should be added to the mortality advantage when considering the impact of treatment strategies for myocardial infarction.