bluuebunny/crossref_metadata_2025 huggingface dataset:
Decreased Expression of Tumor Necrosis Factor-α in Failing Human Myocardium After Mechanical Circulatory Support
Authors: Torre-Amione Guillermo , Stetson Sonny J. , Youker Keith A. , Durand Jean-Bernard , Radovancevic Branislav , Delgado Reynolds M. , Frazier O. H. , Entman Mark L. , Noon George P.
Published: June 2012

Background
—An increasing number of observations in patients with end-stage heart failure suggest that chronic ventricular unloading by mechanical circulatory support may lead to recovery of cardiac function. Tumor necrosis factor-α (TNF-α) is a proinflammatory cytokine capable of producing pulmonary edema, dilated cardiomyopathy, and death. TNF-α is produced in the myocardium in response to volume overload; however, the effects of normalizing ventricular loading conditions on myocardial TNF-α expression are not known. We hypothesize that chronic ventricular unloading by the placement of a left ventricular assist device (LVAD) may eliminate the stress responsible for persistent TNF-α expression in human failing myocardium.

Methods and Results
—Myocardial tissue was obtained from normal hearts and from paired samples of 8 patients with nonischemic end-stage cardiomyopathy at the time of LVAD implantation and removal. Tissue sections were stained for TNF-α, and quantitative analysis of the stained area was performed. We found that TNF-α content decreased significantly after LVAD support. Furthermore, the magnitude of the changes did not correlate with the length of LVAD support, although greater reductions in myocardial TNF-α content were found in patients who were successfully weaned off the LVAD who did not require transplantation.

Conclusions
—These data show for the first time that chronic mechanical circulatory assistance decreases TNF-α content in failing myocardium; furthermore, we suggest that the magnitude of the change may predict which patients will recover cardiac function.
Prognostic Value of the Modified American College of Cardiology/American Heart Association Stenosis Morphology Classification for Long-Term Angiographic and Clinical Outcome After Coronary Stent Placement
Authors: Kastrati Adnan , Schömig Albert , Elezi Shpend , Dirschinger Josef , Mehilli Julinda , Schühlen Helmut , Blasini Rudolf , Neumann Franz-Josef
Published: June 2012

Background
—The modified American College of Cardiology/American Heart Association (ACC/AHA) lesion morphology criteria are predictive of early outcome after various coronary catheter interventions. Their potential prognostic value after stent implantation and, in particular, for restenosis and long-term clinical outcome has not been studied. We assessed the prognostic value of the modified ACC/AHA criteria for the long-term angiographic and clinical outcome of patients after coronary stenting.

Methods and Results
—This study includes 2944 consecutive patients with symptomatic coronary artery disease treated with coronary stent placement. Modified ACC/AHA lesion morphology criteria were used to qualitatively assess the angiograms; type A and B1 lesions were categorized as simple, and type B2 and C lesions were designated complex. Primary end points were angiographic restenosis and 1-year event-free survival. Restenosis rate was 33.2% in complex lesions and 24.9% in simple lesions (
P
<0.001). It was 21.7% for type A, 26.3% for type B1, 33.7% for type B2, and 32.6% for type C lesions. One-year event-free survival was 75.6% for patients with complex lesions and 81.1% for patients with simple lesions (
P
<0.001). It was 85.2% for patients with type A, 79.4% for type B1, 75.9% for type B2, and 75.2% type C lesions. The higher risk for restenosis and an adverse outcome associated with complex lesions was also maintained after multivariate adjustment for other clinical and angiographic characteristics.

Conclusions
—The modified ACC/AHA lesion morphology scheme has significant prognostic value for the outcome of patients after coronary stent placement. Lesion morphology is able to influence the restenosis process and thus the entire 1-year clinical course of these patients.
Use of Sedation During Cardioversion With the Implantable Atrial Defibrillator
Authors: Timmermans Carl , Nabar Ashish , Rodriguez Luz-Maria , Ayers Gregory , Wellens Hein J. J.
Published: June 2012

Background
—The low shock energy used during internal atrial defibrillation may decrease the need for sedation during defibrillation with an implantable atrial defibrillator.

Methods and Results
—The atrial defibrillator (Metrix Atrioverter) was implanted in 12 patients. During the in-hospital treatment of atrial fibrillation (AF) episodes, intravenous sedation was given only on patient request. The Atrioverter was programmed for ambulatory therapy in 4 patients. Efficacy, number of shocks delivered, and sedation requirements were recorded. A total of 393 shocks (1.8±1.6 shocks/AF episode) were delivered to treat 213 AF episodes; 85 of 213 AF episodes (40%) were treated away from the hospital. Sinus rhythm was restored in 195 AF episodes (92%). Five patients never requested sedation. No sedation was needed for ambulatory-treated AF episodes. During the treatment of 26 of 213 AF episodes (12%), 75 shocks were delivered after patients received sedation. The number of shocks required to treat an AF episode determined the need for sedation (4.3±2.1 shocks for AF episodes requiring sedation versus 2±1 shocks for AF episodes requiring no sedation;
P
<0.001). These additional shocks were needed to treat immediate reinitiation of AF (14 episodes) or initial failure to cardiovert (4 episodes). For 8 AF episodes, sedation was requested before the first shock.

Conclusions
—This study suggests that, in a selected group of patients, AF can be treated with Atrioverter therapy without sedation. Successful ambulatory treatment of AF episodes with the Atrioverter, programmed to deliver ≤2 shocks, did not require sedation. When multiple shocks were required to treat an AF episode, the need for sedation increased and included patients initially not requesting sedation.
A Common Variant of the Endothelial Nitric Oxide Synthase (Glu
298
→Asp) Is a Major Risk Factor for Coronary Artery Disease in the UK
Authors: Hingorani Aroon D. , Liang Chia Fan , Fatibene Jenny , Lyon Amelia , Monteith Sue , Parsons Ann , Haydock Stephen , Hopper Ruth V. , Stephens Nigel G. , O’Shaughnessy Kevin M. , Brown Morris J.
Published: June 2012

Background
—Endothelium-derived nitric oxide (NO) is synthesised from
l
-arginine by endothelial nitric oxide synthase (eNOS) encoded by the
NOS 3
gene on chromosome 7. Because reduced NO synthesis has been implicated in the development of coronary atherosclerosis, which has a heritable component, we hypothesised that polymorphisms of
NOS 3
might be associated with increased susceptibility to this disorder.

Methods and Results
—Single-strand conformation polymorphism analysis of
NOS 3
identified a G→T polymorphism in exon 7 of the gene which encodes a Glu→Asp amino acid substitution at residue 298 of eNOS. We investigated the relationship between this Glu
298
→Asp variant and atherosclerotic coronary artery disease (CAD) using 2 independent case-controlled studies. In the first study (CHAOS), cases consisted of 298 unrelated patients with positive coronary angiograms and controls were 138 unrelated healthy individuals ascertained through a population health screen. In the second study (CHAOS II), the cases were 249 patients with recent myocardial infarction (MI), and a further 183 unrelated controls. There was an excess of homozygotes for the Asp
298
variant among patients with angiographic CAD, and among patients with recent MI when compared with their respective controls (35.9% versus 10.2%,
P
<0.0001 in CHAOS, and 18.1% versus 8.7%,
P
<0.02 in CHAOS II). In comparison to Glu
298
homozygotes, homozygosity for Asp
298
was associated with an odds ratio of 4.2 (95% CI, 2.3 to 7.9) for angiographic CAD and 2.5 (95% CI, 1.3 to 4.2) for MI.

Conclusions
—Homozygosity for a common
NOS 3
polymorphism (894 G→T) which encodes a Glu
298
→Asp amino acid substitution in eNOS is a risk factor for angiographic CAD and recent MI in this population.
Heparin Inhibits Ligand Binding to the Leukocyte Integrin Mac-1 (CD11b/CD18)
Authors: Peter Karlheinz , Schwarz Meike , Conradt Christian , Nordt Thomas , Moser Martin , Kübler Wolfgang , Bode Christoph
Published: June 2012

Background
—The clinical benefits of heparin reach beyond its anticoagulative properties. Recently, it has been described that leukocytes adhere on immobilized heparin mediated by the integrin Mac-1 (CD11b/CD18, α
M
β
2
, or CR3). Because inhibition of this versatile adhesion molecule could explain various aspects of the beneficial clinical effects of heparin, we evaluated whether soluble heparin modulates Mac-1 function in vitro and in vivo.

Methods and Results
—Binding of unfractionated heparin to Mac-1 on PMA-stimulated monocytes and granulocytes was directly demonstrated in flow cytometry, whereas no binding of heparin was detected on unstimulated leukocytes. Unfractionated heparin inhibited binding of the soluble ligands fibrinogen, factor X, and iC3b to Mac-1. Adhesion of the monocytic cell line THP-1 and of peripheral monocytes and granulocytes to immobilized ICAM-1 was impaired by unfractionated heparin, to the same extent as with inhibition of Mac-1 by monoclonal antibodies such as c7E3. Low-molecular-weight heparin also inhibits binding of fibrinogen to Mac-1. Additionally, flow cytometry of whole blood preparations of patients treated with unfractionated heparin revealed an inhibitory effect of heparin on the binding of fibrinogen to Mac-1 that correlates (n= 48, r=0.63,
P
<0.001) to the extent of prolongation of the activated partial thromboplastin time.

Conclusions
—We describe a pharmacologically relevant property of heparin that may contribute to its benefits in clinical use. The binding of heparin to Mac-1 and the resulting inhibition in binding of Mac-1 ligands may directly modulate coagulation, inflammation, and cell proliferation.
Acute Right Ventricular Restrictive Physiology After Repair of Tetralogy of Fallot
Authors: Chaturvedi Rajiv R. , Shore Darryl F. , Lincoln Christopher , Mumby Sharon , Kemp Michael , Brierly J. , Petros Andrew , Gutteridge John M.G. , Hooper James , Redington Andrew N.
Published: June 2012

Background
—Acute right ventricular (RV) restrictive physiology after tetralogy of Fallot repair results in low cardiac output and a prolonged stay in the intensive care unit (ICU). However, its mechanism remains uncertain.

Methods and Results
—In the first 24 hours after tetralogy of Fallot repair (n=11 patients), serial prospective measurements were performed of cardiac troponin T, indexes of NO production (NO
2
−
and NO
3
−
combined as NOx), and iron metabolism and antioxidants. RV diastolic function was assessed by transthoracic Doppler echocardiography. Patients who had a long stay in the ICU were characterized by restrictive RV physiology (nonrestrictive group [n=7]: 3.0±0.6 days [mean±SD]; restrictive group [n=4]: 10.7±3.1 days). Troponin T peak concentration and the area under its concentration-time curve (AUC) were higher in the restrictive RV group (peak: restrictive group 17.0±2.8 μg/L, nonrestrictive group 10.4±4.6 μg/L,
P
<0.03; AUC: restrictive group 268.8±73.6 μg · h
−1
· L
−1
, nonrestrictive group 136.2±48.3 μg · h
−1
· L
−1
,
P
<0.03). Plasma NOx/creatinine concentrations were higher in the restrictive group than the nonrestrictive group at 2 hours after bypass (restrictive group 1.3±0.4, nonrestrictive group 0.8±0.2;
P
=0.04) but were similar by 24 hours. Iron loading peaked 2 to 10 hours after bypass and was more severe in the restrictive group (peak transferrin saturation: restrictive group 83.9±13.0%, nonrestrictive group 58.3±16.2%,
P
=0.05; minimum total iron-binding capacity: restrictive group 0.59±0.21%, nonrestrictive group 0.76±0.06%,
P
=0.04; minimum iron-binding antioxidant activity to oxyorganic radicals: restrictive group 9.5±22.4%, nonrestrictive group 50.6±11.4%,
P
=0.01).

Conclusions
—After tetralogy of Fallot repair, acute restrictive RV physiology is associated with greater intraoperative myocardial injury and postoperative oxidative stress with severe iron loading of transferrin.
Estrogen Inhibits Vascular Smooth Muscle Cell–Dependent Adventitial Fibroblast Migration In Vitro
Authors: Li Guohong , Chen Yiu-Fai , Greene Geoffrey L. , Oparil Suzanne , Thompson John A.
Published: June 2012

Background
—Mounting experimental evidence suggests that estrogen treatment protects against neointima formation in response to vascular injury in vivo. Previous studies have suggested that this process includes the activation and migration of adventitial fibroblasts. The present in vitro study was designed to establish a mechanism whereby estrogen attenuates migration of adventitial fibroblasts.

Methods and Results
—Primary cultures of vascular smooth muscle cells (VSMCs) and adventitial fibroblasts were derived from female Sprague-Dawley rats. Reverse transcriptase–polymerase chain reaction and Western blotting were used to determine that expression of the estrogen receptor (ER) was restricted to early-passage VSMCs. Migration of transduced (retrovirally mediated) fibroblasts was determined by counting the number of blue lacZ-expressing cells attached to Boyden-type chambers preconditioned under defined experimental conditions. Compared with growth medium alone, chambers treated with medium conditioned by VSMCs demonstrated a 2-fold increase in fibroblast migration, suggesting that VSMCs release soluble factor(s) competent to bind the Transwell membrane and promote fibroblast migration. In contrast, treatment of VSMCs with 17β-estradiol (10
−9
to 10
−7
mol/L) before preconditioning of the chamber induced a dose-dependent inhibition of fibroblast migration. Cotreatment of VSMCs with 17β-estradiol and the ER antagonist ICI-182780 (10
−7
mol/L) blocked the inhibitory effect of estrogen on fibroblast migration.

Conclusions
—These observations suggest a novel mechanism of hormonal vasoprotection by which estrogen directly modulates VSMC expression of factor(s) controlling migration of adventitial fibroblasts via an ER-dependent mechanism.
Downregulation of the Na
+
-Creatine Cotransporter in Failing Human Myocardium and in Experimental Heart Failure
Authors: Neubauer Stefan , Remkes Helga , Spindler Matthias , Horn Michael , Wiesmann Frank , Prestle Jürgen , Walzel Bernd , Ertl Georg , Hasenfuss Gerd , Wallimann Theo
Published: June 2012

Background
—The failing myocardium is characterized by depletion of phosphocreatine and of total creatine content. We hypothesized that this is due to loss of creatine transporter protein.

Methods and Results
—Creatine transporter protein was quantified in nonfailing and failing human myocardium (explanted hearts with dilated cardiomyopathy [DCM; n=8] and healthy donor hearts [n=8]) as well as in experimental heart failure (residual intact left ventricular tissue, rats 2 months after left anterior descending coronary artery ligation [MI; n=8] or sham operation [sham; n=6]) by Western blotting. Total creatine content was determined by high-performance liquid chromatography. Donor and DCM hearts had total creatine contents of 136.4±6.1 and 68.7±4.6 nmol/mg protein, respectively (*
P
<0.05); creatine transporter protein was 25.4±2.2 optical density units in donor and 17.7±2.5 in DCM (*
P
<0.05). Total creatine was 87.5±4.2 nmol/mg protein in sham and 65.7±4.2 in MI rats (*
P
<0.05); creatine transporter protein was 139.0±8.7 optical density units in sham and 82.1±4.0 in MI (*
P
<0.05).

Conclusions
—Both in human and in experimental heart failure, creatine transporter protein content is reduced. This mechanism may contribute to the depletion of creatine compounds and thus to the reduced energy reserve in failing myocardium. This finding may have therapeutic implications, suggesting a search for treatment strategies targeted toward creatine transport.
Platelet Function During and After Thrombolytic Therapy for Acute Myocardial Infarction With Reteplase, Alteplase, or Streptokinase
Authors: Moser Martin , Nordt Thomas , Peter Karlheinz , Ruef Johannes , Kohler Benedikt , Schmittner Marc , Smalling Richard , Kübler Wolfgang , Bode Christoph
Published: June 2012

Background
—Changes in platelet aggregation (PA) and platelet surface receptor expression induced by thrombolytic therapy for acute myocardial infarction may influence the rate of initial reperfusion and early reocclusion.

Methods and Results
—In the RAPID-1 (Reteplase Angiographic Phase II International Dose-finding study), RAPID-2 (Reteplase vs Alteplase Patency Investigation During myocardial infarction), INJECT (INternational Joint Efficacy Comparison of Thrombolytics), and GUSTO-3 (Global Use of Strategies To Open occluded coronary arteries) trials, 126 patients were enrolled in a single center. Patients were treated with either conventional alteplase (100 mg/180 min; n=15), accelerated alteplase (100 mg/90 min; n=21), reteplase 10+10-U double bolus (n=50), reteplase 10+5-U double bolus (n=15), reteplase 15-U single bolus (n=15), or streptokinase (1.5 MU/60 min; n=10). PA (after stimulation with ADP), P-selectin expression and fibrinogen binding to glycoprotein (GP) IIb/IIIa (determined by flow cytometry with and without stimulation with ADP), and levels of soluble P-selectin, prothrombin fragments F1 and F2, thrombin-antithrombin complexes (TAT), and antithrombin III (ATIII) were determined. PA decreased significantly at 1 and 2 hours in patients treated by 10+10-U reteplase or by streptokinase. Fibrinogen binding to platelet GP IIb/IIIa followed a similar pattern. Significant thrombin generation and significantly elevated thrombin levels during thrombolysis were reflected by increased F1 and F2 fragments and TAT levels in all treatment groups. ATIII levels decreased significantly during thrombolytic therapy.

Conclusions
—A decrease in PA in patients treated by reteplase or streptokinase compared with alteplase could be observed in the early phase. Double bolus (10+10 U) reteplase and streptokinase resulted in lower PA at 1 and 2 hours than therapy with accelerated alteplase. Total fibrinogen and fibrinogen binding to GP IIb/IIIa tended to be lower during the first 2 hours after reteplase than after accelerated alteplase.
Angiographic Patterns of In-Stent Restenosis
Authors: Mehran Roxana , Dangas George , Abizaid Andrea S. , Mintz Gary S. , Lansky Alexandra J. , Satler Lowell F. , Pichard Augusto D. , Kent Kenneth M. , Stone Gregg W. , Leon Martin B.
Published: June 2012

Background
—The angiographic presentation of in-stent restenosis (ISR) may convey prognostic information on subsequent target vessel revascularizations (TLR).

Methods and Results
—We developed an angiographic classification of ISR according to the geographic distribution of intimal hyperplasia in reference to the implanted stent. Pattern I includes focal (≤10 mm in length) lesions, pattern II is ISR>10 mm within the stent, pattern III includes ISR>10 mm extending outside the stent, and pattern IV is totally occluded ISR. We classified a total of 288 ISR lesions in 245 patients and verified the angiographic accuracy of the classification by intravascular ultrasound. Pattern I was found in 42% of patients, pattern II in 21%, pattern III in 30%, and pattern IV in 7%. Previously recurrent ISR was more frequent with increasing grades of classification (9%, 20%, 34%, and 50% for classes I to IV, respectively;
P
=0.0001), as was diabetes (28%, 32%, 39%, and 48% in classes I to IV, respectively;
P
<0.01). Angioplasty and stenting were used predominantly in classes I and II, whereas classes III and IV were treated with atheroablation. Final diameter stenosis ranged between 21% and 28% (
P
=NS among ISR patterns). TLR increased with increasing ISR class; it was 19%, 35%, 50%, and 83% in classes I to IV, respectively (
P
<0.001). Multivariate analysis showed that diabetes (odds ratio, 2.8), previously recurrent ISR (odds ratio, 2.7), and ISR class (odds ratio, 1.7) were independent predictors of TLR.

Conclusions
—The introduced angiographic classification is prognostically important, and it may be used for appropriate and early patient triage for clinical and investigational purposes.
Initiation of Atrial Fibrillation by Ectopic Beats Originating From the Pulmonary Veins
Authors: Chen Shih-Ann , Hsieh Ming-Hsiung , Tai Ching-Tai , Tsai Chin-Feng , Prakash V. S. , Yu Wen-Chung , Hsu Tsui-Lieh , Ding Yu-An , Chang Mau-Song
Published: June 2012

Background
—Atrial fibrillation (AF) can be initiated by ectopic beats originating from the atrial or great venous tissues. This study investigated the anatomic characteristics and electrophysiological properties of pulmonary veins (PVs), as well as the possible mechanisms and response to drugs of ectopic foci, and assessed the effects of radiofrequency (RF) ablation on AF initiated by ectopic beats originating from PVs.

Methods and Results
—Seventy-nine patients with frequent episodes of paroxysmal AF and 10 control patients were included. Distal PVs showed the shortest effective refractory periods (ERPs), and right superior PVs showed a higher incidence of intra-PV conduction block than left superior PVs. Superior and left PVs had longer myocardial sleeves than inferior and right PVs, respectively. These electrophysiological characteristics were similar between AF and control patients. Propranolol, verapamil, and procainamide suppressed ectopic beats that originated from the PVs. Of 116 ectopic foci that initiated AF, 103 (88.8%) originated from PVs. A mean of 7±3 RF applications completely eliminated 110 ectopic foci (94.8%). During the 6±2-month follow-up period, 68 patients (86.1%) were free of AF without any antiarrhythmic drugs. Follow-up transesophageal echocardiogram showed 42.4% of ablated PVs had focal stenosis. One patient had mild exertional dyspnea after ablation, but it resolved 3 months later; 1 patient had onset of mild exertional dyspnea 5 months after ablation.

Conclusions
—Electrophysiological characteristics of PVs are different from those in the atria. Ectopic beats from PVs can initiate AF, and β-adrenergic receptor blocker, calcium channel blockers, and sodium channel blockers can suppress these ectopic beats. Careful mapping and elimination of these ectopic foci can cure paroxysmal AF.
Identification of Risk Factors in Hypertensive Patients
Authors: Gueyffier François , Boissel Jean-Pierre , Pocock Stuart , Boutitie Florent , Coope John , Cutler Jeffrey , Ekbom Tord , Fagard Robert , Friedman Lawrence , Kerlikowske Karla , Perry Mitchell , Prineas Ronald , Schron Eleanor
Published: June 2012

Background
—Predicting individual risk is needed to target preventive interventions toward people with the highest probability of benefit over a given time period. We assessed which prognostic factors should be used in predicting risk for hypertensive patients and in searching for treatment modifiers.

Methods and Results
—Data from 24 390 hypertensive participants who constituted the control groups from 8 controlled trials (1726 deaths over 5 years) were analyzed in multivariate survival models. Outcomes were coronary heart disease death, stroke death, and cardiovascular death. We explored systematically the heterogeneity of results between trials. Left ventricular hypertrophy was electrocardiographically confirmed to be a powerful risk factor and should be included in risk scoring. Height, glomerular filtration rate, and serum uric acid deserve further exploration. Body mass index and heart rate were not confirmed as independent cardiovascular risk factors in this population. The association between male sex and coronary heart disease death was significantly stronger in British cohorts. The lack of prognostic value of diastolic blood pressure was explained by an interaction with age, with a positive association before 65 years and a negative association thereafter. Previous antihypertensive treatment was a significant risk factor.

Conclusions
—Clinical trials provide valuable information for risk prediction. Carefully exploring the heterogeneity among trials is a way to assess the generalizability of findings. This approach, if systematically performed, should increase the ability to identify risk modifiers and to predict individual therapeutic benefit.
Serum From Patients With Severe Heart Failure Downregulates eNOS and Is Proapoptotic
Authors: Agnoletti Laura , Curello Salvatore , Bachetti Tiziana , Malacarne Fabio , Gaia Giuseppina , Comini Laura , Volterrani Maurizio , Bonetti Paolo , Parrinello Giovanni , Cadei Moris , Grigolato Pier Giovanni , Ferrari Roberto
Published: June 2012

Background
—Cytokine activation and endothelial dysfunction are typical phenomena of congestive heart failure (CHF). We tested the hypothesis that incubating human umbilical vein endothelial cells with serum from patients with CHF will downregulate endothelial constitutive nitric oxide synthase (eNOS) and induce apoptosis.

Methods and Results
—We studied 21 patients with severe CHF. Levels of tumor necrosis factor-α (TNF-α) and several neuroendocrine parameters were assessed. eNOS was measured by Western Blot analysis and apoptosis by optical microscopy and flow cytometry. We observed (1) eNOS downregulation (difference versus healthy subjects at 24 hours [
P
<0.05] and 48 hours [
P
<0.001]), (2) nuclear morphological changes typical of apoptosis; and (3) a high apoptotic rate with propidium iodide (increasing from 2.1±0.4% to 11.3±1.2% at 48 hours;
P
<0.001 versus healthy subjects) and annexin V. An anti-human TNF-α antibody did not completely counteract these effects. A strong correlation existed between eNOS downregulation and apoptosis (
r
=−0.89;
P
<0.001).

Conclusions
—Serum from patients with severe CHF downregulates eNOS expression and increases apoptosis. High levels of TNF-α likely play a role, but they cannot be the only factor responsible.
Relationship of MRI Delayed Contrast Enhancement to Irreversible Injury, Infarct Age, and Contractile Function
Authors: Kim Raymond J. , Fieno David S. , Parrish Todd B. , Harris Kathleen , Chen Enn-Ling , Simonetti Orlando , Bundy Jeffrey , Finn J. Paul , Klocke Francis J. , Judd Robert M.
Published: June 2012

Background
—Contrast MRI enhancement patterns in several pathophysiologies resulting from ischemic myocardial injury are controversial or have not been investigated. We compared contrast enhancement in acute infarction (AI), after severe but reversible ischemic injury (RII), and in chronic infarction.

Methods and Results
—In dogs, a large coronary artery was occluded to study AI and/or chronic infarction (n=18), and a second coronary artery was chronically instrumented with a reversible hydraulic occluder and Doppler flowmeter to study RII (n=8). At 3 days after surgery, cine MRI revealed reduced wall thickening in AI (5±6% versus 33±6% in normal,
P
<0.001). In RII, wall thickening before, during, and after inflation of the occluder for 15 minutes was 35±5%, 1±8%, and 21±10% and Doppler flow was 19.8±5.3, 0.2±0.5, and 56.3±17.7 (peak hyperemia) cm/s, respectively, confirming occlusion, transient ischemia, and reperfusion. Gd-DTPA–enhanced MR images acquired 30 minutes after contrast revealed hyperenhancement of AI (294±96% of normal,
P
<0.001) but not of RII (98±6% of normal,
P
=NS). Eight weeks later, the chronically infarcted region again hyperenhanced (253±54% of normal, n=8,
P
<0.001). High-resolution (0.5×0.5×0.5 mm) ex vivo MRI demonstrated that the spatial extent of hyperenhancement was the same as the spatial extent of myocyte necrosis with and without reperfusion at 1 day (
R
=0.99,
P
<0.001) and 3 days (
R
=0.99,
P
<0.001) and collagenous scar at 8 weeks (
R
=0.97,
P
<0.001).

Conclusions
—In the pathophysiologies investigated, contrast MRI distinguishes between reversible and irreversible ischemic injury independent of wall motion and infarct age.
Electrophysiological and Antiarrhythmic Effects of the Atrial Selective 5-HT
4
Receptor Antagonist RS-100302 in Experimental Atrial Flutter and Fibrillation
Authors: Rahme Marc M. , Cotter Bruno , Leistad Elisabeth , Wadhwa Manish K. , Mohabir Rajendra , Ford Anthony P. D. W. , Eglen Richard M. , Feld Gregory K.
Published: June 2012

Background
—Stimulation of 5-HT
4
receptors increases atrial chronotropic and inotropic responses. Whether other electrophysiological effects are produced is unknown. In humans and swine, 5-HT
4
receptors are present only in atrium. Therefore, the effects of a novel 5-HT
4
receptor antagonist, RS-100302, and the partial agonist cisapride on atrial flutter and fibrillation induced in swine were studied to delineate the role of the 5-HT
4
receptor in modulating atrial electrophysiological properties and the antiarrhythmic potential of RS-100302.

Methods and Results
—In 17 anesthetized, open-chest, juvenile pigs, atrial flutter or fibrillation was induced by rapid right atrial pacing with or without a right atrial free wall crush injury, respectively. Atrial effective refractory period (ERP), conduction velocity, wavelength, and dispersion of refractoriness were determined during programmed stimulation via a 56-electrode mapping plaque sutured to the right atrial free wall. Ventricular electrophysiological parameters were also measured. All electrophysiological parameters were measured at baseline and after infusion of RS-100302 and cisapride. In the atrium, RS-100302 prolonged mean ERP (115±8 versus 146±7 ms,
P
<0.01) and wavelength (8.3±0.9 versus 9.9±0.8 cm,
P
<0.01), reduced dispersion of ERP (15±5 versus 8±1 ms,
P
<0.01), and minimally slowed conduction velocity (72±4 versus 67±5 cm/s,
P
<0.01). These effects were all partially reversed by cisapride. RS-100302 produced no ventricular electrophysiological effects. RS-100302 terminated atrial flutter in 6 of 8 animals and atrial fibrillation in 8 of 9 animals and prevented reinduction of sustained tachycardia in all animals.

Conclusions
—The electrophysiological profile of RS-100302 suggests that it may have atrial antiarrhythmic potential without producing ventricular proarrhythmic effects.
Prognostic Value of Myocardial Ischemia and Viability in Patients With Chronic Left Ventricular Ischemic Dysfunction
Authors: Pasquet Agnès , Robert Annie , D’Hondt Anne-Marie , Dion Robert , Melin Jacques A. , Vanoverschelde Jean-Louis J.
Published: June 2012

Background
—Previous studies showed that thallium scintigraphy and dobutamine echocardiography were accurate, noninvasive ways of predicting contractile recovery after revascularization in patients with left ventricular (LV) dysfunction. However, the prognostic impact of such methods remains uncertain.

Methods and Results
—We prospectively studied 137 consecutive patients with coronary disease and LV dysfunction who underwent exercise-redistribution-reinjection thallium scintigraphy and dobutamine echocardiography to identify myocardial ischemia and viability. A total of 94 patients subsequently underwent revascularization, and 43 underwent medical treatment. The primary endpoint was cardiac mortality, and mean follow-up was 33±10 months. Twenty-four patients died of cardiac causes. By Cox’s regression analysis, long-term survival was related to the extent of coronary disease, the presence of diabetes, type of treatment, the presence of ischemic myocardium as determined by thallium scintigraphy, and the presence of viable myocardium as determined by both tests. Three-year survival was greater in patients with ischemic myocardium (as determined by thallium scintigraphy) or viable myocardium (as determined by both tests) who underwent revascularization than in the other groups (
P
=0.018 with thallium;
P
<0.001 with dobutamine). Subgroup analyses indicated that among patients with 1- or 2-vessel disease, only those with ischemic or viable myocardium improved survival after revascularization, whereas in patients with 3-vessel or left main diseases, revascularization always improved survival, albeit more in the presence of ischemic or viable myocardium.

Conclusions
—Among the parameters commonly available in patients with LV ischemic dysfunction, the presence of ischemic myocardium (as determined by thallium scintigraphy) and that of viable myocardium (as determined by dobutamine echocardiography) are independent predictors of subsequent mortality. These observations may be useful in the preoperative selection of patients for revascularization.
Amiodarone-Associated Thyroid Dysfunction
Authors: Thorne Sara A. , Barnes Isobel , Cullinan Paul , Somerville Jane
Published: June 2012

Background
—Amiodarone is widely used in adults with congenital heart disease, but no systematic study has been published on its effects on thyroid function in these patients. A retrospective study was performed to examine the frequency of amiodarone-associated thyroid dysfunction in adults with congenital heart disease and to identify any contributing factors.

Methods and Results
—All adults (16 to 60 years old) with congenital heart disease were identified from a database if they had no preexisting thyroid disease, had taken amiodarone for ≥6 months, and were currently followed up by 1 consultant (J.S.). Ninety-two patients were found and evaluated for thyroid status and cardiac complications. A case-control analysis was performed, with patients matched for duration of amiodarone therapy. Of the 92 patients (age, 34.9±10.2 years; range, 18 to 60 years), 36% developed thyroid dysfunction: 19 became hyperthyroid and 14 hypothyroid. Female sex and complex cyanotic heart disease were significant risk factors for developing thyroid dysfunction (odds ratios, 3.0 and 7.00;
P
=0.04 and 0.01, respectively). Previous Fontan-type surgery also appeared to be a risk factor for developing thyrotoxicosis (odds ratio, 4.0;
P
=0.17), and amiodarone >200 mg/d a risk factor for thyroid dysfunction (odds ratio, 4.0;
P
=0.60).

Conclusions
—Amiodarone-associated thyroid dysfunction is common in adults with congenital heart disease. Women and those with complex cyanotic lesions are at particular risk, as patients may be who have had Fontan-type surgery or are taking >200 mg/d of amiodarone. Amiodarone should be used only when other antiarrhythmics are ineffective or contraindicated. Vigilance is required to detect and treat thyroid dysfunction.
Survival, Integration, and Differentiation of Cardiomyocyte Grafts
Authors: Reinecke Hans , Zhang Ming , Bartosek Trudy , Murry Charles E.
Published: June 2012

Background
—Cardiomyocyte grafting augments myocyte numbers in the heart. We investigated (1) how developmental stage influences graft survival; (2) whether acutely necrotic or healing cardiac lesions support grafts; and (3) the differentiation and integration of cardiomyocyte grafts in injured hearts.

Methods and Results
—Cardiomyocytes from fetal, neonatal, or adult inbred rats were grafted into normal myocardium, acutely cryoinjured myocardium, or granulation tissue (6 days after injury). Adult cardiomyocytes did not survive under any conditions. In contrast, fetal and neonatal cardiomyocytes formed viable grafts under all conditions. Time-course studies with neonatal cardiomyocytes showed that the grafts recapitulated many aspects of normal development. The adherens junction protein N-cadherin was distributed circumferentially at day 1 but began to organize into intercalated disk–like structures by day 6. The gap junction protein connexin43 followed a similar but delayed pattern relative to N-cadherin. From 2 to 8 weeks, there was progressive hypertrophy and the formation of mature intercalated disks. In some hearts, graft cells formed adherens and gap junctions with host cardiomyocytes, suggesting electromechanical coupling. More commonly, however, grafts were separated from the host myocardium by scar tissue. Gap and adherens junctions formed between neonatal and adult cardiomyocytes in coculture, as evidenced by dye transfer and localization of cadherin and connexin43 at intercellular junctions.

Conclusions
—Grafted fetal and neonatal cardiomyocytes form new, mature myocardium with the capacity to couple with injured host myocardium. Optimal repair, however, may require reducing the isolation of the graft by the intervening scar tissue.
Temporal Trends in Event Rates After Q-Wave Myocardial Infarction
Authors: Guidry Ursula C. , Evans Jane C. , Larson Martin G. , Wilson Peter W. F. , Murabito Joanne M. , Levy Daniel
Published: June 2012

Background
—Short-term (<30 day) mortality after Q-wave myocardial infarction (MI) has declined over the decades, but it is unclear if rates of long-term sequelae after Q-wave MI have improved.

Methods and Results
—In 546 Framingham Heart Study subjects (388 men with a mean age of 60 years; 158 women with a mean age of 69 years) with an initial recognized Q-wave MI from 1950 through 1989, we investigated time trends in risk for coronary heart disease (CHD) death (n=199), all-cause mortality (n=287), reinfarction (n=108), and congestive heart failure (CHF; n=121). With 1950 through 1969 as the reference period, hazards ratios (HRs) for these outcomes were determined for the 1970s and 1980s. Trend analyses across the 3 time periods were performed for each outcome. Compared with the 1950 through 1969 reference period, the HRs for CHD death were lower in subsequent decades (1970 through 1979: HR, 0.69; 95% CI, 0.49 to 0.98; 1980 through 1989: HR, 0.48; 95% CI, 0.33 to 0.72). All-cause mortality also declined (1970 through 1979: HR, 0.70; 95% CI, 0.0.52 to 0.94; 1980 through 1989: HR, 0.59; 95% CI, 0.43 to 0.81). There were no significant temporal changes in the risks for recurrent MI or CHF.

Conclusions
—Substantial reductions in risk of CHD death and all-cause mortality occurred over these 4 decades, coincident with improvements in post-MI therapies. The absence of a decline in CHF incidence may be due to improved post-MI survival of individuals with depressed left ventricular systolic function who are at high risk for CHF.
Oxygenation in Patients With a Functionally Univentricular Circulation and Complete Mixing of Blood
Authors: Francis Darrel P. , Willson Keith , Thorne Sara A. , Davies L. Ceri , Coats Andrew J. S.
Published: June 2012

Background
—Perioperative management of patients with complete mixing of pulmonary and systemic blood centers on approximately equating pulmonary (Qp) and systemic (Qs) blood flow (Qp/Qs≈1). This empirically derived target is opposed by theoretical studies advocating a target Qp/Qs well below 1. We studied the cause of this persistent discrepancy.

Methods and Results
—Classic theoretical studies have concentrated on maximizing 1 of many potential combination parameters of arterial oxygen content (Ca
o
2
) and systemic blood flow: total oxygen delivery (D
o
2
)=Ca
o
2
×Qs. We defined “useful” oxygen delivery as the amount of oxygen above a notional saturation threshold (Sat
Thresh
): D(u)
o
2
=carrying capacity×(Sa
o
2
−Sat
Thresh
)×Qs. Whereas D
o
2
peaks at Qp/Qs ratios <1, D(u)
o
2
peaks at higher Qp/Qs ratios, nearer to (or exceeding) 1. Systemic venous saturation (which mirrors tissue oxygen tension) peaks at Qp/Qs=1.

Conclusions
—First, the standard model of single-ventricle physiology can be reexpressed in a form allowing analysis by differential calculus, which allows broader conclusions to be drawn than does computer modeling alone. Second, the classic measure D
o
2
fails to reflect the fact that proportional changes in saturation and flow are not clinically equivalent. Recognizing this asymmetry by using D(u)
o
2
can give a target Qp:Qs balance that better represents clinical experience. Finally, to avoid an arbitrary choice of Sat
Thresh
, systemic venous oxygen saturation (Ssv
o
2
) may be a useful parameter to maximize: this occurs at a Qp/Qs ratio of 1. Attempts to increase D
o
2
by altering Qp/Qs away from this value will inevitably reduce Ssv
o
2
and therefore tissue oxygenation. Oxygen delivery is far from synonymous with tissue oxygen status.
Effect of Potential Confounding Factors on the Thrombolysis in Myocardial Infarction (TIMI) Trial Frame Count and Its Reproducibility
Authors: Abacı Adnan , Oguzhan Abdurrahman , Eryol Namık Kemal , Ergin Ali
Published: June 2012

Background
—The potential factors that introduce variability into TIMI frame count (TFC) have not been systematically investigated. The goal of this study was to determine if nitrate use, dye injection rate, catheter size, the phase of the cardiac cycle in which dye is injected, or heart rate affect the TFC and to investigate the reproducibility of the TFC.

Methods and Results
—The dye injection rate was increased 1 mL/s, and angiography was repeated. A coronary angiogram was taken first with an 8F catheter and then with a 6F catheter. After taking angiograms, intracoronary nitrate was given to the patient, and the second angiography was performed. Basal heart rate was increased 20 beats/min, and angiography was repeated. Dye injection was performed at the beginning of systole and diastole. The TFC was not significantly changed by increasing the dye injection rate (
P
=0.467) or by changing catheter size (
P
=0.693). Nitrate administration significantly increased the TFC from 26.4±11.9 to 32.8±13.3 frames (
P
<0.001). Dye injection at the beginning of diastole significantly decreased the TFC from 30.1±8.8 to 24.4±7.9 frames (
P
<0.001) for the left coronary artery and from 24.16±4.49 to 21.24±4.45 frames (
P
<0.001) for the right coronary artery. Increasing heart rate significantly decreased the TFC from 30.4±6.1 to 25.3±7.2 frames (
P
<0.001). Intraobserver and interobserver reproducibility of the TFC was good (mean difference, 1.33±1.24 and 2.57±1.72 frames, respectively).

Conclusions
—Nitrate use, heart rate, and the phase of the cardiac cycle in which dye is injected had significant effects on the TFC. Therefore, studies comparing TFC need to consider these factors, and the use of nitrates should be either standardized or randomized.
Serum Glutathione in Adolescent Males Predicts Parental Coronary Heart Disease
Authors: Morrison John A. , Jacobsen Donald W. , Sprecher Dennis L. , Robinson Killian , Khoury Philip , Daniels Stephen R.
Published: June 2012

Background
—Traditional risk factors account for only half of the morbidity and mortality from coronary heart disease (CHD). There is substantial evidence that oxidative injury plays a major role in the atherosclerotic process. Thus, antioxidants may protect against development of atherosclerosis. Glutathione, an intracellular tripeptide with antioxidant properties, may be protective.

Methods and Results
—This case-control study compared total serum glutathione (tGSH) in 81 adolescent male offspring of parents with premature CHD (ie, before 56 years of age) and 78 control male offspring of parents without known or suspected CHD. Case offspring had significantly lower tGSH than control offspring. In multiple logistic regression with parental CHD status as the dependent variable, age entered as a covariate, and other CHD risk factors competing to enter the model as significant independent predictor variables, LDL cholesterol (odds ratio [OR], 2.15 [units=1.5 SD]; 95% CI, 1.21 to 3.82), tGSH (OR, 0.40; 95% CI, 0.22 to 0.71), HDL cholesterol (OR, 0.42; 95% CI, 0.22 to 0.78), and total serum homocysteine (OR, 2.6; 95% CI, 1.35 to 5.02) entered the model as significant predictors of parental CHD status.

Conclusions
—Low tGSH in adolescent boys is a significant independent predictor of parental CHD, in addition to elevated LDL cholesterol, low HDL cholesterol, and elevated total serum homocysteine concentrations.
Resistance Artery Mechanics, Structure, and Extracellular Components in Spontaneously Hypertensive Rats
Authors: Intengan Hope D. , Thibault Gaétan , Li Jin-Sheng , Schiffrin Ernesto L.
Published: June 2012

Background
—Altered vascular mechanics resulting from changes in collagen and integrins may influence resistance artery structure and function and, therefore, peripheral resistance and blood pressure in spontaneously hypertensive rats (SHR).

Methods and Results
—Effects of age, angiotensin-converting enzyme inhibition (fosinopril, 10 to 30 mg/kg per day), and AT
1
-receptor antagonism (irbesartan, 50 mg/kg per day) on vascular structure, mechanics, and composition were assessed in SHR. Systolic blood pressure was elevated in young SHR (130±2 mm Hg) compared with Wistar-Kyoto (WKY) rats (106±2 mm Hg). In adult SHR, the rise in systolic blood pressure (44±3 mm Hg) was blunted by fosinopril (18±1 mm Hg) and irbesartan (9±3 mm Hg). Lumen diameter of mesenteric resistance arteries was smaller and media/lumen ratio was greater in young and adult SHR versus WKY rats. Growth index was 24% in untreated adult SHR versus WKY rats; these values were −35% for fosinopril-treated and −29% for irbesartan-treated SHR versus untreated SHR. Isobaric wall stiffness was normal despite increased stiffness of wall components in adult SHR vessels. Irbesartan partially prevented stiffening of wall components in SHR. The collagen/elastin ratio was greater in adult SHR vessels (6.5±1.3) than in WKY (3.2±0.4) vessels. Expression of α
v
β
3
and α
5
β
1
integrins was increased in SHR aged 20 versus 6 weeks. Expression of α
5
β
1
integrins was lower in young SHR, and α
v
β
3
integrins were overexpressed in adult SHR versus WKY rats. Irbesartan and fosinopril attenuated differences in the collagen/elastin ratio and integrin expression.

Conclusions
—Wall components of mesenteric resistance arteries stiffen with age in SHR. Interrupting the renin-angiotensin system has normalizing effects on integrin expression and composition, stiffness, and growth of the arterial wall.
Long-Term Coronary Vascular Response to
32
P β-Particle–Emitting Stents in a Canine Model
Authors: Taylor Allen J. , Gorman Patrick D. , Farb Andrew , Hoopes Timothy G. , Virmani Renu
Published: June 2012

Background
—The arterial placement of
32
P β-particle–emitting stents in various experimental animal models results in discordant effects on neointimal formation. We studied the vascular effects of β-particle–emitting stents in normal canine coronary arteries because compared with pigs and rabbits, the canine model may more closely mimic the vascular response of humans.

Methods and Results
—Thirty stents (control nonradioactive, n=10; low-activity
32
P, 3.5 to 6.0 μCi, n=11; high-activity
32
P, 6.5 to 14.4 μCi, n=8) were implanted in normal canine coronary arteries through the use of a single balloon inflation at nominal pressure. Histological analysis after 15 weeks included the measurement of neointimal and adventitial area and thickness. Neointimal fibrin area was measured with the use of computer-assisted color segmentation on Movat pentachrome sections. Luminal stenosis was significantly increased in
32
P stents compared with control stents (44.6±16.8% versus 32.7±10.8%;
P
=0.05) and was highest in the high-activity group (45.5±24.3%). No evidence of an “edge effect” was seen in adjacent, nonstented coronary segments. All
32
P stents showed incomplete vascular healing as indicated by a dose-dependent increase in fibrin area with increasing stent activity. Arterial radiation resulted in a decrease in adventitial size, which was maximal for high-activity
32
P stents, indicating an inhibitory effect on the adventitial response to injury.

Conclusions
—
32
P β-particle–emitting stents have adverse vascular effects at 15 weeks in the canine normal coronary artery model. Vascular brachytherapy with this device causes increased neointimal formation and prominent, dose-dependent lack of healing.