bluuebunny/crossref_metadata_2025 huggingface dataset:
Pulmonary Autograft Procedure for Aortic Valve Disease
Authors: Chambers John C. , Somerville Jane , Stone Susan , Ross Donald N.
Published: June 2012

Background
Pulmonary autograft replacement of the diseased aortic valve has not been widely practiced due to concerns regarding late autograft competence and the consequences of creating pulmonary valve disease. To investigate this, the fate of the pioneering series of patients has been determined.

Methods and Results
The 131 hospital survivors of the pulmonary autograft operation at the National Heart Hospital from 1967 to 1984 were identified and their outcomes determined to 1994. Age at operation was 11 to 52 years, and 109 patients were male. Autograft implantation was orthotopic subcoronary (107), free-standing root (20), or Dacron mounted (2). In 113 patients, homografts replaced the native pulmonary valve. Ten and 20 years after operation, survival was 85% and 61%, freedom from autograft replacement was 88% and 75%, and freedom from replacement of pulmonary position homografts was 89% and 80%, respectively. Causes of deaths (53) included chronic heart failure (13), complications of reoperation (12), and endocarditis (7). Autograft regurgitation, the most common indication for reoperation, appeared primarily technical in nature, usually due to cusp prolapse. Degeneration was found in only 3 of 30 explanted autografts, and the young patients showed no increase in late valve failure. Homografts outperformed other valve replacements in the pulmonary position, but patients with orthotopic subcoronary and root autografts survived similarly.

Conclusions
The pulmonary autograft offers low rates of degeneration, endocarditis, and thromboembolism for a period lasting >20 years, particularly in the young, with reoperation mainly required for malpositioning of the autograft cusps. The capacity of the autograft to maintain viability with minimal degeneration is not matched by any other biological valve replacement.
Local Delivery of Ethanol Inhibits Intimal Hyperplasia in Pig Coronary Arteries After Balloon Injury
Authors: Liu Ming Wei , Anderson Peter G. , Luo Jian Fung , Roubin Gary S.
Published: June 2012

Background
Smooth muscle cell (SMC) hyperplasia is an important mechanism of restenosis after coronary angioplasty and the primary mechanism of restenosis within coronary stents. Ethanol has been shown to reduce the response of SMCs to local growth stimulants in vitro. This study was carried out to determine whether local delivery of ethanol solution could reduce intimal hyperplasia induced by balloon injury.

Methods and Results
Three groups of juvenile domestic pigs underwent oversized balloon dilation injury of the left anterior descending and left circumflex coronary arteries. Immediately after the balloon injury, one of the arteries was randomized to local delivery of 15% ethanol with a local delivery balloon catheter, and the other received no further treatment. Histological and morphometric studies were carried out at 2 weeks in group 1 (n=16) and at 4 weeks in group 2 (n=10). In the third group (n=15), animals were killed at days 4, 8, and 14 after balloon injury, and coronary artery segments were studied by immunohistochemical staining against proliferating cell nuclear antigen (PCNA) and bromodeoxyuridine (BrdU). Histological injury scores were not different between the ethanol-treated and untreated arterial segments in either group 1 or 2. The neointimal areas were significantly smaller in the ethanol-treated arterial segments than in the untreated segments (0.25±0.08 versus 0.57±0.08 mm
2
,
P
=.004, at 2 weeks; 0.33±0.05 versus 0.54±0.07 mm
2
,
P
=.03, at 4 weeks). SMC proliferative activity was significantly lower in ethanol-treated arteries than in untreated arteries at 4 and 8 days after injury by BrdU and PCNA staining.

Conclusions
Local delivery of 15% ethanol solution to pig coronary arteries significantly decreased the SMC proliferative activity and neointimal formation induced by balloon dilation injury.
Relation Between Muscle Contraction Speed and Hydraulic Performance in Skeletal Muscle Ventricles
Authors: Jarvis Jonathan C. , Kwende Martin M.N. , Shortland Adam , Eloakley Reida M. , Gilroy Stephen J. , Black Richard A. , Salmons Stanley
Published: June 2012

Background
The fatigue resistance and power-to-weight ratio of skeletal muscle that has been conditioned by electrical stimulation makes cardiac assistance from a graft of such muscle a realistic prospect. A skeletal muscle must be surgically reconfigured to act on the circulating blood, but little is known about the power losses that accompany such interventions. We investigated in acute experiments the hydraulic performance of approximately cylindrical pumps made from sheep latissimus dorsi (LD) muscles, having first characterized the performance of each muscle in situ.

Methods and Results
Force-length and force-velocity relations were measured in situ for LD that had received either 8 weeks of stimulation at 2 Hz or no chronic stimulation. Two sizes of skeletal muscle ventricle (SMV) were formed from the same muscles, and their hydraulic performance was measured. The hydraulic performance was also calculated from the linear data, models of the force-length and force-velocity curves, and a description of the stress distribution within the SMV wall. The model predicted well the isovolumetric function of the ventricles and the optimum afterload but overestimated the flow and therefore the power. In conditioned ventricles the performance was particularly poor because of the slow contractile properties of the muscles.

Conclusions
If SMVs are to pump effectively against the arterial impedance, the pressure drop caused by flow (or the internal resistance) should be lower than that of the ventricles we constructed. Progress can be made through refinement of surgical technique and stimulation protocols that generate faster fatigue-resistant muscles.
Characterization of Low Right Atrial Isthmus as the Slow Conduction Zone and Pharmacological Target in Typical Atrial Flutter
Authors: Tai Ching-Tai , Chen Shih-Ann , Chiang Chern-En , Lee Shih-Huang , Ueng Kwo-Chang , Wen Zu-Chi , Huang Jin-Long , Chen Yi-Jen , Yu Wen-Chung , Feng An-Ning , Chiou Chuen-Wang , Chang Mau-Song
Published: June 2012

Background
Previous electrophysiological studies in patients with typical atrial flutter suggested that the slow conduction zone might be located in the low right atrial isthmus, which is a path formed by orifice of inferior vena cava, eustachian valve/ridge, coronary sinus ostium, and tricuspid annulus. The conduction characteristics during atrial pacing and responses to antiarrhythmic drugs of this anatomic isthmus were unknown.

Methods and Results
Forty-four patients, 20 patients with paroxysmal supraventricular tachycardia (group 1) and 24 patients with clinically documented paroxysmal typical atrial flutter (group 2), were studied. A 20-pole halo catheter was situated around the tricuspid annulus. Incremental pacing from the low right atrium and coronary sinus ostium was performed to measure the conduction time and velocity along the isthmus and lateral wall in the baseline state and after intravenous infusion of procainamide or sotalol. In both groups, conduction velocity in the isthmus during incremental pacing was significantly lower than that in the lateral wall before and after infusion of antiarrhythmic drugs. Furthermore, gradual conduction delay with unidirectional block in the isthmus was relevant to initiation of typical atrial flutter. Compared with group 1, group 2 had a lower conduction velocity in the isthmus and shorter right atrial refractory period. Procainamide significantly decreased the conduction velocity, but sotalol did not change it. In contrast, sotalol significantly prolonged the atrial refractory period with a higher extent than procainamide. After infusion of procainamide, the increase of conduction time in the isthmus accounted for 52±19% of the increase in flutter cycle length, and 5 of 12 patients (42%) had spontaneous termination of typical flutter. After infusion of sotalol, typical flutter was induced in only 6 of 12 patients (50%) without significant prolongation of flutter cycle length.

Conclusions
The low right atrial isthmus with rate-dependent slow conduction properties is critical to initiation of typical human atrial flutter. It may be the potentially pharmacological target of antiarrhythmic drugs in the future.
Assessment of Atrioventricular Junction Ablation and DDDR Mode-Switching Pacemaker Versus Pharmacological Treatment in Patients With Severely Symptomatic Paroxysmal Atrial Fibrillation
Authors: Brignole Michele , Gianfranchi Lorella , Menozzi Carlo , Alboni Paolo , Musso Giacomo , Bongiorni Maria Grazia , Gasparini Maurizio , Raviele Antonio , Lolli Gino , Paparella Nelly , Acquarone Simonetta
Published: June 2012

Background
The purpose of the study was to evaluate the effect of AV junction ablation and pacemaker implantation on quality of life and specific symptoms in patients with paroxysmal atrial fibrillation (AF) not controlled by drugs.

Methods and Results
We performed a multicenter, randomized, 6-month evaluation of the clinical effects of AV junction ablation and DDDR mode-switching pacemaker (Abl+Pm) versus pharmacological treatment in 43 patients with intolerable, recurrent paroxysmal AF of three or more episodes in the previous 6 months not controlled with three or more antiarrhythmic drugs. Before completion of the study, 3 patients in the drug group withdrew because of the severity of their symptoms and 1 patient assigned to the Abl+Pm group in whom the ablation procedure failed. At the end of the 6 months, the 21 patients of the Abl+Pm group who completed the study showed, in comparison with the 18 of the drug group, lower scores in the Living with Heart Failure Questionnaire (−51%,
P
=.0006), palpitations (−71%,
P
=.0000), effort dyspnea (−36%,
P
=.04), exercise intolerance score (−46%,
P
=.001), and easy fatigue (−51%,
P
=.02). The scores for rest dyspnea, chest discomfort, and NYHA functional classification were also lower (−56%, −50%, and −17%, respectively) in the Abl+Pm group, although not significantly. At the end of the study, palpitations were no longer present in 81% of the Abl+Pm group and in 11% of the drug group (
P
=.0000). AF was documented in 31 of 122 visits (25%) in the Abl+Pm group and in 9 of 107 examinations (8%) in the drug group (
P
=.0005); chronic AF developed in 5 (24%) and 0 (0%) in the two groups, respectively (
P
=.04).

Conclusions
In patients with paroxysmal AF not controlled by pharmacological therapy, Abl+Pm treatment is highly effective and superior to drug therapy in controlling symptoms and improving quality of life. The discontinuation of drug therapy exposes patients to further recurrences of paroxysmal AF and the risk of developing permanent AF.
Internal Cardioversion of Atrial Fibrillation
Authors: Cooper Randolph A. S. , Smith William M. , Ideker Raymond E.
Published: June 2012

Background
The ultimate acceptance of a fully automatic atrial defibrillator will depend on the reduction of pain to acceptable levels, requiring a marked decrease in defibrillation thresholds. The purpose of this study was to determine whether atrial defibrillation thresholds can be reduced by sequential shocks delivered through two current pathways.

Methods and Results
Sustained atrial fibrillation was induced with rapid atrial pacing in 12 adult sheep. Defibrillation electrodes were positioned in the right atrial appendage (RAap), distal coronary sinus (DCS), proximal coronary sinus (CSos), main/left pulmonary artery junction (PA), and right ventricular apex (RV). Single-capacitor biphasic waveforms (3/1 ms) were delivered through combinations of these electrodes. Probability-of-success curves were determined for single shocks with a single current pathway and sequential shocks with either single- or dual current pathways. The ED
50
for delivered energy for the dual current pathway RAap to DCS then CSos to PA was 0.36±0.13 J, which was significantly lower than the ED
50
of the standard single current pathway RAap to DCS (1.31±0.3 J) and was significantly lower than all other configurations tested.

Conclusions
Internal atrial defibrillation thresholds can be markedly reduced with two sequential biphasic shocks delivered over two current pathways compared with the standard single shock delivered over a single current pathway or with sequential shocks delivered over a single current pathway.
Hypercholesterolemia Exacerbates Transplant Arteriosclerosis via Increased Neointimal Smooth Muscle Cell Accumulation
Authors: Shi Chengwei , Lee Wen-Sen , Russell Mary E. , Zhang Dorothy , Fletcher Donald L. , Newell John B. , Haber Edgar
Published: June 2012

Background
Hypercholesterolemia is thought to be a significant risk factor for coronary vasculopathy in cardiac transplant recipients.

Methods and Results
We examined the development of arteriosclerosis in mouse carotid artery loops allografted from B.10A(2R) (H-2
h2
) donors to normocholesterolemic C57BL/6J (H-2
b
) recipients and hypercholesterolemic C57BL/6J recipients in which the apolipoprotein (apo) E gene had been knocked out. Luminal occlusion and cross-sectional neointimal area were greater in arteries allografted into hypercholesterolemic recipients at 15 and 30 days after transplantation. We also measured cellular and extracellular matrix components of the neointima by computerized planimetry of the fractional areas subtended by smooth muscle cells (anti–α-actin stain), collagen (Masson’s trichrome), lipid (oil red O), and leukocytes (anti-CD45). The neointimal area stained for smooth muscle cells was significantly greater in hypercholesterolemic recipients than in normocholesterolemic recipients at 15 and 30 days after allografting. Lipid contributed to neointimal area to a lesser degree, and there was no significant increase in the contribution of collagen or leukocytes.

Conclusions
Smooth muscle cell accumulation appears to be the principal contributor to the increase in neointimal area observed in arteries allografted into hypercholesterolemic mice.
Effects of Coronary Stenting on Restenosis and Occlusion After Angioplasty of the Culprit Vessel in Patients With Recent Myocardial Infarction
Authors: Bauters Christophe , Lablanche Jean-Marc , Van Belle Eric , Niculescu Rodica , Meurice Thibaud , Mc Fadden Eugène P. , Bertrand Michel E.
Published: June 2012

Background
PTCA of an infarct-related lesion is associated with a high rate of restenosis and/or vessel occlusion. Recent studies have shown that coronary stenting in patients with stable or unstable angina is associated with a significant reduction in the restenosis rate compared with conventional balloon angioplasty. However, no information is available concerning the long-term effect of coronary stenting at infarct-related lesions compared with balloon angioplasty alone.

Methods and Results
One hundred consecutive patients undergoing stent implantation at an infarct-related lesion and systematic 6-month angiographic follow-up were matched for major pre-PTCA clinical and angiographic variables with a group of patients undergoing conventional angioplasty. Preprocedural, postprocedural, and 6-month follow-up angiograms were analyzed with quantitative angiography. Coronary stenting was performed as a bailout procedure after failed balloon angioplasty in 20%, for a suboptimal result after balloon angioplasty in 71%, and electively in 9%. Stent implantation was associated with a higher acute gain than balloon angioplasty. At follow-up, the minimal lumen diameter was significantly (
P
<.0001) larger in the stent group (1.72±0.69 versus 1.23±0.72 mm). Restenosis (>50% DS at follow-up) occurred in 27% of the stent group versus 52% of the balloon group (
P
<.005). At follow-up, total occlusion at the dilated site occurred in 1% of the stent group versus 14% of the balloon group (
P
<.005).

Conclusions
Coronary stenting of infarct-related lesions is associated with a highly beneficial effect on 6-month angiographic outcome compared with balloon angioplasty alone. Further studies are needed to establish whether the beneficial effect of coronary stenting on long-term vessel patency is associated with an improvement in left ventricular function or in clinical outcome.
Disturbed Intracoronary Hemodynamics in Myocardial Bridging
Authors: Klues Heinrich G. , Schwarz Ernst R. , vom Dahl Jürgen , Reffelmann Thorsten , Reul Helmut , Potthast K. , Schmitz C. , Minartz Jürgen , Krebs Winfried , Hanrath iPeter
Published: June 2012

Background
The purpose of this study was to evaluate the hemodynamic mechanisms leading to myocardial ischemia in patients with myocardial bridging. Myocardial bridging is known to induce angina and even severe myocardial ischemia.

Methods and Results
In 12 symptomatic patients with myocardial bridges, quantitative coronary angiography was performed to obtain systolic/diastolic vessel diameters within the bridged segments. Coronary flow velocities, flow reserve, and pressures were determined with a 0.014-in Doppler and a 0.014-in pressure microtransducer. In 3 symptomatic patients, coronary stents were implanted and hemodynamic measurements were repeated immediately and after 7 weeks. An in vitro validation of the pressure measurements was performed. Angiography revealed a systolic diameter reduction of 80.6±9.2% and a persistent diastolic reduction of 35.3±11% within the bridged segment. Diastolic flow velocities (cm/s) were increased (31.5±14.3 within versus 17.3±5.7 proximal and 15.2±6.3 distal,
P
<.001). Coronary flow reserve distal to the bridge was 2.5±0.5. There was an increased peak systolic pressure within the bridged segment (171±48 versus 113±10 mm Hg proximal,
P
<.001). Stent placement abolished the phasic lumen compression, the diastolic flow abnormalities, the intracoronary peak systolic pressure, and clinical symptoms. Coronary flow reserve improved to 3.8±0.3.

Conclusions
Coronary hemodynamics in myocardial bridges are characterized by a phasic systolic vessel compression with a localized peak pressure, persistent diastolic diameter reduction, increased blood flow velocities, retrograde flow, and a reduced flow reserve. These alterations may explain the occurrence of symptoms and ischemia in these patients. Intracoronary stent placement abolished all hemodynamic abnormalities and may improve clinical symptoms in otherwise unsuccessfully treated patients with myocardial bridges.
Superiority of Nitrate-Enhanced
201
Tl Over Conventional Redistribution
201
Tl Imaging for Prognostic Evaluation After Myocardial Infarction and Thrombolysis
Authors: Basu Sumit , Senior Roxy , Raval Usha , Lahiri Avijit
Published: June 2012

Background
201
Tl imaging has been widely used for postinfarction risk stratification. However, thrombolytic therapy and aspirin have significantly changed outcome, and there are few nuclear imaging studies that assess prognosis in such patients. Furthermore, newer techniques of
201
Tl imaging, such as reinjection and nitrate-enhanced rest
201
Tl imaging, have been shown to improve the detection of viable but jeopardized myocardium.

Methods and Results
We studied 100 consecutive patients, who remained event free 6 weeks after myocardial infarction and thrombolysis. Patients underwent conventional exercise and 4-hour redistribution imaging, followed on a separate day by nitrate-enhanced rest
201
Tl study. Planar images were reported semiquantitatively by two experienced observers blinded to clinical data. Redistribution and rest injection images were classified as demonstrating reversible ischemia if they showed improvement in uptake by at least two grades in at least two segments in comparison with the initial exercise scintigram. Patients were followed up for 8 to 32 months (mean, 21 months); during this period, 37 patients had first cardiac events. Reversible ischemia was present in 29 patients on redistribution, of whom 14 (48%) had events; of 71 without reversible defects, 23 (32%) had events (hazard ratio, 1.5; 95% CI, 0.8 to 3.0;
P
=NS). Nitrate-enhanced rest
201
Tl imaging detected reversible defects in 68 patients, of whom 33 (49%) had events, whereas of 32 without reversible defects, only 4 (13%) had subsequent cardiac events (hazard ratio, 8.1; 95% CI, 2.7 to 23.8;
P
<.001).

Conclusions
Thus, after myocardial infarction and thrombolysis, even “stable” patients have a high (68%) incidence of viable but jeopardized myocardium, causing a high event rate. Those identified to be at high risk by perfusion imaging may benefit from early intervention.
Comparison of Immediate and Intermediate-Term Results of Intravascular Ultrasound Versus Angiography-Guided Palmaz-Schatz Stent Implantation in Matched Lesions
Authors: Albiero Remo , Rau Thomas , Schlüter Michael , Di Mario Carlo , Reimers Bernhard , Mathey Detlef G. , Tobis Jonathan M. , Schofer Joachim , Colombo Antonio
Published: June 2012

Background
Intravascular ultrasound (IVUS) provides more precise information than angiography about vascular dimensions. This information is used by some centers to optimize intracoronary stent implantation. There are no direct comparisons of the effects on restenosis of optimal IVUS-guided versus angiography-directed high-pressure stenting.

Methods and Results
Lesions of patients who had a 6-month angiographic follow-up study were eligible for matching. From 445 consecutive lesions treated by Palmaz-Schatz (P-S) stenting guided by IVUS (IVUS group) in Milan, 173 lesions were individually matched with 173 of 476 consecutive lesions treated by P-S stenting directed by angiography (Angio group) in Hamburg. Lesions were selected by a computerized program according to baseline clinical, angiographic, and procedural variables. Immediate and 6-month angiographic results were retrospectively compared, distinguishing an “early phase” from a “late phase.” This distinction was based on the more aggressive dilation strategy with larger balloons and more demanding IVUS criteria for optimal stent expansion used in Milan in the early phase. In both phases, a larger minimum lumen diameter (MLD) immediately after stenting and after 6 months was achieved in the IVUS group than in the Angio group. In the early phase, the dichotomous restenosis rate was lower in the IVUS group than in the Angio group (9.2% versus 22.3%;
P
=.04). In the late phase, there was no difference in restenosis between the groups (22.7% versus 23.7%;
P
=1.0).

Conclusions
In matched lesions treated with high-pressure stenting, IVUS guidance achieved a larger MLD than angiographic guidance. However, in the IVUS group, the restenosis rate was lower only in the early phase, when balloons larger than currently used were selected to maximize the stent lumen area.
Evaluation of the Spatial Aspects of T-Wave Complexity in the Long-QT Syndrome
Authors: Priori Silvia G. , Mortara David W. , Napolitano Carlo , Diehl Livia , Paganini Vincenzo , Cantù Francesco , Cantù Giacomo , Schwartz Peter J.
Published: June 2012

Background
The duration of the QT interval is only a gross estimate of repolarization. Besides its limited accuracy and reproducibility, it does not provide information on the morphology of the T wave; thus, morphologic alterations such as notches can be only qualitatively described but not objectively quantified.

Methods and Results
To measure the complexity of repolarization in the long-QT syndrome (LQTS) patients, we previously applied principal component analysis to body surface mapping and found it useful in distinguishing normal from abnormal repolarization patterns (sensitivity, 87%). In the present study, we applied principal component analysis to 12-lead Holter recordings. The index of complexity of repolarization that we have developed (CR
24h
) reflects the average 24-hour complexity of repolarization and is mathematically defined as the average ratio between the second and the first eigenvalue. We studied 36 LQTS patients and 40 control subjects. A mean of 22±1.3 ECG recordings at 1-hour intervals was used in each patient, and a total of 1655 recordings were analyzed. CR
24h
was significantly higher in LQTS than in control subjects (34±12% versus 13±3%;
P
<.0001). A CR
24h
exceeding 2 SD above the mean of the control group (>20%) was present in 32 of 36 patients (88%). The negative predictive value of CR
24h
in LQTS was 88%, and the combination of prolonged QT and abnormal CR
24h
identified all LQTS patients from normal subjects, including 4 affected symptomatic individuals with a normal QT interval duration, suggesting that CR
24h
provides information independent of QT duration.

Conclusions
Our data suggest that principal component analysis applied to 24-hour, 12-lead Holter recording adequately quantifies the complexity of ventricular repolarization and may become a useful noninvasive diagnostic tool in LQTS.
Adjunctive Intracardiac Echocardiography to Guide Slow Pathway Ablation in Human Atrioventricular Nodal Reentrant Tachycardia
Authors: Fisher Westby G. , Pelini Michael A. , Bacon Martin E.
Published: June 2012

Background
Because of the inability of fluoroscopy to image intracardiac structures, the precise anatomic location of successful slow pathway (SP) ablation is controversial. We hypothesized that adjunctive intracardiac echocardiography (ICE) in concert with conventional fluoroscopy and electrogram guidance could identify the anatomic site of successful SP ablation.

Methods and Results
In 25 patients, radiofrequency ablation was performed in the triangle of Koch directed by biplane fluoroscopy and a 6.2F, 12.5-MHz ICE catheter positioned adjacent to the triangle of Koch. Persistent SP conduction, number of radiofrequency applications, presence of junctional tachycardia, and fluoroscopy times were evaluated. As demonstrated by ICE, anterograde SP ablation was achieved between 2 and 7 mm from the tricuspid valve in imaging planes containing the AV muscular septum in all cases. Radiofrequency energy applications applied at other sites within the triangle of Koch failed to interrupt SP conduction. A mean of three radiofrequency energy applications (3±2; range, 1 to 12) successfully ablated all evidence of anterograde SP conduction in all patients studied. Junctional tachycardia was seen in 96% (71/74) of the radiofrequency energy applications.

Conclusions
Radiofrequency ablation at the tricuspid valve’s insertion into the AV muscular septum as identified by ICE reliably terminates anterograde SP conduction, supporting the hypothesis that the SP consistently traverses this anatomic location.
Endothelin-1 Is Involved in Stretch-Induced Early Activation of B-Type Natriuretic Peptide Gene Expression in Atrial but Not in Ventricular Myocytes
Authors: Magga Jarkko , Vuolteenaho Olli , Marttila Minna , Ruskoaho Heikki
Published: June 2012

Background
The precise role of paracrine and autocrine factors in mechanical load–induced activation of cardiac gene expression is unknown. Here we report the effects of endothelin-1 (ET-1) and angiotensin II (Ang II) receptor antagonism on acute pressure overload–induced activation of cardiac B-type natriuretic peptide (BNP) gene expression in spontaneously hypertensive rats (SHRs) in vivo and on mechanical stretch–induced increase in atrial BNP gene expression in vitro.

Methods and Results
Acute pressure overload produced in conscious SHRs by infusion of arginine
8
-vasopressin (0.05 μg · kg
−1
· min
−1
) for 2 hours resulted in an increase in BNP mRNA levels in the left ventricle as well as in the atrium. Bolus injections of bosentan (mixed ET
A
/ET
B
receptor antagonist, 10 mg/kg IV) but not losartan (AT
1
receptor antagonist, 10 mg/kg IV) blocked the increase of the BNP mRNA levels produced by pressure overload in the left atria, whereas the elevation of BNP mRNA levels was similar (a 1.9-fold increase) in the left ventricles of vehicle-, losartan-, and bosentan-infused SHRs. In an isolated perfused rat heart preparation, infusion of bosentan (1 μmol/L) for 2 hours inhibited the mechanical stretch–induced increase in BNP mRNA levels in the right atria, whereas an AT
1
receptor antagonist, CV-11974 (10 nmol/L), had no effect.

Conclusions
The findings of the present study demonstrate that Ang II and ET-1 are not obligatorily required for stretch to trigger the increased BNP gene expression in ventricular myocytes in vivo. In contrast, mechanical load on the atrial myocytes did initiate an ET-1–dependent expression of BNP gene showing that endogenous ET-1 production differentially regulates BNP gene expression in atrial and ventricular myocytes.
Myocardial Osteopontin Expression Is Associated With Left Ventricular Hypertrophy
Authors: Graf Kristof , Do Yung S. , Ashizawa Naoto , Meehan Woerner P. , Giachelli Cecilia M. , Marboe Charles C. , Fleck Eckart , Hsueh Willa A.
Published: June 2012

Background
Osteopontin (OP) has been identified in cultured rat cardiac fibroblasts, where it contributes to angiotensin II (AII)-induced remodeling processes; in cultured cardiomyocytes; and in macrophages in cardiac tissues with inflammation. However, the presence of OP has not been reported in histological sections of myocardial tissue. In the present study, we investigated (1) the regulation of OP mRNA expression in cultured rat cardiomyocytes; (2) the localization of OP mRNA in neonatal and adult normal and hypertrophied rat hearts; and (3) the histology of OP expression in myocardial specimens from humans either with myocyte hypertrophy or with no pathological changes.

Methods and Results
Cultured neonatal cardiomyocytes expressed OP mRNA and were immunoreactive for OP. Endothelin-1 (ET-1) and norepinephrine (NE) increased both OP and atrial natriuretic peptide (ANP) mRNA levels twofold to threefold (
P
<.01). OP mRNA was prominent in ventricular tissue from neonatal and adult rats with renovascular hypertension and aortic banding, whereas barely detectable levels were observed in normal adult cardiac tissue. ANP and OP mRNA levels in normal and hypertrophied ventricles correlated (
r
2
=.87,
P
<.001). OP immunoreactivity and mRNA transcripts were predominantly found in cardiomyocytes not associated with inflammatory cells in sections from neonatal and adult hypertrophied hearts. No staining was detectable in normal adult hearts. Human myocardium with extensive fibrosis and cardiomyocyte hypertrophy obtained from explanted hearts with either idiopathic (n=5) or ischemic cardiomyopathy (n=7) demonstrated substantial myocyte immunoreactivity for both OP and ANP in right and left ventricles that was not associated with leukocyte infiltration. In situ hybridization identified cardiomyocytes as the major source of OP mRNA transcripts in these hearts. In contrast, OP immunoreactivity was not detectable in four of five endomyocardial biopsies with normal histology.

Conclusions
The present study provides the first evidence that cardiomyocytes are a prominent source of OP in vivo and suggests that induction of OP expression is strongly associated with ventricular hypertrophy.
Importance of Endogenous Adenosine During Ischemia and Reperfusion in Neonatal Porcine Hearts
Authors: Sommerschild Hilchen T. , Grund Frank , Offstad Jon , Jynge Per , Ilebekk Arnfinn , Kirkebøen Knut A.
Published: June 2012

Background
Adenosine has several potentially cardioprotective effects. We hypothesized that the effects of endogenous adenosine vary with degree of ischemia and that elevating endogenous levels is protective.

Methods and Results
Isolated blood-perfused piglet hearts underwent 120 minutes of low-flow ischemia (10% flow) or 90 minutes of zero-flow ischemia, all with 60 minutes of reperfusion. Hearts were treated with either saline, the adenosine receptor blocker 8-sulfophenyltheophylline (8SPT, 300 μmol · L
−1
), or the nucleoside transport inhibitor draflazine (1 μmol · L
−1
). In separate groups, biopsies were obtained before and at the end of ischemia. Compared with saline, 8SPT did not significantly alter functional recovery in either protocol. Draflazine significantly improved percent recovery of left ventricular systolic pressure both in the low-flow protocol (92±3% versus 75±2% [saline] and 73±3% [8SPT],
P
<.001 for both) and in the zero-flow protocol (76±3% versus 59±4% [saline] and 46±9% [8SPT],
P
<.05 for both). In the zero-flow protocol, draflazine also significantly reduced ischemic contracture and release of creatine kinase. Tissue adenosine at the end of ischemia was elevated by draflazine compared with saline-treated hearts: after low-flow ischemia to 0.10±0.05 versus 0.00±0.00 μmol · g
−1
dry wt (
P
<.05) and after zero-flow ischemia to 1.73±0.82 versus 0.15±0.03 μmol · g
−1
dry wt (
P
<.05).

Conclusions
In neonatal porcine hearts, endogenous adenosine produced during ischemia does not influence ischemic injury or functional recovery. Elevating endogenous adenosine by draflazine elicits cardioprotection in both low-flow and zero-flow conditions.
Pulmonary Big Endothelin Affects Coronary Tone and Leads to Enhanced, ET
A
-Mediated Coronary Constriction in Early Endothelial Dysfunction
Authors: Stangl Karl , Dschietzig Thomas , Laule Michael , Alexiou Konstantin , Wernecke Klaus D. , Baumann Gert
Published: June 2012

Background
Lung tissue produces a variety of mediators; however, little is known regarding how these mediators affect coronary regulation and myocardial contractility. In a novel rabbit lung-heart model, we investigated the possible influence exerted by pulmonary mediators on coronary tone both under normal conditions and in early endothelial dysfunction.

Methods and Results
In our model, the effluent from the isolated lung is used to serially perfuse the coronary vessels of the isolated heart of the same animal. Compared with the hearts of control rabbits, isolated hearts of Watanabe rabbits revealed pharmacological evidence of endothelial dysfunction and a significant steeper decrease of coronary flow during serial perfusion of the coronary vessels with lung effluent (75±6% versus 89±3%). This decline in coronary flow was prevented by the nonselective endothelin (ET) antagonist PD-145065, the ET
A
antagonists BQ-123 and A-127722, and the endothelin-converting enzyme inhibitor phosphoramidon. The concentration of big ET in lung effluent ranged from 5.5 to 5.8 pmol/L in both control and Watanabe groups, with levels in corresponding coronary effluent falling to 0.9 to 1.1 pmol/L in controls and to 1.0 to 1.2 pmol/L in the Watanabe group. In either group, ET was not detected in lung effluent, but it rose significantly in coronary effluent during serial perfusion.

Conclusions
Pulmonary big ET, locally converted into ET during coronary passage, causes an ET
A
-mediated elevation in coronary tone under basal conditions as well as an enhanced coronary constriction when early endothelial dysfunction is present.
Stem Cell Factor in Mast Cells and Increased Mast Cell Density in Idiopathic and Ischemic Cardiomyopathy
Authors: Patella Vincenzo , Marinò Isabella , Arbustini Eloisa , Lamparter-Schummert Bärbel , Verga Laura , Adt Monika , Marone Gianni
Published: June 2012

Background
—We compared cardiac mast cell (HHMC) density and the immunological and nonimmunological release of mediators from mast cells isolated from heart tissue of patients with idiopathic dilated (DCM) (n=24) and ischemic cardiomyopathy (ICM) (n=10) undergoing heart transplantation and from control subjects (n=10) without cardiovascular disease.

Methods and Results
—HHMC density in DCM (18.4±1.6 cells/mm
2
) and ICM (18.4±1.5 cells/mm
2
) was higher than that in control hearts (5.3±0.7 cells/mm
2
;
P
<.01). The histamine and tryptase contents of DCM and ICM hearts were higher than those of control hearts. The histamine content of the hearts was correlated with mast cell density (
r
s
=.91;
P
<.001). Protein A/gold staining of heart tissue revealed stem cell factor (SCF), the principal growth, differentiating, and activating factor of human mast cells, in HHMC secretory granules. Histamine release from cardiac mast cells caused by immunological (anti-IgE and rhSCF) and nonimmunological stimuli (Ca
2+
ionophore A23187) was higher in patients with DCM and ICM compared with control subjects. Immunological activation of HHMC induced a significantly greater release of tryptase and LTC
4
in patients with DCM and ICM compared with control subjects.

Conclusions
—Histamine and tryptase content and mast cell density are higher in failing hearts than in control hearts. SCF, present in secretory granules of HHMC, might represent an autocrine factor sustaining mast cell hyperplasia in heart tissue in these patients. The increased local release of fibrogenic factors (eg, histamine, tryptase, and leukotriene C
4
) might contribute to collagen accumulation in the hearts of patients with cardiomyopathy.
Induction of Rat Aortic Smooth Muscle Cell Growth by the Lipid Peroxidation Product 4-Hydroxy-2-Nonenal
Authors: Ruef Johannes , Rao Gadiparthi N. , Li Fengzhi , Bode Christoph , Patterson Cam , Bhatnagar Aruni , Runge Marschall S.
Published: June 2012

Background
—Atherosclerotic lesion formation is a complex process, in part mediated by inflammatory and oxidative mechanisms including lipid peroxidation. To further characterize the potential role of lipid peroxidation products in atherogenesis, we studied the effects of 4-hydroxy-2-nonenal (HNE) on rat aortic smooth muscle cell growth.

Methods and Results
—HNE, at concentrations of 1.0 and 2.5 μmol/L, significantly stimulated rat aortic smooth muscle cell growth as determined by cell counts, [
3
H]-thymidine uptake, and incorporation of bromo-deoxyuridine. To characterize the mechanism of HNE-induced mitogenesis, its effect on activation of intracellular growth signaling pathways was examined. Treatment with HNE resulted in activation of extracellular signal-regulated protein kinases ERK1 and ERK2, induction of c-
fos
and c-
jun
protein expression, and an increase in transcription factor AP-1 DNA binding activity. In addition, HNE induced expression of platelet-derived growth factor-AA (PDGF-AA) protein, and an anti–PDGF-AA antibody specifically inhibited HNE-mediated DNA synthesis, suggesting that growth factor induction may play a role in HNE-induced vascular smooth muscle cell growth. The role of redox-sensitive mechanisms in this process was further supported by the observation that HNE-induced DNA synthesis and AP-1 activation were inhibited by the antioxidants
N
-acetylcysteine and pyrrolidine dithiocarbamate.

Conclusions
—These data demonstrate that HNE, one of several important lipid peroxidation products, induces rat aortic smooth muscle cell growth through redox-sensitive mechanisms and growth factor expression. These observations are consistent with a role for lipid peroxidation products in vascular smooth muscle cell growth in atherogenesis.
Combined Hormone Replacement Therapy Does Not Protect Women Against the Age-Related Decline in Endothelium-Dependent Vasomotor Function
Authors: Sorensen Keld E. , Dorup Inge , Hermann Anne P. , Mosekilde Leif
Published: June 2012

Background
—Improvement in endothelial function may be an important mechanism by which estrogen replacement therapy protects postmenopausal women against coronary artery disease. However, combined hormone replacement therapy is more frequently used owing to the risk of uterine cancer with estrogen-only therapy. Concurrent progesterone treatment may attenuate the beneficial effects of estrogens not only on the lipid profile but also on the endothelium.

Methods and Results
—We studied endothelial vasomotor function in 100 healthy postmenopausal women aged 53.3±2.9 years randomized to either combined hormone replacement therapy (n=46) or no substitution (n=54) 2.9±0.5 years earlier. In addition, 30 healthy premenopausal women aged 30.3±4.2 years were studied. With external ultrasound, brachial artery diameter was measured at rest, during reactive hyperemia (with increased flow causing endothelium-dependent dilation), and after sublingual nitroglycerin (causing endothelium-independent dilation). Compared with premenopausal women, flow-mediated dilation was significantly reduced in both postmenopausal groups. In the postmenopausal women, total cholesterol was lower in the treated women (5.66±0.83 versus 6.13±0.92 mmol/L;
P
=.025), whereas HDL cholesterol was similar (1.91±0.53 versus 1.85±0.46 mmol/L;
P
=NS). Dilation to flow and to nitroglycerin was similar in the two postmenopausal groups (flow: 2.5±2.9% versus 2.2±2.2%,
P
=NS; nitrate: 18.7±5.9% versus 17.2±6.2%,
P
=NS).

Conclusions
—Long-term combined oral hormone replacement therapy is without beneficial effects on endothelial vasomotor function in healthy postmenopausal women. This supports the view that progesterone may attenuate the beneficial effects of unopposed estrogen replacement.
New Mutations in the
KVLQT1
Potassium Channel That Cause Long-QT Syndrome
Authors: Li Hua , Chen Qiuyun , Moss Arthur J. , Robinson Jennifer , Goytia Veronica , Perry James C. , Vincent G. Michael , Priori Silvia G. , Lehmann Michael H. , Denfield Susan W. , Duff Desmond , Kaine Stephen , Shimizu Wataru , Schwartz Peter J. , Wang Qing , Towbin Jeffrey A.
Published: June 2012

Background
—Long-QT syndrome (LQTS) is an inherited cardiac arrhythmia that causes sudden death in young, otherwise healthy people. Four genes for LQTS have been mapped to chromosome 11p15.5 (
LQT1
), 7q35–36 (
LQT2
), 3p21–24 (
LQT3
), and 4q25–27 (
LQT4
). Genes responsible for
LQT1
,
LQT2
, and
LQT3
have been identified as cardiac potassium channel genes (
KVLQT1
,
HERG
) and the cardiac sodium channel gene (
SCN5A
).

Methods and Results
—After studying 115 families with LQTS, we used single-strand conformation polymorphism (SSCP) and DNA sequence analysis to identify mutations in the cardiac potassium channel gene,
KVLQT1
. Affected members of seven LQTS families were found to have new, previously unidentified mutations, including two identical missense mutations, four identical splicing mutations, and one 3-bp deletion. An identical splicing mutation was identified in affected members of four unrelated families (one Italian, one Irish, and two American), leading to an alternatively spliced form of
KVLQT1
. The 3-bp deletion arose de novo and occurs at an exon-intron boundary. This results in a single base deletion in the
KVLQT1
cDNA sequence and alters splicing, leading to the truncation of
KVLQT1
protein.

Conclusions
—We have identified LQTS-causing mutations of
KVLQT1
in seven families. Five
KVLQT1
mutations cause the truncation of
KVLQT1
protein. These data further confirm that
KVLQT1
mutations cause LQTS. The location and character of these mutations expand the types of mutation, confirm a mutational hot spot, and suggest that they act through a loss-of-function mechanism or a dominant-negative mechanism.
Effects of the Intracoronary Infusion of Cocaine on Left Ventricular Systolic and Diastolic Function in Humans
Authors: Pitts William R. , Vongpatanasin Wanpen , Cigarroa Joaquin E. , Hillis L. David , Lange Richard A.
Published: June 2012

Background
—In dogs, a large amount of intravenous cocaine causes a profound deterioration of left ventricular (LV) systolic function and an increase in LV end-diastolic pressure. This study was done to assess the influence of a high intracoronary cocaine concentration on LV systolic and diastolic function in humans.

Methods and Results
—In 20 patients (14 men and 6 women aged 39 to 72 years) referred for cardiac catheterization for the evaluation of chest pain, we measured heart rate, systemic arterial pressure, LV pressure and its first derivative (dP/dt), and LV volumes and ejection fraction before and during the final 2 to 3 minutes of a 15-minute intracoronary infusion of saline (n=10, control subjects) or cocaine hydrochloride 1 mg/min (n=10). No variable changed with saline. With cocaine, the drug concentration in blood obtained from the coronary sinus was 3.0±0.4 (mean±SD) mg/L, similar in magnitude to the blood cocaine concentration reported in abusers dying of cocaine intoxication. Cocaine induced no significant change in heart rate, LV dP/dt (positive or negative), or LV end-diastolic volume, but it caused an increase in systolic and mean arterial pressures, LV end-diastolic pressure, and LV end-systolic volume, as well as a decrease in LV ejection fraction.

Conclusions
—In humans, the intracoronary infusion of cocaine sufficient in amount to achieve a high drug concentration in coronary sinus blood causes a deterioration of LV systolic and diastolic performance.
Human Endothelial Nitric Oxide Synthase Gene Transfer Inhibits Vascular Smooth Muscle Cell Proliferation and Neointima Formation After Balloon Injury in Rats
Authors: Janssens Stefan , Flaherty Declan , Nong Zengxuan , Varenne Olivier , van Pelt Natasha , Haustermans Carine , Zoldhelyi Pierre , Gerard Robert , Collen Desire
Published: June 2012

Background
—Loss of endothelial NO production after arterial injury may contribute to restenosis, characterized by neointima formation and elastic recoil. Adenovirus-mediated transfer of the gene encoding NO synthase (NOS) in balloon-injured arteries may restore NO production and inhibit neointima formation.

Methods and Results
—After balloon injury, rat carotid arteries were transduced with 3×10
10
pfu/mL recombinant adenovirus carrying the human endothelial constitutive NOS cDNA (AdCMVceNOS, n=8) or no cDNA (AdRR5, n=8). ceNOS expression was confirmed by immunoblot analysis of vascular extracts and was localized by immunostaining in 30% of medial smooth muscle cells (SMCs) and in the adventitia of AdCMVceNOS-transduced arteries. Vascular cGMP levels were reduced from 3.9 pmol/g wet wt in uninjured arteries to 0.7 pmol cGMP/g after AdRR5 but were restored after ceNOS gene transfer (3.8 pmol cGMP/g wet wt,
P
<.05 versus AdRR5). Intima-to-media ratio 2 weeks after injury was significantly reduced (0.19±0.02 in AdCMVceNOS-infected versus 0.69±0.07 in AdRR5-infected arteries,
P
<.05). In vitro, BrdU incorporation of AdCMVceNOS-infected SMCs was reduced by 28% compared with AdRR5-infected SMCs. Transduced cells from injured carotid arteries subjected to FACS sorting showed a significantly lower BrdU labeling index in ceNOS-infected rats (29±6% versus 43±5% and 45±4% in control, injured, and AdRR5-infected rats, respectively,
P
<.05).

Conclusions
—AdCMVceNOS gene transfer to balloon-injured rat carotid arteries restores vascular NO productionand reduces neointima formation, at least in part because of an antiproliferative effect on medial SMCs. Adenovirus-mediated ceNOS gene transfer might reduce arterial restenosis after balloon angioplasty.