bluuebunny/crossref_metadata_2025 huggingface dataset:
Three-Dimensional Reconstruction of the Color Doppler–Imaged Vena Contracta for Quantifying Aortic Regurgitation
Authors: Mori Yoshiki , Shiota Takahiro , Jones Michael , Wanitkun Suthep , Irvine Timothy , Li Xiaokui , Delabays Alain , Pandian Natesa G. , Sahn David J.
Published: June 2012

Background
—The purpose of this study was to investigate the use of 3-dimensional (3D) reconstruction of color Doppler flow maps to image and extract the vena contracta cross-sectional area to determine the severity of aortic regurgitation (AR) in an animal model. Evaluation of the vena contracta with 2-dimensional imaging systems may not be sufficiently robust to fully characterize this region, which may be asymmetrically shaped.

Methods and Results
—In 6 sheep with surgically induced chronic AR, 18 hemodynamically different states were studied. Instantaneous regurgitant flow rates were obtained by aortic and pulmonary electromagnetic flowmeters (EMFs) as reference standards, and aortic regurgitant effective orifice areas (EOAs) were determined from EMF regurgitant flow rates divided by continuous-wave (CW) Doppler velocities. Composite video data for color Doppler imaging of the aortic regurgitant flows were transferred into a TomTec computer after computer-controlled 180° rotational acquisition. After the 3D data transverse to the flow jet were sectioned, the smallest proximal jet cross section was identified for direct measurement of the vena contracta area. Peak regurgitant flow rates and regurgitant stroke volumes were calculated as the product of these areas and the CW Doppler peak velocities and velocity-time integrals, respectively. There was an excellent correlation between the 3D-derived vena contracta areas and reference EOAs (
r
=0.99, SEE=0.01 cm
2
) and between 3D and reference peak regurgitant flow rates and regurgitant stroke volumes (
r
=0.99, difference=0.11 L/min;
r
=0.99, difference=1.5 mL/beat, respectively).

Conclusions
—3D-based determination of the vena contracta cross-sectional area can provide accurate quantification of the severity of AR.
Effects of Ischemia on Discontinuous Action Potential Conduction in Hybrid Pairs of Ventricular Cells
Authors: Wilders Ronald , Verheijck E. Etienne , Joyner Ronald W. , Golod David A. , Kumar Rajiv , van Ginneken Antoni C. G. , Bouman Lennart N. , Jongsma Habo J.
Published: June 2012

Background
—Acute ischemia often occurs in cardiac tissue that has prior injury, resulting in spatially inhomogeneous distributions of membrane properties and intercellular coupling. Changes in action potential conduction with ischemia, which can be associated with release of catecholamines, may be particularly important in tissue that has discontinuous conduction resulting from prior infarction, hypertrophy, or myopathy.

Methods and Results
—Isolated guinea pig ventricular myocytes were electrically coupled by a coupling-clamp circuit to a comprehensive computer model of a guinea pig ventricular myocyte to assess alterations in the critical value of coupling conductance required for action potential conduction from the real cell to the model cell when the real cell was exposed to a solution that included hypoxia, acidosis, and an elevated extracellular potassium concentration to simulate acute ischemia. The “ischemic” solution increased critical coupling conductance from 6.2±0.1 to 7.4±0.2 nS and decreased the associated maximum conduction delay from 31±1 to 23±1 ms (mean±SEM, n=11). The ischemic solution plus 1 μmol/L norepinephrine decreased critical coupling conductance from 5.9±0.2 to 5.0±0.1 nS and increased maximum conduction delay from 31±2 to 54±4 ms (mean±SEM, n=8).

Conclusions
—The release of catecholamines with ischemia, in a setting of partially uncoupled cells, may play a major role in producing long conduction delays, which may allow reentrant pathways.
Blood Pressure Response During Treadmill Testing as a Risk Factor for New-Onset Hypertension
Authors: Singh Jagmeet P. , Larson Martin G. , Manolio Teri A. , O’Donnell Christopher J. , Lauer Michael , Evans Jane C. , Levy Daniel
Published: June 2012

Background
—Although systolic blood pressure (SBP) response to exercise has been shown to predict subsequent hypertension in small samples of men, this association has not been studied in a large population-based sample of middle-aged men and women. The purpose of this study was to examine, in normotensive subjects, the relations of SBP and diastolic blood pressure (DBP) during the exercise and recovery periods of a graded treadmill test to the risk of developing new-onset hypertension.

Methods and Results
—BP data from exercise testing in 1026 men and 1284 women (mean age, 42±10 years; range, 20 to 69 years) from the Framingham Offspring Study who were normotensive at baseline were related to the incidence of hypertension 8 years later. New-onset hypertension, defined as an SBP ≥140 mm Hg or DBP ≥90 mm Hg or the initiation of antihypertensive drug treatment, occurred in 228 men (22%) and 207 women (16%). Exaggerated SBP (Ex-SBP 2) and DBP (Ex-DBP 2) response and delayed recovery of SBP (R-SBP 3) and DBP (R-DBP 3) were defined as an age-adjusted BP greater than the 95th percentile during the second stage of exercise and third minute of recovery, respectively. After multivariable adjustment, Ex-DBP 2 was highly predictive of incident hypertension in both men (OR, 4.16; 95% CI, 2.15, 8.05) and women (OR, 2.17; CI, 1.19, 3.96). R-SBP 3 was predictive of hypertension in men in a multivariable model that included exercise duration and peak exercise BP (OR, 1.92; CI, 1.00, 3.69). Baseline resting SBP (χ
2
, 23.4 in men and 34.7 in women) and DBP (χ
2
, 11.3 in men and 13.1 in women) had stronger associations with new-onset hypertension than exercise DBP (χ
2
, 16.4 in men and 6.1 in women) and recovery SBP (χ
2
, 6.5 in men and 2.1 in women) responses.

Conclusions
—An exaggerated DBP response to exercise was predictive of risk for new-onset hypertension in normotensive men and women. An elevated recovery SBP was predictive of hypertension in men. These findings may reflect subtle pathophysiological features in the preclinical stage of hypertension.
Prediction of Sustained Ventricular Tachycardia Inducible by Programmed Stimulation in Patients With Coronary Artery Disease
Authors: Buxton Alfred E. , Hafley Gail E. , Lehmann Michael H. , Gold Michael , O’Toole Michael , Tang Anthony , Coromilas James , Hook Bruce , Stamato Nicholas J. , Lee Kerry L.
Published: June 2012

Background
—Cardiologists often use clinical variables to determine the need for electrophysiological studies to stratify patients for risk of sudden death. It is not clear whether this is rational in patients with coronary artery disease, left ventricular dysfunction, and nonsustained ventricular tachycardia.

Methods and Results
—We analyzed the first 1721 patients enrolled in the Multicenter UnSustained Tachycardia Trial to determine whether clinical variables could predict which patients would have inducible sustained monomorphic ventricular tachycardia. The rate of inducibility of sustained ventricular tachycardia was significantly higher in patients with a history of myocardial infarction and in men compared with women. There was a progressively increased rate of inducibility with increasing numbers of diseased coronary arteries. There was a significantly lower rate of inducibility in patients with prior coronary artery bypass surgery and in patients who also had noncoronary cardiac disease. The rate of inducibility was higher in patients of white race, patients with recent (≤6 weeks) angina, left ventricular dyskinesis, and in patients with greater numbers of fixed thallium defects. Inducibility was more likely in patients who had a prior myocardial infarction complicated by congestive heart failure, ventricular tachycardia, or fibrillation ≤48 hours after the onset of infarction. Although these associations are statistically significant, the accuracy of the clinical variables in discriminating between patients with and those without inducible ventricular tachycardia is only modest (receiver operator characteristic area <0.70).

Conclusions
—Multiple clinical variables are independently associated with inducible sustained ventricular tachycardia. However, they have limited utility to guide clinical decisions regarding the use of electrophysiological testing for risk stratification in this patient population.
Intracranial Arteries of Human Fetuses Are More Resistant to Hypercholesterolemia-Induced Fatty Streak Formation Than Extracranial Arteries
Authors: Napoli Claudio , Witztum Joseph L. , de Nigris Filomena , Palumbo Giuseppe , D’Armiento Francesco P. , Palinski Wulf
Published: June 2012

Background
—Atherosclerotic lesions in intracranial arteries occur later and are less extensive than in extracranial arteries. To investigate potential mechanisms responsible for this difference, in particular the atherogenic response to hypercholesterolemia and LDL oxidation, we compared the extent of fatty streak formation and the composition of these very early lesions in intracranial arteries of human fetuses from normocholesterolemic and hypercholesterolemic mothers with those in extracranial arteries.

Methods and Results
—Lesions were quantified by computer-assisted image analysis of 30 oil red O–stained sections, each from the middle cerebral, basilar, and common carotid arteries and the abdominal aorta of human fetuses (spontaneous abortions and premature newborns who died within 12 hours of birth; both of fetal age 6.2±1.3 months) from 43 hypercholesterolemic mothers and 34 normocholesterolemic mothers. Macrophages, apolipoprotein B, and 2 epitopes of oxidized LDL in lesions were determined immunocytochemically. Activities of superoxide dismutase, catalase, and glutathione peroxidase in the arterial wall were also determined. Lesion numbers and sizes were dramatically greater in the abdominal aorta (area of the largest lesion per section: 66.5±10.9 ×10
3
μm
2
) and the carotid (11.6±5.3 ×10
3
μm
2
) than in the basilar and middle cerebral artery (0.4±0.1 and 0.8±0.2 ×10
3
μm
2
, respectively;
P
<0.0001). Hypercholesterolemia resulted in a significant increase of lesion size in extracranial arteries but only a marginal increase in intracranial arteries. In analogy, hypercholesterolemia induced a much greater increase in the intimal presence of macrophages, apolipoprotein B, and oxidized LDL (oxidation-specific epitopes) in extracranial than in intracranial arteries. Immunocytochemistry did not indicate that lesions of intracranial arteries contain relatively less oxidized LDL than similar-size lesions of extracranial arteries. Activities of Mn–superoxide dismutase but not of Zn–superoxide dismutase, catalase, or glutathione peroxidase were significantly higher in both intracranial arteries.

Conclusions
—Exposure to hypercholesterolemia during fetal development results in extensive formation of fatty streaks in extracranial but not intracranial arteries. The fact that such a difference in lesion formation occurs in the absence of many other atherogenic risk factors found later in life suggests that differences in the atherogenic response to hypercholesterolemia are an important contributor to the slower onset of the disease in intracranial vessels in adults. Fetal arteries may allow elucidation of the mechanisms responsible, for example, better protection of intracranial arteries against free radical–mediated atherogenic processes.
Tracheal Aspirate as a Substrate for Polymerase Chain Reaction Detection of Viral Genome in Childhood Pneumonia and Myocarditis
Authors: Akhtar Noorullah , Ni Jiyuan , Stromberg Daniel , Rosenthal Geoffrey L. , Bowles Neil E. , Towbin Jeffrey A.
Published: June 2012

Background
—Infectious respiratory disorders are important causes of childhood morbidity and mortality. Viral causes are common and may lead to rapid deterioration, requiring mechanical ventilation; myocardial dysfunction may accompany respiratory decompensation. The etiologic viral diagnosis may be difficult with classic methods. The purpose of this study was to evaluate polymerase chain reaction (PCR) as a diagnostic method for identification of causative agents.

Methods and Results
—PCR was used to amplify sequences of viruses known to cause childhood viral pneumonia and myocarditis. Oligonucleotide primers were designed to amplify specific sequences of DNA virus (adenovirus, cytomegalovirus, herpes simplex virus, and Epstein-Barr virus) and RNA virus (enterovirus, respiratory syncytial virus, influenza A, and influenza B) genomes. Tracheal aspirate samples were obtained from 32 intubated patients and nucleic acid extracted before PCR. PCR results were compared with results of culture, serology, and antigen detection methods when available. In cases of myocarditis (n=7), endomyocardial biopsy samples were analyzed by PCR and compared with tracheal aspirate studies. PCR amplification of viral genome occurred in 18 of 32 samples (56%), with 3 samples PCR positive for 2 viral genomes. Amplified viral sequences included RSV (n=3), enterovirus (n=5), cytomegalovirus (n=4), adenovirus (n=3), herpes simplex virus (n=2), Epstein-Barr virus (n=1), influenza A (n=2), and influenza B (n=1). All 7 cases of myocarditis amplified the same viral genome from heart as found by tracheal aspirate.

Conclusions
—PCR is a rapid and sensitive diagnostic tool in cases of viral pneumonia with or without myocarditis, and tracheal aspirate appears to be excellent for analysis.
Increased NADH-Oxidase–Mediated Superoxide Production in the Early Stages of Atherosclerosis
Authors: Warnholtz Ascan , Nickenig Georg , Schulz Eberhard , Macharzina Roland , Bräsen Jan Hinrich , Skatchkov Mikhail , Heitzer Thomas , Stasch Johannes P. , Griendling Kathy K. , Harrison David G. , Böhm Michael , Meinertz Thomas , Münzel Thomas
Published: June 2012

Background
—Angiotensin II activates NAD(P)H-dependent oxidases via AT
1
-receptor stimulation, the most important vascular source of superoxide (O
2
·
−
). The AT
1
receptor is upregulated in vitro by low-density lipoprotein. The present study was designed to test whether hypercholesterolemia is associated with increased NAD(P)H-dependent vascular O
2
·
−
production and whether AT
1
-receptor blockade may inhibit this oxidase and in parallel improve endothelial dysfunction.

Methods and Results
—Vascular responses were determined by isometric tension studies, and relative rates of vascular O
2
·
−
production were determined by use of chemiluminescence with lucigenin, a cypridina luciferin analogue, and electron spin resonance studies. AT
1
-receptor mRNA was quantified by Northern analysis, and AT
1
-receptor density was measured by radioligand binding assays. Hypercholesterolemia was associated with impaired endothelium-dependent vasodilation and increased O
2
·
−
production in intact vessels. In vessel homogenates, we found a significant activation of NADH-driven O
2
·
−
production in both models of hyperlipidemia. Treatment of cholesterol-fed animals with the AT
1
-receptor antagonist Bay 10-6734 improved endothelial dysfunction, normalized vascular O
2
·
−
and NADH-oxidase activity, decreased macrophage infiltration, and reduced early plaque formation. In the setting of hypercholesterolemia, the aortic AT
1
receptor mRNA was upregulated to 166±11%, accompanied by a comparable increase in AT
1
-receptor density.

Conclusions
—Hypercholesterolemia is associated with AT
1
-receptor upregulation, endothelial dysfunction, and increased NADH-dependent vascular O
2
·
−
production. The improvement of endothelial dysfunction, inhibition of the oxidase, and reduction of early plaque formation by an AT
1
-receptor antagonist suggests a crucial role of angiotensin II–mediated O
2
·
−
production in the early stage of atherosclerosis.
Mechanisms of Retarded Apical Filling in Acute Ischemic Left Ventricular Failure
Authors: Steine Kjetil , Stugaard Marie , Smiseth Otto A.
Published: June 2012

Background
—We examined the hypothesis that retardation of apical filling as measured by color M-mode Doppler echocardiography in the diseased left ventricle (LV) reflects a decrease in the intraventricular mitral-to-apical pressure gradient.

Methods and Results
—In 9 open-chest anesthetized dogs, micromanometers were placed near the mitral tip and in the apical region. From the color M-mode Doppler images, the time delay (TD) between peak velocity at the mitral tip and the apical region was determined as an index of LV flow propagation. Acute ischemic LV failure was induced by coronary microembolization. Induction of ischemia caused a marked increase in LV end-diastolic pressure and a decrease in LV ejection fraction. The time constant of LV isovolumic apical pressure decay (τ) increased from 31±8 to 49±16 ms (
P
<0.001). The peak early diastolic mitral-to-apical pressure gradient (ΔPLV
mitral-apex
) decreased from 1.9±0.9 to 0.7±0.5 mm Hg (
P
<0.01), and TD increased from 5±3 to 57±26 ms (
P
<0.001). The slowing of flow propagation was limited to the apical portion of the LV cavity. The TD correlated with ΔPLV
mitral-apex
(
r
=−0.94,
P
<0.01) and with τ (
r
=0.92,
P
<0.01). Before ischemia, the mitral-to-apical flow propagation velocity far exceeded the velocity of the individual blood cells, whereas during ischemia, flow propagation velocity approximated the blood velocity.

Conclusions
—Retardation of apical filling in acute ischemic failure was attributed to a decrease in the mitral-to-apical driving pressure, reflecting slowing of LV relaxation. The slowing of flow propagation appeared to represent a shift in apical filling from a pattern of column motion to a pattern dominated by convection.
Augmented α-Adrenergic Constriction of Atherosclerotic Human Coronary Arteries
Authors: Baumgart Dietrich , Haude Michael , Görge Günter , Liu Fengqi , Ge Junbo , Große-Eggebrecht Claudia , Erbel Raimund , Heusch Gerd
Published: June 2012

Background
—Although adrenergic activation plays a major role in the initiation of experimental myocardial ischemia, the significance of α-adrenergic coronary constriction in humans has been questioned. The present study assessed the impact of selective α-adrenergic receptor activation in patients with normal or atherosclerotic coronary arteries.

Methods and Results
—In 39 patients, coronary blood flow (CBF, mL/min) was determined from combined angiography and Doppler measurements. In 8 patients with normal coronary arteries (group 1) and 9 with single coronary artery stenosis (group 2), doses of 1, 2.5, 5, and 10 mg IC of the α
1
-agonist methoxamine (M) were injected. Identical doses of the α
2
-agonist BHT933 (B) were injected in 8 patients with normal coronary arteries (group 3) and 8 with single stenosis (group 4). In 6 additional patients with single stenosis (group 5), aortocoronary sinus lactate differences were measured in response to M and B. CBF remained unchanged in group 1. In contrast, CBF was decreased dose-dependently in group 2, with a maximum at 10 mg M (39.0±9.4 versus 15.2±7.0). In groups 3 and 4, CBF was also decreased dose-dependently, with a maximum at 10 mg B (63.3±24.8 versus 49.1±27.9 and 41.5±19.0 versus 12.7±8.0, respectively). In group 5, there was more net lactate production with B than with M (−0.34±0.11 versus −0.04±0.09 mmol/L).

Conclusions
—In normal coronary arteries, α
1
-adrenergic activation does not reduce CBF, whereas α
2
-adrenergic activation reduces CBF by microvascular constriction. Both α
1
- and α
2
-adrenergic epicardial and microvascular constriction are augmented by atherosclerosis and can induce myocardial ischemia.
Vascular Endothelin-1 Gene Expression and Synthesis and Effect on Renal Type I Collagen Synthesis and Nephroangiosclerosis During Nitric Oxide Synthase Inhibition in Rats
Authors: Tharaux Pierre-Louis , Chatziantoniou Christos , Casellas Daniel , Fouassier Laura , Ardaillou Raymond , Dussaule Jean-Claude
Published: June 2012

Background
—The progression of hypertension during NO deficiency is associated with renal vascular fibrosis due to increased extracellular matrix (mainly collagen I) formation. The purpose of the present study was to investigate whether endothelin-1 (ET-1) is involved in this pathophysiological process.

Methods and Results
—Treatment of rats for 4 weeks with the NO synthase inhibitor
N
ω
-nitro-
l
-arginine methyl ester (L-NAME) 50 mg · kg
−1
· d
−1
increased systolic blood pressure to 159±12 mm Hg. In animals treated with L-NAME, histological evaluation of renal sections revealed an increased formation of extracellular matrix (Masson’s trichrome), and specifically of collagens (Sirius red). A part of this fibrosis was attributed to abnormal collagen I presence, because mRNA expression of the collagen I α1 chain (reverse transcription–polymerase chain reaction) and procollagen I formation (radioimmunoassay) were increased 3- and 2.5-fold, respectively, in the renal resistance vessels of hypertensive animals. In subsequent experiments, we examined whether ET-1 was involved in activation of collagen I formation. mRNA expression (RNase protection assay) of preproET-1 and ET-1 content (radioimmunoassay) were 10-fold and 3-fold increased, respectively, in renal microvessels of rats treated with L-NAME. Interestingly, in these vessels, ET-1 (immunostaining) was colocalized with sudanophilic lesions. Bosentan, an ET receptor antagonist (20 mg · kg
−1
· d
−1
), coadministered with L-NAME canceled the increased mRNA expression and synthesis of collagen I and attenuated the severity of renal vascular lesions without affecting L-NAME–induced high blood pressure.

Conclusions
—These data demonstrate that ET-1 synthesis is increased in renal microvessels when NO production is suppressed. In this model of hypertension, ET-1 is a major activator of collagen I formation in renal resistance vessels and participates in the development of renal fibrosis without affecting systolic blood pressure.
Significance of Late Diastolic Potential Preceding Purkinje Potential in Verapamil-Sensitive Idiopathic Left Ventricular Tachycardia
Authors: Tsuchiya Takeshi , Okumura Ken , Honda Toshihiro , Honda Takashi , Iwasa Atsushi , Yasue Hirofumi , Tabuchi Toshifumi
Published: June 2012

Background
—Verapamil-sensitive idiopathic left ventricular tachycardia (VT) is due to reentry with an excitable gap. A late diastolic potential (LDP) is recorded during endocardial mapping of this VT, but its relation to the reentry circuit and significance in radiofrequency (RF) ablation remain to be elucidated.

Methods and Results
—Sixteen consecutive patients with this specific VT were studied (12 men and 4 women; mean age, 32 years). In all patients, sustained VT was induced and during left ventricular endocardial mapping, LDP preceding Purkinje potential (PP) was recorded at the basal (11 patients), middle (3 patients), or apical septum (2 patients). The area with LDP recording was confined to a small region (0.5 to 1.0 cm
2
) in each patient and was included in the area where PP was recorded (2 to 3 cm
2
). The relative activation times of LDP, PP, and local ventricular potential (V) at the LDP recording site to the onset of QRS complex were −50.4±18.9, −15.2±9.6, and 3.0±13.3 ms, respectively. The earliest ventricular activation site during VT was identified at the posteroapical septum and was more apical in the septum than the region with LDP in every patient. In 9 patients, VT entrainment was done by pacing from the right ventricular outflow tract while recording LDP. During entrainment, LDP was orthodromically captured, and as the pacing rate was increased, the LDP-to-PP interval was prolonged, whereas stimulus-to-LDP and PP-to-V interval were constant. In 3 patients, the pressure applied to the catheter tip at the LDP region resulted in conduction block between LDP and PP and in VT termination. RF energy application at the LDP recording site successfully eliminated VT.

Conclusions
—LDP was suggested to represent the excitation at the entrance to the specialized area with a conduction delay in response to the increase in the rate within the critical slow conduction zone participating in the reentry circuit of this VT. LDP can be a useful marker for successful RF ablation for this VT.
Atrial Pacing Periablation for Prevention of Paroxysmal Atrial Fibrillation
Authors: Gillis Anne M. , Wyse D. George , Connolly Stuart J. , Dubuc Marc , Philippon François , Yee Raymond , Lacombe Pierre , Rose M. Sarah , Kerr Charles D.
Published: June 2012

Background
—This study tested the hypothesis that rate-adaptive atrial pacing would prevent paroxysmal atrial fibrillation (PAF) in patients with frequent PAF in the absence of symptomatic bradycardia.

Methods and Results
—Patients (n=97) with antiarrhythmic drug-refractory PAF received a Medtronic Thera DR pacemaker 3 months before planned AV node ablation. Patients were randomized to no pacing (n=48) or to atrial rate-adaptive pacing (n=49). After a 2-week stabilization period, patients were followed up for an additional 10 weeks. The time to first recurrence of sustained PAF, the interval between successive episodes of PAF, and the frequency of PAF were compared between the 2 groups in intention-to-treat analysis. Time to first episode of sustained PAF was similar in the no-pacing (4.2 days; 95% CI, 1.8 to 9.5) and the atrial-pacing (1.9 days; 95% CI, 0.8 to 4.6;
P
=NS) groups. PAF burden was lower in the no-pacing (0.24 h/d; 95% CI, 0.10 to 0.56) than in the atrial-pacing (0.67 h/d; 95% CI, 0.30 to 1.52;
P
=0.08) group. Paired crossover analysis in 11 patients revealed that time to first PAF was shorter during atrial pacing (1.6 days; 95% CI, 0.6 to 4.9) than with no pacing (6.0 days; 95% CI, 2.4 to 15.0;
P
=0.13), and PAF burden was greater during atrial pacing (1.00 h/d; 95% CI, 0.35 to 2.91) than with no pacing (0.32 h/d; 95% CI, 0.09 to 1.13;
P
<0.016).

Conclusions
—Atrial rate-adaptive pacing does not prevent PAF over the short term in patients with antiarrhythmic drug-resistant PAF without symptomatic bradycardia.
Doppler-Derived Mitral Deceleration Time
Authors: Cerisano Giampaolo , Bolognese Leonardo , Carrabba Nazario , Buonamici Piergiovanni , Santoro Giovanni Maria , Antoniucci David , Santini Alberto , Moschi Guia , Fazzini Pier Filippo
Published: June 2012

Background
—The relation between remodeling and left ventricular (LV) diastolic function has not yet been fully investigated. The aim of this study was to determine whether early assessment of Doppler-derived mitral deceleration time (DT), a measure of LV compliance and filling, may predict progressive LV dilation after acute myocardial infarction (AMI).

Methods and Results
—Fifty-one patients (aged 61±11 years; 6 women) with anterior AMI successfully treated with direct coronary angioplasty underwent 2-dimensional and Doppler echocardiographic examinations within 24 hours of admission, at days 3, 7, and 30 and 6 months after the index infarction. Mitral flow velocities were obtained from the apical 4-chamber view with pulsed Doppler. End-diastolic volume index (EDVI) and end-systolic volume index (ESVI) were calculated with the Simpson’s rule algorithm. Patients were divided according to the DT duration assessed at day 3 in 2 groups: group 1 (n=33) with DT >130 ms and group 2 (n=18) with DT ≤130 ms. Patency and restenosis rate at 6 months were similar between the 2 groups (94% group 1 vs 89% group 2;
P
=0.52; 27% group 1 vs 33% group 2;
P
=0.64, respectively). LV volume indexes were similar in both groups at baseline (EDVI: 71±3 group 1 vs 70±3 mL/m
2
group 2,
P
=0.42; ESVI: 43±3 group 1 vs 48±3 mL/m
2
group 2,
P
=0.13, respectively). From day 3 on, LV volume indexes progressively increased in group 2 and were significantly larger than those of group 1 at 6 months (LVEDVI 61±3 group 1 vs 104±6 mL/m
2
group 2,
P
=0.00001; LVESVI 31±3 group 1 vs 73±6 mL/m
2
group 2,
P
=0.00001, respectively). A significant inverse correlation was found between DT and changes in EDVI at 6 months (
r
=−0.68;
P
<0.0000001). By stepwise multiple regression analysis among several clinical, demographic, angiographic, and echocardiographic variables, DT was the most powerful predictor of EDVI changes at 6 months (
P
=0.02).

Conclusions
—These data suggest that early estimation (day 3) of Doppler-derived mitral DT provides a simple and accurate mean to predict late LV dilation after reperfused AMI.
Unique Cardioprotective Action of the New Calcium Antagonist Mibefradil
Authors: Schulz Rainer , Post Heiner , Jalowy Andreas , Backenköhler Ulrich , Dörge Hilmar , Vahlhaus Christian , Heusch Gerd
Published: June 2012

Background
—Mibefradil is a calcium antagonist with few negative inotropic effects at therapeutic concentrations.

Methods and Results
—The effect of mibefradil on infarct size (IS) was compared with those of placebo, amlodipine, and verapamil in 64 anesthetized pigs. In placebo pigs, after 90 minutes of ischemia and 120 minutes of reperfusion, IS (by triphenyl tetrazolium chloride staining) was 15.3±10.8% (SD) of the area at risk. Mibefradil (0.60 mg/kg IV) reduced heart rate and left ventricular (LV) pressure, and IS was 1.9±3.9% (
P
<0.05 versus placebo). Verapamil (0.15 mg/kg IV) also decreased heart rate, LV pressure, and IS (6.1±4.2%,
P
<0.05 versus placebo). Amlodipine (0.20 mg/kg IV) did not alter heart rate, LV pressure, or IS (9.9±5.4%,
P
=NS versus placebo). When heart rate was maintained constant by left atrial pacing and LV pressure was adjusted to that of the placebo group by an intra-aortic balloon, mibefradil still decreased IS (3.8±3.0%,
P
<0.05 versus placebo), but verapamil did not (11.6±8.3%,
P
=NS versus placebo). With glibenclamide infusion, mibefradil no longer reduced IS (13.1±4.3% versus 17.8±5.6% with glibenclamide alone,
P
=NS).

Conclusions
—The IS-limiting effect of mibefradil, in contrast to that of verapamil, was not dependent on favorable hemodynamics but was abolished by glibenclamide, suggesting a direct cardioprotective action of mibefradil.
Hyperkalemia Enhances the Effect of Adenosine on I
K,ADO
in Rabbit Isolated AV Nodal Myocytes and on AV Nodal Conduction in Guinea Pig Isolated Heart
Authors: Martynyuk Anatoly E. , Morey Timothy E. , Belardinelli Luiz , Dennis Donn M.
Published: June 2012

Background
—The atrioventricular (AV) node is insensitive to changes in extracellular potassium concentration, [K
+
]
o
, because of the absence of the inward rectifier potassium current (I
K1
). However, we propose that in the presence of adenosine, elevated [K
+
]
o
should increase the adenosine-activated inward rectifier potassium current (I
K,ADO
) in AV nodal myocytes and hence augment the negative dromotropic effect of the nucleoside.

Methods and Results
—The effects of normal (4.8 mmol/L) and high (8.0 mmol/L) [K
+
]
o
on adenosine-induced changes in resting membrane potential (V
m
), I
K,ADO
, and membrane resistance (R
m
) in rabbit isolated AV nodal myocytes and in AV nodal conduction delay (atrium-to-His bundle, AH, interval) in guinea pig isolated hearts were determined with the use of whole-cell patch-clamp and His bundle electrogram techniques, respectively. High [K
+
]
o
alone did not significantly affect membrane current, R
m
, or V
m
in AV nodal myocytes. However, high [K
+
]
o
in the presence of adenosine (3 μmol/L) markedly increased I
m
(−0.249±0.038 to −0.571±0.111 nA,
P
<0.05) at −100 mV and reduced R
m
(151±21 to 77±8 MΩ,
P
<0.02). Adenosine still hyperpolarized V
m
from −48±2 to −65±1 mV (
P
<0.001). High [K
+
]
o
alone did not significantly affect the AH interval in isolated hearts. However, high [K
+
]
o
markedly lengthened the AH interval prolongation caused by adenosine (4 μmol/L, 7.9±0.8 vs 22.1±3.0 ms,
P
<0.001). The potentiating effect of high [K
+
]
o
on adenosine-induced delay in AV nodal conduction was abolished by BaCl
2
(100 μmol/L).

Conclusions
—By increasing I
K,ADO
and decreasing R
m
of AV nodal myocytes, elevated [K
+
]
o
, augments the depressant effect of adenosine on AV nodal conduction.
Ultrasound Enhances Reporter Gene Expression After Transfection of Vascular Cells In Vitro
Authors: Lawrie Allan , Brisken Axel F. , Francis Sheila E. , Tayler David I. , Chamberlain Janet , Crossman David C. , Cumberland David C. , Newman Christopher M.
Published: June 2012

Background
—Restenosis after percutaneous coronary intervention remains a serious clinical problem. Progress in local gene therapy to prevent restenosis has been hindered by concerns over the safety and efficacy of viral vectors and the limited efficiency of nonviral techniques. This study investigates the use of adjunctive ultrasound to enhance nonviral gene delivery.

Methods and Results
—Cultured porcine vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) were transfected with naked or liposome-complexed luciferase reporter plasmid for 3 hours. Ultrasound exposure (USE) for 60 seconds at 1 MHz, 0.4 W/cm
2
, 30 minutes into this transfection period enhanced luciferase activity 48 hours later by 7.5-fold and 2.4-fold, respectively. Luciferase activity after lipofection of ECs was similarly enhanced 3.3-fold by adjunctive USE. USE had no effect on cell viability, although it inhibited VSMC but not EC proliferation.

Conclusions
—Adjunctive USE was associated with enhanced transgene expression in VSMCs and ECs and reduced VSMC but not EC proliferation in vitro, which suggests that ultrasound-assisted local gene therapy has potential as an antirestenotic therapy.
Intravascular Ultrasound Evidence for Coarctation Causing Symptomatic Renal Artery Stenosis
Authors: Leertouwer Trude C. , Gussenhoven Elma J. , van Dijk Lukas C. , van Essen Jeroen A. , Honkoop Jan , Deinum Jaap , Pattynama Peter M. T.
Published: June 2012

Background
—A recent study of human cadaveric renal arteries revealed that renal artery narrowing could be due not only to atherosclerotic plaque compensated for by adaptive remodeling, but also to hitherto undescribed focal narrowing of an otherwise normal renal arterial wall (ie, coarctation). The present study investigated whether vessel coarctation could be identified in patients with symptomatic renal artery stenosis (RAS).

Methods and Results
—Consecutive symptomatic patients with angiographically proven atherosclerotic RAS who were referred for stent placement were studied by 30-MHz intravascular ultrasound before intervention (n=18) or after predilatation (n=18). Analysis included assessment of the media-bounded area and plaque area (PLA) at the most stenotic site and at a distal reference site (most distal cross-section in the main renal artery with normal appearance). Coarctation was considered present whenever the target/reference media-bounded area was ≤85%. Before intervention, coarctation was observed in 9 of 18 patients and adaptive remodeling in 9 of 18 patients. Coarctation lesions had a significantly smaller PLA than adaptive remodeled lesions (
P
=0.001). Similarly, despite predilatation, coarctation was seen in 8 of 18 patients who had significantly smaller PLAs (
P
=0.008) when compared with those patients who had adaptive remodeled lesions. No differences in severity of RAS or angiographic or clinical parameters were observed.

Conclusions
—Low-plaque coarctation may cause a considerable proportion of symptomatic RAS, which is angiographically and clinically indistinguishable from plaque-rich RAS.
Comparing AMI Mortality Among Hospitals in Patients 65 Years of Age and Older
Authors: Krumholz Harlan M. , Chen Jersey , Wang Yongfei , Radford Martha J. , Chen Ya-Ting , Marciniak Thomas A.
Published: June 2012

Background
—Interest in the reporting of risk-adjusted outcomes for patients with acute myocardial infarction is growing. A useful risk-adjustment model must balance parsimony and ease of data collection with predictive ability.

Methods and Results
—From our analysis of 82 359 patients ≥65 years of age admitted with acute myocardial infarction to 2401 hospitals, we derived a parsimonious model that predicts 30-day mortality. The model was validated on a similar group of 78 699 patients from 2386 hospitals. Of the 73 candidate predictor variables examined, 7 variables describing patient characteristics on arrival were selected for inclusion in the final model: age, cardiac arrest, anterior or lateral location of myocardial infarction, systolic blood pressure, white blood cell count, serum creatinine, and congestive heart failure. The area under the receiver-operating characteristic curve for the final model was 0.77 in the derivation cohort and 0.77 in the validation cohort. The rankings of hospitals by performance (in deciles) with this model were most similar to a comprehensive 27-variable model based on medical chart review and least similar to models based on administrative billing codes.

Conclusions
—A simple 7-variable risk model performs as well as more complex models in comparing hospital outcomes for acute myocardial infarction. Although there is a continuing need to improve methods of risk adjustment, our results provide a basis for hospitals to develop a simple approach to compare outcomes.
Plasminogen Activator Inhibitor-1 Is a Major Determinant of Arterial Thrombolysis Resistance
Authors: Zhu Yanhong , Carmeliet Peter , Fay William P.
Published: June 2012

Background
—Platelet-rich thrombi are resistant to lysis by tissue plasminogen activator (tPA). Plasminogen activator inhibitor-1 (PAI-1), a rapid inhibitor of tPA, may contribute to arterial thrombolysis resistance. However, few data are available regarding the effect of PAI-1 on arterial thrombolysis in animals. We used a murine carotid injury model to test the hypothesis that PAI-1 inhibits thrombolysis mediated by pharmacological concentrations of tPA.

Methods and Results
—Platelet-rich thrombi were induced in wild-type mice (
PAI-1
+/+; n=11) and PAI-1–deficient mice (
PAI-1
−/−; n=11) with ferric chloride. Baseline carotid blood flows and mean occlusion times did not differ between
PAI-1
+/+ and
PAI-1
−/− mice. Clot lysis was induced by infusion of heparin (200 U/kg bolus, 70 U · kg
−1
· h
−1
drip), human plasminogen (50 mg/kg), and tPA at 20 (n=10) or 100 (n=12) μg · kg
−1
· min
−1
. Mean plasma tPA antigens were 2.7 μg/mL (tPA infusion, 20 μg · kg
−1
· min
−1
) and 5.5 μg/mL (tPA infusion, 100 μg · kg
−1
· min
−1
), with no significant differences between
PAI-1
+/+ mice and
PAI-1
−/− mice. Reperfusion after tPA 20 μg · kg
−1
· min
−1
occurred in 1 of 5
PAI-1
+/+ mice versus 5 of 5
PAI-1
−/− mice (
P
=0.0006). Reperfusion occurred in all mice that received tPA 100 μg · kg
−1
· min
−1
, but reperfusion times were significantly shorter in
PAI-1
−/− mice (17.8±2.6 minutes, n=6) than in
PAI-1
+/+ mice (35.7±5.1 minute, n=6;
P
=0.01). Histological analyses confirmed that carotid thrombi were platelet rich and that PAI-1 was distributed uniformly throughout thrombi from
PAI-1
+/+ mice. Lysates of
PAI-1
+/+ platelets inhibited human tPA, whereas
PAI-1
−/− platelet lysates did not.

Conclusions
—PAI-1 is a major determinant of the resistance of platelet-rich arterial thrombi to lysis by pharmacological concentrations of tPA. Strategies to inhibit or resist PAI-1 may enhance thrombolysis.
Iron-Dependent Human Platelet Activation and Hydroxyl Radical Formation
Authors: Praticò Domenico , Pasin Mehtap , Barry Orla P. , Ghiselli Andrea , Sabatino Giuseppe , Iuliano Luigi , FitzGerald Garret A. , Violi Francesco
Published: June 2012

Background
—Iron is an important modulator of lipid peroxidation, and its levels have been associated with the progression of atherosclerosis. Little is known about the possibility that this metal, when released from tissue stores, may modulate the reactivity of blood cell components, in particular platelets. Therefore, we investigated a possible link between iron, oxygen free radical formation, and platelet function.

Methods and Results
—Human whole blood was stimulated with collagen 2 μg/mL, and an irreversible aggregation with thromboxane (Tx)B
2
formation was observed (15±4 versus 130±10 ng/mL). Deferoxamine (DSF), a specific iron chelator, and catalase, an H
2
O
2
scavenger, inhibited collagen-induced whole-blood aggregation. The aggregation was accompanied by an increase in hydroxyl radical (OH·) levels (30±8 versus 205±20 nmol/L dihydroxybenzoates), which were reduced by DSF and by 2 specific OH· scavengers, mannitol and deoxyribose. Iron (Fe
2+
) dose-dependently induced platelet aggregation, TxB
2
formation (6±2 versus 135±8 ng/mL), and protein kinase C (PKC) translocation from the cytosol to the cell membrane when added to platelets that have been primed with a low concentration of collagen (0.2 μg/mL). In the same system, an increase in OH· levels was observed (37±12 versus 230±20 nmol/L dihydroxybenzoates). Mannitol and deoxyribose, but not urea, were able to reduce OH· formation, PKC activation, and platelet aggregation. Selective inhibition of PKC activity by GF 109203X prevented iron-dependent platelet aggregation without influencing OH· production.

Conclusions
—The present study shows that iron can directly interact with human platelets, resulting in their activation. Its action is mediated by OH· formation and involves PKC activity. Our findings provide an additional contribution to the understanding of the mechanism(s) by which iron overload might promote atherosclerosis and coronary artery disease.
Congenital Long-QT Syndrome Caused by a Novel Mutation in a Conserved Acidic Domain of the Cardiac Na
+
Channel
Authors: Wei Jian , Wang Dao W. , Alings Marco , Fish Frank , Wathen Mark , Roden Dan M. , George Alfred L.
Published: June 2012

Background
—Congenital long-QT syndrome (LQTS) is an inherited condition of abnormal cardiac excitability characterized clinically by an increased risk of ventricular tachyarrhythmias. One form, LQT3, is caused by mutations in the cardiac voltage–dependent sodium channel gene,
SCN5A
. Only 5
SCN5A
mutations have been associated with LQTS, and more work is needed to improve correlations between
SCN5A
genotypes and associated clinical syndromes.

Methods and Results
—We researched a 3-generation white family with autosomal dominant LQTS who exhibited a wide clinical spectrum from mild bradycardia to sudden death. Molecular genetic studies revealed a single nucleotide substitution in
SCN5A
exon 28 that caused the substitution of Glu1784 by Lys (E1784K). The mutation occurs in a highly conserved domain within the C-terminus of the cardiac sodium channel containing multiple, negatively charged amino acids. Two-electrode voltage-clamp recordings of a recombinant E1784K mutant channel expressed in
Xenopus
oocytes revealed a defect in fast inactivation characterized by a small, persistent current during long membrane depolarizations. Coexpression of the mutant with the human sodium channel β
1
-subunit did not affect the persistent current, even though we did observe shifts in the voltage dependence of steady-state inactivation. Neutralizing multiple, negatively charged residues in the same region of the sodium channel C-terminus did not cause a more severe functional defect.

Conclusions
—We characterized the genetics and molecular pathophysiology of a novel
SCN5A
sodium channel mutation, E1784K. The functional defect exhibited by the mutant channel causes delayed myocardial repolarization, and our data on the effects of multiple charge neutralizations in this region of the C-terminus suggest that the molecular mechanism of channel dysfunction involves an allosteric rather than a direct effect on channel gating.
Isoproterenol to Evaluate Resumption of Conduction After Right Atrial Isthmus Ablation in Type I Atrial Flutter
Authors: Nabar Ashish , Rodriguez Luz-Maria , Timmermans Carl , Smeets Joep L. R. M. , Wellens Hein J. J.
Published: June 2012

Background
—After radiofrequency (RF) ablation of atrial flutter (AFL), the demonstration of bidirectional isthmus conduction (BIC) block is considered the hallmark of a successful procedure. The purpose of our study was to test the persistence of BIC block after isoproterenol administration and to evaluate the importance of this finding with regard to AFL recurrences.

Methods and Results
—RF ablation of AFL was performed in 44 consecutive patients with type I AFL by linear ablation of the posterior isthmus (n=29 patients), septal isthmus (n=4 patients), or both right atrial (RA) isthmi (n=11 patients). The procedural end point was complete BIC block and noninducibility of AFL. In case of noninducibility and apparent BIC block, the pacing protocol was repeated under isoproterenol infusion (1 to 3 μg/min). Reversal of apparent BIC block occurred in 7 (15.9%) of 44 patients. Six patients had bidirectional and 1 had unidirectional resumption of isthmus conduction. Counterclockwise AFL could be reinduced in 4 of these patients. Two to 24 (median, 4) additional RF applications were required to achieve permanent BIC block. At a mean follow-up of 7.3±7.6 months (range, 2 to 31 months), 2 (4.5%) of 44 patients had AFL recurrences.

Conclusions
—Partial linear RF ablation could possibly aggravate preexisting nonuniform anisotropic conduction in the RA isthmus, resulting in profound conduction slowing and apparent BIC block. Isoproterenol can unmask apparent BIC block, thus providing an opportunity to assess the possibility of reversal of BIC block and completeness of isthmus ablation during the same procedure. The low incidence (4.5%) of AFL recurrences at follow-up suggests that noninducibility and BIC block under isoproterenol infusion may be a better end point for successful AFL ablation.
Shed Membrane Microparticles With Procoagulant Potential in Human Atherosclerotic Plaques
Authors: Mallat Ziad , Hugel Bénédicte , Ohan Jeanny , Lesèche Guy , Freyssinet Jean-Marie , Tedgui Alain
Published: June 2012

Background
—The specific role of apoptosis in human atherosclerosis remains unknown. During apoptotic cell death, phosphatidylserine exposure on the cell surface confers a high tissue-factor (TF)–dependent procoagulant activity.

Methods and Results
—In this study, we examined the role of apoptotic cell death in the promotion of plaque thrombogenicity. TF expression and its relation to apoptosis was analyzed in 16 human atherosclerotic plaques by the use of immunohistochemical techniques. The presence of shed membrane apoptotic microparticles was analyzed in extracts from 6 human atherosclerotic plaques and 3 underlying arterial walls. The microparticles were captured by annexin V and their amounts estimated with respect to their phospholipid content by use of a prothrombinase assay. The prothrombogenic potential of the microparticles was further assessed by the measurement of total and microparticle-dependent TF activity in the extracts. The cell origin of the microparticles was determined after capture by specific antibodies. We were able to detect marked TF expression in the plaques in close proximity to apoptotic cells and debris, suggesting a potential interaction between TF and the apoptotic cell surfaces. High levels of shed membrane apoptotic microparticles were detected in extracts from atherosclerotic plaques but not in the underlying arterial walls (29.5±3.7 nmol/L phosphatidylserine equivalent versus 1.3±0.4 nmol/L, respectively,
P
<0.02). The microparticles were mainly of monocytic and lymphocytic origin and retained 97±2% of total TF activity, indicating a direct causal relationship between shed membrane microparticles and procoagulant activity of plaque extracts.

Conclusions
—These results indicate that shed membrane microparticles with procoagulant potential are produced in human atherosclerotic plaques. Apoptosis could be a critical determinant of plaque thrombogenicity after plaque rupture.