bluuebunny/crossref_metadata_2025 huggingface dataset:
1,25-Dihydroxyvitamin D
3
Increases In Vitro Vascular Calcification by Modulating Secretion of Endogenous Parathyroid Hormone–Related Peptide
Authors: Jono Shuichi , Nishizawa Yoshiki , Shioi Atsushi , Morii Hirotoshi
Published: June 2012

Background
—A significant association between vascular calcification and osteoporosis has been noted, suggesting that calcium homeostasis is important in vascular calcification as well as in osteoporosis. Moreover, results of our previous studies suggest that calcium-regulating hormones such as parathyroid hormone–related peptide (PTHrP) may modulate vascular calcification. Therefore, we hypothesized that 1α,25-dihydroxyvitamin D
3
[1,25(OH)
2
D
3
] may have a direct impact on the calcium-regulating system of vascular smooth muscle cells, resulting in deposition of calcium in vascular wall.

Methods and Results
—We investigated the effect of 1,25(OH)
2
D
3
on in vitro calcification by bovine vascular smooth muscle cells (BVSMCs). 1,25(OH)
2
D
3
dose dependently increased BVSMC calcification and alkaline phosphatase activity. 1,25(OH)
2
D
3
also decreased secretion of PTHrP by BVSMCs in a dose-dependent manner and depressed its gene expression. Furthermore, exogenous PTHrP (fragment 1-34) antagonized the stimulatory effect of 1,25(OH)
2
D
3
on BVSMCs. Finally, 1,25(OH)
2
D
3
dose dependently increased the expression of the osteopontin gene, one of the bone matrix proteins in BVSMCs, contributing to its stimulatory action on BVSMC calcification.

Conclusions
—These data suggest that 1,25(OH)
2
D
3
exerts a stimulatory effect on vascular calcification through direct inhibition of the expression of PTHrP in BVSMCs as an endogenous inhibitor of vascular calcification. Moreover, the stimulatory effects of 1,25(OH)
2
D
3
on alkaline phosphatase activity and osteopontin expression may contribute to its promoting action in vascular calcification.
Reduction of Recurrent Ischemia With Abciximab During Continuous ECG-Ischemia Monitoring in Patients With Unstable Angina Refractory to Standard Treatment (CAPTURE)
Authors: Klootwijk Peter , Meij Simon , Melkert Rein , Lenderink Timo , Simoons Maarten L.
Published: June 2012

Background
—In the CAPTURE (c7E3 Fab Anti Platelet Therapy in Unstable REfractory angina) trial, 1265 patients with refractory unstable angina were treated with abciximab or placebo, in addition to standard treatment from 16 to 24 hours preceding coronary intervention through 1 hour after intervention. To investigate the incidence of recurrent ischemia and the ischemic burden, a subset of 332 patients (26%) underwent continuous vector-derived 12-lead ECG-ischemia monitoring.

Methods and Results
—Patients were monitored from start of treatment through 6 hours after coronary intervention. Ischemic episodes were detected in 31 (18%) of the 169 abciximab and in 37 (23%) of the 163 placebo patients (NS). Only 9 (5%) of abciximab versus 22 (14%) of placebo patients had ≥2 ST episodes (
P
<0.01). In patients with ischemia, abciximab significantly reduced total ischemic burden (
P
<0.02), which was calculated alternatively as the total duration of ST episodes per patient, the area under the curve of the ST vector magnitude during episodes, or the sum of the areas under the curves of 12 leads during episodes. Twenty-one patients (6%) suffered a myocardial infarction (MI) (18) or died (3) within 5 days of treatment. The presence of asymptomatic and symptomatic ST episodes during the monitoring period preceding coronary intervention was associated with an increased relative risk of these events of 3.2 (95% CI 1.4, 7.4) and 4.1 (95% CI 1.4, 12.2), respectively.

Conclusions
—Recurrent ischemia predicts MI or death within 5 days of follow-up. Treatment with abciximab is associated with a reduction of frequent ischemia and a reduction of total ischemic burden in patients with refractory unstable angina. As such, patients with ischemia derive particularly high benefit from abciximab.
Dysfunctional Voltage-Gated K
+
Channels in Pulmonary Artery Smooth Muscle Cells of Patients With Primary Pulmonary Hypertension
Authors: Yuan Jason Xiao-Jian , Aldinger Ann M. , Juhaszova Magdalena , Wang Jian , Conte John V. , Gaine Sean P. , Orens Jonathan B. , Rubin Lewis J.
Published: June 2012

Background
—Primary pulmonary hypertension (PPH) is a rare disease of unknown cause. Although PPH and secondary pulmonary hypertension (SPH) share many clinical and pathological characteristics, their origins may be disparate. In pulmonary artery smooth muscle cells (PASMCs), the activity of voltage-gated K
+
(K
V
) channels governs membrane potential (E
m
) and regulates cytosolic free Ca
2+
concentration ([Ca
2+
]
cyt
). A rise in [Ca
2+
]
cyt
is a trigger of vasoconstriction and a stimulus of smooth muscle proliferation.

Methods and Results
—Fluorescence microscopy and patch clamp techniques were used to measure [Ca
2+
]
cyt
, E
m
, and K
V
currents in PASMCs. Mean pulmonary arterial pressures were comparable (46±4 and 53±4 mm Hg;
P
=0.30) in SPH and PPH patients. However, PPH-PASMCs had a higher resting [Ca
2+
]
cyt
than cells from patients with SPH and nonpulmonary hypertension disease. Consistently, PPH-PASMCs had a more depolarized E
m
than SPH-PASMCs. Furthermore, K
V
currents were significantly diminished in PPH-PASMCs. Because of the dysfunctional K
V
channels, the response of [Ca
2+
]
cyt
to the K
V
channel blocker 4-aminopyridine was significantly attenuated in PPH-PASMCs, whereas the response to 60 mmol/L K
+
was comparable to that in SPH-PASMCs.

Conclusions
—These results indicate that K
V
channel function in PPH-PASMCs is inhibited compared with SPH-PASMCs. The resulting membrane depolarization and increase in [Ca
2+
]
cyt
lead to pulmonary vasoconstriction and PASMC proliferation. Our data suggest that defects in PASMC K
V
channels in PPH patients may be a unique mechanism involved in initiating and maintaining pulmonary vasoconstriction and appear to play a role in the pathogenesis of PPH.
“Apoptotic” Myocytes in Infarct Area in Rabbit Hearts May Be Oncotic Myocytes With DNA Fragmentation
Authors: Ohno Michiya , Takemura Genzou , Ohno Atsuko , Misao Jun , Hayakawa Yukihiro , Minatoguchi Shinya , Fujiwara Takako , Fujiwara Hisayoshi
Published: June 2012

Background
—Modes of cell death have been defined morphologically as apoptosis and oncosis. Infarcted myocytes have been reported to show apoptosis, as revealed by DNA fragmentation by DNA ladder and by in situ terminal deoxynucleotidyl transferase–mediated dUTP nick end-labeling (TUNEL) at the light microscopic level. We investigated whether TUNEL-positive infarcted myocytes have apoptotic or oncotic ultrastructures by using electron microscopic TUNEL, which can simultaneously observe the ultrastructure and DNA fragmentation of the same myocytes.

Methods and Results
—Thirty rabbits were divided into 5 groups (n=6 each) that were subjected to a sham operation or to 30-minute ischemia followed by 0-minute, 30-minute, 2-hour, or 4-hour reperfusion of a coronary artery. In the 2- and 4-hour reperfusion groups only, DNA electrophoresis showed a ladder pattern, and the light microscopic TUNEL finding was positive in the nuclei of myocytes localized in the infarcted area (6±2% and 11±3%, respectively). Electron microscopic TUNEL showed that nuclei with a significant accumulation of immunogold particles (indicating an electronic microscopic TUNEL–positive result) were observed only in the infarcted myocytes with irreversibly oncotic ultrastructures that were found in the hearts of the 2- and 4-hour reperfusion groups (41±3% and 83±4%, respectively). Irreversibly oncotic myocytes (indicated by swelling, inhomogeneously clumped chromatin in nuclei, dense bodies in mitochondria, and/or ruptured plasma membranes) were also seen in the 0- and 30-minute reperfusion groups, which did not exhibit TUNEL-positive myocytes. There was no evidence of apoptotic ultrastructures in the myocytes.

Conclusions
—DNA fragmentation occurs in the myocytes that had already shown irreversibly oncotic, but not apoptotic, ultrastructures with ischemia and/or reperfusion. Therefore, DNA fragmentation itself does not always mean apoptosis, and so-called apoptotic infarcted myocytes may belong to a category of cell death other than apoptosis.
Prospective Study of Heart Rate Variability and Mortality in Chronic Heart Failure
Authors: Nolan James , Batin Phillip D. , Andrews Richard , Lindsay Steven J. , Brooksby Paul , Mullen Michael , Baig Wazir , Flapan Andrew D. , Cowley Alan , Prescott Robin J. , Neilson James M.M. , Fox Keith A.A.
Published: June 2012

Background
—Patients with chronic heart failure (CHF) have a continuing high mortality. Autonomic dysfunction may play an important role in the pathophysiology of cardiac death in CHF. UK-HEART examined the value of heart rate variability (HRV) measures as independent predictors of death in CHF.

Methods and Results
—In a prospective study powered for mortality, we recruited 433 outpatients 62±9.6 years old with CHF (NYHA functional class I to III; mean ejection fraction, 0.41±0.17). Time-domain HRV indices and conventional prognostic indicators were related to death by multivariate analysis. During 482±161 days of follow-up, cardiothoracic ratio, SDNN, left ventricular end-systolic diameter, and serum sodium were significant predictors of all-cause mortality. The risk ratio for a 41.2-ms decrease in SDNN was 1.62 (95% CI, 1.16 to 2.44). The annual mortality rate for the study population in SDNN subgroups was 5.5% for >100 ms, 12.7% for 50 to 100 ms, and 51.4% for <50 ms. SDNN, creatinine, and serum sodium were related to progressive heart failure death. Cardiothoracic ratio, left ventricular end-diastolic diameter, the presence of nonsustained ventricular tachycardia, and serum potassium were related to sudden cardiac death. A reduction in SDNN was the most powerful predictor of the risk of death due to progressive heart failure.

Conclusions
—CHF is associated with autonomic dysfunction, which can be quantified by measuring HRV. A reduction in SDNN identifies patients at high risk of death and is a better predictor of death due to progressive heart failure than other conventional clinical measurements. High-risk subgroups identified by this measurement are candidates for additional therapy after prescription of an ACE inhibitor.
Localization of Optimal Ablation Site of Idiopathic Ventricular Tachycardia from Right and Left Ventricular Outflow Tract by Body Surface ECG
Authors: Kamakura Shiro , Shimizu Wataru , Matsuo Kiyotaka , Taguchi Atsushi , Suyama Kazuhiro , Kurita Takashi , Aihara Naohiko , Ohe Tohru , Shimomura Katsuro
Published: June 2012

Background
—Idiopathic ventricular tachycardia (VT) is known to arise from the right ventricular (RV) and left ventricular outflow tracts (LVOT). However, reliable noninvasive methods to localize the optimum ablation site for VT have not been reported.

Methods and Results
—Body surface maps (BSM) and 12-lead ECGs were investigated in 35 VTs from the RVOT and 5 VTs from the LVOT in which the origin was confirmed during the ablation procedure. The RVOT was classified into 8 subdivisions with the use of a 3-dimensional anatomic relation: anterior (A)–posterior (P), right (R)–left (L), and superior (S)–inferior (I). On the BSM, the following 3 indexes differentiated each location of the origin, with a diagnostic accuracy of 88% (A-P), 92% (R-L), and 77% (S-I): (1) the location of the minimum at the early-to-mid QRS (right, A; left, P), (2) the isopotential distribution in the left shoulder area after 30 ms of QRS (positive, R; negative, L), and (3) the downward moving time of the minimum at the early-to-mid QRS (≥50 ms, S; <50 ms, I). On the 12-lead ECG, (1) the QRS duration (>140 ms, A; ≤140 ms, P) and the R-wave pattern in leads II and III (RR’ or Rr’, A, R, P), (2) the QS wave amplitude in aVR and aVL (aVR≥aVL, R; aVR<aVL, L), and (3) the r-wave amplitude in V
1
and V
2
(high, S; low, I) localized the origin with 80%, 86% (A-P), 80% (R-L), and 66% (S-I) accuracy. R/S≥1 in lead V
3
was an index suggesting the LVOT origin.

Conclusions
—The origin or the optimum ablation site of idiopathic VT from RVOT and LVOT can be localized with the use of indexes obtained with a BSM or 12-lead ECG.
Risk to Patients From Radiation Associated With Radiofrequency Ablation for Supraventricular Tachycardia
Authors: Kovoor Pramesh , Ricciardello Michelle , Collins Lee , Uther John B. , Ross David L.
Published: June 2012

Background
—Radiofrequency ablation may be associated with prolonged fluoroscopy times. Previous studies have calculated radiation risks by measuring the radiation dose at a limited number (6) of body sites. This is an inherently inaccurate measure. Our study aimed to quantify more precisely patient-related radiation risks associated with radiofrequency ablation for supraventricular tachycardia.

Methods and Results
—Nine female patients having radiofrequency ablation for supraventricular tachycardia were studied. The radiation dose was determined at 41 body sites in each patient with the use of thermoluminescent dosimeters and was correlated with that measured simultaneously with a Diamentor dose-area product meter. The estimated mean organ doses (mGy) per 60 minutes of fluoroscopy were: lungs 30.8; bone marrow 4.3; left breast 5.1; right breast 3.5; and thyroid 2.4. From the average organ doses, the estimated mean total lifetime excess risk of a fatal malignancy was 294 per million cases (0.03%) per 60 minutes of fluoroscopy. The risk calculation from the Diamentor dose-area product and thermoluminescent dosimeters were similar, suggesting that radiation dose was measured accurately. The estimated risk of radiation-induced malignancy increased with increasing body mass index (
P
=0.03).

Conclusions
—Prolonged fluoroscopy during radiofrequency ablation may potentially cause a small increase in the lifetime risk of fatal malignancy, with lung malignancy being most likely. This risk is small only with the use of techniques and x-ray equipment optimized to keep radiation as low as possible. The risk is increased in obese patients.
Stenting After Optimal Lesion Debulking (SOLD) Registry
Authors: Moussa Issam , Moses Jeffrey , Di Mario Carlo , Busi Giovanna , Reimers Bernhard , Kobayashi Yoshio , Albiero Remo , Ferraro Massimo , Colombo Antonio
Published: June 2012

Background
—Coronary stenting has reduced restenosis in focal de novo lesions, but its impact has been less pronounced in complex lesion subsets. Preliminary data suggest a role for plaque burden in promoting intimal hyperplasia after stent implantation. The aim of this study was to test the hypothesis that plaque removal with directional atherectomy before stent implantation may lower the intensity of late neointimal hyperplasia, reducing the incidence of in-stent restenosis.

Methods and Results
—Seventy-one patients with 90 lesions underwent directional atherectomy before coronary stenting. Intravascular ultrasound–guided stenting was performed in 73 lesions (81%). Clinical success was achieved in 96% of patients. Procedural complications were as follows: emergency bypass surgery in 1 patient (1.4%), who died 2 weeks later; Q-wave myocardial infarction in 2 patients (2.8%); and non–Q-wave myocardial infarction in 8 patients (11.3%). None of the patients had stent thrombosis at follow-up. Angiographic follow-up was performed in 89% of eligible patients at 5.7±1.7 months. Loss index was 0.33 (95% CI, 0.26 to 0.40), and angiographic restenosis was 11% (95% CI, 5% to 20%). Clinical follow-up was performed in all patients at 18±3 months. Target lesion revascularization was 7% (95% CI, 3% to 14%).

Conclusions
—Directional atherectomy followed by coronary stenting could be performed with good clinical success rate. Also, these data point to a possible reduction in angiographic restenosis and a significant reduction in the need for repeated coronary interventions. Therefore, a randomized clinical trial seems appropriate to test the validity of this approach.
Differential Effects of Glycoprotein IIb/IIIa Antagonists on Platelet Microaggregate and Macroaggregate Formation and Effect of Anticoagulant on Antagonist Potency
Authors: Storey R.F. , Wilcox R.G. , Heptinstall S.
Published: June 2012

Background
—Citrated platelet-rich plasma (PRP) turbidimetry is used for assessing pharmacodynamic effects of glycoprotein (GP) IIb/IIIa antagonists in clinical trials. However, citrate can enhance the potency of at least eptifibatide (Integrilin), and turbidimetry is insensitive to microaggregate formation. We compared PRP turbidimetry, as a measure of macroaggregate formation, with single-platelet counting in both whole blood and PRP as a measure of microaggregate formation, using both citrate and hirudin anticoagulation.

Methods and Results
—Three GP IIb/IIIa antagonists, eptifibatide, MK-0852, and GR144053, were compared in PRP (turbidimetry) and whole blood (platelet counting with an Ultra-Flo 100 Platelet Counter), with ADP and collagen used as agonists. Compared with hirudin, citrate enhanced the potency of eptifibatide by up to 4-fold in both PRP and whole blood (
P
<0.0005), modestly enhanced MK-0852 potency (
P
=0.001), and had no effect on GR144053. Potency measured in PRP was 2- to 3-fold greater compared with whole blood for MK-0852 and GR144053 but 3- to 4-fold greater for eptifibatide. Simultaneous turbidimetry and platelet counting performed in PRP indicated that this is because GP IIb/IIIa antagonists are more potent inhibitors of in vitro macroaggregation than microaggregation, this effect being greater for eptifibatide in hirudinized PRP compared with GR144053 (
P
=0.032).

Conclusions
—GP IIb/IIIa antagonist potency is variably enhanced by citrate. Macroaggregation is inhibited more effectively than microaggregation, most markedly in the case of eptifibatide in hirudinized blood. These observations have implications for the interpretation and comparison of pharmacodynamic assays and possibly for the risk/benefit ratio of different agents.
Combined Effect of Age and Right Ventricular Involvement on Acute Inferior Myocardial Infarction Prognosis
Authors: Bueno Héctor , López-Palop Ramón , Pérez-David Esther , García-García Javier , López-Sendón José L. , Delcán Juan L.
Published: June 2012

Background
—In patients with acute inferior myocardial infarction (AIMI), right ventricular involvement (RVI) is one of the strongest predictors of in-hospital death. We hypothesized that the impact of RVI on AIMI prognosis depends on the patient’s age.

Methods and Results
—The in-hospital clinical outcome of 798 consecutive patients admitted to the coronary care unit within 48 hours of symptom onset with AIMI was analyzed according to patient age and to the presence of RVI diagnosed by ECG and/or echocardiographic criteria. The total incidence of RVI was 37%, and it increased as age advanced. Patients with RVI had a significantly higher incidence of major complications (45% versus 19%,
P
<0.0001) and a higher in-hospital mortality rate (22% versus 6%,
P
<0.0001). The prognostic effect of RVI was independent of sex, smoking, diabetes, shock on admission, left ventricular ejection fraction, and reperfusion therapy, all age-dependent predictors. A multivariate analysis showed a significant (
P
=0.03) interaction between age and RVI on AIMI mortality. RVI increased mortality risk only in the oldest patients.

Conclusions
—In patients with AIMI, RVI substantially increases mortality risk in elderly patients, whereas it has a nonsignificant effect in young subjects.
Cardiac Autonomic Patterns Preceding Occasional Vasovagal Reactions in Healthy Humans
Authors: Furlan Raffaello , Piazza Simona , Dell’Orto Simonetta , Barbic Franca , Bianchi Anna , Mainardi Luca , Cerutti Sergio , Pagani Massimo , Malliani Alberto
Published: June 2012

Background
—The wide range of clinical presentation of orthostatic vasovagal syncope suggests different underlying changes in the cardiac autonomic modulation.

Methods and Results
—To evaluate the beat-by-beat modifications in the neural control of heart period preceding a syncopal event, we studied RR interval variability in 22 healthy subjects who experienced fainting for the first time during a 90° head-up tilt and in 22 control subjects by means of time-variant power spectral analysis. Sympathetic and vagal modulations to the sinoatrial node were assessed by the normalized power of the low-frequency (LF, ≈0.1-Hz) and high-frequency (HF, ≈0.25-Hz) oscillatory components of RR variability. When the patients were supine, no differences were observed in the hemodynamic and spectral parameters of the 2 groups. During the tilt procedure, RR, LF
NU
, and HF
NU
(NU=normalized units) values were relatively stable in control subjects. During early tilt (T
1
), subjects with syncope had reduced RR intervals compared with control subjects. In 13 subjects with syncope, RR decreased while LF
NU
and LF/HF increased in the last minute of tilt before syncope (T
2
). Conversely, in the remaining 9 fainters, LF
NU
and LF/HF decreased from T
1
to T
2
and HF
NU
increased slightly.

Conclusions
—Two different patterns may be recognized in the cardiac autonomic changes preceding an occasional vasovagal event, namely, one characterized by a progressive increase of the marker of cardiac sympathetic modulation up to the onset of syncope, the other by a sympathetic inhibition with an impending vagal predominance. The recognition of different pathophysiological mechanisms in fainters may have important therapeutic implications.
Value of Serial Troponin T Measures for Early and Late Risk Stratification in Patients With Acute Coronary Syndromes
Authors: Newby L. Kristin , Christenson Robert H. , Ohman E. Magnus , Armstrong Paul W. , Thompson Trevor D. , Lee Kerry L. , Hamm Christian W. , Katus Hugo A. , Cianciolo Cresha , Granger Christopher B. , Topol Eric J. , Califf Robert M.
Published: June 2012

Background
—The baseline cardiac troponin T (cTnT) level strongly predicts short-term mortality in acute coronary syndromes, but the added value of later measures to predict short- and long-term outcome and in the context of baseline clinical characteristics is unclear.

Methods and Results
—Relations between baseline, peak, and 8- and 16-hour (late) cTnT results and outcomes were assessed in 734 patients in a GUSTO-IIa substudy. Proportional-hazards models assessed the prognostic information gained from late cTnT when added to a mortality model containing the baseline cTnT result and clinical factors. At baseline, 260 patients were cTnT-positive (>0.1 ng/mL), 323 became positive later, and 151 remained negative (≤0.1 ng/mL). Mortality at 30 days was 10% in the baseline-positive group, 5% in late-positive patients, and 0% in negative patients. After adjustment for baseline characteristics, any positive cTnT result predicted 30-day mortality (baseline, χ
2
=8.96,
P
=0.0113; 8-hour, χ
2
=6.51,
P
=0.0107; 16-hour, χ
2
=8.40,
P
=0.0038). Both the 8- and the 16-hour results added to the strength of the baseline result (baseline+8-hour, χ
2
=12.04,
P
=0.0072; baseline+16-hour, χ
2
=13.52,
P
=0.0036). Only age and ST-segment elevation were stronger predictors of 30-day mortality than baseline cTnT; results were similar for prediction of 1-year mortality. Most of the mortality difference between cTnT-positive and -negative patients occurred within the first 30 days.

Conclusions
—The cTnT level is a strong, independent predictor of short-term outcome in acute coronary syndromes. The addition of later samples to a baseline level is useful to evaluate the risk of serious cardiac events.
Cardiovascular Outcome in White-Coat Versus Sustained Mild Hypertension
Authors: Khattar Rajdeep S. , Senior Roxy , Lahiri Avijit
Published: June 2012

Background
—The aim of this study was to compare the risk conferred by white-coat versus sustained mild hypertension for the development of cardiovascular disease.

Methods and Results
—Patients (n=479) who underwent 24-hour intra-arterial ambulatory blood pressure monitoring on the basis of a persistently elevated clinic systolic blood pressure of 140 to 180 mm Hg were followed up for the development of subsequent cardiovascular events during a 9.1±4.2-year period. White-coat hypertension, defined as a clinic systolic blood pressure of 140 to 180 mm Hg associated with a 24-hour ambulatory systolic blood pressure <140 mm Hg and diastolic blood pressure <90 mm Hg, was present in 126 patients, and the remainder had sustained mild hypertension. A subgroup of patients without complications underwent follow-up echocardiography and carotid ultrasound. White-coat hypertensives were younger (44±12 versus 52±10 years, respectively;
P
<0.001) and had a significantly lower incidence of cardiovascular events (1.32 versus 2.56 events per 100 patient-years, respectively;
P
<0.001) than sustained hypertensives. Multivariate analysis revealed age (
P
=0.002), sex (
P
=0.007), race (
P
=0.001), smoking (
P
=0.005), and the presence of white-coat hypertension (hazard ratio, 0.29; 95% CI, 0.09 to 0.90;
P
=0.04) to be independent predictors of subsequent cardiovascular events. Subgroup analysis in patients without complications revealed a lower incidence of left ventricular hypertrophy and lesser degrees of carotid hypertrophy in the white-coat group.

Conclusions
—These findings indicate a relatively benign outcome in white-coat hypertension compared with sustained mild hypertension.
Characteristics and Distribution of M Cells in Arterially Perfused Canine Left Ventricular Wedge Preparations
Authors: Yan Gan-Xin , Shimizu Wataru , Antzelevitch Charles
Published: June 2012

Background
—Much of the characterization of the M cell to date has been accomplished using isolated tissues and cells. This study uses an arterially perfused wedge preparation to examine the characteristics and distribution of M cells within the anterior wall of the canine left ventricle under more physiological conditions.

Methods and Results
—Floating microelectrodes were used to record transmembrane action potentials simultaneously from epicardial, M region, and endocardial or subendocardial Purkinje sites in isolated arterially perfused canine left ventricular wedge preparations. A transmural ECG was recorded concurrently. M cells with the longest action potentials were found in the deep subendocardium in wedge preparations isolated from the anterior wall of the left ventricle. Fairly smooth transitions in action potential duration (APD) were observed except in the region between epicardium and deep subepicardium. Tissue resistivity increased 2.8-fold in this region and much more modestly in the deep subendocardium. Dispersion of APD
90
across the left ventricular wall averaged 51±19 and 64±25 ms at basic cycle lengths of 1000 and 2000 ms, respectively, whereas transmural dispersion of repolarization time was smaller (34±18 and 45±25 ms), owing to the endocardial to epicardial activation sequence.

Conclusions
—We conclude that the qualitative differences between the 3 ventricular cell types previously described in isolated tissues and cells are maintained in intact canine left ventricular wall preparations in which the myocardial cells are electrically well coupled. As anticipated, differences in APD are quantitatively smaller because of electrotonic interactions among the 3 cell types. Our data indicate that transmural dispersion of repolarization is the result of intrinsic differences in APD of cells spanning the ventricular wall as well as a heterogeneous distribution of tissue resistivity across the wall.
Admission to Hospitals With On-Site Cardiac Catheterization Facilities
Authors: Krumholz Harlan M. , Chen Jersey , Murillo Jaime E. , Cohen David J. , Radford Martha J.
Published: June 2012

Background
—Admission to a hospital with a capability for cardiac procedures is associated with a higher likelihood of referral for a cardiac procedure but not with a better short-term clinical outcome. Whether there are differences in long-term mortality and resource consumption is not clear. We sought to determine whether elderly Medicare patients with acute myocardial infarction admitted to hospitals with on-site cardiac catheterization facilities have lower long-term hospital costs and better outcomes than patients admitted to hospitals without such facilities.

Methods and Results
—As part of the Cooperative Cardiovascular Project pilot in Connecticut, we conducted a retrospective cohort study using data from medical charts and administrative files. The study sample included 2521 patients with acute myocardial infarction covered by Medicare from 1992 to 1993. The cardiac catheterization rate was higher in the hospitals with facilities (38.6% versus 26.9%;
P
<0.001), but the revascularization rate was similar (20.5% versus 19.5%) during the initial episode of care and at 3 years (29.7% versus 29.7%). Mortality rates were similar for patients admitted to the 2 types of hospitals at 30 days (OR, 1.08; 95% CI, 0.83 to 1.42) and at 3 years (OR, 1.02; 95% CI, 0.83 to 1.26). The adjusted readmission rates were significantly lower among patients admitted to hospitals with cardiac catheterization facilities (OR, 0.76; 95% CI, 0.61 to 0.94). However, the overall mean days in the hospital for the 3 years after admission was 25.9 for patients admitted to hospitals with facilities and 24.6 for the other patients (
P
=0.234). Adjusting for baseline patient characteristics, there was no significant difference in the 3-year costs between patients admitted to the 2 types of hospitals.

Conclusions
—With higher rates of cardiac catheterization and lower readmission rates, patients admitted to hospitals with on-site cardiac catheterization facilities did not have significantly different hospital costs compared with patients admitted to hospitals without these facilities. There was also no significant difference in short- or long-term mortality rates.
Ovarian Ablation Alone Promotes Aortic Intimal Hyperplasia and Accumulation of Fibroblast Growth Factor
Authors: Selzman Craig H. , Gaynor Jaime S. , Turner A. Simon , Johnson Sylene M. , Horwitz Lawrence D. , Whitehill Thomas A. , Harken Alden H.
Published: June 2012

Background
—Estrogen-mediated cardiovascular protection is incompletely explained by its beneficial lipid-modifying effects. Previous studies interrogating direct vascular effects of estrogens have used models of either diet- or injury-induced atherosclerosis. The purpose of this study was to determine the influence of ovarian ablation alone on vascular remodeling. We hypothesized that estrogens are atheroprotective, independent of their influence on lipid metabolism, by directly influencing the production and effects of a prototypical atherogenic mediator, basic fibroblast growth factor (bFGF).

Methods and Results
—Twenty-five female sheep were randomized to sham operation, ovariectomy, or ovariectomy plus 17β-estradiol replacement. Serum cholesterol and triglyceride levels were serially measured for 1 year and were similar among groups and in the normal range (30 to 60 mg/dL). At 6, 9, and 12 months, ovariectomy resulted in aortoiliac intimal hyperplasia compared with sham (
P
<0.01) and hormone replacement (
P
<0.01) groups. The neointima of ovariectomized animals was characterized immunohistochemically by increased vascular smooth muscle cells (VSMCs). Levels of bFGF protein were determined in adjacent aortic segments. Ovariectomized sheep had 2-fold more FGF than sham or ovariectomized sheep that received hormone replacement. In vitro, estradiol inhibited the mitogenic effect of bFGF on human aortic VSMCs.

Conclusions
—Without dietary manipulation, ovarian ablation alone induces aortic intimal hyperplasia in the ewe. Estradiol abrogates this response independently of its effects on serum lipids. Hormone replacement decreases the accumulation of the atherogenic peptide bFGF in vivo and inhibits the mitogenic response of VSMCs to bFGF in vitro. These results suggest that estrogens may provide atheroprotection both by modulating local production and by attenuating the influence of bFGF on VSMC growth.
Mechanisms of Residual Lumen Stenosis After High-Pressure Stent Implantation
Authors: Bermejo Javier , Botas Javier , García Eulogio , Elízaga Jaime , Osende Julio , Soriano Javier , Abeytua Manuel , Delcán Juan Luis
Published: June 2012

Background
—Intravascular ultrasound (IVUS) studies have demonstrated that stents are frequently suboptimally expanded despite the use of high pressures for deployment. The purpose of this study was to identify the mechanisms responsible for such residual lumen stenosis.

Methods and Results
—Fifty-seven lesions from 50 patients treated with high-pressure (median±interquartile range, 14±2 atm) elective (44 de novo, 13 restenotic lesions) stenting were prospectively studied (29 Wiktor, Medtronic; 28 Palmaz-Schatz, Cordis Corp). Balloon subexpansion was calculated as the difference between maximal and minimal balloon cross-sectional areas at peak pressure measured by automatic edge detection; elastic recoil was calculated as the difference between minimal measured balloon size and IVUS-derived minimal lumen area within the stent. Angiographic residual diameter stenosis was 10±13% (reference diameter, 3.1±0.7 mm; balloon to artery ratio, 1.12±0.23) and IVUS-derived stent expansion was 80±28%. However, although balloon nominal size was 9.6±1.3 mm

2

and maximal balloon size measured inside the coronary lumen was 12.5±3.2 mm
2
, final stent minimal lumen area was only 7.1±2.2 mm
2
. Balloon subexpansion of 4.0±1.8 mm

2

(33%) and elastic recoil of 1.6±2.3 mm

2

(20%) (both
P
<0.0001) were the two mechanisms responsible for residual luminal stenosis. Wiktor stent and peak inflation pressure correlated with balloon subexpansion, whereas Wiktor stent, de novo lesion, and minimal lumen area at baseline correlated with elastic recoil.

Conclusions
—Despite high-pressure deployment, lumen dimensions after stenting are only 57% of maximal achievable. Inadequate balloon expansion and elastic recoil are responsible for residual lumen stenosis, suggesting that plaque characteristics and stent resistance deserve further investigation.
Evaluation of a Weight-Adjusted Single-Bolus Plasminogen Activator in Patients With Myocardial Infarction
Authors: den Heijer Peter , Vermeer Frank , Ambrosioni Ettore , Sadowski Zygmunt , López-Sendón José L. , von Essen Rainer , Beaufils Philippe , Thadani Udho , Adgey Jennifer , Pierard Luc , Brinker Jeffrey , Davies Richard F. , Smalling Richard W. , Wallentin Lars , Caspi Abraham , Pangerl Andreas , Trickett Linda , Hauck Cynthia , Henry David , Chew Paul
Published: June 2012

Background
—Lanoteplase (nPA) is a rationally designed variant of tissue plasminogen activator with greater fibrinolytic potency and slower plasma clearance than alteplase.

Methods and Results
—InTIME (Intravenous nPA for Treatment of Infarcting Myocardium Early), a multicenter, double-blind, randomized, double-placebo angiographic trial, evaluated the dose-response relationship and safety of single-bolus, weight-adjusted lanoteplase. Patients (n=602) presenting within 6 hours of acute myocardial infarction were randomized and treated with either a single-bolus injection of lanoteplase (15, 30, 60, or 120 kU/kg) or accelerated alteplase. The primary objective was to determine TIMI grade flow at 60 minutes. Angiographic assessments were also performed at 90 minutes and on days 3 to 5. Follow-up was continued for 30 days. Lanoteplase achieved its primary objective, demonstrating a dose-response in TIMI grade 3 flow at 60 minutes (23.6% to 47.1% of subjects,
P
<0.001). Similar results were observed at 90 minutes (26.1% to 57.1%,
P
<0.001). At 90 minutes, coronary patency (TIMI 2 or 3) increased across the dose range up to 83% of subjects at 120 kU/kg lanoteplase compared with 71.4% with alteplase. Thus, at this dose, lanoteplase was superior to alteplase in restoring coronary patency (difference, 12%; 95% CI, 1% to 23%). The early safety experience in this study suggests that lanoteplase was well tolerated at all doses with safety comparable to that of alteplase.

Conclusions
—Lanoteplase, a single-bolus, weight-adjusted agent, increased coronary patency at 60 and 90 minutes in a dose-dependent fashion. Coronary patency at 90 minutes was achieved more frequently with 120 kU/kg lanoteplase than alteplase. In this study, safety with lanoteplase and alteplase was comparable. InTIME-II, a worldwide mortality trial, will evaluate efficacy and safety with this promising new agent.
ACE (I/D) Genotype as a Predictor of the Magnitude and Duration of the Response to an ACE Inhibitor Drug (Enalaprilat) in Humans
Authors: Ueda Shinichiro , Meredith Peter A. , Morton James J. , Connell John M. C. , Elliott Henry L.
Published: June 2012

Background
—We have investigated the possible effects of contrasting ACE (I/D) genotypes on the responses to the ACE inhibitor enalaprilat in normotensive men.

Methods and Results
—Subjects with DD (n=12) and II (n=11) ACE genotypes received an intravenous infusion of enalaprilat or placebo. Pressor responses to stepwise, incremental doses of angiotensin I were measured at 1 and 10 hours after dosing. The dose required to raise mean blood pressure by 20 mm Hg (PD20) was calculated individually, and the ratio of PD20 during enalaprilat to that during placebo (dose ratio, DR) was used for assessment of the extent of ACE inhibition. The pressor response was significantly attenuated at 1 hour after enalaprilat in both groups, but significant attenuation was evident at 10 hours after dose only in the II subjects. The DRs at both 1 hour (median, 5.43 versus 2.82,
P
=0.0035) and 10 hours (2.06 versus 0.84,
P
=0.0008) after enalaprilat were significantly higher in II subjects than in DD subjects.

Conclusions
—The effect of enalaprilat was significantly greater and lasted longer in normotensive men homozygous for the II ACE genotype. By multivariate analysis, ACE (I/D) genotype and plasma angiotensin II levels were predictive of >50% of the variation in response to ACE inhibition.
Chronic Orthostatic Intolerance
Authors: Furlan Raffaello , Jacob Giris , Snell Marie , Robertson David , Porta Alberto , Harris Paul , Mosqueda-Garcia Rogelio
Published: June 2012

Background
—Chronic orthostatic intolerance (COI) is a debilitating autonomic condition in young adults. Its neurohumoral and hemodynamic profiles suggest possible alterations of postural sympathetic function and of baroreflex control of heart rate (HR).

Methods and Results
—In 16 COI patients and 16 healthy volunteers, intra-arterial blood pressure (BP), ECG, central venous pressure (CVP), and muscle sympathetic nerve activity (MSNA) were recorded at rest and during 75° tilt. Spectral analysis of RR interval and systolic arterial pressure (SAP) variabilities provided indices of sympathovagal modulation of the sinoatrial node (ratio of low-frequency to high-frequency components, LF/HF) and of sympathetic vasomotor control (LF
SAP
). Baroreflex mechanisms were assessed (1) by the slope of the regression line obtained from changes of RR interval and MSNA evoked by pharmacologically induced alterations in BP and (2) by the index α, obtained from cross-spectral analysis of RR and SAP variabilities. At rest, HR, MSNA, LF/HF, and LF
SAP
were higher in COI patients, whereas BP and CVP were similar in the two groups. During tilt, BP did not change and CVP fell by the same extent in the 2 groups; the increase of HR and LF/HF was more pronounced in COI patients. Conversely, the increase of MSNA was lower in COI than in control subjects. Baroreflex sensitivity was similar in COI and control subjects at rest; tilt reduced α similarly in both groups.

Conclusions
—COI is characterized by an overall enhancement of noradrenergic tone at rest and by a blunted postganglionic sympathetic response to standing, with a compensatory cardiac sympathetic overactivity. Baroreflex mechanisms maintain their functional responsiveness. These data suggest that in COI, the functional distribution of central sympathetic tone to the heart and vasculature is abnormal.
Influence of Lead Selection and Population on Automated Measurement of QT Dispersion
Authors: Macfarlane P. W. , McLaughlin Stephanie C. , Rodger J. Christine
Published: June 2012

Background
—The study of QT dispersion (QTd) is of increasing clinical interest, but there are very few data in large healthy populations. Furthermore, there is still discussion on the extent to which QTd reflects dispersion of measurement. This study addresses these problems.

Methods and Results
—Twelve-lead ECGs recorded on 1501 apparently healthy adults and 1784 healthy neonates, infants, and children were used to derive normal limits of QTd and QT intervals by use of a fully automated approach. No age gradient or sex differences in QTd were seen and it was found that an upper limit of 50 ms was highly specific. Three-orthogonal-lead ECGs (n=1220) from the Common Standards for Quantitative Electrocardiography database were used to generate derived 12-lead ECGs, which had a significant increase in QTd of 10.1±13.1 ms compared with the original orthogonal-lead ECG but a mean difference of only 1.63±12.2 ms compared with the original 12-lead ECGs. In a population of 361 patients with old myocardial infarction, there was a statistically significant increase in mean QTd compared with that of the adult normal group (32.7±10.0 versus 24.53±8.2 ms;
P
<0.0001). An estimate of computer measurement error was also obtained by creating 2 sets of 1220 ECGs from the original set of 1220. The mean error (difference in QTd on a paired basis) was found to be 0.28±9.7 ms.

Conclusions
—These data indicate that QTd is age and sex independent, has a highly specific upper normal limit of 50 ms, is significantly lower in the 3-orthogonal-lead than in the 12-lead ECG, and is longer in patients with a previous myocardial infarction than in normal subjects.
Cellular Basis for the ECG Features of the LQT1 Form of the Long-QT Syndrome
Authors: Shimizu Wataru , Antzelevitch Charles
Published: June 2012

Background
—This study examines the cellular basis for the phenotypic appearance of broad-based T waves, increased transmural dispersion of repolarization (TDR), and torsade de pointes (TdP) induced by β-adrenergic agonists under conditions mimicking the LQT1 form of the congenital long-QT syndrome.

Methods and Results
—A transmural ECG and transmembrane action potentials from epicardial, M, and endocardial cells were recorded simultaneously from an arterially perfused wedge of canine left ventricle. Chromanol 293B, a specific
I
Ks
blocker, dose-dependently (1 to 100 μmol/L) prolonged the QT interval and action potential duration (APD
90
) of the 3 cell types but did not widen the T wave, increase TDR, or induce TdP. Isoproterenol 10 to 100 nmol/L in the continued presence of chromanol 293B 30 μmol/L abbreviated the APD
90
of epicardial and endocardial cells but not that of the M cell, resulting in widening of the T wave and a dramatic accentuation of TDR. Spontaneous as well as programmed electrical stimulation (PES)-induced TdP was observed only after exposure to the
I
Ks
blocker and isoproterenol. Therapeutic concentrations of propranolol (0.5 to 1 μmol/L) prevented the actions of isoproterenol to increase TDR and to induce TdP. Mexiletine 2 to 20 μmol/L abbreviated the APD
90
of M cells more than that of epicardial and endocardial cells, thus diminishing TDR and the effect of isoproterenol to induce TdP.

Conclusions
—This experimental model of LQT1 indicates that a deficiency of
I
Ks
alone does not induce TdP but that the addition of β-adrenergic influence predisposes the myocardium to the development of TdP by increasing transmural dispersion of repolarization, most likely as a result of a large augmentation of residual
I
Ks
in epicardial and endocardial cells but not in M cells, in which
I
Ks
is intrinsically weak. Our data provide a mechanistic understanding of the cellular basis for the therapeutic actions of β-adrenergic blockers in LQT1 and suggest that sodium channel block with class IB antiarrhythmic agents may be effective in suppressing TdP in LQT1, as they are in LQT2 and LQT3, as well as in acquired (drug-induced) forms of the long-QT syndrome.
Cardiovascular Events and Their Reduction With Pravastatin in Diabetic and Glucose-Intolerant Myocardial Infarction Survivors With Average Cholesterol Levels
Authors: Goldberg Ronald B. , Mellies Margot J. , Sacks Frank M. , Moyé Lemuel A. , Howard Barbara V. , Howard William James , Davis Barry R. , Cole Thomas G. , Pfeffer Marc A. , Braunwald Eugene
Published: June 2012

Background
—Although diabetes is a major risk factor for coronary heart disease (CHD), little information is available on the effects of lipid lowering in diabetic patients. We determined whether lipid-lowering treatment with pravastatin prevents recurrent cardiovascular events in diabetic patients with CHD and average cholesterol levels.

Methods and Results
—The Cholesterol And Recurrent Events (CARE) trial, a 5-year trial that compared the effect of pravastatin and placebo, included 586 patients (14.1%) with clinical diagnoses of diabetes. The participants with diabetes were older, more obese, and more hypertensive. The mean baseline lipid concentrations in the group with diabetes—136 mg/dL LDL cholesterol, 38 mg/dL HDL cholesterol, and 164 mg/dL triglycerides—were similar to those in the nondiabetic group. LDL cholesterol reduction by pravastatin was similar (27% and 28%) in the diabetic and nondiabetic groups, respectively. In the placebo group, the diabetic patients suffered more recurrent coronary events (CHD death, nonfatal myocardial infarction [MI], CABG, and PTCA) than did the nondiabetic patients (37% versus 25%). Pravastatin treatment reduced the absolute risk of coronary events for the diabetic and nondiabetic patients by 8.1% and 5.2% and the relative risk by 25% (
P
=0.05) and 23% (
P
<0.001), respectively. Pravastatin reduced the relative risk for revascularization procedures by 32% (
P
=0.04) in the diabetic patients. In the 3553 patients who were not diagnosed as diabetic, 342 had impaired fasting glucose at entry defined by the American Diabetes Association as 110 to 125 mg/dL. These nondiabetic patients with impaired fasting glucose had a higher rate of recurrent coronary events than those with normal fasting glucose (eg, 13% versus 10% for nonfatal MI). Recurrence rates tended to be lower in the pravastatin compared with placebo group (eg, –50%,
P
=0.05 for nonfatal MI).

Conclusions
—Diabetic patients and nondiabetic patients with impaired fasting glucose are at high risk of recurrent coronary events that can be substantially reduced by pravastatin treatment.