bluuebunny/crossref_metadata_2025_split huggingface dataset:
Angiotensin II increases plasminogen activator inhibitor type 1 and tissue-type plasminogen activator messenger RNA in cultured rat aortic smooth muscle cells.
Authors: van Leeuwen R T , Kol A , Andreotti F , Kluft C , Maseri A , Sperti G 
Published: June 2012

BACKGROUND
The role of angiotensin as a vasoconstrictor is well established. Lately, several other actions of this hormone on vascular smooth muscle (VSM) cells have been recognized including the induction of hypertrophy and/or DNA synthesis. Platelet-derived growth factor (PDGF), a mitogen recently shown to increase plasminogen activator inhibitor type 1 (PAI-1) synthesis in VSM cells, shares with angiotensin II (Ang II) several steps of its intracellular signaling pathway.

METHODS AND RESULTS
The expression of PAI-1 and tissue-type plasminogen activator (TPA) mRNA in cultured rat VSM cells was studied. Northern blot analysis demonstrated a severalfold increase in the PAI-1 mRNA 3 to 8 hours after stimulation with 300 nmol/L Ang II. A similar response for TPA mRNA was observed. This induction did not require the synthesis of an intermediate protein or peptide because it was not affected by cycloheximide. In the cell-conditioned supernatant, the net result was an increase in PAI-1 activity from 4.18 +/- 1.8 to 13.2 +/- 6.8 IU/mL 6 hours after the addition of 300 nmol/L Ang II (mean +/- SD, P < or = .008, n = 6). The Ang II-induced increase in PAI activity was dose related, with a maximal effect at a concentration of 23 nmol/L (n = 3) and an ED50 of 3.3 +/- 1.5 nmol/L (n = 3). [Sar1-Ile8]angiotensin II, a specific competitive antagonist of Ang II, blocked 90 +/- 9% (n = 3) of the PAI activity induced by 10 nmol/L Ang II. In basal conditions, fibrin overlay zymography demonstrated the presence of free TPA. After stimulation with Ang II, lysis caused by the in situ dissociation of TPA was also present in the region of the TPA/PAI-1 complex. Angiotensin I (Ang I) elicited an increase in PAI activity similar to that obtained with equivalent doses of Ang II. Captopril (5 micrograms/mL), an inhibitor of the angiotensin-converting enzyme (ACE), completely prevented the Ang I effect, demonstrating that VSM cells display an ACE-like activity.

CONCLUSIONS
Recent research has demonstrated the existence of a localized vascular renin-angiotensin system. The finding that Ang II can potentially modulate the plasminogen activation in the arterial wall has important biological and therapeutical implications for the evolution of arterial wall thrombi and the migration of cells through the vessel wall in the genesis of atherosclerotic lesions. We speculate that the reduction in thrombotic events observed in patients with a previous myocardial infarction and in high-renin, hypertensive patients treated with ACE inhibitors could be due at least in part to the decreased production of PAI-1 by VSM cells caused by these agents.
Sodium channel blockade reduces hypoxic sodium loading and sodium-dependent calcium loading.
Authors: Haigney M C , Lakatta E G , Stern M D , Silverman H S 
Published: June 2012

BACKGROUND
Studies have shown that the rise in intracellular ionized calcium, [Ca2+]i, in hypoxic myocardium is driven by an increase in sodium, [Na+]i, but the source of Na+ is not known.

METHODS AND RESULTS
Inhibitors of the voltage-gated Na+ channel were used to investigate the effect of Na+ channel blockade on hypoxic Na+ loading, Na(+)-dependent Ca2+ loading, and reoxygenation hypercontracture in isolated adult rat cardiac myocytes. Single electrically stimulated (0.2 Hz) cells were loaded with either SBFI (to index [Na+]i) or indo-1 (to index [Ca2+]i) and exposed to glucose-free hypoxia (PO2 < 0.02 mm Hg). Both [Na+]i and [Ca2+]i increased during hypoxia when cells became inexcitable following ATP-depletion contracture. The hypoxic rise in [Na+]i and [Ca2+]i was significantly attenuated by 1 mumol/L R 56865. Tetrodotoxin (60 mumol/L), a selective Na(+)-channel blocker, also markedly reduced the rise in [Ca2+]i during hypoxia and reoxygenation. Reoxygenation-induced cellular hypercontracture was reduced from 83% (45 of 54 cells) under control conditions to 12% (4 of 32) in the presence of R 56865 (P < .05). Lidocaine reduced hypercontracture dose dependently with 13% of cells hypercontracting in 100 mumol/L lidocaine, 42% in 50 mumol/L lidocaine, and 93% in 25 mumol/L lidocaine. The Na(+)-H+ exchange blocker, ethylisopropylamiloride (10 mumol/L) was also effective, limiting hypercontracture to 12%. R 56865, lidocaine, and ethylisopropylamiloride were also effective in preventing hypercontracture in normoxic myocytes induced by 75 mumol/L veratridine, an agent that impairs Na+ channel inactivation. Ethylisopropylamiloride prevented the veratridine-induced rise in [Ca2+]i without affecting Na(+)-Ca2+ exchange, suggesting that amiloride derivatives can reduce Ca2+ loading by blocking Na+ entry through Na+ channels, an action that may in part underlie their ability to prevent hypoxic Na+ and Ca2+ loading.

CONCLUSIONS
Na+ influx through the voltage-gated Na+ channel is an important route of hypoxic Na+ loading, Na(+)-dependent Ca2+ loading, and reoxygenation hypercontracture in isolated rat cardiac myocytes. Importantly, the Na+ channel appears to serve as a route for hypoxic Na+ influx after myocytes become inexcitable.
L-arginine reduces heart collagen accumulation in the diabetic db/db mouse.
Authors: Khaidar A , Marx M , Lubec B , Lubec G 
Published: June 2012

BACKGROUND
Diabetic cardiomyopathy presents with significant collagen accumulation; decreased solubility, increased glucose-mediated abnormal cross-linking, free radical cross-linking, or glucose-induced increased transcription of collagen is incriminated. In a previous study, we reduced collagen accumulation in the kidneys of diabetic mice by treatment with oral arginine. This observation led us to examine the effect of arginine on cardial fibrosis.

METHODS AND RESULTS
Twenty-nine db/db spontaneously diabetic mice were used in the experiments. Sixteen were given L-arginine (free base, in tap water, 50 mg/kg body wt per day) for 4 months. At the end of the experiment, we determined total collagen content of total ventricular tissue, acid solubility, carboxymethyllysine, O-tyrosine, glutathione, blood glucose, and fructosamine as parameters for glycemic control. Heart collagen level was significantly (P = .0001) reduced in the experimental group (mean, 0.24 +/- 0.05) compared with the control group (mean, 0.49 +/- 0.10 mumol hydroxyproline per 100 mg heart tissue). Significantly more collagen could be eluted from heart samples of the experimental group (P = .02). Carboxymethyllysine and O-tyrosine did not differ when related to heart weight. Glutathione level was significantly higher in the untreated group (P = .003). Parameters of glycemic control did not differ between the groups.

CONCLUSIONS
Our findings clearly indicate that L-arginine reduced total heart collagen and increased acid solubility of heart collagen. Both findings are compatible with the cross-linking hypothesis. The data for carboxymethyllysine, O-tyrosine, and glutathione would rule out the glycoxidation hypothesis and, therefore, free radical cross-linking. The postulated mechanism of action is most likely the blocking of reactive carbonyl functions by L-arginine in analogy to aminoguanidine activity. Correlations of collagen with glycemic control, however, point to an association of glucose with collagen metabolism, a phenomenon documented in cell cultures at the transcriptional level.
Late enlargement of radiofrequency lesions in infant lambs. Implications for ablation procedures in small children.
Authors: Saul J P , Hulse J E , Papagiannis J , Van Praagh R , Walsh E P 
Published: June 2012

BACKGROUND
Despite the current clinical use of radiofrequency (RF) catheter ablation in infants, the acute and late effects of RF lesion production in immature myocardium remain unknown. This study was specifically designed to investigate the pathology of RF lesions in developing sheep myocardium.

METHODS AND RESULTS
In study 1, RF lesions were made on the epicardial left ventricular surface of the beating heart in 15 sheep, 5 approximately 4 weeks of age (11.0 +/- 1.0 kg) and 10 approximately 8 weeks of age (23.8 +/- 3.4 kg), to assess the effects of RF application duration (10 to 90 seconds) and electrode tip temperature (45 degrees to 90 degrees C) on lesion size in immature myocardium. Lesion width and depth increased asymptotically with RF duration, to 7.0 +/- 0.7 and 4.8 +/- 1.0 mm at 90 seconds, respectively. The time to reach one-half lesion size was 6.5 seconds for width and 12.0 seconds for depth. Lesion width increased nearly linearly with tip temperature above 50 degrees C, but depth followed a sigmoid relation, with no increase above 80 degrees C. In study 2, RF lesions were made in all four cardiac chambers under fluoroscopic guidance in 19 infant sheep (10.9 +/- 1.4 kg). Lesion sizes and histological characteristics were assessed acutely (acute, n = 5), at 1.07 +/- 0.02 months (1 month, n = 5), and at 8.5 +/- 0.5 months (late, n = 9). Atrial and ventricular lesions but not atrioventricular groove lesions apparently increased in size during the follow-up period. Atrial lesions width increased from 5.3 +/- 0.5 to 8.7 +/- 0.7 mm at 1 month (164%) but did not increase further at late follow-up, while ventricular lesion width increased from 5.9 +/- 0.8 to 10.1 +/- 0.7 mm (171%) at late follow-up but was not significantly changed at 1 month. Histological evaluation revealed replacement of normal myocytes with fibrous and elastic tissue at 1 month and late follow-up in all locations but also demonstrated a poorly delineated border with multiple extensions of fibrous and elastic tissue into surrounding normal myocardium in late ventricular lesions.

CONCLUSIONS
RF lesion formation in immature sheep myocardium is similar to that in adult myocardium acutely but is associated with late lesion enlargement and fibrous tissue invasion of normal myocardium. These findings may have implications for clinical RF ablation procedures in infants.
Adjunctive thrombolytic therapy during angioplasty for ischemic rest angina. Results of the TAUSA Trial. TAUSA Investigators. Thrombolysis and Angioplasty in Unstable Angina trial.
Authors: Ambrose J A , Almeida O D , Sharma S K , Torre S R , Marmur J D , Israel D H , Ratner D E , Weiss M B , Hjemdahl-Monsen C E , Myler R K 
Published: June 2012

BACKGROUND
Acute closure is increased after angioplasty in unstable angina, and adjunctive intracoronary thrombolytic therapy has been used successfully to increase angiographic success. The role of prophylactic thrombolytic therapy during angioplasty in unstable angina is unknown.

METHODS AND RESULTS
Four hundred sixty-nine patients with ischemic rest pain with or without a recent (< 1 month) infarction were randomized in double-blind fashion to intracoronary urokinase or placebo. Randomization was carried out in two sequential phases. In phase I, 257 patients were randomized to 250,000 U of urokinase or placebo given in divided doses at the time of angioplasty. In phase II, 212 patients were randomized to 500,000 U of urokinase or placebo in divided doses. All patients were pretreated with aspirin, and activated clotting times were followed to maintain them at > 300 seconds during angioplasty. Angiographic end points of thrombus after angioplasty were insignificantly decreased by urokinase (30 [13.8%] versus 41 [18.0%] with placebo; P = NS). Acute closure, on the other hand, was increased with urokinase (23 [10.2%] versus 10 [4.3%] with placebo; P < .02). The difference in acute closure between urokinase and placebo was more striking at the higher dose of urokinase (P < .04) than in phase I at the lower urokinase dose (P = NS). Adverse in-hospital clinical end points (ischemia, infarction, or emergency coronary artery bypass surgery) were also increased with urokinase versus placebo (30 [12.9%] versus 15 [6.3%], respectively; P < .02). Angiographic and clinical end points were worse with urokinase in unstable angina without recent infarction than with angioplasty after a recent infarction.

CONCLUSIONS
Adjunctive urokinase given prophylactically during angioplasty for ischemic rest angina as administered in this trial is associated with adverse angiographic and clinical events. These detrimental effects may be related to hemorrhagic dissection, lack of intimal sealing, or procoagulant or platelet-activating effects of urokinase.
Weekly variation of acute myocardial infarction. Increased Monday risk in the working population.
Authors: Willich S N , Löwel H , Lewis M , Hörmann A , Arntz H R , Keil U 
Published: June 2012

BACKGROUND
Seasonal and circadian variations in the occurrence of myocardial infarction and sudden cardiac death have been documented, suggesting that triggering factors may play a role in the causation of cardiac events. However, there are only sparse and conflicting data on the weekly distribution of the disorders.

METHODS AND RESULTS
To determine the weekly variation of acute myocardial infarction and sudden cardiac death, 5596 consecutive patients (71% men; age, 63 +/- 1 years) were analyzed in a regionally defined population (n = 330,000; age, 25 to 74 years) monitored from 1985 to 1990. The exact time of onset of symptoms was used to determine the day of the event. Patients with myocardial infarction (n = 2636) demonstrated a significant weekly variation (P < .01) with a peak on Monday, whereas patients with sudden cardiac death (n = 2960) were evenly distributed throughout the week. A similar weekly pattern was observed in subgroups of patients with myocardial infarction defined with respect to age, sex, cardiac risk factors, prior cardiac medication, and infarct characteristics. The working population demonstrated a weekly variation of myocardial infarction as opposed to the nonworking population, with a 33% increase in relative risk of disease onset on Monday (P < .05) and a trough on Sunday compared with the expected number of cases, if homogeneity was assumed.

CONCLUSIONS
The onset of acute myocardial infarction demonstrates a peak on Monday primarily in the working population. If this finding is confirmed in other communities, it may aid in identifying acute triggering events of myocardial infarction and perhaps in improving prevention of the disease.
Reduction in QT interval dispersion by successful thrombolytic therapy in acute myocardial infarction. TEAM-2 Study Investigators.
Authors: Moreno F L , Villanueva T , Karagounis L A , Anderson J L 
Published: June 2012

BACKGROUND
QT dispersion (QTd, equals maximal minus minimal QT interval) on a standard ECG has been shown to reflect regional variations in ventricular repolarization and is significantly greater in patients with than in those without arrhythmic events.

METHODS AND RESULTS
To assess the effect of thrombolytic therapy on QTd, we studied 244 patients (196 men; mean age, 57 +/- 10 years) with acute myocardial infarction (AMI) who were treated with streptokinase (n = 115) or anistreplase (n = 129) at an average of 2.6 hours after symptom onset. Angiograms at 2.4 +/- 1 hours after thrombolytic therapy showed reperfusion (TIMI grade > or = 2) in 75% of patients. QT was measured in 10 +/- 2 leads at 9 +/- 5 days after AMI by using a computerized analysis program interfaced with a digitizer. QTd, QRSd, JT (QT minus QRS), and JT dispersion (JTd, equals maximal minus minimal JT interval) were calculated with a computer. There were significant differences in QTd (96 +/- 31, 88 +/- 25, 60 +/- 22, and 52 +/- 19 milliseconds; P < or = .0001) and in JTd (97 +/- 32, 88 +/- 31, 63 +/- 23, and 58 +/- 21 milliseconds; P = .0001) but not in QRSd (25 +/- 10, 22 +/- 7, 28 +/- 9, and 24 +/- 9 milliseconds; P = .24) among perfusion grades 0, 1, 2, and 3, respectively. Similar results were obtained comparing TIMI grades 0/1 with 2/3 and 0/1/2 with 3. Patients with left anterior descending (versus right and left circumflex) coronary artery occlusion showed significantly greater QTd (70 +/- 29 versus 59 +/- 27 milliseconds, P = .003) and JTd (74 +/- 30 versus 63 +/- 27 milliseconds, P = .004). Similarly, patients with anterior (versus inferior/lateral) AMI showed significantly greater QTd (69 +/- 30 versus 59 +/- 27 milliseconds, P = .006) and JTd (73 +/- 30 versus 63 +/- 27 milliseconds, P = .007). Results did not change when Bazett's QTc or JTc was substituted for QT or JT or when ANOVA included adjustments for age, sex, drug assignment, infarct site, infarct vessel, and number of measurable leads. On ANCOVA, the relation of QTd or JTd and perfusion grade was not influenced by heart rate.

CONCLUSIONS
Successful thrombolysis is associated with less QTd and JTd in post-AMI patients. The results are equally significant when either QT or JT is used for analysis. These data support the hypothesis that QTd after AMI depends on reperfusion status as well as infarct site and size. Reduction in QTd and its corresponding risk of ventricular arrhythmia may be mechanisms of benefit of thrombolytic therapy.
Indirect angiogenic cytokines upregulate VEGF and bFGF gene expression in vascular smooth muscle cells, whereas hypoxia upregulates VEGF expression only.
Authors: Brogi E , Wu T , Namiki A , Isner J M 
Published: June 2012

BACKGROUND
Hypoxia and indirect angiogenic factors may stimulate angiogenesis via induction of endothelial cell mitogen(s). To evaluate this hypothesis, we investigated whether low oxygen tension or cytokines known to promote neovascularization in vivo could modulate the expression of either vascular endothelial growth factor (VEGF) or basic fibroblast growth factor (bFGF) in human vascular smooth muscle cells (SMCs).

METHODS AND RESULTS
SMCs were treated with platelet-derived growth factor BB (PDGF-BB) or transforming growth factor-beta 1 (TGF-beta 1) or exposed to low oxygen tension in serum-free medium. Northern analysis detected low basal levels of VEGF and bFGF mRNA in extracts of unstimulated SMCs. However, both VEGF and bFGF transcripts increased after administration of PDGF-BB (10 or 20 ng/mL) or TGF-beta 1 (0.1 to 10 ng/mL). Hypoxia was a potent stimulus for VEGF gene expression but had no apparent effect on bFGF steady-state mRNA levels.

CONCLUSIONS
These results indicate that certain indirect angiogenic cytokines, such as PDGF-BB or TGF-beta 1, may act via induction of bFGF and VEGF gene expression in cells resident near endothelial cells in vivo. Hypoxia constitutes a potent stimulus for VEGF gene expresion but does not regulate bFGF under the same experimental conditions.
Effects of L-arginine on impaired acetylcholine-induced and ischemic vasodilation of the forearm in patients with heart failure.
Authors: Hirooka Y , Imaizumi T , Tagawa T , Shiramoto M , Endo T , Ando S , Takeshita A 
Published: June 2012

BACKGROUND
Endothelium-dependent vasodilation in response to acetylcholine (ACh) and ischemic vasodilation during reactive hyperemia are attenuated in the forearm of patients with heart failure (HF). It has been shown that L-arginine augments endothelium-dependent vasodilation in healthy subjects. Thus, the aim of the present study was to determine if L-arginine improves endothelium-dependent and ischemic vasodilation in the forearm in HF.

METHODS AND RESULTS
Forearm blood flow was measured by a strain-gauge plethysmograph in 20 patients with HF and in 24 age-matched control subjects (C). Resting forearm vascular resistance (FVR) was significantly higher in HF than in C (37 +/- 4 versus 22 +/- 2 U, P < .01). Intra-arterial infusions of ACh or sodium nitroprusside (SNP) at graded doses progressively decreased FVR in HF as well as in C. The magnitude of ACh-induced vasodilation was attenuated in HF (P < .01), whereas SNP-induced vasodilation was similar between the two groups. The minimal FVR during reactive hyperemia after 10 minutes of arterial occlusion was significantly higher in HF (n = 12) than in C (n = 12) (3.2 +/- 0.4 versus 2.1 +/- 0.1 U, P < .05). L-Arginine significantly augmented maximal vasodilation evoked with ACh and decreased minimal FVR during reactive hyperemia in HF (P < .01) but not in C. L-Arginine did not affect SNP-induced vasodilation in HF or C.

CONCLUSIONS
Our results suggest that defective endothelial function may contribute to impaired ischemic vasodilator capacity in HF.
Acute vascular effects of estrogen in postmenopausal women.
Authors: Gilligan D M , Badar D M , Panza J A , Quyyumi A A , Cannon R O 
Published: June 2012

BACKGROUND
Although hormone replacement therapy has been associated with reduction of cardiovascular events in postmenopausal women, the mechanisms that mediate this apparent benefit are unclear. Because improvement in vasomotor function may represent one of the beneficial effects of estrogen administration, we investigated the acute effects of physiological levels of estrogen on the vascular responses of estrogen-deficient postmenopausal women.

METHODS AND RESULTS
The study included 40 postmenopausal women 60 +/- 8 years old (mean +/- SD), 20 of whom had one or more conditions associated with vascular dysfunction (hypertension, hypercholesterolemia, diabetes, or coronary artery disease). The forearm vascular responses to the endothelium-dependent vasodilator acetylcholine were studied before and during infusion of 17 beta-estradiol into the ipsilateral brachial artery. In 31 subjects, the effect of estradiol on the responses to the endothelium-independent vasodilator sodium nitroprusside was also studied. Women with risk factors for vascular dysfunction had significantly reduced vasodilator responses to acetylcholine (P = .01) and to sodium nitroprusside (P < .001) compared with healthy subjects. Intra-arterial infusion of 17 beta-estradiol increased the forearm venous estradiol concentration from 16 +/- 10 to 318 +/- 188 pg/mL, levels typical of reproductive-age women at midcycle, but caused no vasodilation. However, estradiol potentiated the forearm vasodilation induced by acetylcholine by 18 +/- 30% (P < .001) in women with risk factors for vascular dysfunction and by 14 +/- 23% (P = .03) in healthy women. Estradiol also potentiated the forearm vasodilation induced by sodium nitroprusside in women with risk factors for vascular dysfunction by 14 +/- 21% (P < .001) but not in healthy women.

CONCLUSIONS
Physiological levels of 17 beta-estradiol selectively potentiate endothelium-dependent vasodilation in healthy postmenopausal women and potentiate both endothelium-dependent and endothelium-independent vasodilation in post-menopausal women with risk factors for atherosclerosis and evidence of impaired vascular function. These vascular effects may be partly responsible for the long-term benefit of estrogen therapy on cardiovascular events in postmenopausal women.