bluuebunny/crossref_metadata_2025_split huggingface dataset:
Developmental changes in modulation of calcium currents of rabbit ventricular cells by phosphodiesterase inhibitors.
Authors: Akita T , Joyner R W , Lu C , Kumar R , Hartzell H C 
Published: June 2012

BACKGROUND
We have previously shown major differences in beta-adrenergic and muscarinic modulation of L-type calcium currents (ICa) in newborn and adult rabbit heart. However, little is known about developmental changes in modulation of ICa by phosphodiesterases (PDEs), which also regulate intracellular cAMP concentration by its hydrolysis.

METHODS AND RESULTS
Enzymatically isolated adult and newborn (1- to 3-day-old) rabbit ventricular myocytes were used to study the effects of PDE inhibitors on ICa measured by the whole-cell patch-clamp method. 3-Isobutyl-1-methyl-xanthine (IBMX), a nonselective PDE inhibitor, increased ICa in a dose-dependent manner for both groups. The maximal effect of IBMX, expressed as percentage increase in ICa over control levels, was greater for newborn myocytes than for adult myocytes, but the effects of IBMX applied alone were observed only at concentrations > 10 mumol/L. The concomitant use of 0.1 mumol/L isoproterenol produced a significant potentiation of the IBMX effect on ICa, with a significant additive effect of IBMX in newborn myocytes even at 0.05 mumol/L IBMX. The concomitant use of a subthreshold concentration of IBMX (0.1 mumol/L) did not potentiate the dose dependence of adult ICa on isoproterenol but did markedly potentiate the dose dependence of newborn ICa on isoproterenol. The Emax and EC50 of isoproterenol in the presence of 0.1 mumol/L IBMX on newborn ICa were 235% and 8 nmol/L, respectively, whereas the Emax and EC50 of isoproterenol in the absence of IBMX on newborn ICa were 111% and 81 nmol/L, respectively. The addition of 50 mumol/L IBMX to 10 mumol/L isoproterenol markedly increased the newborn ICa density up to a level equivalent to that reached with 200 mumol/L cAMP in the pipette (14.9 +/- 1.2 versus 13.4 +/- 0.7 pA/pF). Our data suggest that the inhibition constant (Ki) of IBMX for inhibiting PDEs that participate in the regulation of ICa is much lower in newborn than in adult myocytes. Milrinone 1 mumol/L, a selective PDE III inhibitor, increased the 0.1 mumol/L isoproterenol-stimulated ICa of adult myocytes but had no significant additive effect for the 0.1 mumol/L isoproterenol-stimulated ICa of newborn myocytes. Rolipram 1 mumol/L, a selective PDE IV inhibitor, increased the 0.1 mumol/L isoproterenol-stimulated ICa for newborn myocytes but had no significant additive effect for the 0.1 mumol/L isoproterenol-stimulated ICa for adult myocytes.

CONCLUSIONS
These results suggest that the most important PDE isozyme for regulation of ICa of rabbit myocytes changes from PDE IV to PDE III during the postnatal period.
Coronary vasodilator reserve, pain perception, and sex in patients with syndrome X.
Authors: Rosen S D , Uren N G , Kaski J C , Tousoulis D , Davies G J , Camici P G 
Published: June 2012

BACKGROUND
It remains unclear whether myocardial ischemia due to coronary microvascular dysfunction is the cause of chest pain in syndrome X (chest pain, ischemic-like stress ECG despite angiographically normal coronary arteries). To assess the function of the coronary microcirculation and its relation to pain perception, we measured myocardial blood flow (MBF) and coronary vasodilator reserve (CVR) in 29 patients with syndrome X and 20 matched normal control subjects.

METHODS AND RESULTS
MBF at rest and after intravenous dipyridamole (0.56 mg.kg-1 over 4 minutes) was measured using positron emission tomography with H2(15)O. CVR was calculated as MBFdipyridamole/MBFrest. ECG changes and chest pain after dipyridamole in syndrome X were compared with those in 35 patients with coronary artery disease (CAD). Resting and postdipyridamole MBFs were homogeneous throughout the left ventricle in syndrome X patients and control subjects. MBF was 1.05 (0.25), mean (SD) versus 1.00 (0.22) mL.min-1.g-1 (P = NS) at rest and 2.73 (0.81) versus 3.00 (1.00) mL.min-1.g-1 (P = NS) after dipyridamole in patients and control subjects, respectively. CVRs were 2.66 (0.76) and 3.06 (1.08) (P = NS) and after correction of resting MBF for rate-pressure product were 2.35 (0.83) and 2.34 (0.90) (P = NS) in patients and control subjects, respectively. Female syndrome X patients had higher resting MBF than males, at 1.18 (0.20) versus 0.88 (0.19) mL.min-1.g-1 (P < .001). Chest pain after dipyridamole occurred in syndrome X as frequently as in CAD (21/29 versus 22/35, P = NS).

CONCLUSIONS
When patients with syndrome X are compared with control subjects, no differences are found in MBF either at rest or after dipyridamole, despite syndrome X patients experiencing chest pain after dipyridamole to the same extent as patients with CAD. These findings, together with the absence of any relation among MBF, chest pain, and ECG changes under stress, cast further doubt on ischemia as the basis of the chest pain, at least in the majority of syndrome X patients.
Persistent activation of coagulation mechanism in unstable angina and myocardial infarction.
Authors: Merlini P A , Bauer K A , Oltrona L , Ardissino D , Cattaneo M , Belli C , Mannucci P M , Rosenberg R D 
Published: June 2012

BACKGROUND
The blood coagulation system is activated in the acute phase of unstable angina and acute myocardial infarction. However, it remains unclear whether augmented function of the hemostatic mechanism serves only as a marker of the acute thrombotic episode or whether a hypercoagulable state persists for a prolonged period after clinical stabilization.

METHODS AND RESULTS
We prospectively measured the plasma concentrations of prothrombin fragment 1 + 2 (F1 + 2) and fibrinopeptide A (FPA) in consecutive patients presenting with unstable angina (n = 81) or acute myocardial infarction (n = 32), respectively. At 6 months, plasma determinations were repeated in patients experiencing an uneventful clinical course (unstable angina, n = 57; myocardial infarction, n = 23). We quantitated the plasma levels of F1 + 2 and FPA in control patients with stable angina (n = 37) or healthy individuals (n = 32) who were matched for age and sex. The median plasma concentrations of F1 + 2 and FPA are significantly higher in patients presenting with unstable angina (F1 + 2, 1.08 nmol/L; FPA, 2.4 nmol/L) or acute myocardial infarction (F1 + 2, 1.27 nmol/L; FPA, 3.55 nmol/L) compared with patients with stable angina (F1 + 2, 0.74 nmol/L; FPA, 1.3 nmol/L; P < .0001) or healthy individuals (F1 + 2, 0.71 nmol/L; FPA, 0.80 nmol/L; P < .0001). At 6 months, the median plasma levels of F1 + 2 in patients exhibiting an uneventful clinical course did not differ from values obtained at admission (unstable angina, 1.26 versus 1.07 nmol/L, P = NS; myocardial infarction, 1.22 versus 1.29 nmol/L, P = NS), whereas the median plasma levels of FPA in the same two subpopulations were significantly reduced (unstable angina, 1.1 versus 2.9 nmol/L, P = .0003; myocardial infarction, 1.1 versus 3.0 nmol/L; P = .0028).

CONCLUSIONS
During the acute phase of unstable angina and myocardial infarction, patients exhibit increased coagulation system activity. Over the next 6 months, patients with unstable angina or myocardial infarction experiencing an uneventful clinical course manifest a persistent hypercoagulable state with minimal generation of fibrin.
Three-dimensional left ventricular deformation in hypertrophic cardiomyopathy.
Authors: Young A A , Kramer C M , Ferrari V A , Axel L , Reichek N 
Published: June 2012

BACKGROUND
In hypertrophic cardiomyopathy, ejection fraction is normal or increased, and force-length relations are reduced. However, three-dimensional (3D) motion and deformation in vivo have not been assessed in this condition. We have reconstructed the 3D motion of the left ventricle (LV) during systole in 7 patients with hypertrophic cardiomyopathy (HCM) and 12 normal volunteers by use of magnetic resonance tagging.

METHODS AND RESULTS
Transmural tagging stripes were automatically tracked to subpixel resolution with an active contour model. A 3D finite-element model was used to interpolate displacement information between short- and long-axis slices and register data on a regional basis. Displacement and strain data were averaged into septal, posterior, lateral, and anterior regions at basal, midventricular, and apical levels. Radial motion (toward the central long axis) decreased slightly in patients with HCM, whereas longitudinal displacement (parallel to the long axis) of the base toward the apex was markedly reduced: 7.5 +/- 2.5mm (SD) versus 12.5 +/- 2.0 mm, P < .001. Circumferential and longitudinal shortening were both reduced in the septum (P < .01 at all levels). The principal strain associated with 3D maximal contraction was slightly depressed in many regions, significantly in the basal septum (-0.18 +/- 0.05 versus -0.22 +/- 0.02, P < .05) and anterior (-0.20 +/- 0.05 versus -0.23 +/- 0.02, P < .05) walls. In contrast, LV torsion (twist of the apex about the long axis relative to the base) was greater in HCM patients (19.9 +/- 2.4 degrees versus 14.6 +/- 2.7 degrees, P < .01).

CONCLUSIONS
HCM patients had reduced 3D myocardial shortening on a regional basis; however, LV torsion was increased.
Transcatheter delivery of c-myc antisense oligomers reduces neointimal formation in a porcine model of coronary artery balloon injury.
Authors: Shi Y , Fard A , Galeo A , Hutchinson H G , Vermani P , Dodge G R , Hall D J , Shaheen F , Zalewski A 
Published: June 2012

BACKGROUND
Smooth muscle cell proliferation and extracellular matrix accumulation are the principal mechanisms leading to vascular restenosis. We have previously demonstrated the growth-inhibitory effect of antisense oligomers targeting the c-myc proto-oncogene in human smooth muscle cells. The goal of this study was to investigate whether c-myc antisense oligomers reduce neointimal formation in balloon-denuded porcine coronary arteries.

METHODS AND RESULTS
First, type I collagen synthesis, which reflects synthetic function, was markedly reduced following c-myc antisense oligomers in porcine vascular smooth muscle cells independent of the growth inhibition. These effects in vitro provided the rationale for assessing c-myc antisense oligomers in the prevention of neointima in vivo. Second, the efficiency of single transcatheter delivery of oligomers into denuded porcine coronary arteries was determined. Despite rapid plasma clearance following local delivery, oligomers persisted at the site of injection for at least 3 days, exceeding by severalfold their concentration in peripheral organs. Third, morphometric analyses were carried out in balloon-denuded coronary arteries at 1 month after transcatheter c-myc antisense oligomer administration. Maximal neointimal area was reduced from 0.80 +/- 0.17 mm2 in the control group (n = 12) to 0.24 +/- 0.06 mm2 in the antisense-treated group (n = 13, P < .01). Likewise, a significant reduction in maximal neointimal thickness was observed in the antisense-treated group (P < .01). These changes in vascular remodeling following denuding injury resulted in an increase in residual lumen from 64 +/- 6% in the control group to 81 +/- 5% in the antisense-treated group (P < .05).

CONCLUSIONS
(1) Single transcatheter administration allowed for endoluminal delivery of oligomers to the site of coronary arterial injury. (2) C-myc antisense oligomers reduced the formation of neointima in denuded coronary arteries, implying a therapeutic potential of this approach for the prevention of coronary restenosis. (3) It is postulated that the c-myc proto-oncogene is involved in the process of vascular remodeling, regulating smooth muscle cell proliferation and extracellular matrix synthesis.
Hirudin in acute myocardial infarction. Safety report from the Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9A Trial.
Authors: Antman E M 
Published: June 2012

BACKGROUND
The Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9A trial compared the efficacy and safety of intravenous hirudin with heparin as adjunctive therapy to thrombolysis and aspirin in patients with acute myocardial infarction. The primary safety end point was the occurrence of major hemorrhage or anaphylaxis.

METHODS AND RESULTS
Based on experience in phase II trials, TIMI 9A used a hirudin bolus of 0.6 mg/kg followed by a fixed-dose 96-hour infusion of 0.2 mg/kg per hour. A modified weight-adjusted heparin regimen was used (5000-U bolus and infusion of 1000 U/h for patients < 80 kg or 1300 U/h for patients > or = 80 kg) with titration to a target activated partial thromboplastin time (aPTT) of 60 to 90 seconds. Because rates of hemorrhage in both treatment arms were higher than expected, randomization was suspended in TIMI 9A after 757 patients had been enrolled. Intracranial hemorrhage occurred in 1.7% of patients treated with hirudin and 1.9% of those treated with heparin (P = NS). Major spontaneous hemorrhage at a nonintracranial site occurred more frequently in hirudin--than in heparin-treated patients (7.0% versus 3.0%; P = .02), whereas major hemorrhage at instrumented sites was similar (5.2% in both hirudin and heparin groups). Patients who developed a major hemorrhage were older (P < .001) and had higher aPTT values, especially in the first 12 hours after thrombolysis (P = .001).

CONCLUSIONS
The rate of major spontaneous hemorrhage for both heparin and hirudin in TIMI 9A was higher than that seen in TIMI 5, TIMI 6, and GUSTO 1. This was possibly a result of high levels of anticoagulation at the doses of heparin and hirudin used, low previous estimates of the hemorrhage risk at the doses of hirudin used in TIMI 9A due to the relatively small number of patients receiving that dose in earlier studies, and enrollment of patients at higher risk of hemorrhage. Because a prolonged aPTT was associated with an increased risk of major hemorrhage in both heparin- and hirudin-treated patients, it now appears important to monitor aPTT on a regular basis when using either antithrombin to identify those patients who require downward adjustment of the infusion. TIMI 9B has therefore been configured with a lower hirudin bolus (0.1 mg/kg) and infusion (0.1 mg/kg per hour) and lower heparin infusion (1000 U/h without weight adjustment). Infusions of both antithrombins will be titrated to a target aPTT of 55 to 85 seconds.
Molecular cloning of human prostacyclin receptor cDNA and its gene expression in the cardiovascular system.
Authors: Nakagawa O , Tanaka I , Usui T , Harada M , Sasaki Y , Itoh H , Yoshimasa T , Namba T , Narumiya S , Nakao K 
Published: June 2012

BACKGROUND
Prostacyclin elicits a potent vasodilation and inhibition of platelet aggregation through binding to its membrane receptor. The impairment of prostacyclin receptor activity is implicated in various human cardiovascular diseases. In the present study, we succeeded in the isolation and characterization of human prostacyclin receptor cDNA and elucidated its gene expression in human tissues.

METHODS AND RESULTS
We isolated a cDNA clone encoding the human prostacyclin receptor from a human lung cDNA library. The isolated cDNA clone encodes a 386-amino acid protein with seven putative transmembrane domains, which belongs to the G protein-coupled receptor superfamily. [3H]iloprost, a prostacyclin receptor agonist, specifically bound to the receptor transiently expressed in COS-7 cells. The binding was inhibited in the rank order of iloprost = cicaprost, another prostacyclin receptor agonist, > prostaglandin E1 (PGE1) > PGE2, PGF2 alpha, PGD2, STA2. In addition, iloprost dose-dependently stimulated cAMP generation in these COS-7 cells. These results are consistent with the characteristics of the human prostacyclin receptor. Northern blotting analysis on human tissues revealed that prostacyclin receptor mRNA is abundantly expressed in the aorta, lung, atrium, ventricle, and kidney.

CONCLUSIONS
We cloned human prostacyclin receptor cDNA and elucidated its abundant gene expression in the human cardiovascular system. The present study will lead to better understanding of the significance of prostacyclin in humans and further facilitate the clinical application of prostacyclin.
Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Asymptomatic Carotid Artery Progression Study (ACAPS) Research Group.
Authors: Furberg C D , Adams H P , Applegate W B , Byington R P , Espeland M A , Hartwell T , Hunninghake D B , Lefkowitz D S , Probstfield J , Riley W A 
Published: June 2012

BACKGROUND
HMG CoA reductase inhibitors (or statins), a new class of lipid-lowering compounds, have raised expectations for more widespread use than that of the older lipid-lowering drugs. Not only are they more effective in lowering LDL cholesterol, but they are better tolerated as well. No data exist concerning the effect of statins on early carotid atherosclerosis and clinical events in men and women who have moderately elevated LDL cholesterol levels but are free of symptomatic cardiovascular disease.

METHODS AND RESULTS
Lovastatin (20 to 40 mg/d) or its placebo was evaluated in a double-blind, randomized clinical trial with factorial design along with warfarin (1 mg/d) or its placebo. This report is limited to the lovastatin component of the trial. Daily aspirin (81 mg/d) was recommended for everyone. Enrollment included 919 asymptomatic men and women, 40 to 79 years old, with early carotid atherosclerosis as defined by B-mode ultrasonography and LDL cholesterol between the 60th and 90th percentiles. The 3-year change in mean maximum intimal-medial thickness (IMT) in 12 walls of the carotid arteries was the primary outcome; change in single maximum IMT and incidence of major cardiovascular events were secondary outcomes. LDL cholesterol fell 28%, from 156.6 mg/dL at baseline to 113.1 mg/dL at 6 months (P < .0001), in the lovastatin groups and was largely unchanged in the lovastatin-placebo groups. Among participants not on warfarin, regression of the mean maximum IMT was seen after 12 months in the lovastatin group compared with the placebo group; the 3-year difference was statistically significant (P = .001). A larger favorable effect of lovastatin was observed for the change in single maximum IMT but was not statistically significant (P = .12). Five lovastatin-treated participants suffered major cardiovascular events--coronary heart disease mortality, nonfatal myocardial infarction, or stroke--versus 14 in the lovastatin-placebo groups (P = .04). One lovastatin-treated participant died, compared with eight on lovastatin-placebo (P = .02).

CONCLUSIONS
In men and women with moderately elevated LDL cholesterol, lovastatin reverses progression of IMT in the carotid arteries and appears to reduce the risk of major cardiovascular events and mortality. Results from ongoing large-scale clinical trials may further establish the clinical benefit of statins.
Open infarct artery, late potentials, and other prognostic factors in patients after acute myocardial infarction in the thrombolytic era. A prospective trial.
Authors: Hohnloser S H , Franck P , Klingenheben T , Zabel M , Just H 
Published: June 2012

BACKGROUND
Successful reperfusion of the infarct-related artery in patients with acute myocardial infarction has been shown to reduce in-hospital as well as 1-year mortality. Besides the thrombolysis-induced myocardial salvage, there is increasing evidence that an open infarct-related artery results in increased electrical stability of the heart and that this effect is at least in part responsible for the favorable long-term outcome of these patients. The exact incidence of arrhythmic events during the first year after myocardial infarction and the predictive value of different risk factors for these complications, however, have not been determined in patients in the thrombolytic era.

METHODS AND RESULTS
A total of 173 patients with acute myocardial infarction, 51% treated with thrombolysis, were prospectively entered into the study. At the time of hospital discharge, signal-averaged ECG, Holter monitoring, radionuclide angiography, coronary angiography, and levocardiography were performed in all patients. An open infarct-related artery was documented in 136 patients. The overall incidence of late potentials was 24% (41 patients). By multivariate analysis, an occluded infarct-related artery (P = .04) and the presence of regional wall motion abnormalities (P = .02) were the strongest independent predictors for the development of a late potential. Residual ischemia was treated by either percutaneous transluminal coronary angioplasty or surgery in 86 of 173 patients (50%). Seventy percent of the patients received beta-blocker therapy. During a mean follow-up of 12 +/- 5 months, 7 patients died suddenly or had ventricular fibrillation documented, while only 2 developed sustained monomorphic ventricular tachycardia. Overall 1-year mortality was 4.1%. Multivariate analysis revealed only an occluded infarct-related artery as an independent predictor of arrhythmic complications (P = .017).

CONCLUSIONS
In patients with acute myocardial infarction treated according to contemporary therapeutic guidelines, with a large proportion of individuals undergoing coronary artery revascularization, a low incidence of arrhythmic events, particularly of ventricular tachycardia, was observed in the first year after the index infarction. The presence or absence of an open infarct-related artery was the strongest independent predictor of these events, whereas other traditional risk factors, such as late potentials, were less helpful in identifying patients prone to sudden death. These findings emphasize the importance of the open artery hypothesis in patients recovering from acute myocardial infarction.