bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural and functional alterations of the intramyocardial coronary arterioles in patients with arterial hypertension.
Authors: Schwartzkopff B , Motz W , Frenzel H , Vogt M , Knauer S , Strauer B E 
Published: June 2012

BACKGROUND
In hypertensive patients with angina pectoris, the coronary vasodilator reserve is frequently impaired despite a normal coronary angiogram. Experimental data indicate that structural alterations of the intramyocardial coronary vasculature contribute to an increased minimal coronary resistance and a diminished coronary flow reserve.

METHODS AND RESULTS
In 14 patients (10 men and 4 women) with arterial hypertension and 8 normotensive subjects, minimal coronary resistance and vasodilator reserve (dipyridamole: 0.5 mg/kg body wt, gas chromatographic argon method) were determined after the angiographic exclusion of relevant coronary artery disease. Coronary reserve was depressed in hypertensive patients (2.7 +/- 2.3 vs 4.6 +/- 1.3, P < or = .05) due to increased minimal coronary resistance (0.64 +/- 30 vs 0.24 +/- 0.055 mm Hg.min.100 g.mL-1, p < or = 0.002). In right septal biopsies, mean external arteriolar diameter (21.6 +/- 2.3 vs 17.2 +/- 2.5 microns, P < or = .001), mean arteriolar wall area (271 +/- 61 vs 172 +/- 62 microns 2, P < or = .01), percent medial wall area (69.9 +/- 4.0 vs 66.0 +/- 3.2%W, P < or = .05), mean periarteriolar fibrosis area (216 +/- 122 vs 104 +/- 68 microns 2, P < or = .05), and volume density of total interstitial fibrosis (3.6 +/- 1.8 vs 1.9 +/- 0.5Vv% fibrosis, P < or = .05) were increased in hypertensive patients compared with normotensive subjects. Minimal coronary resistance correlated with %W (r = .6, P < or = .003) and Vv% fibrosis (r = .62, P < or = .002). Left ventricular mass index (111 +/- 21 vs 97 +/- 17 g/m2, P = NS) and left ventricular end-diastolic pressure (12 +/- 6 vs 8 +/- 3 mm Hg, P = NS) did not correlate significantly with minimal coronary resistance. In multivariate analysis, both %W and Vv% fibrosis explained half of the variability of minimal coronary resistance (r2 = .5, P < or = .002).

CONCLUSIONS
Structural remodeling of the intramyocardial coronary arterioles and the accumulation of fibrillar collagen are decisive factors for a reduced coronary dilatory capacity in patients with arterial hypertension and angina pectoris in the absence of relevant coronary artery stenoses.
MK-383 (L-700,462), a selective nonpeptide platelet glycoprotein IIb/IIIa antagonist, is active in man.
Authors: Peerlinck K , De Lepeleire I , Goldberg M , Farrell D , Barrett J , Hand E , Panebianco D , Deckmyn H , Vermylen J , Arnout J 
Published: June 2012

BACKGROUND
Fibrinogen-dependent cross-linking of glycoprotein (GP) IIb/IIIa on activated platelets is the final mechanism leading to platelet aggregation. Inhibition of this mechanism may result in a novel antithrombotic agent. We studied the activity of MK-383 (L-700,462), a new, nonpeptide GPIIb/IIIa antagonist, in vitro and in vivo, in man.

METHODS AND RESULTS
MK-383, a nonpeptide tyrosine derivative, dose-dependently inhibited fibrinogen-dependent platelet aggregation, in vitro. Binding of 125I-labeled fibrinogen to activated platelets was prevented in a competitive manner with an IC50 of 10 +/- 4.2 nmol/L. The activity and tolerability of MK-383 were evaluated in a two-part double-blind, placebo-controlled, dose-escalation study in healthy male subjects using 1- and 4-hour intravenous infusions. Effects on ADP- and collagen-induced ex vivo platelet aggregation (APA or CPA) and template bleeding time (TBT) were evaluated. Twenty-four subjects participated in the 1-hour part. Six received placebo and 18 MK-383 in doses ranging from 0.05 to 0.40 microgram.kg-1 x min-1. MK-383 inhibited platelet aggregation and prolonged bleeding time in a dose-dependent manner. APA and CPA were totally inhibited at the end of infusion of 0.4 microgram.kg-1 x min-1 and returned to 55% and 89% of baseline, respectively, at 3 hours after infusion. TBT was prolonged at this dose from 5.0 +/- 1.3 minutes predose to 22.7 +/- 6 minutes at the end of the infusion (P < .01) and was normalized by 3 hours after infusion. In the 4-hour infusion part, 15 subjects received MK-383 (0.1 to 0.2 microgram.kg-1 x min-1), and five received placebo. Complete inhibition of ex vivo platelet aggregation was seen at 0.15 and 0.2 microgram.kg-1 x min-1. At 0.2 microgram.kg-1 x min-1, TBT was prolonged from 4.4 +/- 1.2 to 23.9 +/- 4.3 minutes at the end of infusion (P < .01) and remained slightly prolonged 3 hours after infusion (7.2 +/- 1.8 minutes). No adverse effects were observed in any of the 33 subjects receiving MK-383.

CONCLUSIONS
The results from this study indicate that MK-383 appears to be well tolerated and active in man. It is the first nonpeptide GPIIb/IIIa antagonist that can be used to investigate the antithrombotic potential of this new class of antiplatelet agents.
Inhalation of sidestream cigarette smoke accelerates development of arteriosclerotic plaques.
Authors: Penn A , Snyder C A 
Published: June 2012

BACKGROUND
Environmental tobacco smoke has been blamed for approximately 40,000 excess deaths from heart disease annually in the United States. As yet, no pathophysiological process that could be responsible for these deaths has been identified. Environmental tobacco smoke is composed mainly of aged and diluted sidestream smoke but also contains 15% to 20% exhaled mainstream smoke. Carcinogens, including nitrosamines and polynuclear aromatic hydrocarbons, are present in mainstream smoke and sidestream smoke. Carcinogen levels in sidestream smoke, unlike those in mainstream smoke, are not reduced in filtered cigarettes. The US Environmental Protection Agency has designated environmental tobacco smoke as a human (class A) carcinogen. In cockerels, subtumorigenic doses of polynuclear aromatic hydrocarbons carcinogens accelerate aortic arteriosclerotic plaque development.

METHODS AND RESULTS
To determine whether sidestream smoke inhalation affects arteriosclerotic plaque development, we exposed cockerels to sidestream smoke (n = 30) or to filtered air (n = 12) in inhalation chambers for 6 hours per day, 5 days a week from 6 to 22 weeks of age (0.4% of projected lifespan). Chamber levels of carbon monoxide, total suspended particulates, and nicotine were measured regularly during the exposures. The abdominal aorta from each cockerel was cut into 10 segments, and the plaque index (mean plaque cross-sectional area [mm2]/mean luminal circumference [mm] x 100) was calculated for each segment. There were no differences in plaque incidence or distribution between sidestream smoke-exposed and control cockerels; however, plaque indexes were significantly greater for sidestream smoke-exposed than control cockerels in all segments.

CONCLUSIONS
Thus, relatively brief exposures to sidestream smoke early in life are sufficient to enhance arteriosclerotic plaque development.
Propranolol and lidocaine inhibit neural norepinephrine release in hearts with increased extracellular potassium and ischemia.
Authors: Du X J , Riemersma R A , Fox K A , Dart A M 
Published: June 2012

BACKGROUND
Propranolol and lidocaine are effective antiarrhythmic drugs in myocardial ischemia and infarction. As sympathetic nerve activation and norepinephrine release in ischemic hearts are arrhythmogenic, we tested the possibility that both agents inhibit neural norepinephrine release following sympathetic activation in the ischemic environment.

METHODS AND RESULTS
The model used was an in situ perfused innervated rat heart. Norepinephrine release was induced by electrical stimulation of the left cervicothoracic stellate ganglion and analyzed using radioenzymatic assay or high-performance liquid chromatography. In normoxically perfused hearts, evoked norepinephrine release was not affected by either of the two agents at doses of 1 to 10 mumol/L when extracellular K+ concentration was 4 mmol/L but dose-dependently reduced at 10 mmol/L K+ (D,L-propranolol: -53 +/- 4% at 1 mumol/L and -64 +/- 6% at 10 mumol/L K+, lidocaine: -37 +/- 11% at 0.1 mumol/L, -67 +/- 5% at 1 mumol/L, and -75 +/- 6% at 10 mumol/L). At 10 mmol/L K+, norepinephrine release was not affected by timolol or atenolol (both 10 mumol/L but was equally inhibited by D- or L-propranolol at 10 mumol/L (-56 +/- 5% and -53 +/- 9%, respectively), indicating a beta-blocking-independent mechanism. In hearts with metabolic acidosis (pH 6.85) at K+ of 4 mmol/L, neural norepinephrine release was also reduced by propranolol at 10 mumol/L (-37%). Finally, in hearts perfused with 4 mmol/L K+ and subjected to 6-minute periods of ischemia, neural norepinephrine release was similarly suppressed by D,L-propranolol (-38 +/- 6% at 0.1 mumol/L, -44 +/- 5% at 1 mumol/L, and -78 +/- 3% at 10 mumol/L) or lidocaine (-39 +/- 7% at 0.1 mumol/L, -58 +/- 9% at 1 mumol/L, and -91 +/- 3% at 10 mumol/L).

CONCLUSIONS
These data indicate that propranolol and lidocaine inhibit neural norepinephrine release via a Na+ channel-blocking mechanism that is synergistic with changes induced by ischemia, primarily raised extracellular K+. This mechanism may contribute to the anti-ischemic and antiarrhythmic properties of both agents in acute myocardial ischemia, which induces increased extracellular K+ and sympathetic activation.
Excimer laser coronary angioplasty of aorto-ostial stenoses. Results of the excimer laser coronary angioplasty (ELCA) registry in the first 200 patients.
Authors: Eigler N L , Weinstock B , Douglas J S , Goldenberg T , Hartzler G , Holmes D , Leon M , Margolis J , Nobuyoshi M , O'Neill W 
Published: June 2012

BACKGROUND
Percutaneous transluminal coronary angioplasty (PTCA) of aorto-ostial stenosis has been associated with a lower rate of acute success, a high risk of vessel closure, and late restenosis. The purpose of this report is to document a prospective multicenter trial of excimer laser coronary angioplasty (ELCA) of aorto-ostial stenosis involving the coronary arteries and saphenous vein grafts.

METHODS AND RESULTS
Between December 1989 and May 1992, 206 aorto-ostial ELCA procedures were performed on 209 stenoses in 200 patients. Canadian Cardiovascular Society class III or IV angina was present in 76%. The distribution of stenosis locations was left main coronary (LM) in 26 (12%), right coronary (RCA) in 124 (59%), and vein grafts (VG) in 59 (28%). Adjunctive PTCA was performed in 72%. Procedure success defined as < or = 50% diameter stenosis without major complications was achieved in 90% (LM, 92%; RCA, 89%, VG, 90%). Quantitative angiographic analysis documented an improvement in stenosis diameter from 0.8 +/- 0.5 mm or 76 +/- 14% at baseline to 2.1 +/- 0.6 mm or 36 +/- 15% at completion (P < .01). The majority of the acute gain in diameter (1.0 +/- 0.6 mm) resulted from ELCA. A major complication during hospitalization occurred in 3.9% (death, 0%; Q-wave myocardial infarction, 0.5%; bypass surgery, 3.4%). The only logistic regression univariate and multivariate predictor of procedure failure was female gender. Six-month angiographic follow-up, available in 51% of eligible patients, documented an average lumen diameter of 1.7 +/- 1.0 mm and mean diameter stenosis of 46 +/- 26%. Restenosis (> 50% diameter stenosis) occurred in 39% (LM, 64%; RCA, 35%; VG, 35%). Restenosis was less likely when residual stenosis was < or = 35% (28% versus 53%, P < .05). Clinical events at follow-up were death, 2.7%; bypass surgery, 6.5%; myocardial infarction, 2.2%; and repeat angioplasty, 16.2%. Of the remainder, 78% were asymptomatic, class I or II for anginal symptoms. An adverse event during follow-up was more than twice as likely in the group with LM (50.0% versus 21.1%, P < .02).

CONCLUSIONS
ELCA is acutely effective and safe therapy in patients with aorto-ostial stenosis. Six-month restenosis, adverse-event rates were higher and functional status was poorer in the group with LM stenosis. ELCA may be considered as an alternative to bypass surgery in carefully selected patients with isolated aorto-ostial stenosis of the RCA and saphenous vein grafts.
Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults.
Authors: Celermajer D S , Sorensen K E , Georgakopoulos D , Bull C , Thomas O , Robinson J , Deanfield J E 
Published: June 2012

BACKGROUND
Cigarette smoking is the most important modifiable risk factor for atherosclerosis. Endothelial dysfunction is an early event in atherogenesis, and we hypothesized that smoking might be associated with endothelial damage in the systemic arteries of otherwise healthy young adults.

METHODS AND RESULTS
We studied noninvasively the brachial arteries of 200 subjects aged 15 to 57 years, all normotensive, nondiabetic with cholesterol level < or = 240 mg/dL and no family history of premature vascular disease: 80 control subjects aged 16 to 56 years (mean, 35), 80 current smokers aged 15 to 55 years (mean, 33), and 40 former smokers aged 25 to 57 years (mean, 38). Total lifetime amount smoked varied from 1 to 75 pack years in the smokers. Using high-resolution ultrasound, vessel diameter was measured at rest, during reactive hyperemia (with flow increase causing endothelium-dependent dilation), and after sublingual glyceryl trinitrate (GTN, an endothelium-independent vasodilator). Flow-mediated dilation (FMD) was observed in all the control subjects (10 +/- 3.3%; range, 4% to 22%) but was impaired or absent in the smokers (4 +/- 3.9%; range, 0% to 17%; P < .0001). FMD in the smokers was inversely related to lifetime dose smoked (6.6 +/- 4.0% in very light smokers, 4.0 +/- 3.1% in light smokers, 3.2 +/- 3.2% in moderate smokers, and 2.6 +/- 1.2% in heavy smokers; P < .01). FMD for the former smokers was 5.1 +/- 4.1% (range, 0% to 15%). In a multivariate model adjusting for age, sex, cholesterol, smoking history, and vessel size, former smoking was associated with a higher FMD than current smoking (P = .07); when only male former and current smokers were considered, the higher FMD was significant (P = .0001) but not for female smokers (P = .24). GTN caused dilation in all subjects (control subjects, 20 +/- 5.2%; smokers, 17 +/- 5.8%; former smokers, 17.4 +/- 5.4%). Vessel diameter, baseline flow, and degree of reactive hyperemia (Doppler estimated) were similar in all groups.

CONCLUSIONS
Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent arterial dilation in asymptomatic young adults, consistent with endothelial dysfunction.
Exercise-induced upward shift of diastolic left ventricular pressure-volume relation in patients with dilated cardiomyopathy. Effects of beta-adrenoceptor blockade.
Authors: Sato H , Hori M , Ozaki H , Yokoyama H , Imai K , Morikawa M , Takeda H , Inoue M , Kamada T 
Published: June 2012

BACKGROUND
The effectiveness of beta-blocker therapy for dilated cardiomyopathy (DCM) may be attributed to the inhibition of detrimental effects on the failing heart of sympathetic stimulation during exertion. However, the harmful effects of activity as well as the protective effects of beta-blockers have not been demonstrated. Diastolic ventricular function is known to be sensitive to transient myocardial metabolic insult. In this study, we investigated the effect of modest exercise with or without beta-blockade on the diastolic left ventricular pressure-volume (P-V) relation in patients with DCM.

METHODS AND RESULTS
The diastolic left ventricular P-V relation was obtained by high-fidelity pressure measurements and digital subtraction left ventriculography at rest and immediately after modest supine bicycle exercise in 12 patients with DCM. The effects of intravenous administration of 0.1 mg/kg propranolol on resting and exercise P-V relations were studied. The end-diastolic and lowest left ventricular pressures were significantly elevated by exercise (20 +/- 9 to 32 +/- 13 mm Hg, P < .01, and 12 +/- 6 to 21 +/- 11 mm Hg, P < .01, respectively) despite insignificant changes in left ventricular volumes. The administration of propranolol did not alter the resting diastolic P-V relation. However, propranolol significantly attenuated the exercise-induced upward shift of the diastolic P-V relation despite a significant increase in end-diastolic volume. The significant upward shift and attenuation by propranolol were also observed even when the left ventricular pressure was corrected by the subtraction of right atrial pressure.

CONCLUSIONS
These results indicate that even modest exercise exerts detrimental effects on diastolic left ventricular function of the failing heart through beta-adrenergic stimulation. The clinical effectiveness of beta-blocker therapy in patients with DCM can be attributed in part to the inhibition of detrimental myocardial effects of sympathetic stimulation during daily activity.
Pulmonary regurgitation in the late postoperative follow-up of tetralogy of Fallot. Volumetric quantitation by nuclear magnetic resonance velocity mapping.
Authors: Rebergen S A , Chin J G , Ottenkamp J , van der Wall E E , de Roos A 
Published: June 2012

BACKGROUND
Pulmonary regurgitation frequently occurs after surgical correction of tetralogy of Fallot. To date, reliable quantitation of pulmonary regurgitation has not been possible, and therefore the clinical significance of pulmonary regurgitation is controversial. Nuclear magnetic resonance (NMR) velocity mapping allows accurate measurement of volumetric flow. The feasibility and accuracy of NMR velocity mapping to quantify pulmonary regurgitation volumes are studied in patients after Fallot repair.

METHODS AND RESULTS
In 18 patients (mean age, 16.5 +/- 6.5 years), late (12.6 +/- 5.2 years) after Fallot surgery, forward and regurgitant volume flow was measured in the main pulmonary artery with NMR velocity mapping. To validate the measurements of pulmonary forward flow, right ventricular stroke volume was used as an internal reference standard. Pulmonary regurgitation volumes were compared with the differences between the corresponding right and left ventricular stroke volumes. Ventricular volumes were measured with a multisection gradient echo NMR method. In addition, the relation between pulmonary regurgitation and right ventricular volumes was studied. Measurements of pulmonary regurgitation volume with NMR velocity mapping closely corresponded with the tomographically determined volumes (r = .93). Forward pulmonary volume flow was nearly identical to right ventricular stroke volume (r = .98). Pulmonary regurgitation volume was significantly correlated with end-diastolic volume (r = .82, P < .0005), end-systolic volume (r = .63, P < .01), and stroke volume (r = .89, P < .0005) of the right ventricular but not with right ventricular ejection fraction (r = .41, P = NS).

CONCLUSIONS
NMR velocity mapping is an accurate method for the noninvasive, volumetric quantification of pulmonary regurgitation after surgical correction of tetralogy of Fallot.
Ischemic preconditioning fails to limit infarct size in reserpinized rabbit myocardium. Implication of norepinephrine release in the preconditioning effect.
Authors: Toombs C F , Wiltse A L , Shebuski R J 
Published: June 2012

BACKGROUND
Infarct size reduction by ischemic preconditioning is believed to be mediated by adenosine; however, whether adenosine is the factor responsible for the initiation of this protection remains unknown. It is possible that during preconditioning, adenosine stimulates receptors on presynaptic nerve terminals and retards the release of norepinephrine (NE) during the prolonged ischemia or that NE release during preconditioning augments adenosine production.

METHODS AND RESULTS
To test whether the release of NE is involved in the preconditioning phenomenon, rabbits were pretreated with reserpine (5 mg/kg sc, 24 hours before) to deplete presynaptic nerve terminals of NE stores. On the day of the experiment, the rabbits were anesthetized with ketamine-xylazine and instrumented for coronary occlusion. Nonreserpinized animals were used as controls. The control group (n = 7) was subjected to 30 minutes of coronary occlusion and 120 minutes of reperfusion (ischemia-reperfusion) only. The preconditioned group (n = 10) received 5 minutes of preconditioning ischemia and 10 minutes of reperfusion before the prolonged ischemia-reperfusion. Of the reserpinized animals, half (n = 7) received preconditioning before ischemia-reperfusion and the remaining animals (n = 7) did not. At termination of the experiment, an intravenous tyramine challenge (1 mg/kg) was used to confirm NE depletion in reserpinized rabbits. The resulting infarcts were measured with tetrazolium and planimetry. With comparable hemodynamics and areas at risk, infarct size in control animals was 39.8 +/- 2.1% of the risk region. Preconditioned animals showed an expected reduction of infarct size to 14.8 +/- 2.2% of risk region (P < .05 vs control). Of the reserpinized animals, those that received reserpine alone had infarcts that were 38.5 +/- 4.5% of risk region, and those that were preconditioned had infarcts that were 41.4 +/- 3.6% of risk region, which was not significantly different than the control group.

CONCLUSIONS
We conclude that preconditioning fails to protect ischemic-reperfused myocardium in reserpinized rabbit myocardium, indicating that the release of NE during either preconditioning or prolonged ischemia is critical to preconditioning mediated protection.
Mechanism of selective epicardial activation delay during acute myocardial ischemia in dogs.
Authors: Arenal A , Villemaire C , Nattel S 
Published: June 2012

BACKGROUND
Previous studies have shown that acute myocardial ischemia in the dog results in much greater activation delays in epicardial than endocardial tissue. These results have been interpreted to indicate enhanced sensitivity of epicardial conduction properties to acute ischemia. This study was designed to test the hypothesis that the ischemic epicardial activation delay during supraventricular rhythms is due to slow conduction across the ischemic myocardial wall prior to epicardial activation and not to enhanced epicardial conduction slowing per se.

METHODS AND RESULTS
Changes in epicardial and endocardial activation were measured with transmural decapolar needle electrodes during successive 5-minute left anterior descending coronary artery (LAD) occlusions separated by 30-minute reperfusion periods. Occlusions were performed during left atrial pacing, right ventricular pacing with a stimulating electrode located along the longitudinal axis of epicardial fiber orientation in the ischemic zone, or left ventricular pacing in nonischemic tissue located on a line transverse to fiber orientation in the ischemic zone. During both atrial and left ventricular pacing, activation in the ischemic zone began in the endocardium. Epicardial activation resulted from transmural conduction and was markedly delayed compared with endocardial activation during acute myocardial ischemia. During right ventricular stimulation, the ischemic zone epicardium was activated via longitudinal epicardial conduction, and its activation was only slightly delayed by acute ischemia. Epicardial activation mapping was used to assess ischemia-induced changes in longitudinal epicardial conduction velocity and to compare them with changes in transmural velocity during atrial or left ventricular pacing. Longitudinal conduction in the ischemic epicardium was slowed by 13 +/- 4% (mean +/- SE) relative to preischemic control values in contrast to transmural conduction, which was slowed 50 +/- 4% by LAD occlusion during atrial pacing and 49 +/- 5% during left ventricular pacing (both P < .001 versus longitudinal epicardial conduction). Transmural activation studies showed that the midmyocardium is the site of most of the ischemic activation delay during transmural propagation.

CONCLUSIONS
Epicardial activation is more delayed than endocardial by acute ischemia during supraventricular rhythms in dogs because of slowed conduction across the myocardial wall, not because of enhanced sensitivity of epicardial conduction to depression by acute ischemia.