bluuebunny/crossref_metadata_2025 huggingface dataset:
Coronary flow reserve calculated from pressure measurements in humans. Validation with positron emission tomography.
Authors: De Bruyne B , Baudhuin T , Melin J A , Pijls N H , Sys S U , Bol A , Paulus W J , Heyndrickx G R , Wijns W
Published: June 2012

BACKGROUND

Experimental studies have shown that fractional flow reserve (defined as the ratio of maximal achievable flow in a stenotic area to normal maximal achievable flow) can be calculated from coronary pressure measurements only. The objectives of this study were to validate fractional flow reserve calculation in humans and to compare this information with that derived from quantitative coronary angiography.

METHODS AND RESULTS

Twenty-two patients with an isolated, discrete proximal or mid left anterior descending coronary artery stenosis and normal left ventricular function were studied. Relative myocardial flow reserve, defined as the ratio of absolute myocardial perfusion during maximal vasodilation in the stenotic area to the absolute myocardial perfusion during maximal vasodilation (adenosine 140 micrograms.kg-1 x min-1 intravenously during 4 minutes) in the contralateral normally perfused area, was assessed by 15O-labeled water and positron emission tomography (PET). Myocardial and coronary fractional flow reserve were calculated from mean aortic, distal coronary, and right atrial pressures recorded during maximal vasodilation. Distal coronary pressures were measured by an ultrathin, pressure-monitoring guide wire with minimal influence on the trans-stenotic pressure gradient. Minimal obstruction area, percent area stenosis, and calculated stenosis flow reserve were assessed by quantitative coronary angiography. There was no difference in heart rate, mean aortic pressure, or rate-pressure product during maximal vasodilation during PET and during catheterization. Percent area stenosis ranged from 40% to 94% (mean, 77 +/- 13%), myocardial fractional flow reserve from 0.36 to 0.98 (mean, 0.61 +/- 0.17), and relative flow reserve from 0.27 to 1.23 (mean, 0.60 +/- 0.26). A close correlation was found between relative flow reserve obtained by PET and both myocardial fractional flow reserve (r = .87) and coronary fractional flow reserve obtained by pressure recordings (r = .86). The correlations between relative flow reserve obtained by PET and stenosis measurements derived from quantitative coronary angiography were markedly weaker (minimal obstruction area, r = .66; percent area stenosis, r = -.70; and stenosis flow reserve, r = .68).

CONCLUSIONS

Fractional flow reserve derived from pressure measurements correlates more closely to relative flow reserve derived from PET than angiographic parameters. This validates in humans the use of fractional flow reserve as an index of the physiological consequences of a given coronary artery stenosis.
Reflex versus tonic vagal activity as a prognostic parameter in patients with sustained ventricular tachycardia or ventricular fibrillation.
Authors: Hohnloser S H , Klingenheben T , van de Loo A , Hablawetz E , Just H , Schwartz P J
Published: June 2012

BACKGROUND

The autonomic nervous system has been demonstrated to play a decisive role in the genesis of sudden cardiac death. The loss of protective vagal reflexes, in particular, appears to be associated with an increased incidence of malignant ventricular tachyarrhythmias. Two clinically applicable methods for assessment of cardiac autonomic control have been developed: determination of heart rate variability and evaluation of baroreflex sensitivity.

METHODS AND RESULTS

To compare the potential predictive value of both methods, two groups of patients were studied. Group 1 comprised 14 postinfarction patients who had experienced at least one episode of ventricular fibrillation or sustained ventricular tachycardia and who were studied after this event. Group 2 consisted of 14 postinfarction patients without tachyarrhythmic events after their infarct. Both groups were carefully matched with respect to age, sex, infarct location, extent of coronary artery disease, left ventricular ejection fraction, blood pressure, and heart rate at rest. Heart rate variability was assessed from 24-hour Holter recordings, and baroreflex sensitivity was determined by means of the phenylephrine method. Indices of heart rate variability were not significantly different between the two groups (SD of the mean RR interval, 84 +/- 30 milliseconds versus 103 +/- 20 milliseconds; proportion of adjacent RR intervals > 50 milliseconds different, 2.8 +/- 3.2% versus 5.0 +/- 4.1% in group 1 versus 2). Baroreflex sensitivity, however, showed a striking difference: Group 1 patients had a mean value of 1.75 +/- 1.63 ms/mm Hg compared with 9.17 +/- 5.40 ms/mm Hg in group 2 (P = .0002). Eleven of 14 group 1 patients had a baroreflex sensitivity < or = 3.0 ms/mm Hg. By contrast, only 1 of 14 group 2 patients had such a depressed value.

CONCLUSIONS

The results of this study indicate that postmyocardial infarction patients who develop life-threatening ventricular tachyarrhythmias, compared with carefully matched postinfarction patients without major arrhythmic episodes, differ strikingly in terms of baroreflex sensitivity but not in terms of heart rate variability. This finding may have implications for the risk stratification of postinfarction patients and may lead to a differential therapeutic strategy based on autonomic testing.
Relation of regional cross-fiber shortening to wall thickening in the intact heart. Three-dimensional strain analysis by NMR tagging.
Authors: Rademakers F E , Rogers W J , Guier W H , Hutchins G M , Siu C O , Weisfeldt M L , Weiss J L , Shapiro E P
Published: June 2012

BACKGROUND

The mechanism by which small amounts of myofiber shortening lead to extensive wall thickening is unknown. When isolated fibers shorten, they thicken in the two orthogonal directions. In situ fibers, however, vary in their orientation through the wall, and each is tethered to near or distant neighbors, which allows shortening to occur both in the direction of the fibers and also perpendicular to them. This "cross-fiber" shortening may enable the wall to shorten in two directions and thereby thicken extensively in the third.

METHODS AND RESULTS

Nuclear magnetic resonance tagging is a noninvasive method of labeling and tracking myocardium of the entire heart in three dimensions that does not interfere with myocardial motion. To investigate the presence and importance of cross-fiber shortening in the intact left ventricle, 10 closed-chest dogs were studied by nuclear magnetic resonance tagging. Five short-axis and four long-axis images were acquired to reconstruct 32 cubes of myocardium in each dog at end diastole and end systole. Pathological dissection was performed to determine the fiber direction at the epicardium, midwall, and endocardium of each cube. Strain was computed from the three-dimensional cube coordinates in the fiber and cross-fiber directions for epicardial and endocardial surfaces, and thickening of the full wall and its epicardial and endocardial halves was determined. Shear deformations were also calculated. Fiber strain at the epicardium and endocardium was -6.4 +/- 0.7% and -8.5 +/- 0.6% (mean +/- SEM), respectively (difference, P > .05). Cross-fiber strain at epicardium and endocardium was -0.6 +/- 0.5% and -25 +/- 0.6%, respectively (difference, P < .05). Thickening of the full wall reached 32.5 +/- 1.0%, composed of epicardial thickening of 25.5 +/- 0.6% and endocardial thickening of 43.3 +/- 1.0% (difference, P < .05). Fiber/cross-fiber shear strain was small (< 3%). Significant regional differences were present in all strains. A significant correlation was found between the extents of regional thickening and cross-fiber shortening.

CONCLUSIONS

Cross-fiber shortening at the endocardium, therefore, far exceeds cross-fiber shortening at the epicardium and fiber shortening at both epicardium and endocardium. Since no active shortening can occur locally in the cross-fiber direction, the extensive endocardial cross-fiber shortening must result from interaction with differently aligned fibers at a distance. The correlation between regional thickening and cross-fiber shortening supports the hypothesis that this interaction is the mechanism for amplifying small amounts of fiber shortening to cause extensive endocardial thickening.
Both ETA and ETB receptors mediate contraction to endothelin-1 in human blood vessels.
Authors: Seo B , Oemar B S , Siebenmann R , von Segesser L , Lüscher T F
Published: June 2012

BACKGROUND

Endothelin (ET)-1 has potent vascular effects. Two endothelin receptors have been cloned, namely, the ETA receptor, which preferentially binds ET-1, and the ETB receptor, which equally binds ET-1 and ET-3 and preferentially sarafotoxin S6c. We characterized endothelin receptor subtypes on vascular smooth muscle and endothelium of isolated human internal mammary artery (IMA) and vein (IMV) and porcine coronary artery (PCA) using the ETA antagonists FR139317 and BQ-123, the ETB ligand sarafotoxin S6c, and the ETA/ETB antagonist Ro 47-0203 (bosentan).

METHODS AND RESULTS

In endothelium-denuded IMA and PCA and less so in IMV, FR139317 and BQ-123 (in PCA only) shifted the concentration-contraction curves to ET-1 parallel to the right. However, even at 10(-5) mol/L, FR139317 did not inhibit a high-sensitivity portion of the concentration-contraction curve. Moreover, the ETB receptor agonist sarafotoxin S6c induced contraction in vessels preincubated with FR139317. IMV was significantly more sensitive to the contractile effect of ET-1 and sarafotoxin S6c than was IMA (P < .05). Prolonged incubation with sarafotoxin S6c (to downregulate ETB receptors) and FR139317 eliminated the contraction resistant to FR139317. The ETA/ETB receptor antagonist bosentan caused a parallel shift of the concentration-contraction curve to the right at all concentrations of endothelin. ETB receptor mRNA was detected by Northern blot analysis in IMA and aortic smooth muscle cells. In precontracted IMA and PCA with endothelium, sarafotoxin S6c did not cause endothelium-dependent relaxations, whereas transient responses occurred in IMV.

CONCLUSIONS

Vascular smooth muscle cells of human IMA, IMV, and PCA contain both ETA and ETB receptors, whereas the endothelium of IMA and PCA does not express functional ETB receptors linked to nitric oxide and/or prostacyclin production. Hence, inhibition of endothelin-induced contraction in patients requires the use of combined ETA/ETB antagonists.
Endogenous adenosine does not activate ATP-sensitive potassium channels in the hypoxic guinea pig ventricle in vivo.
Authors: Xu J , Wang L , Hurt C M , Pelleg A
Published: June 2012

BACKGROUND

The activation of ATP-sensitive K+ (K+ ATP) channels by K+ ATP openers, eg, pinacidil, hypoxia, and ischemia, is known to shorten the ventricular action potential. Since adenosine is released in increased amounts during cardiac hypoxia and ischemia, the hypothesis that endogenous adenosine activates K+ ATP channels was tested in vivo in a guinea pig model.

METHODS AND RESULTS

Anesthetized animals (n = 37) were subjected to transient acute global hypoxia by ventilation with 100% N2. Monophasic action potentials (MAP) were recorded in ventricular and atrial myocardium by use of custom-made Ag/AgCl electrode catheters. In addition, right atrial and left ventricular electrograms as well as systemic arterial blood pressure were monitored throughout the experiments. Under normoxic conditions, pinacidil (1.8 microgram/kg i.v., n = 8), a K+ ATP channel opener, shortened ventricular MAP duration (APD); this effect was reversed by glibenclamide, a potent K+ ATP channel blocker, but not by 8-cyclopentyl-1,3-dimethylxanthine (CPT), a potent A1-selective adenosine antagonist. Global hypoxia shortened atrial and ventricular APD. Glibenclamide but not CPT reversed this effect of hypoxia on ventricular but not atrial MAP. CPT but not glibenclamide reversed the effect of hypoxia on atrial MAP. In addition, CPT delayed the appearance of the atrioventricular (AV) nodal conduction block associated with global hypoxia. Finally, the ability of CPT to selectively attenuate A1-adenosine receptor-mediated effects of adenosine agonists in ventricular and supraventricular tissues was confirmed in 17 animals. CPT reversed the negative dromotropic effect of adenosine on AV nodal conduction and the antiadrenergic effect of N6-cyclopentyladenosine (CPA) mediated by A1-adenosine receptor but not the adenosine-induced decrease in systemic blood pressure caused by the vasodilatory action of the nucleoside mediated by A2-adenosine receptor.

CONCLUSIONS

(1) Endogenous adenosine released during global cardiac hypoxia mediates, in part, AV nodal conduction delay and shortening of atrial but not ventricular APD. (2) The action of adenosine on atrial APD is mediated by A1 adenosine receptors, probably via IK,Ado,Ach. (3) Endogenous adenosine apparently does not play an important role in the early stages of acute global hypoxia-induced activation of K+ ATP channels. The present results are consistent with the hypothesis that the shortening of ventricular APD in the hypoxic heart is due, in part, to activation of K+ ATP channels.
Infarct size-limiting effect of ischemic preconditioning is blunted by inhibition of 5'-nucleotidase activity and attenuation of adenosine release.
Authors: Kitakaze M , Hori M , Morioka T , Minamino T , Takashima S , Sato H , Shinozaki Y , Chujo M , Mori H , Inoue M
Published: June 2012

BACKGROUND

We have previously reported that ischemic preconditioning increases 5'-nucleotidase activity and adenosine release during ischemia and reperfusion. However, its direct cause-and-effect relation has not been proven. To test the idea that the infarct size-limiting effect of ischemic preconditioning is blunted by inhibition of ectosolic 5'-nucleotidase activity, we assessed 5'-nucleotidase activity, adenosine release, and infarct size caused by sustained ischemia with and without an exposure to alpha,beta,-methylene adenosine 5'-diphosphate (AOPCP) in the ischemia-preconditioned myocardium.

METHODS AND RESULTS

In 67 open-chest dogs, the left anterior descending coronary artery was cannulated and perfused with an extracorporeal bypass tube from the carotid artery. After hemodynamic stabilization, the coronary artery was occluded four times for 5 minutes separated by 5 minutes of reperfusion (ischemic preconditioning, n = 10). After this procedure, the coronary artery was occluded for 90 minutes followed by 6 hours of reperfusion. Infarct size normalized by the risk area was smaller than the control group (n = 8, 41.0 +/- 2.6% versus 6.8 +/- 1.9%), although there were no significant differences in the endomyocardial collateral flow measured at 80 minutes of ischemia (8.5 +/- 1.1 versus 9.4 +/- 1.0 mL/100 g per minute). Ectosolic and cytosolic 5'-nucleotidase activity and adenosine release were increased during reperfusion in the ischemic preconditioning group compared with the control group, and the activity of ectosolic 5'-nucleotidase was markedly reduced by AOPCP (n = 10). AOPCP affected neither adenosine-induced coronary vasodilation nor increases in myocardial oxygen consumption during an intracoronary infusion of isoproterenol (n = 10). To test whether the increase in 5'-nucleotidase activity decreases infarct size, we infused AOPCP 10 minutes before the ischemic preconditioning procedure and continued for 60 minutes after the onset of reperfusion (n = 8). AOPCP blunted the infarct size-limiting effect (infarct size, 38.8 +/- 4.9%). AOPCP without ischemic preconditioning did not increase infarct size (n = 9). Furthermore, when AOPCP was infused during the ischemic preconditioning procedure (n = 6) or during 60 minutes of reperfusion (n = 6), the infarct size-limiting effect was partially blunted (infarct size, 21.3 +/- 2.5% and 19.5 +/- 2.4%, respectively).

CONCLUSIONS

Increases in ectosolic 5'-nucleotidase activity and adenosine release are primarily responsible for the infarct size-limiting effect of ischemic preconditioning. Exposures to adenosine during the ischemic preconditioning procedure and enhanced release of adenosine during reperfusion synergistically contribute to the infarct size-limiting effects.
Specific factor Xa inhibition reduces restenosis after balloon angioplasty of atherosclerotic femoral arteries in rabbits.
Authors: Ragosta M , Gimple L W , Gertz S D , Dunwiddie C T , Vlasuk G P , Haber H L , Powers E R , Roberts W C , Sarembock I J
Published: June 2012

BACKGROUND

Balloon angioplasty of atherosclerotic arteries results in activation of the coagulation cascade. Several coagulation factors, including factor Xa and thrombin, are mitogenic for vascular smooth muscle cells in vitro and thus may play a role in restenosis after balloon angioplasty. Specific inhibition of factor Xa can be achieved with recombinant antistasin (rATS) or tick anticoagulant peptide (rTAP). We hypothesized that inhibition of Xa would limit restenosis after balloon angioplasty in an atherosclerotic rabbit model.

METHODS AND RESULTS

Focal femoral atherosclerosis was induced by air desiccation injury and a high-cholesterol diet in 38 New Zealand White rabbits. Recombinant antistasin (n = 20 arteries) or rTAP (n = 14 arteries) was administered by intravenous bolus at the time of balloon angioplasty and followed by a 2-hour infusion; controls (n = 21 arteries) received bolus heparin alone (150 U/kg). Therapeutic prolongation of the activated partial thromboplastin time occurred, and antithrombotic drug levels were achieved in all animals. Luminal diameter in millimeters by quantitative angiography did not differ between treatment groups before (1.1 +/- 0.2 for controls, 1.1 +/- 0.2 for rATS, and 1.1 +/- 0.3 for rTAP) or after balloon angioplasty (1.5 +/- 0.3 for controls, 1.4 +/- 0.2 for rATS, and 1.4 +/- 0.2 for rTAP). At 28 days, treatment with factor Xa inhibitors tended to result in arteries with larger luminal diameter than controls (1.2 +/- 0.3 for rATS, 1.2 +/- 0.3 for rTAP versus 1.0 +/- 0.3 for control, P = .09 by one-way ANOVA). Restenosis, defined as reduction in angiographic luminal diameter (in mm) from 2 hours after angioplasty to 28 days after angioplasty was less in the rATS group than in controls (-0.2 +/- 0.1 versus -0.5 +/- 0.4, P < .001) and tended to be less in the rTAP group (-0.3 +/- 0.2 versus -0.5 +/- 0.4, P = .07). Quantitative histopathological analysis showed less percent cross-sectional area narrowing by plaque in both rATS- and rTAP-treated arteries compared with controls (42 +/- 21%, 47 +/- 18%, and 63 +/- 14%, respectively; P < .01 by one-way ANOVA).

CONCLUSIONS

We conclude that a 2-hour infusion of rATS or rTAP reduced angiographic restenosis and resulted in less luminal cross-sectional narrowing by plaque compared with controls.
Effects of intensive multiple risk factor reduction on coronary atherosclerosis and clinical cardiac events in men and women with coronary artery disease. The Stanford Coronary Risk Intervention Project (SCRIP).
Authors: Haskell W L , Alderman E L , Fair J M , Maron D J , Mackey S F , Superko H R , Williams P T , Johnstone I M , Champagne M A , Krauss R M
Published: June 2012

BACKGROUND

Recent clinical trials have shown that modification of plasma lipoprotein concentrations can favorably alter progression of coronary atherosclerosis, but no data exist on the effects of a comprehensive program of risk reduction involving both changes in lifestyle and medications. This study tested the hypothesis that intensive multiple risk factor reduction over 4 years would significantly reduce the rate of progression of atherosclerosis in the coronary arteries of men and women compared with subjects randomly assigned to the usual care of their physician.

METHODS AND RESULTS

Three hundred men (n = 259) and women (n = 41) (mean age, 56 +/- 7.4 years) with angiographically defined coronary atherosclerosis were randomly assigned to usual care (n = 155) or multifactor risk reduction (n = 145). Patients assigned to risk reduction were provided individualized programs involving a low-fat and -cholesterol diet, exercise, weight loss, smoking cessation, and medications to favorably alter lipoprotein profiles. Computer-assisted quantitative coronary arteriography was performed at baseline and after 4 years. The main angiographic outcome was the rate of change in the minimal diameter of diseased segments. All subjects underwent medical and risk factor evaluations at baseline and yearly for 4 years, and reasons for all hospitalizations and deaths were documented. Of the 300 subjects randomized, 274 (91.3%) completed a follow-up arteriogram, and 246 (82%) had comparative measurements of segments with visible disease at baseline and follow-up. Intensive risk reduction resulted in highly significant improvements in various risk factors, including low-density lipoprotein cholesterol and apolipoprotein B (both, 22%), high-density lipoprotein cholesterol (+12%), plasma triglycerides (-20%), body weight (-4%), exercise capacity (+20%), and intake of dietary fat (-24%) and cholesterol (-40%) compared with relatively small changes in the usual-care group. No change was observed in lipoprotein(a) in either group. The risk-reduction group showed a rate of narrowing of diseased coronary artery segments that was 47% less than that for subjects in the usual-care group (change in minimal diameter, -0.024 +/- 0.066 mm/y versus -0.045 +/- 0.073 mm/y; P < .02, two-tailed). Three deaths occurred in each group. There were 25 hospitalizations in the risk-reduction group initiated by clinical cardiac events compared with 44 in the usual-care group (rate ratio, 0.61; P = .05; 95% confidence interval, 0.4 to 0.9).

CONCLUSIONS

Intensive multifactor risk reduction conducted over 4 years favorably altered the rate of luminal narrowing in coronary arteries of men and women with coronary artery disease and decreased hospitalizations for clinical cardiac events.
Heparin neutralization by platelet-rich thrombi. Role of platelet factor 4.
Authors: Eitzman D T , Chi L , Saggin L , Schwartz R S , Lucchesi B R , Fay W P
Published: June 2012

BACKGROUND

Platelets contain several factors that inhibit heparin. This study was designed to assess the heparin-neutralizing activity present in acute, platelet-rich arterial thrombi formed at sites of arterial injury in animals.

METHODS AND RESULTS

Platelet-rich thrombi (n = 3) were induced in pig coronary arteries by balloon catheter-mediated arterial injury. Soluble extracts were prepared from each thrombus and assayed for the capacity to inhibit heparin in an in vitro clotting assay (activated partial thromboplastin time). Mean heparin-neutralizing activity was 28 U of heparin neutralized per milliliter of thrombus, indicating that 1 vol of coronary thrombus completely inhibited the heparin present in 140 vols of therapeutically anticoagulated (0.2 U heparin/mL) plasma. In contrast, thrombus extracts had no effect on the anticoagulant activity of hirudin, a direct-acting thrombin inhibitor. The heparin-neutralizing activity present in coronary thrombi bound to heparin-agarose and was eluted from it by 1.4 mol/L NaCl, suggesting that platelet factor 4 mediated the antiheparin effect of thrombi. Consistent with this hypothesis, a murine monoclonal antibody to rabbit platelet factor 4 nearly completely inhibited the heparin-neutralizing activity present in rabbit thrombi (n = 3) generated by carotid artery injury.

CONCLUSIONS

Extracts prepared from platelet-rich arterial thrombi significantly inhibit the in vitro anticoagulant potency of heparin but not of hirudin. This antiheparin effect appears to be mediated by platelet factor 4. These results are consistent with the hypothesis that localized inhibition of heparin at sites of platelet activation may reduce its antithrombotic efficacy. In addition, they suggest an additional mechanism for the apparent superiority of hirudin over heparin as a thrombin inhibitor at sites of arterial injury.
Endothelin in human congestive heart failure.
Authors: Wei C M , Lerman A , Rodeheffer R J , McGregor C G , Brandt R R , Wright S , Heublein D M , Kao P C , Edwards W D , Burnett J C
Published: June 2012

BACKGROUND

Although recent investigations report the elevation of plasma endothelin (ET) in congestive heart failure (CHF), it remains unclear if this elevation is that of the biologically active peptide ET-1 or of its precursor big-ET. Furthermore, it is unclear if such elevation is associated with increased myocardial ET and if the molecular form from cardiac tissue is altered ET. Last, it remains to be established whether circulating ET is increased at the earliest stage of CHF in patients with asymptomatic left ventricular dysfunction and correlates with the magnitude of ventricular dysfunction.

METHODS AND RESULTS

The present study was designed to investigate concentrations and molecular forms of ET in plasma and cardiac tissue in healthy subjects and CHF patients with New York Heart Association (NYHA) class I through IV using cardiac radionuclide angiogram, cardiac myocardial biopsy, radioimmunoassay, gel permeation chromatography (GPC), and immunohistochemical staining (IHCS). Plasma ET was increased only in patients with moderate (NYHA class III) or severe (NYHA class IV) CHF compared with healthy subjects and individuals with asymptomatic (NYHA class I) or mild (NYHA class II) CHF. The elevation of circulating ET in CHF showed a negative correlation with left ventricular ejection fraction and cardiac index and a positive correlation with functional class and left ventricular end-diastolic volume index. GPC demonstrated that immunoreactive plasma ET was ET-1 in healthy subjects and both mature ET-1 and its precursor big-ET in severe CHF patients, with big-ET the predominant molecular form. Cardiac tissue concentrations and IHCS revealed ET presence in healthy atrial and ventricular tissue, which were not different in severe CHF. GPC revealed that the molecular form of cardiac ET was ET-1 in both healthy and CHF hearts.

CONCLUSIONS

The present study establishes for the first time that the elevation of plasma ET in severe human CHF represents principally elevation of big-ET. Second, ET is present in healthy and failing myocardia, and its activity by both immunohistochemistry and radioimmunoassay is not changed in CHF. Furthermore, the elevated plasma ET is characteristic of severe CHF and not asymptomatic or mild CHF. In addition, the degree of plasma elevation of ET correlates with the magnitude of alterations in cardiac hemodynamics and functional class. The present study confirms and extends previous investigations of ET in human CHF and establishes the evolution of circulating and local cardiac ET in the spectrum of human CHF.
Effect of L-arginine on coronary endothelial function in cardiac transplant recipients. Relation to vessel wall morphology.
Authors: Drexler H , Fischell T A , Pinto F J , Chenzbraun A , Botas J , Cooke J P , Alderman E L
Published: June 2012

BACKGROUND

Coronary endothelial vasodilator dysfunction is a common finding in cardiac transplant recipients and may represent an early marker for the development of intimal thickening and graft atherosclerosis. The present study tested the hypothesis that endothelial dysfunction precedes intimal thickening and that administration of L-arginine, the precursor of endothelium-derived relaxing factor, improves endothelial vasodilator function of coronary conduit and resistance vessels if given at an early stage of graft atherosclerosis.

METHODS AND RESULTS

Acetylcholine (10(-6), 10(-5), 10(-4) mol/L) was infused into the left anterior descending or circumflex artery and repeated after intravenous infusion of L-arginine (10 mg.kg-1.min-1 over 20 minutes) in 18 cardiac transplant recipients. Epicardial responses were evaluated by quantitative angiography, and the microcirculation was studied by determination of coronary blood flow with a Doppler flow velocity wire. Intimal thickening was assessed by intravascular ultrasound (n = 14). In epicardial coronary arteries, acetylcholine tended to elicit vasoconstriction. Epicardial coronary vasoconstriction elicited by acetylcholine was attenuated by infusion of L-arginine (10(-4) mol/L, -6.8% versus -2.8%; P < .01); this beneficial effect was observed predominantly in patients with normal intravascular ultrasound characteristics. In coronary resistance vessels, acetylcholine induced vasodilation, reflected by increases in coronary blood flow. The acetylcholine-induced increase in blood flow was significantly enhanced with L-arginine (at a dose of 10(-4) mol/L, + 121% versus 176%; before versus after L-arginine, P < .002).

CONCLUSIONS

The coronary vasculature of cardiac transplant recipients exhibits a generalized endothelial dysfunction of conduit and resistance vessels. L-Arginine improves endothelial dysfunction of both coronary microvasculature and epicardial coronary arteries. The reversibility of epicardial endothelial dysfunction by L-arginine is more likely in vessels with normal wall morphology.
Dose-response of chronic beta-blocker treatment in heart failure from either idiopathic dilated or ischemic cardiomyopathy. Bucindolol Investigators.
Authors: Bristow M R , O'Connell J B , Gilbert E M , French W J , Leatherman G , Kantrowitz N E , Orie J , Smucker M L , Marshall G , Kelly P
Published: June 2012

BACKGROUND

Small-scale clinical investigations have demonstrated that single doses of beta-blocking agents can improve left ventricular function in heart failure from idiopathic dilated cardiomyopathy (IDC). The purpose of this multicenter clinical trial was to determine the dose-effect characteristics of beta-blockade in a heart failure population that includes ischemic dilated cardiomyopathy (ISCD).

METHODS AND RESULTS

Bucindolol is a nonselective beta-blocking agent with mild vasodilatory properties. One hundred forty-one subjects with class II or III heart failure, left ventricular ejection fraction (LVEF) < or = 0.40, and background therapy of angiotensin-converting enzyme inhibitors, digoxin, and diuretics were given an initial challenge dose of bucindolol 12.5 mg. One hundred thirty-nine subjects (99 with IDC, 40 with ISCDC) tolerated challenge and were randomized to treatment with placebo or bucindolol 12.5 mg/d (low dose), 50 mg/d (medium dose), or 200 mg/d (high dose). At the end of 12 weeks, left ventricular function and other parameters were measured and compared with baseline values. There was a dose-related improvement in left ventricular function in bucindolol-treated subjects. In the high-dose bucindolol group, radionuclide-measured LVEF improved by 7.8 EF units (%) compared with 1.8 units in the placebo group (P < .05), and compared with the placebo group, a greater percentage of subjects had an increase in LVEF by > or = 5 units. In contrast, all three bucindolol doses prevented deterioration of myocardial function as defined by an LVEF decline of > or = 5 units.

CONCLUSIONS

In heart failure from systolic dysfunction, beta-blockade with bucindolol produces a dose-related improvement in and prevents deterioration of left ventricular function.
Detection of myocardial ischemia by 31P magnetic resonance spectroscopy during handgrip exercise.
Authors: Yabe T , Mitsunami K , Okada M , Morikawa S , Inubushi T , Kinoshita M
Published: June 2012

BACKGROUND

The metabolic changes of myocardial ischemia in patients with coronary artery disease assessed by 31P magnetic resonance spectroscopy (MRS) have been reported previously. A significant decrease in the ratio of phosphocreatine (PCr) to ATP during handgrip exercise in a group of patients with severe coronary artery disease has been demonstrated. However, there are no reports at present that directly compare cardiac 31P MRS data with exercise 201Tl myocardial scintigraphy, now established as one of the most important clinical methods to assess myocardial ischemia. The purpose of this study was to investigate whether 31P MRS with handgrip exercise testing is able to detect myocardial ischemia, demonstrated by exercise 201Tl scintigraphy.

METHODS AND RESULTS

Twenty-seven patients with severe stenosis of the left anterior descending coronary artery (> or = 75%) and 11 normal control subjects composed the present study. Patients were divided into two groups on the basis of exercise 201Tl scintigraphy: a reversible 201Tl defect group (RD[+]) who demonstrated redistribution at the late image and a fixed 201Tl defect group (RD[-]). While lying supine within the magnet, subjects performed handgrip exercise at 30% of maximal force once in every two cardiac cycles. 31P MR spectra were collected before and during handgrip exercise. Data were corrected for the saturation factor. ANOVA revealed significant differences among the three groups with respect to the mean +/- SD PCr/ATP ratio at rest (control, 1.85 +/- 0.28 > RD(+), 1.60 +/- 0.19 > RD(-), 1.24 +/- 0.30; P < .05). The PCr/ATP ratio decreased significantly from 1.60 +/- 0.19 at rest to 0.96 +/- 0.28 during exercise (P < .001) in the RD(+) group (n = 15). However, in the RD(-) group (n = 12), the ratio did not change significantly during handgrip exercise (1.24 +/- 0.30 at rest versus 1.19 +/- 0.28 during exercise). Similarly, the ratio did not change in the control group (n = 11) (1.85 +/- 0.28 at rest versus 1.90 +/- 0.23 during exercise).

CONCLUSIONS

Contrary to normal subjects or patients with fixed thallium defects, the PCr/ATP ratio was significantly altered by exercise in patients with reversible thallium defects. These results suggest that 31P MRS with handgrip exercise testing is a sensitive method for detecting myocardial ischemia.
Liposome-bound prostaglandin E1 often prevents cyclic flow variations in stenosed and endothelium-injured canine coronary arteries.
Authors: Willerson J T , Yao S K , McNatt J , Cui K , Anderson H V , Swensen C , Ostro M , Buja L M
Published: June 2012

BACKGROUND

Prostaglandin E1 is a potent vasodilator with anti-inflammatory and antiplatelet effects. We tested the hypothesis that prostaglandin E1 attenuates or prevents platelet aggregation-associated cyclic flow variations (CFVs) in severely stenosed and endothelium-injured coronary arteries.

METHODS AND RESULTS

We induced CFVs in 21 dogs by placing an external constrictor around the left anterior descending coronary artery at the site where the endothelium had been mechanically injured. The blood flow velocity in the artery was monitored by a pulsed Doppler flow probe. Sixty minutes after CFVs were established, liposome-bound prostaglandin E1, a stable formulation, was administered intravenously to 12 dogs at incremental doses of 0.25, 0.5, 1, and 2 micrograms/kg body wt; it abolished CFVs in 8 of the 12 dogs (67%). After CFVs were eliminated, epinephrine was infused intravenously, and at a dose of 6.6 +/- 1.6 micrograms/min, it restored CFVs in 7 of 7 dogs. Control dogs (n = 9) were treated with free prostaglandin E1, which did not abolish CFVs in any dog.

CONCLUSIONS

Liposome-bound but not free prostaglandin E1 effectively diminishes CFVs in severely stenosed and endothelium-injured canine coronary arteries.
Marked reduction in myocardial infarct size due to prolonged infusion of an antioxidant during reperfusion.
Authors: Horwitz L D , Fennessey P V , Shikes R H , Kong Y
Published: June 2012

BACKGROUND

There has been controversy about whether early reperfusion of myocardial infarcts causes further necrosis mediated by reactive oxygen species or other mechanisms. Unequivocal evidence that therapeutic agents given only during reperfusion can prevent, rather than delay or modify, injury has been sparse. Failure to account for variables, such as collateral blood flow, that influence infarct size independently and attempts to measure infarct size too early in reperfusion may have limited the sensitivity and specificity of some previous studies.

METHODS AND RESULTS

After 90 minutes of coronary occlusion and 48 hours of reperfusion in a canine model, we examined the effect on infarct size of intravenous infusion of N-(2-mercaptopropionyl)-glycine (MPG), a diffusible antioxidant. Infarct size and region at risk were measured by post-mortem dual perfusion with triphenyl tetrazolium chloride and Evans blue dyes, and regional myocardial blood flow was measured with radioactive microspheres. Infusion of MPG 100 mg.kg-1.h-1, beginning either 15 minutes before the onset of reperfusion or 30 minutes after the onset of reperfusion and continued until 4 hours of reperfusion and followed by an intramuscular dose, reduced infarct size, normalized for both region at risk and the level of collateral blood flow, by 60% and 45%, respectively. When infusion of MPG was limited to the last 15 minutes of ischemia and the first hour of reperfusion only, the normalized infarct size was reduced by 26%. Heart rate, blood pressure, and their product did not differ among the four groups studied. The plasma half-time of MPG was < 10 minutes. In in vitro experiments MPG was a scavenger of hydrogen peroxide but not of superoxide radical.

CONCLUSIONS

After 90 minutes of coronary ligation, infusion of the diffusible hydrogen peroxide scavenger, MPG, for several hours, beginning as late as 30 minutes after the onset of reperfusion, substantially reduced infarct size measured 48 hours later. In this model, necrosis caused by processes during reperfusion may be more extensive than necrosis caused by ischemia alone. Since infusion of this agent for only the first hour of reperfusion was considerably less effective, it appears that most of the oxidant injury leading to necrosis occurred after the first 60 minutes but within the first 4 hours of reperfusion.
In vivo assessment of left atrial contractile performance in normal and pathological conditions using a time-varying elastance model.
Authors: Hoit B D , Shao Y , Gabel M , Walsh R A
Published: June 2012

BACKGROUND

Contractile function of the ex vivo, isolated left atrium (LA) has been described by a time-varying elastance, but this atrial chamber property has not been shown in vivo.

METHODS AND RESULTS

Instantaneous LA pressure-volume (P-V) relations were studied in 12 anesthetized, autonomically blocked, atrially paced dogs. LA volume was calculated from orthogonal sonomicrometer pairs using a cast-validated formula. Data were collected during increases in LA pressure produced by a phenylephrine bolus (200 to 400 micrograms IV). Isochronal P-V points from 5 beats, representing a wide range of atrial pressures, were fitted by linear regression analysis (range of R2, .92 to .99). There were significant time-dependent increases in the slopes [E(t)] and small but statistically insignificant decreases in the volume axis intercepts [VO(t)] of the instantaneous LA P-V relations during atrial contraction; maximal elastance (Emax) occurred 29 +/- 16 milliseconds before atrial end systole (minimal LA volume). Emax was not significantly different than the slopes of either the nonisochronal end-systolic P-V relation (Ees) or the nonisochronal maximal P-to-V relation (EmaxPV): 5.5 +/- 2.8, 4.3 +/- 1.5, and 5.4 +/- 4.2 mm Hg/mL, respectively. In 7 dogs, data were collected both before and after a rapid infusion of calcium gluconate (1 to 2 g IV). Emax increased significantly with a calcium-induced increase in inotropic state (4.5 +/- 1.6 to 5.7 +/- 1.8 mm Hg/mL, P < .01), but the volume axis intercept was unchanged (3.6 +/- 0.7 versus 3.4 +/- 1.9, P = NS). In 4 additional dogs with heart failure (mean LA pressure, 26 +/- 6 mm Hg) produced by 3 weeks of rapid right ventricular pacing, LA stroke volume was significantly greater than and elastance determinations were similar to those of normal dogs. However, the effects of calcium infusion on LA function were attenuated in these animals.

CONCLUSIONS

We conclude that (1) in the intact heart, LA contraction may be approximated by time-varying elastance with time-dependent changes in E(t) and that (2) LA systolic P-V relations using either the nonisochronal maximum P-to-V ratio or end systole may be useful as an estimate of Emax, are highly linear and sensitive to calcium-induced changes in inotropic state, and may be useful in identifying LA chamber adaptation to chronic hemodynamic loads.
Recombinant human superoxide dismutase (h-SOD) fails to improve recovery of ventricular function in patients undergoing coronary angioplasty for acute myocardial infarction.
Authors: Flaherty J T , Pitt B , Gruber J W , Heuser R R , Rothbaum D A , Burwell L R , George B S , Kereiakes D J , Deitchman D , Gustafson N
Published: June 2012

BACKGROUND

Animal studies have demonstrated a burst of oxygen free radical generation after reperfusion of ischemic myocardium that could be blocked by administration of the free radical scavenger recombinant human superoxide dismutase (h-SOD). A multicenter, randomized, placebo-controlled clinical trial was designed to test the hypothesis that free radical-mediated reperfusion injury could be reduced by intravenous administration of h-SOD begun before percutaneous transluminal coronary angioplasty (PTCA) in patients with acute transmural myocardial infarction.

METHODS AND RESULTS

One hundred twenty patients were randomized to receive placebo (n = 59) or h-SOD (n = 61) given as a 10-mg/kg intravenous bolus followed by a 60-minute infusion of 0.2 mg.kg-1.min-1. Left ventricular function was analyzed via paired contrast left ventriculograms performed before PTCA and after 6 to 10 days and paired radionuclide ventriculograms performed within 24 hours of PTCA and after 4 to 6 weeks. Both h-SOD- and placebo-treated patients showed improvement in global and regional left ventricular function after successful reperfusion. Compared with the placebo group, no additional improvement was observed in the patients treated with h-SOD.

CONCLUSIONS

The results of this clinical trial failed to demonstrate a beneficial effect of h-SOD on global or regional left ventricular function in patients who underwent successful PTCA for treatment of acute myocardial infarction.
Prospective study of phobic anxiety and risk of coronary heart disease in men.
Authors: Kawachi I , Colditz G A , Ascherio A , Rimm E B , Giovannucci E , Stampfer M J , Willett W C
Published: June 2012

BACKGROUND

To examine prospectively the association between self-reported symptoms of phobic anxiety and subsequent risk of coronary heart disease, a 2-year follow-up study was conducted of a cohort of 33,999 US male health professionals, aged 42 to 77 years in 1988, who were free of diagnosed cardiovascular disease at baseline. Levels of phobic anxiety were assessed using the Crown-Crisp index, a short, diagnostic self-rating scale used for common phobias. Main outcomes were incidents of coronary heart disease consisting of nonfatal myocardial infarction (MI) and fatal coronary heart disease (CHD).

METHODS AND RESULTS

One hundred sixty-eight incident cases of CHD occurred during 2 years of follow-up (128 cases of nonfatal MI and 40 cases of fatal CHD). The age-adjusted relative risk of fatal CHD among men with highest levels of phobic anxiety (scoring 4 or higher on the Crown-Crisp index) was 3.01 (95% confidence interval, 1.31 to 6.90) compared with men with the lowest levels of anxiety (scoring 0 or 1 on the phobia index). Risk of fatal CHD increased with levels of phobic anxiety (P trend = .002). When fatal CHD was further categorized into sudden and nonsudden coronary death, the excess risk was confined to sudden death (relative risk among men scoring 3 or higher on the phobia index was 6.08; 95% confidence interval, 2.35 to 15.73). No association was found between phobic anxiety and risk of nonfatal MI. These findings remained essentially unchanged after adjusting for a broad range of cardiovascular risk factors.

CONCLUSIONS

The specificity, strength, and dose-response gradient of the association, together with the consistency and biological plausibility of the experimental and epidemiologic evidence, support a strong causal association between phobic anxiety and fatal CHD.
Efficient repopulation of denuded rabbit arteries with autologous genetically modified endothelial cells.
Authors: Conte M S , Birinyi L K , Miyata T , Fallon J T , Gold H K , Whittemore A D , Mulligan R C
Published: June 2012

BACKGROUND

In an effort to determine whether specific genetic modifications of cells of the vascular system might improve the efficacy of existing clinical procedures such as endarterectomy, atherectomy, and percutaneous angioplasty, we investigated the utility of gene transfer to rapidly and efficiently repopulate injured arteries with genetically modified cells in an animal model.

METHODS AND RESULTS

The method involves the harvest of autologous venous-derived endothelial cells, the efficient genetic modification of the cells through the use of recombinant retroviruses, and the subsequent implantation of the genetically modified cells on the surface of balloon-denuded arterial segments. With a rabbit model, freshly isolated endothelial cells were transduced with a recombinant retrovirus encoding the bacterial enzyme beta-galactosidase. The autologous transduced cells were then implanted on the surface of balloon-denuded ileofemoral arterial segments at different cell densities; after 1 to 14 days, the animals were killed, and the vessel segments were examined. Cells expressing the bacterial gene product, as determined by in situ staining for beta-galactosidase, were found to be present on the surface of 28 of the 32 arteries seeded with genetically modified cells. Vessels examined at 4 to 7 days after seeding displayed 40% to 90% coverage with transduced cells, even when seeded at subconfluent density, and an intact endothelial cell monolayer, as evidenced by scanning electron microscopy studies. Vessels examined at 14 days after seeding revealed more variable staining for beta-galactosidase yet, again, in most cases, an intact endothelial cell monolayer.

CONCLUSIONS

These studies indicate the feasibility of generating segments of arterial vessels containing genetically modified cells in a rapid and efficient fashion. Further studies are now necessary to determine whether the local expression of specific polypeptides within a region of vessel for a finite period of time will be clinically useful.
Genetic modification of the vessel wall. Comparison of surgical and catheter-based techniques for delivery of recombinant adenovirus.
Authors: Willard J E , Landau C , Glamann D B , Burns D , Jessen M E , Pirwitz M J , Gerard R D , Meidell R S
Published: June 2012

BACKGROUND

Gene transfer can potentially alter vessel wall biology and intervene in the pathogenesis of human disease. Although several methods for vector delivery have been described, systematic comparisons of these methods are unavailable. Therefore, this study compared three catheter-based strategies and a surgical technique to assess efficient and selective gene transfer to the vascular wall.

METHODS AND RESULTS

The common carotid arteries and internal jugular veins of New Zealand White rabbits were infected with recombinant adenovirus encoding either firefly luciferase or a nuclear-localizing variant of beta-galactosidase. Delivery of recombinant virus was achieved by one of four methods: (1) instillation within a surgically isolated vessel segment (dwell), (2) a double-balloon catheter, (3) a perforated balloon catheter (Wolinsky), or (4) an angioplasty balloon catheter coated with a hydrophilic adsorbent polymer (Hydrogel). Vessel segments were analyzed 4 days after infection for luciferase and beta-galactosidase activity and for the extent of injury to the vessel wall. Luciferase activity in vessels infected using the double-balloon method was substantially greater than that achieved by catheter-based methods (P < .05). The dwell and double-balloon methods yielded selective expression in intimal cells, whereas arteries infected using perforated or Hydrogel-coated balloon catheters demonstrated expression primarily in medial cells. Tissue injury was most pronounced with the perforated balloon catheter.

CONCLUSIONS

Prototype catheters permit relatively efficient direct gene transfer to vascular endothelium; however, delivery methods for targeting the medial cells are inefficient. Modifications are needed to optimize direct gene transfer and minimize tissue injury.