bluuebunny/crossref_metadata_2025 huggingface dataset:
Recovery of a normal coronary vascular reserve after rejection therapy in acute human cardiac allograft rejection.
Authors: Nitenberg A , Tavolaro O , Benvenuti C , Loisance D , Foult J M , Hittinger L , Castaigne A , Cachera J P , Vernant P
Published: June 2011

During acute rejection, coronary vascular reserve is severely impaired in human orthotopic heart transplants. To evaluate the effects of rejection therapy on coronary vascular reserve, the ratio of peak-to-resting coronary flow velocity was assessed with a coronary Doppler catheter and a maximally vasodilating dose of intracoronary papaverine (12 mg) in nine allograft recipients without rejection (group 1) and in six recipients before and after treatment of an acute episode of rejection (group 2). All the patients had normal epicardial coronary arteries and were free of left ventricular hypertrophy. In group 2 during rejection, the coronary vascular reserve was significantly lower than in group 1, in which all the patients had a peak-to-resting coronary flow velocity ratio greater than 4 (2.3 +/- 0.5 vs. 5.4 +/- 0.8, respectively, p less than 0.001). In group 2 after treatment of rejection, the peak-to-resting coronary flow velocity ratio was similar to that of group 1 (4.7 +/- 0.8). Heart rate, left ventricular volumes and pressures, hemoglobin concentration, and arterial oxygen pressure were similar in the two groups. This study provides evidence that alterations of coronary vascular reserve because of acute rejection were reversible after treatment of the rejection episode.
Effects of long-term pressure overload on regional myocardial glucose and free fatty acid uptake in rats. A quantitative autoradiographic study.
Authors: Kagaya Y , Kanno Y , Takeyama D , Ishide N , Maruyama Y , Takahashi T , Ido T , Takishima T
Published: June 2011

To investigate the effects of long-term pressure overload on regional myocardial substrate use, we performed quantitative autoradiography using 2-deoxy-D-[U-14C]glucose (14C-DG) and beta-methyl[1-14C]heptadecanoic acid (14C-BMHDA) in conscious rats with a 10-week ascending aortic constriction. Heart weight/body weight ratio increased by 27% in aortic-constricted rats as compared with sham-operated rats (p less than 0.01). Myocardial 14C-DG uptake increased (258 +/- 63 vs. 144 +/- 41 nCi/g, p less than 0.01, n = 6 for each group); however, 14C-BMHDA extraction decreased (251 +/- 69 vs. 342 +/- 75 nCi/g, p less than 0.05, n = 7 for each group) in aortic-constricted rats as compared with sham-operated rats. In sham-operated rats, both 14C-DG and 14C-BMHDA uptakes were higher in the left ventricular anterior and lateral walls as compared with the posterior wall or the interventricular septum. In aortic-constricted rats, 14C-DG uptake also increased in the interventricular septum, as well as in the left ventricular anterior and lateral walls, as compared with the posterior wall. There was, however, no regional difference in 14C-BMHDA extraction among these four regions. Myocardial blood flow distribution determined by 4-[N-methyl-14C]iodoantipyrine or myocyte width showed no regional variations among the four regions, either in aortic-constricted or sham-operated rats. Regional interstitial fibrosis was small in either group. The present study suggests that myocardial substrate uptake is altered nonhomogeneously, and that the nonhomogeneity is not because of regional variations in blood flow distribution, myocyte hypertrophy, or interstitial fibrosis. The results of angiotensin II-induced acute pressure overloading in other sham-operated rats, in which a remarkable increase in myocardial 14C-BMHDA extraction (n = 3, p less than 0.01) and no difference in 14C-DG uptake (n = 3) as compared with normotensive sham-operated rats were elicited, suggest that the findings in aortic-constricted rats are not direct responses to increased left ventricular pressure itself but rather should be explained by still unknown factors related to prolonged pressure overload.
Left ventricular unloading during reperfusion does not limit myocardial infarct size.
Authors: Van Winkle D M , Matsuki T , Gad N M , Jordan M C , Downey J M
Published: June 2011

To determine whether venting the left ventricle during coronary reperfusion limits myocardial infarct size, we studied paced (200 beats/min) Langendorff rabbit hearts, perfused with blood from a support rabbit. A left coronary artery was occluded for 60 minutes, followed by 2 hours of reperfusion. Four experimental conditions, as follows, were used: In group 1 (control), the hearts contracted isovolumetrically on a fluid-filled balloon in the left ventricle during both occlusion and reperfusion. In group 2, the balloon was present only during occlusion, and the heart was vented during reperfusion. Hearts in group 3 were vented during occlusion and developed pressure during reperfusion. In group 4, the left ventricle was vented during occlusion and reperfusion. Perfusion pressure (91.2 +/- 0.9 mm Hg) and coronary flow (0.88 +/- 0.03 ml/min/g) were not different between groups. Left ventricular pressures (mean of all groups) were 87.3 +/- 1.5 mm Hg systolic and 6.5 +/- 0.6 mm Hg diastolic. Infarcted myocardium was assessed by triphenyl tetrazolium staining and expressed as a percentage of the area at risk, as measured by fluorescent particles. Venting during both ischemia and reperfusion (n = 10) did result in significantly smaller infarcts than in the unvented controls (n = 10), that is, 13 +/- 5% vs. 41 +/- 6%, respectively. Venting only during reperfusion (n = 10) or occlusion (n = 11) did not significantly limit infarct size (57 +/- 6% and 32 +/- 5%, respectively), as compared with controls. Thus, the clinically feasible intervention of left ventricular venting during reperfusion was not cardioprotective.
Effects of calcium antagonists on beta-receptors of cultured cardiac myocytes isolated from neonatal rat ventricle.
Authors: Yonemochi H , Saikawa T , Takakura T , Ito S , Takaki R
Published: June 2011

The effects of calcium antagonists (verapamil, diltiazem, and nicardipine) on beta-adrenergic receptors of cultured cardiac myocytes isolated from neonatal rat ventricle were studied with the hydrophilic ligand [3H]CGP-12177, which identifies cell surface-bound beta-receptors. The three calcium antagonists suppressed spontaneous beating of the myocytes, increased the number of beta-receptors, but did not alter the affinity (Kd). These effects were dose and time dependent. Verapamil (10(-6) M) increased the beta-receptor density by about 13% after 6 hours of incubation, and this increase in density reached a plateau of about 45% after 24 hours of incubation. beta-Receptor density increased by 15% with 5 x 10(-7) M and by 37% with 10(-6) M verapamil. The increased beta-receptors appeared to retain their normal function, as assessed by the increased spontaneous beating of the myocytes in response to applied isoproterenol. The increase in beta-receptors was abolished by colchicine but not by cycloheximide. When the calcium ion concentration of the medium was lowered to 0.1 mM, no significant change occurred in the density of beta-receptors compared with that in 1.8-mM Ca2+ medium. The results suggest that calcium antagonists increase beta-receptors by accelerating recycling by microtubules but not by decreasing the inward calcium current. Such effects of calcium antagonists may be clinically important and promise insight into the mechanism of the withdrawal phenomenon of calcium antagonists.
Automatic implantable cardioverter/defibrillator discharges and acute myocardial injury.
Authors: Avitall B , Port S , Gal R , McKinnie J , Tchou P , Jazayeri M , Troup P , Akhtar M
Published: June 2011

Multiple defibrillations by the automatic implantable cardioverter/defibrillator (AICD) have been reported to result in localized epicardial damage. No data exist, however, regarding whether this damage can be detected in the clinical setting or whether it interferes with the detection of true myocardial infarction. Forty-nine patients who received defibrillations by patch electrodes were studied prospectively. We attempted to document the presence of myocardial injury with the following three commonly used modalities for the detection of myocardial infarction: serial electrocardiographic changes, serial creatine phosphokinase (CPK) and CPK-MB release, and technetium 99m pyrophosphate scanning. Fifteen patients received defibrillations by AICD patches at the time of AICD generator replacement. Nine patients received defibrillations at the time of new AICD lead placement. The average total energy delivered was 85 +/- 29 J. None of these patients had detectable myocardial injury. Ten patients had defibrillations by the AICD patches at the time of bypass operation. One patient in this group developed acute myocardial infarction in the inferior wall after posterior descending coronary bypass operation, as detected by electrocardiogram, 99mTc pyrophosphate scanning, and CPK-MB analysis. Fifteen patients were evaluated for spontaneous AICD discharges. Thirteen had a maximum of five consecutive shocks, and cumulative energy delivered was not greater than 330 J. None of these patients had detectable injury. Two patients had CPK-MB release of 15.3% and 7.5%, respectively. One of these patients had a positive 99mTc pyrophosphate scan. These two patients received 12 and 17 rapid and consecutive AICD discharges, respectively, with cumulative delivered energy of 360 and 510 J, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Resetting of ventricular tachycardia by single extrastimuli. Relation to slow conduction within the reentrant circuit.
Authors: Kay G N , Epstein A E , Plumb V J
Published: June 2011

Although both transient entrainment and resetting with single extrastimuli have been demonstrated during sustained ventricular tachycardia related to previous myocardial infarction, the relation between these phenomena has not been defined. Because transient entrainment is only demonstrated when the mechanism of a tachycardia is reentry with an excitable gap, the resetting response to timed premature extrastimuli was studied in patients with ventricular tachycardia and correlated with the ability to demonstrate transient entrainment. The importance of the location of pacing and recording electrodes relative to regions of slow conduction within the reentry circuit for demonstrating specific characteristics of the resetting response after single extrastimuli was examined in 16 patients with 21 distinct morphologies of ventricular tachycardia related to coronary artery disease. At electrophysiological study, intracardiac electrograms were recorded simultaneously from four sites in the right ventricle and four sites in the left ventricle during ventricular tachycardia. Both resetting and transient entrainment could be demonstrated for 18 of the 21 (86%) ventricular tachycardias. The resetting response at each intracardiac recording site was defined as orthodromic or antidromic, based on the conduction time from the pacing stimulus to the recording site and the morphology of the captured (advanced) electrogram. An orthodromic resetting response was associated with demonstration of transient entrainment at 76 of 82 (93%) recording sites, implying that the pacing site was proximal and the recording site was distal to a region of slow conduction. In contrast, an antidromic resetting response was associated with transient entrainment at only six of 154 (4%) recording sites, suggesting that the pacing site was not separated from the recording site by a region of slow conduction (p = 0.001). The return cycle at the site of pacing exceeded the tachycardia cycle length in all episodes of ventricular tachycardia. At orthodromically activated recording sites, however, resetting was associated with a return cycle less than the tachycardia cycle length. Thus, orthodromic resetting demonstrates that a pause is not an integral part of the resetting response but that premature extrastimuli preexcite the reentrant circuit by entering the excitable gap, conducting through a region of slow conduction, and emerging distally without a change in activation sequence. In all episodes of ventricular tachycardia, the slope of the return cycle at the pacing site was determined by the conduction properties to the orthodromically activated sites, with increasing patterns (n = 6) produced by progressive conduction delay in the reentrant circuit at shorter coupling intervals and flat patterns (n = 3) produced by a constant orthodromic conduction interval.(ABSTRACT TRUNCATED AT 400 WORDS)
Redistribution of regional and organ blood volume and effect on cardiac function in relation to upright exercise intensity in healthy human subjects.
Authors: Flamm S D , Taki J , Moore R , Lewis S F , Keech F , Maltais F , Ahmad M , Callahan R , Dragotakes S , Alpert N
Published: June 2011

To determine the effect of relative exercise intensity on organ blood volume and its relation to cardiac function, changes in relative blood volume and cardiac function were monitored with radionuclide techniques in 14 healthy volunteers. After labeling the subject's red cells with technetium 99m, we acquired data at rest, zero-load cycling, and at 50%, 75%, and 100% of maximal oxygen uptake. From rest to zero-load cycling, leg blood volume decreased 32 +/- 2% (mean +/- SEM), whereas relative end-diastolic blood volume increased 9.6 +/- 1.2%, and lung blood volume increased 18 +/- 2%, suggesting that the lungs may act as a blood volume buffer during periods of acutely increased venous return. With relative increasing exercise, leg blood volume stabilized, and then the blood volume in the abdominal organs decreased, further augmenting cardiopulmonary blood volume; leg blood volume and abdominal blood volume decreased by 23 +/- 2% and 19 +/- 2% from baseline, respectively, whereas thoracic blood volume increased 38 +/- 4%. In the abdomen, large decreases in blood volume were observed in the spleen (46 +/- 2%), kidney (24 +/- 4%), and liver (18 +/- 4%). In contrast, lung blood volume increased 50 +/- 4%, with the upper lung fields increasing more than the lower. Blood sampling revealed an increase in the hematocrit level by 4.3 +/- 0.4 units at peak exercise that paralleled the decrease in splenic blood volume (r2 = -0.64, p less than 0.001), suggesting a role for the spleen in augmenting cardiovascular performance by the release of concentrated red blood cells into general circulation. We conclude that upright exercise results in marked blood volume shifts from the legs and abdominal organs to the heart and lungs in a dynamic process correlating closely with oxygen consumption.
Involvement of endothelin in the regulation of human vascular tonus. Potent vasoconstrictor effect and existence in endothelial cells.
Authors: Miyauchi T , Tomobe Y , Shiba R , Ishikawa T , Yanagisawa M , Kimura S , Sugishita Y , Ito I , Goto K , Masaki T
Published: June 2011

Endothelin, a recently discovered endothelium-derived peptide, has been reported to produce potent vasoconstriction in various vessels of experimental animals. To study the involvement of endothelin in the regulation of vascular tonus in humans, isolated human mesenteric arteries were investigated by both pharmacological and immunohistochemical methods. The vasoconstrictor action of endothelin-1 was examined on ring segments of human mesenteric arteries. Endothelin-1 induced a slowly developing and sustained contraction, with an EC50 value (half-maximal effective concentration) of 2.9 x 10(-9) M, two orders of magnitude smaller than that of norepinephrine (EC50 of 3.9 x 10(-7) M), indicating that the vasoconstrictor action of endothelin-1 is about 100 times more potent than that of norepinephrine. The contractile effect of endothelin-1 was affected neither by adrenergic, cholinergic, histaminergic, nor serotonergic antagonists, nor by inhibitors of arachidonic acid metabolism. The vasoconstrictor response to endothelin-1 was effectively antagonized by nicardipine, a dihydropyridine Ca2+ channel blocker. Endothelin-1 profoundly augmented contractile response to Ca2+ in partially depolarized tissues. Immunohistochemical studies revealed for the first time that endothelin-like immunoreactivity was localized in endothelial cells of human mesenteric artery. The results of the present study indicate that endothelin-1 is one of the most potent vasoconstrictors in the human mesenteric artery and that it induces vasoconstriction via an ultimately accelerating Ca2+ influx through voltage-dependent Ca2+ channels. Since endothelin-1 can be located in human endothelial cells, it may play an important physiological or pathophysiological role.
Myocardial lactate release during ischemia in swine. Relation to regional blood flow.
Authors: Guth B D , Wisneski J A , Neese R A , White F C , Heusch G , Mazer C D , Gertz E W
Published: June 2011

To determine the relation between regional myocardial blood flow, contractile function, and myocardial lactate release during mild-to-moderate regional myocardial ischemia, nine open-chest swine were instrumented for measurement of regional myocardial blood flow (microsphere method), contractile function (sonomicrometry), and hemodynamics. L-[1-14C]Lactate or L-[U-13C]lactate was infused intravenously using a primed continuous infusion technique to quantify regional myocardial lactate release. D-[U-13C]glucose or D-[6-14C]glucose was simultaneously infused to determine the contribution of exogenous glucose to lactate release. Graded coronary ischemia (two to three levels) was created in the left anterior descending coronary arterial distribution by mechanically constricting the artery in five animals or by decreasing flow through a cannulated left anterior descending artery in four animals. In all nine animals, subendocardial blood flow was 0.99 +/- 0.21 (ml/min)/g during control and 0.34 +/- 0.14 (ml/min)/g during the most severe grade of underperfusion (p less than 0.001) in the left anterior descending coronary arterial distribution. Regional myocardial lactate release was 0.15 +/- 0.09 and 1.19 +/- 0.75 mumols/ml, respectively (p less than 0.003). A highly significant inverse correlation was observed between subendocardial blood flow and myocardial lactate release during the graded reductions in blood flow (r = -0.71, p less than 0.001). Results from sonomicrometry showed a significant reduction in contractile ventricular function in the anterior wall during the graded reductions in blood flow. The regional arterial-venous glucose difference increased significantly with underperfusion in the left anterior descending coronary arterial distribution, from 0.14 +/- 0.15 to 0.56 +/- 0.37 mumols/ml (p less than 0.003). The contribution of exogenous glucose to lactate release also increased significantly; 0.04 +/- 0.03 mumols/ml of the lactate came from exogenous glucose during control compared with 0.64 +/- 0.59 mumols/ml during the most severe underperfusion (p less than 0.02). A significant positive correlation exists between lactate release and lactate from exogenous glucose during graded underperfusion (r = 0.96, p less than 0.001). In summary, these data demonstrate a close inverse relation between regional myocardial lactate release and regional subendocardial blood flow during graded ischemia.
Carotid sinus baroreceptor sensitivity in experimental heart failure.
Authors: Wang W , Chen J S , Zucker I H
Published: June 2011

Single-unit carotid sinus baroreceptor activity was recorded in normal and heart-failure (pacing-induced) dogs. The sensitivity of these units was compared between the two groups of dogs. After development of clinical heart failure, the animals were anesthetized, and the left carotid sinus was vascularly isolated and perfused with oxygenated Krebs-Henseleit solution. Single-unit baroreceptor discharge was recorded from the carotid sinus nerve in response to stepwise increases in carotid sinus pressure (CSP). In addition, the carotid sinus diameter was measured with sonomicrometer crystals. In this way, both CSP-discharge and CSP-diameter curves were constructed for both normal and heart-failure dogs. Analysis of these curves demonstrated that the heart-failure group exhibited a significant decrease in peak discharge (48.1 +/- 3.0 vs. 22.2 +/- 2.2 spikes/sec; p less than 0.001) and a significant elevation in threshold pressure compared with the normal animals (91.0 +/- 5.0 vs. 119.1 +/- 4.4 mm Hg; p less than 0.001). The peak slope of the CSP-discharge curve was also significantly lower in the heart-failure group (0.63 +/- 0.06 vs. 0.40 +/- 0.09 spikes/sec/mm Hg; p less than 0.05). In the heart-failure group, perfusion of the carotid sinus with ouabain (0.01 micrograms/ml) caused a significant decrease in threshold pressure and a significant increase in peak discharge frequency, as well as an increase in slope of the CSP-discharge curve. There were no changes in CSP-diameter relations in response to ouabain. This dose of ouabain had no effect on pressure-discharge relations or carotid sinus diameters in normal dogs.(ABSTRACT TRUNCATED AT 250 WORDS)
Assessment of abnormal systolic intraventricular flow patterns by Doppler imaging in patients with left ventricular dyssynergy.
Authors: Garrahy P J , Kwan O L , Booth D C , DeMaria A N
Published: June 2011

Few data exist regarding the consequences of abnormalities of segmental contraction on intraventricular flow patterns. The development of color Doppler flow imaging has now permitted the visualization of intraventricular blood flow patterns. Therefore, we performed Doppler flow mapping in 41 patients (12 with normal left ventricular contraction, eight with hypokinesis or akinesis, and 21 with dyskinesis) and compared these findings with left ventriculography. Systolic blood flow by Doppler mapping in subjects with normal ventricular contraction was characterized primarily by flow through the left ventricular outflow tract and into the aorta. In patients with dyskinesis, paradoxical systolic flow toward the abnormal segment was present, and persisted for at least 50% of systole in 18 of 21 patients. Mean duration of paradoxical flow in dyskinetic patients was 77% of systole. Paradoxical flow was also observed in two of five patients with akinesis but in no patients with hypokinesis. A good correlation was observed between the duration of paradoxical systolic flow and indexes of regional wall motion (radian shortening of the involved myocardium) (r = 0.77) and global ejection fraction derived from cineangiography (r = 0.79). Correlations between the area of the paradoxical systolic flow stream in midsystole and indexes of left ventricular function were less close, with r equaling 0.57 for both regional wall motion and ejection fraction. Thus, paradoxical systolic flow can be detected in most patients with left ventricular dyskinesis, and correlates with the magnitude of regional and global left ventricular dysfunction by cineangiography.
Determinants of hemodynamic compromise with severe right ventricular infarction.
Authors: Goldstein J A , Barzilai B , Rosamond T L , Eisenberg P R , Jaffe A S
Published: June 2011

To elucidate determinants of hemodynamic compromise in patients with acute right ventricular (RV) infarction, we studied 16 patients with hemodynamically severe RV infarction by right heart catheterization and two-dimensional ultrasound. Severe RV systolic dysfunction, evident by ultrasound in all patients as RV dilatation and depressed RV free wall motion, was associated with a broad sluggish RV waveform, diminished peak RV systolic pressure (27.6 +/- 4.5 mm Hg), and depressed RV stroke work (4.6 +/- 2.4 g.m/m2). Paradoxical septal motion was consistently noted. In some cases, the septum bulged into the right ventricle in a pistonlike fashion and appeared to mediate systolic ventricular interaction through which left ventricular septal contraction contributed to RV pressure generation. RV diastolic dysfunction was indicated by elevated RV end-diastolic pressures (13.7 +/- 2.7 mm Hg), RV "dip and plateau," equalization of diastolic filling pressures, and reversal of diastolic septal curvature toward the volume-deprived left ventricle. A prominent right atrial (RA) X and blunted Y descent, indicative of impairment of RV filling throughout diastole, were confirmed in all patients by their relation to RV systolic events. Patients manifested one of two distinct RA waveform morphologies differentiated by A wave amplitude and associated with disparate clinical courses. In eight patients, an RA W pattern was evident, characterized by augmented A waves; eight others manifested an M pattern constituted by depressed A waves. Compared with those with an M pattern, patients with a W pattern had higher peak RV pressures (29.6 +/- 3.8 versus 25.5 +/- 4.3 mm Hg, p less than 0.05), better cardiac output (3.4 +/- 0.3 versus 2.9 +/- 0.7 l/min, p less than 0.05), more favorable response to volume and inotropes, and less frequently required emergency revascularization for refractory shock (none versus five for those with an M pattern). Patients with a W pattern were more severely compromised if atrioventricular dyssynchrony developed and were more dramatically improved by restoration of physiological rhythm. Angiography in patients with depressed A waves demonstrated more proximal coronary obstruction leading to ischemic compromise of RA function, whereas in those with augmented A waves, the culprit lesion was proximal to the RV but distal to the RA branches. These results indicate that hemodynamic compromise in patients with RV infarction is exacerbated by decreased preload reserve that is dependent on atrial systole. The amplitude of the RA A wave, an indication of the status of RA function, is an important determinant of RV performance and hemodynamic compromise.
A hemodynamically responsive antitachycardia system. Development and basis for design in humans.
Authors: Cohen T J , Liem L B
Published: June 2011

Current automatic implantable cardioverter-defibrillators detect tachyarrhythmias primarily by rate-only algorithms and cannot adequately distinguish hemodynamically stable from unstable tachyarrhythmias. The responses of right atrial (mean) and right ventricular pressures (mean, systolic, diastolic, and pulse) to 64 induced and paced supraventricular and ventricular tachyarrhythmias were studied in 10 patients (left ventricular ejection fraction of 32 +/- 6%) to develop an algorithm capable of differentiating stable from unstable rhythms. Tachyarrhythmias were defined as hemodynamically unstable when mean arterial pressure decreased by 25 mm Hg or more during 15 seconds. Mean right atrial, right ventricular systolic, and right ventricular pulse pressures were found to be useful in distinguishing the hemodynamic significance of a tachyarrhythmia. A combined detection algorithm was developed that identified a hemodynamically unstable rhythm when the heart rate was 150 beats/min or more and mean right atrial pressure increased by 4 mm Hg or more and right ventricular systolic pressure decreased by 5 mm Hg or more during 15 seconds. This algorithm was then applied to the next 20 consecutive patients (left ventricular ejection fraction of 34 +/- 4%) and compared with the current rate-only algorithm (heart rate of 150 beats/min or more) in 143 tachyarrhythmias, and the sensitivity and specificity for detection of hemodynamically unstable tachyarrhythmias were determined. The rate-only detection algorithm had 100% sensitivity but only 68% specificity for detection of unstable tachyarrhythmias, whereas the combined rate-mean right atrial pressure-right ventricular systolic pressure detection algorithm had sensitivity and specificity of 100%. Therefore, the performance of an antitachycardia system may be significantly improved by detection algorithms that integrate hemodynamic and rate criteria.
In vivo induction of "focal" triggered ventricular arrhythmias and responses to overdrive pacing in the canine heart.
Authors: Furukawa T , Kimura S , Catstellanos A , Bassett A L , Myerburg R J
Published: June 2011

Delayed afterdepolarizations and triggered activity were evoked in focal areas of myocardium in vivo by local exposure of endocardium to ouabain by means of a catheter electrode system capable of recording monophasic action potentials (MAPs) and delivering ouabain to the recording site. MAPs were recorded from the septum and the posterior wall of the left ventricle with silver-silver chloride electrode catheters. Ouabain (10(-5) M) was infused through the MAP recording catheter onto the endocardial surface of the septum. After infusion of 10 micrograms/kg ouabain, the amplitude of MAPs recorded from the septum (the site of ouabain infusion) decreased from 37.4 +/- 11.8 to 32.0 +/- 10.1 mV (p less than 0.01), MAP duration at 50% repolarization shortened from 160 +/- 29 to 148 +/- 34 msec (p less than 0.01), and MAP duration at 90% repolarization shortened from 198 +/- 38 to 189 +/- 46 msec (p less than 0.01). MAPs recorded from the posterior wall (the reference site) were unchanged. Delayed afterdepolarizations were recorded at the site of ouabain infusion, but not at the reference site, when the heart was paced at cycle lengths of 200-600 msec. Additional infusion of ouabain induced sustained monomorphic ventricular tachycardia (VT) (mean cycle length, 369 +/- 12 msec) in all 15 dogs studied. The mean concentration of ouabain required to induce VT was 20.9 +/- 10.0 micrograms/kg. Paced QRS complexes when stimulated at the site of ouabain infusion had the same morphology as those of spontaneous VT. Local perfusion of verapamil, 0.015-0.034 mg/kg, through the MAP recording catheter onto the site of ouabain infusion completely eliminated VT and premature ventricular contractions. After perfusion of verapamil, delayed afterdepolarizations could no longer be induced by pacing. These observations indicate that induced VT originated from the site of ouabain infusion, and the presence of delayed afterdepolarizations before development of VT strongly suggests that the induced VT was due to triggered activity. Using this model, we examined the responses to rapid ventricular pacing of "focal" triggered VT. The first beat of the reinitiated tachycardia displayed the same morphology as the spontaneous VT. Local perfusion of verapamil, 0.015-0.034 mg/kg, through the MAP recording catheter onto the site of ouabain infusion completely eliminated VT and premature ventricular contractions. After perfusion of verapamil, delayed afterdepolarizations could no longer be induced by pacing. These observations indicate that induced VT originated from the site of ouabain infusion, and the presence of delayed afterdepolarizations before development of VT strongly suggests that the induced VT was due to triggered activity.(ABSTRACT TRUNCATED AT 400 WORDS)
Heparin-resistant thrombus formation by endovascular stents in baboons. Interruption by a synthetic antithrombin.
Authors: Krpski W C , Bass A , Kelly A B , Marzec U M , Hanson S R , Harker L A
Published: June 2011

Intravascular mechanical support has been proposed as a solution to the frequent occurrence of vascular narrowing and occlusion after transluminal balloon angioplasty or surgical endarterectomy. Although several endovascular stents are currently in clinical use for angioplasty of larger vessels, acute thrombosis is a troublesome complication of their use with coronary angioplasty. To study thrombus formation associated with metallic mesh endoprostheses, we have evaluated stents placed inside 3-mm expanded polytetrafluoroethylene (ePTFE) grafts incorporated into chronic exteriorized arteriovenous silicone rubber shunts in baboons. We have also compared the antithrombotic capacities of heparin and the synthetic antithrombin D-phenylalanyl-L-prolyl-L-arginyl-chloromethylkene (D-FPRCH2Cl) to interrupt this platelet-dependent process for two different endovascular stents. Acute platelet deposition was continuously measured during 1 hour using gamma camera imaging of platelets labeled with indium-111 oxine. On untreated control ePTFE grafts (n = 11), 0.87 +/- 0.15 x 10(9) platelets/cm were deposited during 60 minutes. In contrast, balloon-expandable endovascular stents within ePTFE (n = 6) accumulated 4.37 +/- 0.68 x 10(9) platelets/cm (p = 0.003 compared with controls), and self-expandable stents (n = 6) accumulated 3.91 +/- 0.42 x 10(9) platelets/cm (p = 0.006 compared with controls); no difference between stents was detected in this test system (p greater than 0.5). Systemic heparin treatment did not reduce platelet deposition (4.20 +/- 0.41 x 10(9) platelets/cm at 60 minutes; p greater than 0.5).(ABSTRACT TRUNCATED AT 250 WORDS)
Inhibition of thrombus formation by activated recombinant protein C in a primate model of arterial thrombosis.
Authors: Gruber A , Hanson S R , Kelly A B , Yan B S , Bang N , Griffin J H , Harker L A
Published: June 2011

Activated protein C (APC) is an antithrombotic enzyme. The therapeutic potential of infused human recombinant APC (rAPC) was studied in a primate model of platelet-dependent thrombosis. Eight baboons with chronic femoral arteriovenous shunts received rAPC infusions for 1 hour. The shunts were extended with 5-cm long, 4-mm-i.d. thrombogenic Dacron graft segments for the time of infusion. The plasma level of the enzyme, the blood flow in the shunt, and the deposition of indium-111-labeled platelets and iodine-125 fibrinogen on the graft were measured. The influence of rAPC infused at doses of 0.25 and 1.0 mg/kg-hr was compared with the effects of control infusions of saline. Five of eight control grafts occluded within 60 minutes, whereas there was no change in the blood flow during rAPC infusion. Deposition of platelets was inhibited by 13 +/- 10% and by 42 +/- 13% (mean +/- SEM) after 30 minutes of infusion at the two doses, which gave rise to circulating rAPC plasma concentrations of 0.4 and 1.9 mg/l, respectively. Both doses significantly inhibited fibrin deposition in the graft. Circulating plasma markers of thrombus formation and of fibrinolysis did not increase significantly during rAPC infusion; measurements of bleeding time were also within normal limits. Thus, rAPC, like human plasma-derived APC, inhibited thrombus formation without impairing primary hemostasis.
Mechanism of myocardial "stunning".
Authors: Bolli R
Published: June 2011

Among the numerous mechanisms proposed for myocardial stunning, three appear to be more plausible: 1) generation of oxygen radicals, 2) calcium overload, and 3) excitation-contraction uncoupling. First, the evidence for a pathogenetic role of oxygen-derived free radicals in myocardial stunning is overwhelming. In the setting of a single 15-minute coronary occlusion, mitigation of stunning by antioxidants has been reproducibly observed by several independent laboratories. Similar protection has been recently demonstrated in the conscious animal, that is, in the most physiological experimental preparation available. Furthermore, generation of free radicals in the stunned myocardium has been directly demonstrated by spin trapping techniques, and attenuation of free radical generation has been repeatedly shown to result in attenuation of contractile dysfunction. Numerous observations suggest that oxyradicals also contribute to stunning in other settings: after global ischemia in vitro, after global ischemia during cardioplegic arrest in vivo, and after multiple brief episodes of regional ischemia in vivo. Compelling evidence indicates that the critical free radical damage occurs in the initial moments of reflow, so that myocardial stunning can be viewed as a sublethal form of oxyradical-mediated "reperfusion injury." Second, there is also considerable evidence that a transient calcium overload during early reperfusion contributes to postischemic dysfunction in vitro; however, the importance of this mechanism in vivo remains to be defined. Third, inadequate release of calcium by the sarcoplasmic reticulum, with consequent excitation-contraction uncoupling, may occur after multiple brief episodes of regional ischemia, but its role in other forms of postischemic dysfunction has not been explored. It is probable that multiple mechanisms contribute to the pathogenesis of myocardial stunning. The three hypotheses outlined above are not mutually exclusive and in fact may represent different steps of the same pathophysiological cascade. Thus, generation of oxyradicals may cause sarcoplasmic reticulum dysfunction, and both of these processes may lead to calcium overload, which in turn could exacerbate the damage initiated by oxygen species. The concepts discussed in this review should provide not only a conceptual framework for further investigation of the pathophysiology of reversible ischemia-reperfusion injury but also a rationale for developing clinically applicable interventions designed to prevent postischemic ventricular dysfunction.
Body surface mapping of ectopic left and right ventricular activation. QRS spectrum in patients without structural heart disease.
Authors: SippensGroenewegen A , Spekhorst H , van Hemel N M , Kingma J H , Hauer R N , Janse M J , Dunning A J
Published: June 2011

The value of simultaneous 62-lead electrocardiographic recordings in localizing the site of origin of ectopic ventricular activation in a structurally normal heart was assessed by examining body surface QRS integral maps in 12 patients during left and right ventricular (LV and RV) pacing at 182 distinct endocardial sites. A data base of 38 characteristic mean integral maps was composed after visually selecting subgroups with nearly identical total QRS integral morphology and numerically evaluating intrasubgroup pattern uniformity and intersubgroup pattern variability. Corresponding endocardial pacing site locations were computed by a biplane cineradiographic method and outlined as segments on a standardized LV and RV polar projection. LV pacing resulted in 25 markedly different mean total QRS integral patterns, showing higher electrocardiographic sensitivity for anteroseptal (18 patterns) compared with posterolateral regions (seven patterns). RV pacing demonstrated 13 mean total QRS integral patterns, exhibiting less intersubgroup variation and comparatively low electrocardiographic sensitivity for the basal anterior and outflow regions. Comparison of LV with RV pacing revealed that QRS configurations produced at LV apical and LV midseptal sites closely resembled QRS configurations generated at RV apical, RV septal, and RV anterior sites, respectively. Total QRS time integral amplitudes showed considerable intrasubgroup variation but permitted global differentiation of spatially similar QRS patterns obtained during pacing at LV and RV sites. This study demonstrates that the QRS pattern of the total body surface electrocardiogram allows discrimination among 38 different LV and RV segments of ectopic endocardial impulse formation in patients with normal cardiac anatomy.
Thrombolytic activity of a novel plasminogen activator, LY210825, compared with recombinant tissue-type plasminogen activator in a canine model of coronary artery thrombosis.
Authors: Jackson C V , Crowe V G , Craft T J , Sundboom J L , Grinnell B W , Bobbitt J L , Burck P J , Quay J F , Smith G F
Published: June 2011

LY210825, a recombinant tissue-type plasminogen activator (rt-PA), which contains the kringle-2 and serine protease functional domains of native tissue-type plasminogen activator, was previously produced by site-directed mutagenesis in a Syrian hamster cell line. We studied the thrombolytic potential of this molecule in a canine thrombosis model. Male hounds (16-22 kg) were anesthetized; a 2.0-cm segment of the left circumflex coronary artery (LCX) was isolated proximal to the first main branch, and the dogs were instrumented with an electromagnetic flow probe to measure coronary blood flow. An occlusive thrombus was formed after injury of the intimal surface of the LCX with an electrical current applied by a needle-tipped anode placed distal to the electromagnetic flow probe. After 1 hour of occlusion, either LY210825 or rt-PA was administered intravenously according to the following protocols: 1) a 1-hour infusion of either 0.25 mg/kg LY210825 or 0.4 mg/kg rt-PA, 2) single injections of 0.15-0.6 mg/kg LY210825, and 3) a single injection of 0.45 mg/kg LY210825 and a 3-hour infusion of 1.0 or 1.7 mg/kg rt-PA. Plasma half-lives of LY210825 and rt-PA were 58 +/- 7 and 3.3 +/- 0.3 minutes, respectively. LY210825 produced more rapid reperfusion of the LCX than did rt-PA. In the third study, 90% of the rt-PA-treated vessels reoccluded within 1 hour after cessation of drug, whereas only 25% of the LY210825-treated vessels reoccluded during a 4-hour washout period. There were significant, but relatively small, reductions produced by both plasminogen activators on plasma fibrinogen and plasminogen (25-35% decreases). Because of its longer plasma half-life, LY210825 could be administered intravenously as a single injection. In a canine model of coronary artery thrombosis, LY210825 was a more effective thrombolytic agent than was rt-PA.
Significance of initial ST segment elevation and depression for the management of thrombolytic therapy in acute myocardial infarction. European Cooperative Study Group for Recombinant Tissue-Type Plasminogen Activator.
Authors: Willems J L , Willems R J , Willems G M , Arnold A E , Van de Werf F , Verstraete M
Published: June 2011

To determine the ability of initial ST segment elevation and depression to predict infarct size limitation by thrombolytic therapy, data were analyzed in 721 patients with acute myocardial infarction who were admitted to a randomized, placebo-controlled study of intravenous recombinant tissue-type plasminogen activator. Patients with QRS duration of 120 msec or more or with previous history of myocardial infarction were excluded, leaving 322 in the treatment and 333 in the placebo group. Cumulative 72-hour release of alpha-hydroxybutyrate dehydrogenase and global ejection fraction as well as left ventricular wall motion derived from angiography were used as independent measures of infarct size. Electrocardiograms obtained at admission, 6 hours after start of therapy, and before discharge were analyzed. All ST measurements were made by hand at the J point and 60 msec after the J point. Patients with high ST segment elevation at admission (i.e., sum of ST elevation at 60 msec after the J point was 20 mm or more) had significantly larger infarction and higher hospital mortality when compared with those with lower (less than 20 mm) ST elevation. Reciprocal ST segment depression also showed a linear relation with infarct size and mortality, independent from ST elevation, both in anterior and inferior myocardial infarction. The sum of deviations measured at the J point and 60 msec after the J point differed significantly, especially in anterior myocardial infarction at admission (mean, 16 +/- 9 versus 23 +/- 11 mm). The prognostic value of one measurement was not, however, superior over the other. Treatment with recombinant tissue-type plasminogen activator was most effective in those with large ST deviations at admission, but patients with anterior infarction and smaller ST shifts also appeared to benefit from therapy. Results in individual patients were variable, and the overall correlation of initial ST shifts with enzymatic infarct size was rather low. In conclusion, the present study shows that the magnitude of initial ST elevation and also of reciprocal ST depression in the admission electrocardiogram is valuable for the management and assessment of thrombolytic therapy in patients with acute myocardial infarction.
Coronary morphologic and clinical determinants of procedural outcome with angioplasty for multivessel coronary disease. Implications for patient selection. Multivessel Angioplasty Prognosis Study Group.
Authors: Ellis S G , Vandormael M G , Cowley M J , DiSciascio G , Deligonul U , Topol E J , Bulle T M
Published: June 2011

To assess the likelihood of procedural success in patients with multivessel coronary disease undergoing percutaneous coronary angioplasty, 350 consecutive patients (1,100 stenoses) from four clinical sites were evaluated. Eighteen variables characterizing the severity and morphology of each stenosis and 18 patient-related variables were assessed at a core angiographic laboratory and at the clinical sites. Most patients had Canadian Cardiovascular Society class III or IV angina (72%) and two-vessel coronary disease (78%). Left ventricular function was generally well preserved (mean ejection fraction, 58 +/- 12%; range, 18-85%) and 1.9 +/- 1.0 stenoses per patient had attempted percutaneous coronary angioplasty. Procedural success (less than or equal to 50% final diameter stenosis in one or more stenoses and no major ischemic complications) was achieved in 290 patients (82.8%), and an additional nine patients (2.6%) had a reduction in diameter stenosis by 20% or more with a final diameter stenosis 51-60% and were without major complications. Major ischemic complications (death, myocardial infarction, or emergency bypass surgery) occurred in 30 patients (8.6%). In-hospital mortality was 1.1%. Stepwise regression analysis determined that a modified American College of Cardiology/American Heart Association Task Force (ACC/AHA) classification of the primary target stenosis (with type B prospectively divided into type B1 [one type B characteristic] and type B2 [greater than or equal to two type B characteristics]) and the presence of diabetes mellitus were the only variables independently predictive of procedural outcome (target stenosis modified ACC/AHA score; p less than 0.001 for both success and complications; diabetes mellitus: p = 0.003 for success and p = 0.016 for complications). Analysis of success and complications on a per stenosis dilated basis showed, for type A stenoses, a 92% success and a 2% complication rate; for type B1 stenoses, an 84% success and a 4% complication rate; for type B2 stenoses, a 76% success and a 10% complication rate; and for type C stenoses, a 61% success and a 21% complication rate. The subdivision into types B1 and B2 provided significantly more information in this clinically important intermediate risk group than did the standard ACC/AHA scheme. The stenosis characteristics of chronic total occlusion, high grade (80-99% diameter) stenosis, stenosis bend of more than 60 degrees, and excessive tortuosity were particularly predictive of adverse procedural outcome. This improved scheme may improve clinical decision making and provide a framework on which to base meaningful subgroup analysis in randomized trials assessing the efficacy of percutaneous coronary angioplasty.