bluuebunny/crossref_metadata_2025 huggingface dataset:
Oral administration of DuP 753, a specific angiotensin II receptor antagonist, to normal male volunteers. Inhibition of pressor response to exogenous angiotensin I and II.
Authors: Christen Y , Waeber B , Nussberger J , Porchet M , Borland R M , Lee R J , Maggon K , Shum L , Timmermans P B , Brunner H R
Published: June 2012

BACKGROUND

The purpose of the present study was to assess the inhibitory effect of DuP 753, an orally active angiotensin II receptor antagonist, on the pressor action of exogenous angiotensin I and II in healthy male volunteers.

METHODS AND RESULTS

In the first study (single-dose study), eight volunteers were included in a 2-day protocol repeated four times at 1-week intervals. In each phase, a different dose of drug (2.5, 5, 10, 20, or 40 mg) or placebo was given. The peak systolic blood pressure response to a test-dose of angiotensin I was determined serially before and after oral administration of DuP 753 by continuously monitoring finger blood pressure using a photoplethysmographic method. DuP 753 reduced the systolic blood pressure response to angiotensin I in a dose-dependent fashion. Three, 6, and 13 hours after the 40-mg dose, blood pressure response decreased to 31 +/- 5%, 37 +/- 6%, and 45 +/- 3% of the control values (mean +/- SEM, n = 7), respectively. In the second study, 29 volunteers were treated for 8 days with either a placebo or DuP 753 (5, 10, 20, or 40 mg p.o. q.d.) and challenged on the first, fourth, and eighth days with bolus injections of angiotensin II. Again, the inhibitory effect on the systolic blood pressure response to angiotensin II was clearly dose dependent. Six hours after 40 mg DuP 753, the systolic blood pressure response to the test-dose of angiotensin II was reduced to 37 +/- 7%, 40 +/- 4%, and 38 +/- 6% of baseline values (mean +/- SEM, n = 6) on days 1, 4, and 8, respectively. With this latter dose, there was still a blocking effect detectable 24 hours after the drug. Similar to angiotensin converting enzyme and renin inhibitors, DuP 753 induced a dose-dependent increase in plasma renin that was more pronounced on the eighth than on the first day of drug administration. In these normal volunteers, no consistent clinically significant side effects were observed. There was no evidence for an agonist effect.

CONCLUSIONS

DuP 753 appears to be a well-tolerated, orally active, potent, and long-lasting antagonist of angiotensin II in men.
Chronic pulmonary thromboembolism in dogs treated with tranexamic acid.
Authors: Moser K M , Cantor J P , Olman M , Villespin I , Graif J L , Konopka R , Marsh J J , Pedersen C
Published: June 2012

BACKGROUND

Many questions remain regarding the pathogenesis, natural history, diagnosis, and treatment of chronic thromboembolic pulmonary hypertension in patients. To answer such questions, we developed an animal model of this disorder. The brisk thrombolytic response of canines to acute embolism has, previously, prevented the establishment of such a model.

METHODS AND RESULTS

The fibrinolytic inhibitor tranexamic acid was given orally to canines before, and for intervals after, pulmonary emboli were released from venous thrombi formed in vivo in femoral veins or the inferior vena cava. Preliminary studies disclosed that embolic residuals from femoral vein thrombi were not sufficient to cause significant, persistent pulmonary hypertension. With repetitive, larger thrombi embolized from the inferior vena cava, however, persistent pulmonary hypertension was achieved in most animals.

CONCLUSIONS

Resolution of emboli in the canine can be inhibited by tranexamic acid. As in humans, a spectrum of embolic residuals is encountered, and the perfusion lung scan consistently underestimates the extent of embolic residuals. Studies of this animal model continue.
No effect of coronary perfusion on regional myocardial function within the autoregulatory range in pigs. Evidence against the Gregg phenomenon.
Authors: Schulz R , Guth B D , Heusch G
Published: June 2012

BACKGROUND

The hypothesis that increases in coronary perfusion increase ventricular performance independently from providing enhanced oxygen supply ("Gregg phenomenon") remains controversial.

METHODS AND RESULTS

To study the physiological significance of changes in coronary perfusion on global and regional myocardial function in situ, the left anterior descending coronary artery of isoflurane-anesthetized swine was cannulated, and perfusion was varied. In one group of swine (n = 5), coronary arterial pressure was increased in four steps from 88 +/- 11 to 186 +/- 11 mm Hg by increasing the speed of the pump circuit providing coronary blood flow. No changes in left ventricular end-diastolic pressure, peak pressure, or maximum left ventricular dP/dt were observed. Subendocardial blood flow (by radiolabeled microspheres) increased from 0.96 +/- 0.27 to 2.04 +/- 0.73 ml/min/g without any increase in systolic wall thickening (by sonomicrometry) or myocardial oxygen consumption of the anterior myocardium. In a second group of swine (n = 8), coronary arterial pressure was kept constant and coronary blood flow was increased stepwise by intracoronary adenosine infusion. End-diastolic pressure, peak pressure, and maximum left ventricular dP/dt remained unchanged when coronary blood flow increased from 21.7 +/- 9.8 to 93.8 +/- 34.1 ml/min. Subendocardial blood flow increased from 0.89 +/- 0.26 to 3.28 +/- 1.02 ml/min/g, again without any increase in systolic wall thickening (45.6 +/- 8.6 versus 42.6 +/- 9.8%) and myocardial oxygen consumption (5.75 +/- 1.18 versus 5.87 +/- 1.67 ml/min/100 g). In a third group of swine (n = 10), coronary arterial pressure was lowered by intracoronary adenosine infusion during constant coronary inflow. Left ventricular hemodynamics remained unchanged. With a decrease in coronary arterial pressure from 130 +/- 25 to 71 +/- 14 mm Hg, no decreases in subendocardial blood flow and systolic wall thickening were observed. Only when coronary arterial pressure was further reduced to 57 +/- 13 mm Hg did systolic wall thickening fall to 25.7 +/- 9.9% (control, 31.1 +/- 11.1%), associated with a decrease in subendocardial blood flow from 1.17 +/- 0.39 to 0.87 +/- 0.52 ml/min/g.

CONCLUSIONS

Thus, the Gregg phenomenon plays no significant role within or above the autoregulatory pressure-flow range normally seen in anesthetized swine in situ.
Strokes in Asians and Pacific-Islanders, Hispanics, and Native Americans.
Authors: Yatsu F M
Published: June 2012

Stroke in Asian and Pacific-Islander populations remains the principal cause of death among adults, but its incidence in the United States approximates that of Caucasians. Although controversial, uncontrolled hypertension in certain population groups (e.g., northern Japanese) and high dietary saturated fat in others (e.g, Pacific-Islanders) are believed to be responsible for the high stroke incidence rates. The recent reduction in stroke frequency rates in these areas is thought to be the result of better hypertension control. In the Ni-Hon-San Study, the level of hypertension and its frequency were similar in Hawaii and Japan, but ischemic infarction and intracerebral hemorrhage were less frequent in Hawaii. Reduced meat and fat intake may contribute to small vessel disease in Japan. Stroke is the third major cause of death among Hispanic-Americans and Native Americans, yet there is a paucity of information, especially about stroke, in subgroups of these populations. There is also considerable ignorance and controversy about risk factors for stroke in these populations. The need for additional research is urgent.
Renal vascular disease in African-Americans and other racial minorities.
Authors: Shulman N B , Hall W D
Published: June 2012

Hypertensive end-stage renal disease is about 10-fold more common nationwide in African-Americans than in Caucasians and 17-fold higher in some sections of the United States. These figures are alarming and require a much greater effort in understanding the causes of this disparity and improving blood pressure control in this population to prevent catastrophic renal damage. More information is also needed about the renovascular status of other minorities. Financial obstacles to antihypertensive care appear to be an important contributing factor to the disparities of end-stage renal disease in African-Americans and perhaps other minorities.
On the mechanisms of ventricular tachycardia acceleration during programmed electrical stimulation.
Authors: Brugada J , Brugada P , Boersma L , Mont L , Kirchhof C , Wellens H J , Allessie M A
Published: June 2012

BACKGROUND

The pathophysiological mechanisms leading to acceleration of ventricular tachycardia (VT) are still unclear.

METHODS AND RESULTS

High-resolution epicardial mapping was used to study the mechanisms of VT acceleration by programmed electrical stimulation (PES) in a model of sustained reentrant VT in Langendorff-perfused rabbit hearts (n = 40). Three different mechanisms responsible for acceleration of VT were identified: 1) induction of double-wave reentry (n = 6), defined as the occurrence of two successive activation waves circulating in the same direction in the same circuit; 2) change to a functionally determined circuit (n = 4), defined as reentry of the impulse around a functional line of block without involvement of a fixed obstacle; and 3) change of the reentrant circuit to reentry within a different, faster anatomic pathway (n = 3). Analysis of 81 episodes of sustained monomorphic VT induced by PES in 74 patients with clinically documented sustained VT in the setting of chronic coronary artery disease showed that in 22 episodes VT was suddenly accelerated by PES (mean cycle length, from 345 +/- 73 to 277 +/- 71 msec, p less than 0.01).

CONCLUSIONS

With the observations made in the experimental model, the following tentative classification of the mechanisms of VT acceleration of the 22 episodes was made: 1) induction of double-wave reentry in two, 2) change to a functionally determined circuit in four, and 3) change to reentry within a faster anatomic circuit in 16. Simple criteria suggest that these mechanisms may apply in the clinical situation.
Circus movement atrial flutter in canine sterile pericarditis model. Activation patterns during entrainment and termination of single-loop reentry in vivo.
Authors: Schoels W , Restivo M , Caref E B , Gough W B , el-Sherif N
Published: June 2012

BACKGROUND

Recently, we used a custom designed "jacket" electrode with 127 bipolar electrodes in a flexible nylon matrix to map the total atrial epicardial surface in the in situ canine heart. Atrial flutter in dogs with sterile pericarditis was shown to be due to a single wave front circulating around a combined functional/anatomic obstacle, with the arc of functional conduction block contiguous with one or more of the atrial vessels.

METHODS AND RESULTS

In the present study, this model was used to analyze the activation pattern during pacing-induced entrainment and termination of single reentrant loops in a syncytium without anatomically predetermined pathways. Sustained atrial flutter was induced in five dogs with 3-5-day-old sterile pericarditis. Atrial pacing at a cycle length 5-30 msec shorter than the spontaneous cycle length entrained the arrhythmia and could result in a "classical" activation pattern, characterized by an antidromic stimulated wave that collided with the reentrant orthodromic wave front of the previous beat at a constant site. However, two variations of this classical activation pattern were also observed: 1) Pacing at short cycle lengths could lead to localized conduction block in antidromic direction, forcing a change in the pathway of the antidromic wave front. This could prevent the expected shift of the site of collision in antidromic direction. 2) The stimulated orthodromic wave front could also use a pathway different from that of the original reentrant impulse, so that a different circuit was active during the pacing period. Termination of atrial flutter by rapid atrial stimulation was associated with progressive slowing and finally blocking of the paced orthodromic wave front and a progressive shift of the site of collision in antidromic direction. The occurrence of conduction block was determined by the cycle length of stimulation and the number of stimulated beats. A longer train at the critical cycle length or the critical number of beats at a shorter cycle length could reinduce the same reentrant circuit or a different reentrant circuit, respectively, during stimulated cycles following the beat that terminated reentry.

CONCLUSIONS

The epicardial activation sequence during entrainment of reentrant arrhythmias does not necessarily follow a standard activation pattern. Instead, the stimulated orthodromic as well as the antidromic wave front might use a pathway different from that of the original reentrant wave front. The mechanisms of termination, failure of termination, and reinitiation of single-loop reentry are similar to those in the "figure-eight" reentrant circuit.
Response of atrial natriuretic factor to acute and chronic increases of atrial pressures in experimental heart failure in dogs. Role of changes in heart rate, atrial dimension, and cardiac tissue concentration.
Authors: Moe G W , Grima E A , Angus C , Wong N L , Hu D C , Howard R J , Armstrong P W
Published: June 2012

BACKGROUND

This study evaluated the role of changes in heart rate, atrial pressure, volume, and cardiac tissue atrial natriuretic factor (ANF) concentration in the modulation of plasma ANF concentration in a model of pacing-induced heart failure.

METHODS AND RESULTS

The effects of acute right ventricular pacing (250 beats/min), acute volume expansion (35 ml/min), and volume expansion after 1 week of right ventricular pacing on plasma ANF concentration were compared in eight dogs (group 1). As shown during right ventricular pacing previously, volume expansion produced significant increases in cardiac filling pressures and left atrial volume. Right ventricular pacing and volume expansion produced similar increments in plasma ANF concentration: from 32 +/- 12 to 168 +/- 153 pg/ml (p less than 0.05) and from 32 +/- 9 to 137 +/- 113 pg/ml (p less than 0.05), respectively. When pacing was initiated after volume expansion, plasma ANF concentration increased further to 462 +/- 295 pg/ml (p less than 0.05) despite little change in filling pressures and left atrial volume. With repeated volume expansion after 1 week of pacing, there were no significant further increases in left atrial volume and plasma ANF concentrations (from 332 +/- 121 to 407 +/- 113 pg/ml) despite significant increases in filling pressures. Atrial and ventricular tissue samples were also obtained from 21 dogs paced to severe heart failure (group 2) and from 14 normal dogs (controls). In all groups, atrial ANF was higher than ventricular ANF concentration. At 1 week (group 1), left atrial appendage ANF concentration (6.2 +/- 2.5 versus 16.1 +/- 10.3 ng/mg) was reduced, whereas left ventricular free wall ANF concentration (0.62 +/- 0.31 versus 0.24 +/- 0.16 pg/mg) was increased compared with that of controls (both p less than 0.001). At severe heart failure (group 2), atrial ANF remained low, whereas ventricular ANF concentration was similar to that of the controls.

CONCLUSIONS

These data indicate that in pacing-induced heart failure, changes in heart rate, atrial pressure, and volume all contribute to the increased plasma ANF concentration. However, by 1 week (early heart failure), ANF release is attenuated, perhaps because of the inability of the atria to be stretched further and because of reduced atrial ANF concentration. In addition, the ventricle may be an additional source of ANF.
Hemodynamic and electrophysiological actions of cocaine. Effects of sodium bicarbonate as an antidote in dogs.
Authors: Beckman K J , Parker R B , Hariman R J , Gallastegui J L , Javaid J I , Bauman J L
Published: June 2012

BACKGROUND

Cocaine abuse has been implicated as a cause of death due to sudden cardiac arrest.

METHODS AND RESULTS

We examined the hemodynamic and electrophysiological effects of cocaine administered as a series of 5-mg/kg i.v. boluses coupled with a continuous infusion in anesthetized dogs. Sodium bicarbonate (50 meq i.v.) was administered as a potential antidote in 11 of 15 dogs, and intravenous 5% dextrose was given in the remaining four. In a dose-dependent fashion, cocaine significantly decreased blood pressure, coronary blood flow, and cardiac output; increased PR, QRS, QT, and QTc intervals and sinus cycle length; and increased ventricular effective refractory period and dispersion of ventricular refractoriness. No afterdepolarizations were noted in the monophasic action potential recording. Nonsustained monomorphic ventricular tachycardia occurred spontaneously in two dogs, and sustained ventricular tachycardia could be induced by programmed stimulation at the end of the dosing protocol in five of 11 animals. Sodium bicarbonate promptly decreased cocaine-induced QRS prolongation to nearly that measured at baseline but had no effect on the other electrocardiographic or hemodynamic variables. In one dog, sodium bicarbonate administration was associated with reversion of ventricular tachycardia to sinus rhythm.

CONCLUSIONS

We conclude that high-dose cocaine possesses negative inotropic and potent type I electrophysiological effects. Sodium bicarbonate selectively reversed cocaine-induced QRS prolongation and may be a useful treatment of ventricular arrhythmias associated with slowed ventricular conduction in the setting of cocaine overdose.
Kinetics of use-dependent ventricular conduction slowing by antiarrhythmic drugs in humans.
Authors: Ranger S , Talajic M , Lemery R , Roy D , Villemaire C , Nattel S
Published: June 2012

BACKGROUND

Rate-dependent conduction slowing by class I antiarrhythmic agents has clinically important consequences. Class I drugs are known to produce use-dependent sodium channel blockade. If rate-dependent conduction slowing by class I agents is due to sodium channel blocking actions, the kinetics of conduction slowing should be similar to those of depression of sodium current indexes in vitro. The purpose of the present investigation was to study the onset time course of ventricular conduction slowing caused by a variety of class I agents in humans.

METHODS AND RESULTS

Twenty-seven patients undergoing electrophysiological evaluation for antiarrhythmic therapy were studied. Changes in QRS duration at initiation of ventricular pacing at cycle lengths of 400 and 500 msec were used to evaluate the kinetics of drug action. Mean time constants for each drug were similar to values for Vmax depression reported in vitro studies: flecainide, 24.9 +/- 11.6 beats in eight patients (versus 34.5 beats reported for Vmax block); propafenone, 17.8 +/- 6.9 beats in five patients (versus 8.4-20.8 beats); quinidine, 7.0 +/- 2.4 beats in six patients (versus 5.6-6.2 beats); and amiodarone, 3.6 +/- 2.0 beats for eight patients (versus 3.0 beats). Time constants were significantly different among the various drugs tested (p = 0.0002 at a cycle length of 400 msec; p = 0.002 at 500 msec), and there was a strong correlation (r = 0.89, p less than 0.0001) between values obtained at a cycle length of 400 msec and those at a cycle length of 500 msec. No rate-dependent changes in QRS duration were seen at onset of ventricular pacing among eight age- and disease-matched control patients not taking class I antiarrhythmic drugs, including three patients subsequently showing such changes during type I antiarrhythmic drug therapy.

CONCLUSIONS

We conclude that class I agents produce use-dependent QRS prolongation in humans with characteristic kinetics for each agent that are similar to the kinetics of Vmax depression in vitro. These results suggest that rate-dependent ventricular conduction slowing by antiarrhythmic drugs in humans is due to use-dependent sodium channel blockade.
Left ventricular diastolic collapse. An echocardiographic sign of regional cardiac tamponade.
Authors: Chuttani K , Pandian N G , Mohanty P K , Rosenfield K , Schwartz S L , Udelson J E , Simonetti J , Kusay B S , Caldeira M E
Published: June 2012

BACKGROUND

Cardiac tamponade after cardiac surgical procedures is often associated with hemodynamically significant localized pericardial effusions. The localized collection of pericardial effusion in the postoperative period and the atypical presentation of cardiac tamponade limit the use of conventional clinical and echocardiographic signs usually seen with a circumferential pericardial effusion. Observation of left ventricular diastolic collapse in the echocardiogram of a patient with postoperative regional cardiac tamponade prompted us to explore the frequency of this sign in regional cardiac tamponade.

METHODS AND RESULTS

We retrospectively analyzed the echocardiograms of 18 patients with postoperative cardiac tamponade for the following echocardiographic findings: right atrial collapse, right ventricular diastolic collapse, left atrial collapse, and left ventricular diastolic collapse. Three of the 18 patients had circumferential pericardial effusion, and 15 had loculated pericardial effusion; in 10, the effusion was predominantly posterior, and in the other five, it extended laterally or inferiorly. The conventional echocardiographic signs of cardiac tamponade such as right atrial collapse, right ventricular diastolic collapse, and left atrial collapse were present in only 3, 1, and 3 of these 15 patients, respectively, but all exhibited left ventricular diastolic collapse. Increasing pressure within the compartment of a loculated pericardial effusion reaching the limit of pericardial distensibility and consequent transient reversal of transmural left ventricular pressure during diastole are most likely the basis for diastolic collapse of the thick-walled ventricle in a setting of regional cardiac tamponade.

CONCLUSIONS

We conclude that left ventricular diastolic collapse is a frequent sign of regional cardiac tamponade and could be a useful marker of tamponade in postoperative patients.
Inhaled nitric oxide. A selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction.
Authors: Frostell C , Fratacci M D , Wain J C , Jones R , Zapol W M
Published: June 2012

Background. The gas nitric oxide (NO) is an important endothelium-derived relaxing factor, inactivated by rapid combination with heme in hemoglobin. Methods and Results. Awake spontaneously breathing lambs inhaled 5-80 ppm NO with an acutely constricted pulmonary circulation due to either infusion of the stable thromboxane endoperoxide analogue U46619 or breathing a hypoxic gas mixture. Within 3 minutes after adding 40 ppm NO or more to inspired gas, pulmonary hypertension was reversed. Systemic vasodilation did not occur. Pulmonary hypertension resumed within 3-6 minutes of ceasing NO inhalation. During U46619 infusion pulmonary vasodilation was maintained up to 1 hour without tolerance. In the normal lamb, NO inhalation produced no hemodynamic changes. Breathing 80 ppm NO for 3 hours did not increase either methemoglobin or extravascular lung water levels nor modify lung histology compared with control lambs. Conclusions. Low dose inhaled NO (5-80 ppm) is a selective pulmonary vasodilator reversing both hypoxia- and thromboxane-induced pulmonary hypertension in the awake lamb [corrected].
Abnormal automatic rhythms in ischemic Purkinje fibers are modulated by a specific alpha 1-adrenergic receptor subtype.
Authors: Anyukhovsky E P , Rosen M R
Published: June 2012

BACKGROUND

Recent advances in adrenergic pharmacology have made possible the identification of alpha 1-adrenergic receptor subtypes using the specific blockers chloroethylclonidine and WB 4101.

METHODS AND RESULTS

In the present study, we used these two blockers to determine the mechanisms responsible for automatic rhythms occurring during simulated ischemia and reperfusion of isolated canine Purkinje fibers. Experiments were done in the presence of propranolol to minimize beta-adrenergic contributions to the rhythms studied. In the control situation, all fibers showed membrane potentials greater than -90 mV and normal automatic rhythms. During simulated ischemia, membrane potential depolarized to the -60 mV range. Abnormal automaticity was seen in 20% of fibers not treated with phenylephrine and in 50% of those superfused with 1 x 10(-7) M phenylephrine. The incidence of abnormal automaticity was reduced to 0% by WB 4101 (which blocks phosphoinositide metabolic effects of alpha 1-adrenergic stimulation in the heart) and was increased to 90% by chloroethylclonidine (which blocks Na-K pump-stimulating effects of alpha-agonists). Moreover, the ischemic fibers were significantly more hyperpolarized during superfusion with WB 4101 than with chloroethylclonidine. Triggered activity induced by delayed or early after depolarizations was not seen in any experiment.

CONCLUSIONS

Automatic arrhythmias induced by alpha 1-adrenergic stimulation during simulated ischemia may be attributed to a specific alpha 1-adrenergic receptor subtype that is blocked by WB 4101. These results have important implications with respect to the induction of arrhythmias in the setting of ischemia and the means for their prevention or treatment.
Effect of calcification on in vivo mechanical response of rabbit arteries to balloon dilation.
Authors: Demer L L
Published: June 2012

BACKGROUND

Atherosclerosis has been associated with loss of artery wall distensibility in human cadavers and in experimental animal models, giving it the lay term "hardening of the arteries."

METHODS AND RESULTS

To assess the effect of calcification on arterial distensibility, balloon pressure and volume were recorded during dilation of calcified aortas in Watanabe heritable hyperlipidemic (WHHL) rabbits in vivo. Calcification was induced by dietary supplements of cholesterol, vitamin D2, and calcium. Balloon pressure, volume, and time signals were acquired at high frequency with controls for temperature and balloon inflation rate. Resistance to balloon dilation was minimal in control rabbit aortas (delta Vmax = 5.0 +/- 3.5 microliters) and in excised nonatherosclerotic human coronary arteries, and it was small in aortas from cholesterol-fed rabbits (12.3 +/- 8 microliters), even when lipid levels were markedly elevated by a high cholesterol diet (611 +/- 347 mg/dl). With dietary cholesterol, vitamin D2, and calcium supplements, WHHL rabbits developed mild hypercalcemia (15 +/- 1.9 mg/dl), hypercholesterolemia (1,100 +/- 633 mg/dl), moderate-to-marked aortic calcification, and high resistance to balloon dilation (38 +/- 27) comparable to that seen in angioplasty patients.

CONCLUSIONS

It is concluded that experimentally induced calcification decreases the distensibility of the rabbit aorta in vivo and that it yields to balloon dilation by plastic deformation closely resembling that seen in balloon angioplasty of human coronary arteries. These findings suggest that calcification contributes to arterial "hardening" associated with atherosclerosis.
Fetal cardiovascular morphology of truncus arteriosus with or without truncal valve insufficiency in the rat.
Authors: Momma K , Ando M , Takao A , Miyagawa-Tomita S
Published: June 2012

BACKGROUND

Recent advances in fetal echocardiography have necessitated further study on fetal in situ cardiovascular morphology of truncus arteriosus and the effects of truncal valve insufficiency.

METHODS AND RESULTS

We studied 55 fetal rats with truncus arteriosus among 300 fetuses from 40 virgin females treated with 200 mg fertilysin on the 10th day of pregnancy. After rapid whole-body freezing on the 21st day, the fetuses were studied by means of serial cross-sectional photographs of the frozen thorax. Thirty-five fetuses with a normal heart treated with fertilysin served as controls. Truncus arteriosus was characterized by a large ventricular septal defect, a solitary artery (truncus arteriosus) overriding the ventricular septum, the right and left pulmonary arteries originating from the truncus arteriosus with or without a common trunk (main pulmonary artery), and absent ductus arteriosus. Fetuses with truncal valve insufficiency had thick truncal valves, a large truncus arteriosus, and large ventricles. The subgroup of 12 fetuses with a large truncus (truncal diameter greater than 160% of the ascending aorta diameter in the controls) showed significantly greater values for right ventricular volume (200% of control) and mass (120% of control), left ventricular volume (170% of control) and mass (110% of control), right (120% of control) and left (110% of control) atrial volume, and pericardial fluid (140% of control) than the controls. These changes were less prominent and ventricular volumes were not increased in the remaining subgroup with a truncal diameter of 160% or less of aorta diameter in the controls.

CONCLUSIONS

In fetal truncus arteriosus, truncal valve insufficiency was associated with increased ventricular volume load and incomplete cardiac compensation in rats.
Intravenous nitroglycerin infusion inhibits cyclic blood flow responses caused by periodic platelet thrombus formation in stenosed canine coronary arteries.
Authors: Folts J D , Stamler J , Loscalzo J
Published: June 2012

BACKGROUND

Nitroglycerin and other clinically relevant organic nitrate derivatives have been shown to inhibit platelet aggregation in vitro. This antithrombotic effect of nitrates is potentiated by reduced thiol. To determine the potential relevance of this mechanism of action in vivo, we examined the effect of intravenous nitroglycerin infusion on periodic platelet thrombus formation in a canine model of coronary artery stenosis.

METHODS AND RESULTS

We used a canine model of coronary artery stenosis associated with cyclic reductions in coronary blood flow that have been shown to depend on periodic platelet thrombus formation. We quantified the frequency of cycles per 40-minute observation period and monitored the effect of a continuous infusion of intravenous nitroglycerin on the cycle frequency. The administration of 10-15 micrograms/kg/min nitroglycerin reduced cyclic platelet thrombus formation significantly and did so without a significant change in coronary artery blood flow. Pretreatment with the reduced thiol, N-acetylcysteine (100 mg/kg during 30 minutes), led to inhibition of cyclic platelet thrombus formation by intravenous nitroglycerin at doses that alone had no such effect (5 micrograms/kg/min).

CONCLUSION

These data suggest that one mechanism by which intravenous nitroglycerin improves ischemia in acute coronary artery disease syndromes may be by inhibition of platelet thrombus formation and may highlight the potential importance of reduced thiol in this mechanism.
Racial (black-white) differences in serum lipoprotein (a) distribution and its relation to parental myocardial infarction in children. Bogalusa Heart Study.
Authors: Srinivasan S R , Dahlen G H , Jarpa R A , Webber L S , Berenson G S
Published: June 2012

BACKGROUND

The value of lipoprotein (a) [Lp(a)] in the prediction of coronary artery disease risk very early in life remains to be established in different racial groups.

METHODS AND RESULTS

Serum Lp(a) distribution and its relation to parental histories of myocardial infarction were examined in 2,438 children (8-17 years old) from a biracial community. Parental myocardial infarction was used as a surrogate measure of future risk of disease in the offspring. Lp(a) levels averaged 1.7-fold higher in blacks than in whites (p less than 0.0001). A small but significant sex difference (females greater than males, p less than 0.05) was seen in both races. Race was the only independent variable that contributed appreciably (9%) to the variability of Lp(a) in serum. White children with parental myocardial infarction (n = 90) had increased levels of Lp(a) compared with those without parental myocardial infarction (22.4 versus 17.1 mg/dl, p less than 0.01). Furthermore, among white children, the prevalence of parental myocardial infarction was higher in those with Lp(a) levels of more than 25 mg/dl than in those with values of 25 mg/dl or less (9.5% versus 5.4%, p less than 0.01). In contrast, the relation of Lp(a) to parental myocardial infarction was not seen in black children. No associations were observed between parental myocardial infarction and serum levels of any of the lipids or lipoprotein cholesterol classes in children of either race.

CONCLUSIONS

Serum Lp(a) levels may prove valuable in the assessment of coronary artery disease risk early in life among white populations. These findings also emphasize the need to evaluate the atherogenic potential of Lp(a) in different racial groups.
Canine myocardial creatine kinase isoenzymes after chronic coronary artery occlusion.
Authors: Sharkey S W , Murakami M M , Smith S A , Apple F S
Published: June 2012

BACKGROUND

Creatine kinase (CK) exists as three cytosolic isoenzymes, CK-MM, CK-MB, and CK-BB, and one mitochondrial isoenzyme. Animal and human observations suggest that the CK-MB content of myocardium is dynamic and may increase in response to ischemia, but the response of the myocardial CK system to chronic coronary artery occlusion is not well-defined.

METHODS AND RESULTS

We measured serial changes in myocardial total CK, percent CK-MB, and percent CK-BB before and 3 weeks after coronary artery occlusion in 17 pentobarbital-anesthetized dogs. Tissue biopsies were obtained from the left anterior descending (LAD) coronary artery myocardium, the right coronary artery (RCA) myocardium, and the circumflex coronary artery myocardium at baseline and 3 weeks after LAD occlusion (n = 6), RCA occlusion (n = 5), and no coronary artery occlusion (n = 6). Tissue samples were assayed for total CK, percent CK-MB, and percent CK-BB. Samples were also examined by electron microscopy for evidence of ischemic myopathy. Total myocardial CK activity did not change over 3 weeks. Percent CK-MB increased significantly in the tissue supplied by the occluded artery (4.1-fold in dogs with LAD occlusion and 6.7-fold in dogs with RCA occlusion). Percent CK-BB did not change. Dogs with LAD occlusion had ultrastructural evidence of myopathic fibers interspersed with normal fibers in the LAD myocardium. Dogs with RCA occlusion had no ultrastructural evidence of myopathic fibers in the RCA myocardium.

CONCLUSIONS

Chronic coronary artery occlusion causes a pronounced change in the canine myocardial CK system that is limited to the tissue supplied by the occluded coronary artery. These biochemical alterations do not correlate with any cellular ultrastructural changes. Myocardial CK-MB content is dynamic, varies geographically within the heart, and increases rapidly after coronary artery occlusion.
Effect of ST segment measurement point on performance of standard and heart rate-adjusted ST segment criteria for the identification of coronary artery disease.
Authors: Okin P M , Bergman G , Kligfield P
Published: June 2012

BACKGROUND

Recent reports critical of the performance of heart rate-adjusted indexes of ST depression during exercise electrocardiography have used J-point rather than ST segment measurements. However, no standard exists for the optimal time after the J-point at which to measure ST segment deviation.

METHODS AND RESULTS

To assess the effect of ST segment measurement position on performance of standard exercise electrocardiographic criteria, the delta ST segment/heart rate (delta ST/HR) index, and the ST segment/heart rate (ST/HR) slope for the detection of coronary artery disease, the exercise electrocardiograms of 50 clinically normal subjects and 80 patients with known or likely coronary disease were analyzed using ST depression measured at both the J-point and at 60 msec after the J-point (J + 60). A positive exercise electrocardiogram by standard criteria, defined as 0.1 mV or more of additional horizontal or downsloping ST depression at end exercise, had a specificity of 96% when ST depression was measured at either the J-point or J + 60. There was no difference in sensitivity of standard electrocardiographic criteria at J + 60 and J point (both 59%, p = NS). However, at matched specificity of 96%, the delta ST/HR index and ST/HR slope calculated using ST depression at J + 60 were significantly more sensitive (90% and 93%) than when calculated using J-point depression (64% and 61%, each p less than 0.001). Comparison of areas under respective receiver operating characteristic curves confirmed the superior performance of J + 60 as opposed to J-point measurements for both the delta ST/HR index (0.98 versus 0.89, p = 0.006) and the ST/HR slope (0.96 versus 0.87, p = 0.007) and also demonstrated modestly improved overall test performance for standard electrocardiographic criteria using J + 60 measurements (0.88 versus 0.82, p = 0.001).

CONCLUSIONS

Use of J-point measurements significantly degrades performance of heart rate-adjusted indexes of ST depression but has less effect on standard criteria.
Cardiovascular neural regulation explored in the frequency domain.
Authors: Malliani A , Pagani M , Lombardi F , Cerutti S
Published: June 2012

A consistent link appears to exist between predominance of vagal or sympathetic activity and predominance of HF or LF oscillations, respectively: RR variability contains both of these rhythms, and their relative powers appear to subserve a reciprocal relation like that commonly found in sympathovagal balance. In this respect, it is our opinion that rhythms and neural components always interact, just like flexor and extensor tones or excitatory and inhibitory cardiovascular reflexes, and that it is misleading to separately consider vagal and sympathetic modulations of heart rate. In humans and experimental animals, functional states likely to be accompanied by an increased sympathetic activity are characterized by a shift of the LF-HF balance in favor of the LF component; the opposite occurs during presumed increases in vagal activity. In addition, LF oscillation evaluated from SAP variability appears to be a convenient marker of the sympathetic modulation of vasomotor activity. Although based on indirect markers, the exploration in the frequency domain of cardiovascular neural regulation might disclose a unitary vision hard to reach through the assemblage of more specific but fragmented pieces of information.
Left ventricular thrombus in anterior acute myocardial infarction after thrombolysis. A GISSI-2 connected study.
Authors: Vecchio C , Chiarella F , Lupi G , Bellotti P , Domenicucci S
Published: June 2012

BACKGROUND

Streptokinase reduces the incidence of left ventricular thrombosis after acute myocardial infarction. However, it is unknown whether a similar effect can be obtained with different thrombolytic agents and whether subcutaneous calcium heparin can have an additional efficacy.

METHODS AND RESULTS

To compare the effects of two different thrombolytic agents combined or not with heparin on the incidence and features of left ventricular thrombi and their related embolic events, we performed a GISSI-2 ancillary echocardiographic study (the first echocardiogram obtained within 48 hours of symptoms onset and the second before hospital discharge) that enrolled 180 consecutive patients (mean age, 63 +/- 11 years, 142 men) with a first anterior acute myocardial infarction. Patients were randomized into four groups of treatment: recombinant tissue-type plasminogen activator (rt-PA) (n = 47), rt-PA plus heparin (n = 45), streptokinase (n = 39), and streptokinase plus heparin (n = 49). Left ventricular thrombosis was observed in 51 of 180 patients (28%). No significant differences were found concerning the incidence of thrombi in the four treatment groups. Mural shape of left ventricular thrombi was found more frequently than the protruding shape (71% versus 29% at the first examination, 64% versus 36% at the second), particularly in heparin-treated patients (93% versus 7% at first examination, 70% versus 30% at the second). Only one embolic event (0.5%) occurred during the hospitalization.

CONCLUSIONS

We conclude that 1) the rate of left ventricular thrombi does not differ in patients with acute myocardial infarction treated either with streptokinase or rt-PA, 2) subcutaneous heparin, when begun 12 hours after intravenous thrombolysis, does not appear to further reduce the occurrence of thrombi but seems to influence the shape of left ventricular thrombi, and 3) during the predischarge period, embolic events are rare in patients treated by thrombolysis.
Clinical implications of late proven patency after successful coronary angioplasty.
Authors: Weintraub W S , Ghazzal Z M , Cohen C L , Douglas J S , Liberman H , Morris D C , King S B
Published: June 2012

BACKGROUND

The introduction of percutaneous transluminal coronary angioplasty (PTCA) has changed the pattern of intervention in coronary artery disease. However, the long-term results in patients undergoing successful, elective, native-vessel PTCA are not yet fully characterized. Because the healing and subsequent proliferative response after angioplasty are time related, it was the purpose of the present study to determine the long-term outcome in patients whose dilated arteries have been demonstrated to be patent 4-12 months after successful, uncomplicated PTCA.

METHODS AND RESULTS

The patients were grouped on the basis of the 4-12 month catheterization into those whose vessels were angiographically "normal" or had luminal irregularities only at the PTCA sites (396 patients), those whose vessels also had luminal irregularities elsewhere with or without PTCA site luminal irregularities (680 patients), and those with significant obstructive disease (more than 50% diameter narrowing) at sites other than the PTCA sites (426 patients). Of 1,502 such patients, long-term follow-up was available in 1,491. At the time of the original angioplasty, the normal patients had a 1.8% incidence of multivessel disease; luminal irregularity patients, 9.4%; and obstructive disease patients, 58.7%. At angiographic restudy, 16.4% of the obstructive disease patients continued to have multivessel disease. The patients were followed for the events of death, myocardial infarction, coronary surgery, and repeat PTCA. The 6-year survival rate was 95%; cardiac survival, 96%; and freedom from all events, 65%. The strongest correlate of events during follow-up was the angiographic status of the undilated segments. At 6 years, freedom from cardiac events was noted in 77% of the normal group, 61% of the luminal irregularity group, and 55% of the obstructive disease group. Diabetes and hypertension were also independent correlates of events.

CONCLUSIONS

Results from the present study show that associated disease in undilated segments is a strong predictor of late events in patients after successful, uncomplicated, reatenosis-free PTCA. However, the need for further revascularization was frequent even in patients without obstructive disease. Completeness of revascularization is appropriate when possible, and limiting progression of coronary disease at sites remote from those dilated should improve on these late results.
Expression of perforin in infiltrating cells in murine hearts with acute myocarditis caused by coxsackievirus B3.
Authors: Seko Y , Shinkai Y , Kawasaki A , Yagita H , Okumura K , Takaku F , Yazaki Y
Published: June 2012

BACKGROUND

Cell-mediated autoimmunity has been strongly implicated in the pathogenesis of viral myocarditis.

METHODS AND RESULTS

Using a murine model of acute myocarditis caused by coxsackievirus B3, we analyzed the phenotypes and morphology of the infiltrating cells in the hearts by immunofluorescence and electron microscopy. We also examined the expression of a cytolytic factor, perforin, in the infiltrating cells by immunoperoxidase and in situ hybridization. We found that the dominant population of the infiltrating cells were asialo GM1 positive, were negative for T-cell markers, and had electron-dense cytoplasmic granules, which is consistent with a morphology of large granular lymphocytes. Perforin was found in the cytoplasmic granules of the infiltrating cells expressing perforin messenger RNA. These findings provide for the first time the direct evidence that the first wave of cell infiltration in hearts mainly consists of killer cells and strongly suggests that perforin plays, in part, an important role in myocardial cell damage involved in acute viral myocarditis. T-helper cells and cytotoxic T lymphocytes made up the second wave of cell infiltration.

CONCLUSIONS

As we previously reported, the expression of major histocompatibility complex class I antigen on cardiac myocytes induced by the infiltrating cells, such as killer cells, may facilitate the interaction between cardiac myocytes and cytotoxic T lymphocytes, and may lead to further myocardial cell damage in a later phase.
Role of oxygen-derived free radicals in myocardial edema and ischemia in coronary microvascular embolization.
Authors: Hori M , Gotoh K , Kitakaze M , Iwai K , Iwakura K , Sato H , Koretsune Y , Inoue M , Kitabatake A , Kamada T
Published: June 2012

BACKGROUND

Oxygen-derived free radicals are thought to injure the ischemic heart during coronary microvascular embolization.

METHODS AND RESULTS

To test this idea, microspheres (15 microns in diameter) were repetitively administered into the left anterior descending coronary artery to cause microvascular embolization in dogs. Myocardial contractile and metabolic dysfunctions were significantly attenuated after treatments with recombinant human superoxide dismutase, an acyl derivative of ascorbic acid (CV3611, 2-O-octadecylascorbic acid), and xanthine oxidase inhibitor (allopurinol). The free radical scavengers and inhibitor enhanced the coronary hyperemic flow response during embolization, and the total number of microspheres causing maximal embolization was increased by these drugs. When 8-phenyltheophylline was additionally administered with superoxide dismutase, these beneficial effects were abolished, indicating that coronary effects of these drugs may be due to increased release of adenosine during coronary microvascular embolization.

CONCLUSIONS

We conclude that oxygen radicals worsen the ischemic injury in coronary microembolization.