bluuebunny/crossref_metadata_2025 huggingface dataset:
The epidemiology of diet and blood pressure.
Authors: Cappuccio F P
Published: June 2012

Epidemiological studies of diet and blood pressure support the concept that some dietary nutrients are strongly related to blood pressure and are amenable to modifications, with a likely impact on the incidence of hypertension and of related vascular events. For other potential nutrients, the evidence is more difficult to obtain. Further studies are required to establish 1) the practical value of assessment of individual nutrients versus dietary patterns in risk prediction, 2) the effects of changes of these individual nutrients versus dietary patterns on blood pressure, and 3) whether long-term changes in these individual nutrients or dietary patterns reduce the incidence of hypertension and can be implemented at a population level.
Increased expression and regional differences of atrial myosin light chain 1 in human ventricles with old myocardial infarction. Analyses using two monoclonal antibodies.
Authors: Nakao K , Yasue H , Fujimoto K , Jougasaki M , Yamamoto H , Hitoshi Y , Takatsu K , Miyamoto E
Published: June 2012

BACKGROUND

This study was designed to examine the expression of atrial/fetal-type myosin light chain 1 (ALC1) in human ventricles with old myocardial infarction and in control hearts.

METHODS AND RESULTS

The expression of immunoreactive (ir) ALC1 was examined in the subendocardial and subepicardial myocardium of the infarcted and the noninfarcted regions in the left ventricles with old myocardial infarction (n = 12) and of the control left ventricles (n = 8). For the analysis, we prepared two monoclonal antibodies, KA1 and KB1, that were specific for only ALC1 and for both ALC1 and ventricular myosin light chain 1 (VLC1), respectively. The ir-ALC1 expression ratio [ALC1/(ALC1 + VLC1), %] of the subendocardial myocardium, determined densitometrically by Western blotting with KB1, was significantly higher in the infarcted region (11.4 +/- 7.3%) than in the noninfarcted region (4.7 +/- 2.3%, p < 0.001) and the control ventricle (1.0 +/- 1.5%, p < 0.0001). In the infarcted region, the subendocardial myocardium contained a significantly greater percentage of ir-ALC1 than the subepicardial myocardium (5.8 +/- 6.7%, p < 0.005). The ir-ALC1 expression ratio had a significant negative correlation with the value of tissue protein concentration (milligrams protein per gram wet weight). The immunohistochemical study with KA1 revealed that the surviving myocytes included in the infarcted region, especially in the ventricular aneurysm, expressed ir-ALC1 strongly in comparison with those in the noninfarcted or the control ventricles.

CONCLUSIONS

These results demonstrate increased expression of ALC1 and the regional differences in the failing left ventricles with old myocardial infarction. We conclude that the reexpression of ALC1 in infarcted ventricles occurs as one of the regional responses to increased load and may be a useful biochemical marker for the appearance of fetal-type myocytes.
Epinephrine augments von Willebrand factor-dependent shear-induced platelet aggregation.
Authors: Goto S , Ikeda Y , Murata M , Handa M , Takahashi E , Yoshioka A , Fujimura Y , Fukuyama M , Handa S , Ogawa S
Published: June 2012

BACKGROUND

Shear-induced platelet aggregation (SIPA) is an important mechanism in thrombogenesis. von Willebrand factor (vWF) binding to platelet glycoprotein Ib (GP Ib) has been found to be crucial for platelet aggregation under the high shear force probably generated in stenosed coronary artery. The physiological significance of vWF-dependent SIPA has not been clarified.

METHODS AND RESULTS

Blood samples were collected from 23 normal volunteers. SIPA was continuously monitored using a modified cone-plate viscometer adapted for measuring the transmitted light intensity of the material. The effects of low concentrations of epinephrine, ADP, and collagen on SIPA under both low shear (12 dyne/cm2) and high shear (108 dyne/cm2) force were investigated. All agonists tested enhanced SIPA under low shear force, whereas only epinephrine augmented SIPA under high shear force. The maximum extents of SIPA under high shear force in the absence and presence of epinephrine (10 ng/ml) were 37.9 +/- 11.5% and 59.7 +/- 13.9%, respectively. The antagonist of the alpha 2-adrenergic receptor yohimbine (1 microgram/ml) antagonized the effects of epinephrine. The monoclonal antibody NMC-4 against vWF, which was shown to inhibit its binding to GP Ib, completely abolished SIPA under high shear force, even in the presence of epinephrine. However, this antibody only partially inhibited SIPA under low shear force.

CONCLUSIONS

Our findings suggest that epinephrine is the agonist that enhances SIPA mediated by vWF through its specific receptor. This may be clinically important because occlusion of the coronary artery often occurs in stenosed atherosclerotic vessels under sympathetic stimulation.
Contribution of myocardium responsible for ventricular tachycardia to abnormalities detected by analysis of signal-averaged ECGs.
Authors: Hood M A , Pogwizd S M , Peirick J , Cain M E
Published: June 2012

BACKGROUND

Current methods of signal-averaged ECG analysis interrogate the terminal 40 msec of the QRS complex and/or the ST segment and have a low positive-predictive accuracy for detecting vulnerability to sustained ventricular tachycardia (VT). The extent to which abnormalities detected during these ECG intervals are generated by myocardial tissue responsible for VT has not been well defined. The purpose of this study was to determine when, during sinus rhythm, myocardium responsible for VT is activated.

METHODS AND RESULTS

Three-dimensional ventricular activation maps were analyzed during sinus rhythm and during 10 VTs in eight patients with healed myocardial infarctions undergoing arrhythmia surgery for sustained monomorphic VT. The mechanism of VT was focal in five instances and macroreentrant in five. During sinus beats, myocardium responsible for all focal VTs activated 43 +/- 38 msec before the onset of the terminal 40-msec interval of the QRS complex. During sinus rhythm, activation of the myocardium critical to macroreentrant VT began 72 +/- 13 msec before the onset of the terminal QRS interval and in only three instances extended 2-25 msec into the terminal 40 msec of the QRS complex. Electrograms recorded during the ST segment represented late activation of epicardial sites overlying zones of infarction that were temporally and spatially remote from tissue critical to VT.

CONCLUSIONS

Current methods of signal-averaged ECG analysis limiting interrogation to the terminal QRS/ST segment exclude detection of > 95% of the signals generated by myocardium responsible for sustained VT. These results establish a pathophysiological basis for expanding signal-averaged ECG analysis to include more of the cardiac cycle.
Control of sympathetic nerve activity by vagal mechanoreflexes is blunted in heart failure.
Authors: Dibner-Dunlap M E , Thames M D
Published: June 2012

BACKGROUND

Previous studies have documented abnormalities of arterial baroreflexes in animals and patients with congestive heart failure. This study determined whether cardiopulmonary reflex control of sympathetic nerve activity was abnormal in a canine model of low-output heart failure induced by rapid ventricular pacing.

METHODS AND RESULTS

We stimulated mechanoreceptors throughout the cardiopulmonary region by volume expansion and left atrial mechanoreceptors selectively by inflating small balloons at the junctions of the pulmonary veins and left atrium. Responses of renal sympathetic nerve activity and left atrial and systemic arterial pressures were recorded. In the control group, 15% volume expansion raised left atrial pressure 3.5 +/- 0.8 mm Hg and resulted in a 70 +/- 8% reduction in renal nerve activity. In the heart failure group, 15% volume expansion resulted in a 6.8 +/- 3.0 mm Hg rise in left atrial pressure with only a 16 +/- 20% reduction in renal nerve activity (p < 0.01). When volume expansion was performed after pretreatment with hemorrhage to lower left atrial pressure to the normal range in the heart failure group, the markedly attenuated response in the heart failure group persisted. After vagotomy, volume expansion elicited no change in renal nerve activity. Inflation of the atrial balloons caused a 28 +/- 9% reduction in renal sympathetic nerve activity and a 13 +/- 4 mm Hg decrease in arterial pressure in the control group. Renal nerve activity (-5 +/- 3%) and mean arterial pressure (-1 +/- 1 mm Hg) did not change with balloon inflation in the heart failure group.

CONCLUSIONS

We conclude that dogs with low-output heart failure exhibit marked attenuation of cardiopulmonary mechanoreflex control of sympathetic nerve activity. This attenuated response is mediated via cardiac vagal afferent fibers and is due to either abnormalities in cardiopulmonary baroreceptors or abnormalities in the central nervous system.
Effects of calcium and EMD-53998 on oxygen consumption in isolated canine hearts.
Authors: de Tombe P P , Burkhoff D , Hunter W C
Published: June 2012

BACKGROUND

Most positive inotropic agents increase cardiac contractility by increasing the amount of Ca2+ cycled with each beat. The additional amount of oxygen that is consumed by the heart to cycle this additional Ca2+ is believed to reduce myocardial efficiency. On the other hand, it has been suggested that the agent EMD-53998 increases the Ca2+ sensitivity of the contractile proteins without affecting the intracellular Ca2+ transient in cardiac muscle. Therefore, application of this agent may increase cardiac contractility without decreasing myocardial efficiency. The purpose of the present study was to test this hypothesis.

METHODS AND RESULTS

We measured myocardial oxygen consumption (MVO2) in six isolated, isovolumically beating blood-perfused canine hearts. The hearts were paced at 120 beats per minute. Contractility was varied in each heart by infusion of either CaCl2 or EMD-53998. With infusion of either agent, MVO2 was a linearly proportional function of contractility. No significant difference between CaCl2 and EMD-53998 could be detected in the interrelation between contractility and MVO2.

CONCLUSIONS

We conclude that the "calcium-sensitizing agent" EMD-53998 is a potent positive inotropic agent in the isolated, blood-perfused canine heart. However, EMD-53998 does not provide an energetic advantage over currently used positive inotropic agents.
Effects of vagal stimulation on cesium-induced early afterdepolarizations and ventricular arrhythmias in rabbits.
Authors: Takahashi N , Ito M , Ishida S , Fujino T , Saikawa T , Arita M
Published: June 2012

BACKGROUND

Previous evidence has shown that increased sympathetic tone enhances the cesium chloride (Cs)-induced early afterdepolarizations (EADs) and ventricular tachycardias (VTs).

METHODS AND RESULTS

We assessed the effects of vagal stimulation on Cs-induced EADs and ventricular arrhythmias in the rabbit heart. Monophasic action potentials (MAPs) of the left ventricular endocardium were recorded simultaneously with surface ECG. Two protocols were used: 1) While in their intrinsic sinus rhythm, 11 rabbits were given three intravenous Cs injections (1 mM/kg) 20 minutes apart, and the effects of vagal stimulation on the ventricular arrhythmias thus induced were examined. 2) Under constant atrial pacing (cycle length, 250 msec), EAD amplitude was measured after Cs injection (1 mM/kg) without (five rabbits, control group) or with (four rabbits, vagal stimulation group) vagal stimulation. We observed the following. 1) Cs produced EADs and VTs of polymorphic (PVT) and monomorphic (MVT) types. During PVT, the take-off potential of repetitive premature action potentials in MAP recordings was about the same as the peak level of EADs, and during MVT, the take-off potential was the level of full repolarization. Vagal stimulation suppressed PVT but not MVT. Vagal stimulation after spontaneous termination of MVT restarted MVT of the same morphology at a rate much slower than the preceding sinus rate. 2) EAD amplitude was significantly smaller in the vagal stimulation group than in the control group.

CONCLUSIONS

The results suggest that PVT originated from triggering by EADs, whereas MVT was of different origin, and that vagal stimulation suppressed PVT by decreasing the amplitude of EADs.
Pace mapping using body surface potential maps to guide catheter ablation of accessory pathways in patients with Wolff-Parkinson-White syndrome.
Authors: Dubuc M , Nadeau R , Tremblay G , Kus T , Molin F , Savard P
Published: June 2012

BACKGROUND. A pace mapping technique using body surface potential maps (BSPMs) was developed to guide the positioning of an ablation catheter at the ventricular insertion point of accessory pathways (AP) in patients with the Wolff-Parkinson-White syndrome (WPW). METHODS AND RESULTS. The study was performed on 30 WPW patients. BSPMs were recorded with 63 leads distributed over the entire torso surface. The catheter used for radiofrequency ablation was first placed in the vicinity of the ventricular preexcitation site predicted by BSPMs recorded during the delta wave. BSPMs were then recorded during pacing with this catheter, the comparison between the preexcited and paced BSPMs indicated whether the pacing site was too anterior or posterior with respect to the preexcitation site, and the catheter was moved accordingly. This process was repeated until the preexcited and paced BSPMs were highly correlated (r > or = 0.8), and ablation then was attempted. It was possible to successfully ablate the AP in 28 patients after an investigation that lasted 54 +/- 44 minutes between the recording of the first paced BSPM and that of the BSPM paced at the successful ablation site. Patients with left free wall pathways needed less investigation time compared with patients with pathways of other locations (46 +/- 9 versus 100 +/- 25 minutes, p = 0.031). The sensitivity of BSPM pace mapping was assessed using pacing with a multipolar catheter, and significant changes were observed on the BSPMs for beats with pacing sites that were only 5 mm apart. CONCLUSIONS, BSPM pace mapping allowed us to achieve a 93% success rate with short investigation durations, provides significant information that cannot be obtained with the standard 12-lead ECG, is a self-correcting procedure that reduces the importance of BSPM alterations due to individual differences in the shape of the torso or heart, and is applicable only to patients with AP showing antegrade conduction.
Altered left ventricular chamber stiffness and isovolumic relaxation in dogs with chronic pulmonary hypertension caused by emphysema.
Authors: Gomez A , Unruh H , Mink S N
Published: June 2012

BACKGROUND

In chronic obstructive lung disease, a right to left ventricular septal shift that occurs as a consequence of right ventricular pressure overload is the usual mechanism given to explain a decrease in left ventricular (LV) diastolic performance. The purpose of the present study was to examine the extent to which this mechanism could account for a decrease in LV diastolic function in a canine model in which pulmonary artery pressure was elevated to a level found in human disease.

METHODS AND RESULTS

Severe emphysema was produced in dogs by repeated instillations of the enzyme papain into the lung. To assess LV diastolic function, we used sonomicrometry, in which three pairs of subendocardial crystal transducers were implanted along the three orthogonal axes of the LV. LV end-diastolic dimensions and pressure-strain relations along the three axes, as well as the time constant of LV isovolumic relaxation (T), were measured before (baseline) and after 1 year of emphysema (post-1-year study). The results showed that after 1 year of pulmonary hypertension, LV pressure-strain relations were decreased along the septal-lateral and anterior-posterior axes, but a right to left ventricular septal shift was not detected. The relation of average midwall circumferential stress to midwall circumferential strain was used to describe the intrinsic compliance of the LV. The results showed that myocardial stiffness increased in emphysema but that chamber volume was not reduced. At the post-1-year study, T was abnormally increased in the emphysema group in response to augmented preload and afterload compared with preemphysema measurements.

CONCLUSIONS

We conclude that mechanisms other than ventricular interdependence may be operative in leading to altered LV diastolic filling in chronic emphysema.
A history of the American Heart Association's Council on Clinical Cardiology.
Authors: Fye W B
Published: June 2012

This essay reviews the founding and early history of the Council on Clinical Cardiology of the American Heart Association (AHA), the largest of the AHA's 14 councils. Based on archival research, it stresses the factors that led to the council's formation and shaped its agenda. The council was established in the context of the AHA's transition from a professional society to a voluntary health organization in 1948. But the direct stimulus for its creation was the American College of Cardiology's (ACC) first membership drive 3 years later. When the AHA's Section (later Council) on Clinical Cardiology was formally established in 1952, its official purpose was to "facilitate and encourage investigation, prevention, treatment and education in the field of clinical cardiology." Originally strained, the relations between the AHA and the ACC improved as the organizations came to view each other as potential partners rather than rivals.
Interstitial dendritic cells of the rat heart. Quantitative and ultrastructural changes in experimental myocardial infarction.
Authors: Zhang J , Yu Z X , Fujita S , Yamaguchi M L , Ferrans V J
Published: June 2012

BACKGROUND

This study was undertaken to investigate the qualitative and quantitative changes that interstitial dendritic cells (IDC) of the heart undergo during the time course of experimental myocardial infarction.

METHODS AND RESULTS

Left coronary arterial ligations were performed in 43 rats that were killed 2, 4, 7, 14, and 21 days after surgery. Thirteen unoperated and 39 sham-operated rats were used as controls. Frozen sections were stained with monoclonal antibodies (OX 6 and W3/25) to identify and count IDC by light microscopy. Immunoelectron microscopy was also used to identify IDC. The number of IDC per mm2 of tissue section was calculated for all hearts. In hearts with myocardial infarction, IDC were counted in three areas: the center of the myocardial infarction, the border zone, and the noninfarcted left ventricle. In OX 6 antibody-stained preparations, the number of IDC per mm2 was 82 +/- 10 in the left ventricle of unoperated rats. Hearts with myocardial infarction showed marked increases in the numbers of IDC per mm2 in the border zone (796 +/- 79 at 7 days and 528 +/- 98 at 14 days). In the border zone, IDC often were associated with small clusters of T-helper lymphocytes, which reacted with W3/25 antibody (the rat homologue of human CD4). The center of the myocardial infarction showed an increase in IDC only on day 7 (120 +/- 18). By 21 days, IDC in the border zone were only slightly increased (159 +/- 15).

CONCLUSIONS

These findings suggest that IDC migrate to the myocardial infarction border zone. They participate in the activation of lymphocytes and in the initiation of immune responses and decrease in number as inflammation subsides and scarring develops.
Frequency domain measures of heart rate variability before the onset of nonsustained and sustained ventricular tachycardia in patients with coronary artery disease.
Authors: Huikuri H V , Valkama J O , Airaksinen K E , Seppänen T , Kessler K M , Takkunen J T , Myerburg R J
Published: June 2012

BACKGROUND

Low heart rate variability (HRV) is associated with an increased risk of arrhythmic death and ventricular tachycardia (VT). The purpose of this study was to examine whether there is a temporal relation between changes in HRV and the onset of spontaneous episodes of VT in patients at high risk of life-threatening arrhythmias.

METHODS AND RESULTS

Components of HRV in the frequency domain were analyzed before the onset of 28 episodes of nonsustained VT (more than four impulses; duration < 30 seconds) and 12 episodes of sustained VT (> 30 seconds or requiring defibrillation) in 18 patients with coronary artery disease. Seven patients had survived cardiac arrest not associated with acute myocardial infarction, and 11 had a history of sustained VT. All frequency domain measures of HRV, i.e., total power (p < 0.001), high-frequency power (p < 0.05), low-frequency power (p < 0.01), very-low-frequency power (p < 0.01), and ultralow-frequency power (p < 0.05), were significantly lower before the onset of sustained VT than before nonsustained VT. Total power of HRV was also lower during the 1-hour period before the onset of sustained VT than the average 24-hour HRV (p < 0.05). An indirect correlation existed between the length of VT and the total power of HRV analyzed during the 15 minutes before the onset of VT (r = 0.54, p < 0.01). HRV had a trend toward increasing values before the onset of nonsustained VT (p < 0.01) but not before the sustained VT episodes. The ratio between low-frequency and high-frequency powers increased substantially before both nonsustained and sustained VT episodes (p = 0.06 and p = 0.05, respectively). The rate of VT or the coupling interval initiating the VT did not differ significantly between the nonsustained and sustained VT.

CONCLUSIONS

Spontaneous episodes of VT are preceded by changes in HRV in the frequency domain. Divergent dynamics of HRV before the onset of nonsustained and sustained VT episodes may reflect differences in factors that can facilitate the perpetuation of these arrhythmias.
Functional dissociation of cellular activation as a mechanism of Mobitz type II atrioventricular block.
Authors: Gonzalez M D , Scherlag B J , Mabo P , Lazzara R
Published: June 2012

BACKGROUND

Several mechanisms have been advanced to explain Mobitz type II atrioventricular block in the ischemically damaged His-Purkinje system. Only recently, however, has an animal model been developed to study this form of conduction defect in vivo and in vitro.

METHODS AND RESULTS

Conduction defects were induced in anesthetized dogs by ischemic damage to the proximal His-Purkinje system after anterior septal artery ligation. Stable 2:1 atrioventricular block, localized within the His bundle or in the proximal bundle branches, was obtained in each dog by atrial pacing at an average rate of 239 +/- 20 beats per minute (n = 12). In vitro studies were then performed from the same hearts. Action potentials and electrograms were simultaneously recorded from the His bundle and the proximal right bundle branch at the site of damage. At slow rates of pacing (40-60 beats per minute), the action potential amplitude was 85 +/- 4 mV, and some cells (10 +/- 3%) showed dissociation from the electrical activity in the bundle. At fast rates (149 +/- 11 beats per minute), during 1:1 conduction, the frequency of cellular dissociation increased to 57 +/- 6% (p < 0.001), and the action potential amplitude decreased (-31 +/- 4%, p < 0.001). The frequency of dissociation closely correlated with the reduction in action potential amplitude (r = 0.87, p < 0.001). These changes were markedly attenuated once 2:1 block developed. The site of block was not constant but rather showed a dynamic behavior with spatial shifting in response to changes in pacing rate or the introduction of extrastimuli.

CONCLUSIONS

These results indicate that in the ischemically damaged proximal His-Purkinje system, an increase in rate leads to reduced and asynchronous cellular activation before 2:1 block. The latter provides a more stable activation pattern, because the frequency of dissociation is markedly reduced.
Circus movement atrial flutter in the canine sterile pericarditis model. Cryothermal termination from the epicardial site of the slow zone of the reentrant circuit.
Authors: Isber N , Restivo M , Gough W B , Yang H , el-Sherif N
Published: June 2012

BACKGROUND

We have shown that atrial flutter (AF) in dogs with sterile pericarditis is commonly due to a single-loop reentrant circuit in the lower right atrium comprised of a functional or functional/anatomic obstacle and a slow zone of conduction (SZ) between the central obstacle and the atrioventricular (AV) ring. The goals of the present study were 1) to establish that the epicardial SZ is the critical component of circus movement AF and 2) to identify the optimal site within the epicardial SZ at which interruption of circus movement can be accomplished by ablative techniques.

METHODS AND RESULTS

We analyzed the atrial activation patterns during epicardial cooling of the SZ with as N2O-cooled probe in eight dogs (five with clockwise [CW] reentrant circuit, one with counterclockwise [CCW] reentrant circuit, and two with both CW and CCW reentrant circuits around the same pathway). In all eight dogs, cooling (-5 to +5 degrees C for 5-20 seconds) the narrow isthmus at the inferoposterior part of the SZ between the central obstacle and the AV ring reversibly terminated the reentrant circuit, whereas cooling outside this area failed to terminate the reentrant circuit. The circus movement was not observed to continue along alternate pathways when conduction in this critical zone was interrupted. Both CW and CCW reentrant circuits could be terminated from the same site within the SZ. Cooling resulted in slowing of conduction in the SZ (55 +/- 15 msec) in both CW and CCW reentrant circuits. Cooling-induced termination of CW reentrant circuits was characteristically associated with oscillations of conduction in the cooled zone of the last three cycles before termination and conduction block occurred within the cooled zone. The last "manifest" reentrant cycle was associated with the longest conduction delay in the cooled zone. However, this delay was not necessarily reflected in the length of the last reentrant cycle because of compensatory acceleration of conduction in the rest of the pathway. On the other hand, in CCW reentrant circuits, conduction block occurred abruptly at the distal border of the SZ and without significant oscillations of conduction.

CONCLUSIONS

The present study provides convincing evidence that single-loop circus movement in this model is critically dependent on an obligatory conduction in a SZ in the inferoposterior portion of the free right atrial wall between a functional obstacle and the AV ring. Because the atrial myocardium behaves electrophysiologically as a two-dimensional surface, the results of this study may help to guide the endocardial electrode catheter ablative technique for treatment of clinical AF.
Congestive heart failure alters receptor-dependent cAMP-mediated relaxation of canine pulmonary arteries.
Authors: Mathew R , Wang J , Gewitz M H , Hintze T H , Wolin M S
Published: June 2012

BACKGROUND

Alterations in myocardial function and systemic vascular tone are well documented in congestive heart failure (CHF), but little information is available on the effects of CHF on pulmonary vessels. We examined the mechanisms of tone regulation of canine pulmonary arteries during pacing-induced CHF.

METHODS AND RESULTS

Rings 3-4 mm wide from lobar pulmonary arteries were prepared from normal dogs, dogs paced at 210 beats per minute for 3 weeks (paced group, nonfailure), and dogs also paced at 240 beats per minute during the fourth week to induce severe heart failure (CHF group). Contractile responses to 60 mmol/L KCl and phenylephrine and relaxation responses to acetylcholine, bradykinin (endothelium-dependent cyclic GMP [cGMP]-mediated), isoproterenol, arachidonic acid, prostacyclin (receptor-dependent cyclic AMP [cAMP]-mediated), forskolin (direct stimulator of adenylate cyclase), a forskolin analogue (devoid of adenylate cyclase-dependent activity), and RO 20-1724 (phosphodiesterase inhibitor) were characterized. The paced group did not show alterations in vascular reactivity. Contractile response to phenylephrine and cGMP-mediated relaxation responses were not altered in the CHF group; however, receptor-mediated cAMP-induced relaxation responses were significantly inhibited (p < 0.05). Relaxation responses to isoproterenol (10(-6) mol/L), arachidonic acid (10(-5) mol/L), and prostacyclin (10(-5) mol/L) were reduced by 56%, 72%, and 74%, respectively. The relaxation response to RO 20-1724 was not affected by CHF, and this probe did not enhance the impaired relaxation response to isoproterenol. Forskolin-induced relaxation was not altered, and the forskolin analogue produced minimal relaxation compared with forskolin.

CONCLUSIONS

These findings suggest that in pacing-induced CHF, canine pulmonary arteries show a selective defect in receptor coupling to cAMP-dependent relaxation mechanisms. There is no evidence of enhanced degradation of cAMP.
Coronary thrombolysis with recombinant staphylokinase in patients with evolving myocardial infarction.
Authors: Collen D , Van de Werf F
Published: June 2012

BACKGROUND

Staphylokinase (STA), a protein with known profibrinolytic properties, is produced by transduced Staphylococcus aureus strains. In experimental animal models, recombinant staphylokinase (STAR) is less immunogenic and more active toward platelet-rich arterial blood clots than streptokinase.

METHODS AND RESULTS

In the present study, 10 mg STAR given intravenously over 30 minutes was found to induce angiographically documented coronary artery recanalization within 40 minutes in four of five patients with acute myocardial infarction. Plasma fibrinogen and alpha 2-antiplasmin levels were unaffected, and allergic reactions were not observed. Postinfusion disappearance of STAR antigen followed a biphasic mode with a t1/2 alpha of 6.3 +/- 0.6 minutes (mean +/- SD) and a t1/2 beta of 37 +/- 15 minutes, corresponding to a plasma clearance of 270 +/- 100 mL/min. Neutralizing antibodies against STAR could not be demonstrated at baseline and up to 6 days after infusion, but STAR neutralizing activity, which did not cross-react with streptokinase, was consistently demonstrable in plasma at 14-35 days.

CONCLUSIONS

STAR can induce clot-selective coronary thrombolysis in patients with evolving myocardial infarction without concomitant induction of a systemic lytic state. STAR, a small protein that can be easily produced by recombinant DNA technology, may therefore offer promise for thrombolytic therapy in patients with thromboembolic disease.
Characterization of ventricular fibrillation based on monophasic action potential morphology in the human heart.
Authors: Swartz J F , Jones J L , Fletcher R D
Published: June 2012

BACKGROUND

Recent studies examining mechanisms of defibrillation have focused on prolongation of graded cellular response duration during refractory period stimulation. This mechanism assumes that defibrillation shocks interact with ventricular cells during the process of repolarization.

METHODS AND RESULTS

To test this assumption, we examined monophasic action potentials (MAPs) from 171 episodes of induced ventricular dysrhythmia associated with loss of systemic perfusion pressure in 22 patients undergoing nonthoracotomy defibrillator implantation. Ventricular fibrillation (VF)/polymorphic ventricular tachycardia (PVT), defined by an irregular limb lead I morphology, was present in 156 dysrhythmia episodes. Monomorphic ventricular tachycardia (VT), present in the remaining 15 episodes, was associated with regular limb lead morphology. All episodes were examined for MAP cycle length, variation, fractionation, and repolarization. VF/PVT cycle length was 215 +/- 28 msec, with a 14 +/- 7% (33 +/- 20-msec) cycle length variability. Nonfractionated MAP recordings were found in 122 of 156 VF/PVT episodes. Episodes characterized as VF by ECG criteria (n = 136) showed lack of MAP diastole and had a mean cycle length of 213 +/- 27 msec. Episodes characterized as PVT (n = 20) were associated with amiodarone therapy and had occasional MAP diastole and a significantly longer mean cycle length of 257 +/- 22 msec (p < 0.001). Monomorphic VT had a mean cycle length of 261 +/- 29 msec, minimal cycle length variation (1 +/- 3%), absence of MAP fractionation, and consistent degree of repolarization before restimulation.

CONCLUSIONS

These results suggest that human VF cycle length is limited by cellular refractory periods so that defibrillating shocks interact with cells primarily during their refractory period.
A communitywide perspective of sex differences and temporal trends in the incidence and survival rates after acute myocardial infarction and out-of-hospital deaths caused by coronary heart disease.
Authors: Goldberg R J , Gorak E J , Yarzebski J , Hosmer D W , Dalen P , Gore J M , Alpert J S , Dalen J E
Published: June 2012

BACKGROUND

The purpose of the study was to examine overall differences and temporal trends therein between men and women regarding the incidence rates, in-hospital and long-term survival after initial acute myocardial infarction (AMI), and out-of-hospital deaths caused by coronary disease.

METHODS AND RESULTS

This nonconcurrent prospective study was carried out in 16 teaching and community hospitals in Worcester, Mass., in six time periods between 1975 and 1988. A total of 3,148 patients hospitalized with validated initial AMI comprised the study sample. The age-adjusted incidence rates of initial AMI increased between 1975 and 1981 in the two sexes, with a marked decrease thereafter; these rates declined by 26% in men and by 22% in women between 1975 and 1988. The overall unadjusted in-hospital case-fatality rates after initial AMI were significantly higher in women (21.7%) than in men (12.7%). Age- and multivariable-adjusted in-hospital case-fatality rates, however, were not significantly different for men compared with women (multivariate-adjusted OR, 0.90; 95% CI, 0.70, 1.16). No clear trends in in-hospital case-fatality rates were observed in men or women over the periods under study. There were no significant sex differences in the age-adjusted long-term survival rates of discharged hospital survivors of AMI. The multivariate-adjusted risk of total mortality among discharged hospital survivors, however, was significantly increased in men (multivariate-adjusted OR, 1.20; 95% CI, 1.03, 1.39); neither of the sexes experienced an improvement over time in long-term prognosis. The incidence rates of out-of-hospital deaths caused by coronary disease declined by 60% in men and 69% in women between 1975 and 1988.

CONCLUSIONS

The results of this multihospital, community-based study suggest declines in the incidence rates of AMI and out-of-hospital deaths caused by coronary disease in men and women over the period under study (1975-1988). No significant sex differences in in-hospital survival were observed, whereas a poorer long-term survival experience after hospital discharge was observed for men compared with women after controlling for potentially confounding prognostic factors.
Effect of disrupting the mitral apparatus on left ventricular function in dogs.
Authors: Shintani H , Glantz S A
Published: June 2012

BACKGROUND

The importance of the mitral apparatus to left ventricular function has been suggested in clinical studies. The effect of disruption of the mitral apparatus on left ventricular diastolic and systolic properties has not been fully documented.

METHODS AND RESULTS

We investigated the end-diastolic and end-systolic pressure-volume and stroke work-end-diastolic volume relations and measured the isovolumic relaxation time constant (tau infinity) during nonfilling beats before and after disruption of the mitral apparatus under different loading conditions in 14 dogs using our recently developed volume-clamping technique for the in situ left ventricle. Disruption of the mitral apparatus increased left ventricular diastolic equilibrium volume (V0d) without changing the slope of the end-diastolic pressure-volume relation (Sd) and increased end-systolic pressure-volume relation dead volume (V0s) and volume-axis intercept of stroke work-end-diastolic volume relation (V0sw) without changing the slopes of these relations (maximum elastance, Ees, and Ssw). Disruption of the mitral apparatus increased tau infinity.

CONCLUSION

Disruption of the mitral apparatus increases the equilibrium volume without changing left ventricular diastolic stiffness or contractility and slows left ventricular relaxation. These results support and help explain the clinical observation that it is desirable to maintain the mitral apparatus during mitral valve replacement surgery.
The structure of cardiological revolutions. James B. Herrick Lecture.
Authors: Sobel B E
Published: June 2012

Four revolutions are transforming the cardiology of our day. The first is a social revolution. It has resulted in plummeting esteem for the medical profession reflecting disenchantment coupled with the rapid emergence of the recognition that health care is a right rather than a privilege. The second revolution, interventional cardiology, has provided powerful therapeutic tools demanding technical as well as cognitive expertise. The third, the revolution in molecular and cellular biology, is transforming our understanding of mechanisms underlying disease. Because of the seminal importance of progress in basic science to advances in clinical cardiology, features of these three revolutions are being synthesized in a fourth, a revolution transforming cardiology itself. Novel approaches are needed for optimal training of clinicians with diverse areas of interest, investigators in fundamental and clinical research, house staff, and students; for optimal use of clinical and research resources; and for optimal responsiveness to the needs of patients. They must be developed with cognizance of and fidelity to our clinical and scientific heritage.
Transdermal modification of platelet function. A dermal aspirin preparation selectively inhibits platelet cyclooxygenase and preserves prostacyclin biosynthesis.
Authors: Keimowitz R M , Pulvermacher G , Mayo G , Fitzgerald D J
Published: June 2012

BACKGROUND

Even low doses of oral aspirin inhibit prostacyclin (prostaglandin [PG] I2) formation and cause gastrointestinal toxicity. We examined the skin as a novel route for continuous low-dose aspirin administration and selective inhibition of platelet cyclooxygenase in humans.

METHODS AND RESULTS

Aspirin 250 or 750 mg/d for 10 days induced a dose-dependent inhibition of serum thromboxane (TX) B2. At the highest dose, five of six subjects responded, with a mean reduction in serum TXB2 of 95 +/- 3% (P = .003). Urinary 2,3-dinor TXB2, an index of in vivo TXA2 formation, decreased by 68 +/- 7% and recovered slowly, consistent with inhibition of platelet cyclooxygenase in vivo. In contrast, PGI2 biosynthesis, determined as excretion of 2,3-dinor-6-keto PGF1 alpha, was 81 +/- 5% of baseline at 10 days. Intravenous bradykinin increased PGI2 biosynthesis 5.1 +/- 1.6-fold (n = 4) before aspirin treatment. Oral aspirin 75 mg/d for 14 days abolished bradykinin-induced PGI2 formation, whereas dermal aspirin 750 mg/d had no effect despite similar inhibition of TXA2 biosynthesis. In five subjects, plasma aspirin and salicylate were determined after a single application of 750 mg. Aspirin was absorbed slowly, with peak levels of 0.24 +/- 0.11 micrograms/mL at 3 hours. Salicylate levels peaked at 6 to 12 hours, with plasma levels of 0.79 +/- 0.14 micrograms/mL.

CONCLUSIONS

Thus, it is possible to achieve selective inhibition of platelet cyclooxygenase by aspirin applied to the skin. This approach may be applicable to other antiplatelet agents and be useful in patients at risk for gastrointestinal bleeding or toxicity.
Functional significance of intimal thickening as detected by intravascular ultrasound early and late after cardiac transplantation.
Authors: Anderson T J , Meredith I T , Uehata A , Mudge G H , Selwyn A P , Ganz P , Yeung A C
Published: June 2012

BACKGROUND

Detection of transplant coronary disease remains difficult. Both intravascular ultrasound (IVUS) imaging and functional coronary vasomotion studies have been used to evaluate this process. However, the time course of intimal thickening as assessed by IVUS and the relation between structure and function have not been explored.

METHODS AND RESULTS

In 40 patients 1 to 8 years after transplantation, 108 coronary artery segments were analyzed by IVUS. Intimal index [% intimal area (lumen+intimal area)] and maximal thickness were used to quantify intimal thickening. Abnormal IVUS was present in 53 of 108 segments (49%) (mean intimal index of diseased segments, 23 +/- 2%; maximal thickness, 530 +/- 47 microns). For those patients with intimal thickening in all segments of the analyzed artery, more time had elapsed since transplantation (4.3 +/- 0.6 years) than for those whose arteries contained some normal (2.6 +/- 0.3 years) or all normal segments (2.2 +/- 0.6 years, P < .05). Both the proportion of segments with intimal thickening and the degree of thickening increased as a function of time after transplantation (P < .5). By multivariate analysis, the independent predictors of intimal thickening were increasing time after transplantation and pretransplantation hypercholesterolemia (P = .02). Within the cohort of 40 patients, endothelium-dependent vasomotor function was evaluated in 26 matched segments from 11 patients studied 1 year after transplantation and in 15 matched segments from 8 patients studied > or = 5 years after transplantation by serial infusions of acetylcholine (10(-8) to 10(-6) mol/L). Of the 26 segments assessed for structure/function correlation at 1 year after transplantation, 22 had no intimal thickening by IVUS. However, endothelial dysfunction was present in 13 of these normal segments (mean diameter constriction, 18.8 +/- 2.3%). Of the 15 segments studied > or = 5 years after transplantation, 11 had intimal thickening. Nine of these 11 segments had preserved endothelial function (mean diameter dilation, 8.6 +/- 2.9%). There was no relation between the degree of intimal thickening and the magnitude of the endothelium-dependent response to acetylcholine.

CONCLUSIONS

This study has shown that intimal thickening after transplantation begins as a heterogeneous process and increases in extent and magnitude over time. Also, endothelial dysfunction occurs early before the intimal thickening; yet in those patients surviving > or = 5 years, endothelial function may recover even in the presence of moderate intimal pathology. The variable relation between intimal pathology and endothelial function is probably a result of the episodic nature of immune injury.
Endothelin antiserum decreases volume-stimulated and basal plasma concentration of atrial natriuretic peptide.
Authors: Fyhrquist F , Sirviö M L , Helin K , Saijonmaa O , Metsärinne K , Paakkari I , Järvinen A , Tikkanen I
Published: June 2012

BACKGROUND

Endothelin-1 (ET-1) is the most powerful factor known to release atrial natriuretic peptide (ANP) in vivo and in cultured cardiac myocytes or preparations of atrium. We tested the role of endogenous ET-1 in the regulation of ANP release by passive immunization in anesthetized rats.

METHODS AND RESULTS

Intravenous injection of antiserum against ET-1 was shown to decrease basal and volume-stimulated plasma concentrations of ANP, whereas control serum was without effect. Antiserum generated in rabbits cross-reacted 100% with endothelin-2 and -3. In pentobarbital-anesthetized Wistar rats treated with ET-1 antiserum, plasma ANP concentration measured by radioimmunoassay was reduced by 37% from starting level after 10 minutes and by 30% after 60 minutes. Control rat serum had no effect on plasma ANP. Rapid intravenous infusion of 8 mL of 0.9% NaCl caused a sixfold increase of plasma ANP concentration in control rats but only twofold in rats pretreated with ET-1 antiserum (P < .01). This effect of ET-1 antiserum was dose dependent. ET-1 antiserum changed neither blood pressure nor heart rate significantly in anesthetized rats. Pretreatment with ET-1 antiserum did not affect the initial hypotensive response to intravenous ET-1 0.5 nmol/kg but significantly attenuated the subsequent hypertensive response to endothelin.

CONCLUSIONS

Endothelin may be a physiological modulator of both basal and stimulated ANP release.
Both increased and decreased platelet adhesion to thermally injured subendothelium is caused by denaturation of von Willebrand factor.
Authors: Bos A N , Post M J , de Groot P G , Sixma J J , Borst C
Published: June 2012

BACKGROUND

Thermal angioplasty methods heat the arterial wall. We related platelet adhesion to the temperature to which subendothelium and purified adhesive proteins had been exposed.

METHODS AND RESULTS

Cultured subendothelium, purified von Willebrand factor, collagen types I and III, or fibronectin was applied to glass coverslips. Coverslips were mounted on a heating device that applied a temperature gradient from 30 to 100 degrees C. De-endothelialized umbilical arteries were heated by immersion in phosphate-buffered saline. After cooling to room temperature, the surfaces were perfused with blood at 37 degrees C (shear rate, 1600 sec-1). Compared with 37 degrees C, platelet adhesion to endothelial cell matrix was significantly reduced by 25%, 50% or 75% after heating to 69 +/- 1 degree C (mean +/- SEM, P < .05), 72 +/- 1 degree C, or 75 +/- 1 degree C, respectively. Platelet coverage to umbilical artery subendothelium was in the same way significantly reduced after heating to 71 +/- 1 degree C, or 77 +/- 1 degree C, respectively. In contrast to endothelial cell matrix, however, heating to about 55 degrees C increased platelet coverage from 30 +/- 5% to 54 +/- 6% (P < .05). Both platelet adhesion to von Willebrand factor and monoclonal antibody binding against the GpIb binding site of von Willebrand factor showed a comparable temperature dependence as platelet adhesion to subendothelium, provided the proper von Willebrand factor concentration was used. Platelet adhesion to heated collagen types I and III was increased and maximal at 57 +/- 2 degrees C and 62 +/- 2 degrees C, respectively. Preincubation of collagen III with proteins resulted in decreased platelet adhesion with increasing temperatures. Heating did not affect the reactivity of fibronectin.

CONCLUSIONS

In vitro platelet adhesion to human subendothelium is reduced by more than 50% after heating it briefly to more than 74 degrees C. Temperatures in excess of 80 degrees C reduce platelet adhesion by at least 85%. Thermal denaturation of von Willebrand factor is responsible not only for the decreased thrombogenicity above 71 degrees C but also for the increased thrombogenicity near 55 degrees C, provided that the von Willebrand factor concentration is low.