bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanisms Causing Sustained Ventricular Tachycardia With Multiple QRS Morphologies
Authors: Costeas Constantinos , Peters Nicholas S. , Waldecker Bernd , Ciaccio Edward J. , Wit Andrew L. , Coromilas James
Published: June 2012

Background
Sustained reentrant ventricular tachycardias (VTs) with different QRS morphologies have been observed to occur spontaneously and during programmed stimulation in human hearts. We determined mechanisms that can cause tachycardias with multiple morphologies in a canine model of myocardial infarction by mapping reentrant circuits.

Methods and Results
Reentrant VT with multiple QRS morphologies was induced in 11 canine hearts with 4-day-old infarcts. Comparison of activation maps of the reentrant circuits in the epicardial border zone associated with each morphology indicated two basic mechanisms. Less frequently, VTs of different morphologies in the same heart were caused by reentrant circuits in different regions of the infarct. Most commonly, the reentrant circuits associated with different morphologies were in the same region. Three different factors caused different exit routes from circuits in the same region, leading to the multiple morphologies. (1) The reentrant wave front for each morphology rotated around the same line of block but in different directions. (2) Reentrant circuits associated with each morphology were similar, but there were small changes in the extent of the central line of block. (3) Reentrant circuits with completely different sizes and shapes caused different morphologies.

Conclusions
In this canine model, tachycardias with multiple morphologies most commonly arise from reentrant circuits in the same region of the infarct, suggesting that most often only one area has electrophysiological properties necessary to sustain reentry.
Premature Coronary Artery Disease Associated With a Disruptive Mutation in the Estrogen Receptor Gene in a Man
Authors: Sudhir Krishnankutty , Chou Tony M. , Chatterjee Kanu , Smith Eric P. , Williams Timothy C. , Kane John P. , Malloy Mary J. , Korach Kenneth S. , Rubanyi Gabor M.
Published: June 2012

Background
While estrogens protect against coronary artery disease in women, it is unclear whether they influence cardiovascular function in men. The present report describes coronary vascular abnormalities and the lipoprotein profile of a male patient with estrogen insensitivity caused by a disruptive mutation in the estrogen-receptor gene.

Methods and Results
Stress thallium scintigraphy, echocardiography, and electron-beam computed tomography (CT) scanning of the coronary arteries and detailed lipoprotein analysis were performed. Electron-beam CT scanning of the coronary arteries showed calcium in the left anterior descending artery. Lipoprotein analysis showed relatively low levels of total (130 mg/dL), LDL (97 mg/dL), and HDL (34 mg/dL) cholesterol; apolipoprotein A-I (91.7 mg/dL;); and lipoprotein(a) (4.1 nmol/L), but normal levels of triglycerides (97 mg/dL) and pre-β-1-HDL cholesterol (61 μg/mL).

Conclusions
The absence of functional estrogen receptors may be a novel risk factor for coronary artery disease in men.
Population Versus Clinical View of Case Fatality From Acute Coronary Heart Disease
Authors: Chambless Lloyd , Keil Ulrich , Dobson Annette , Mähönen Markku , Kuulasmaa Kari , Rajakangas Anna-Maija , Löwel Hannelore , Tunstall-Pedoe Hugh
Published: June 2012

Background
The clinical view of case fatality (CF) from acute myocardial infarction (AMI) in those reaching the hospital alive is different from the population view. Registration of both hospitalized AMI cases and out-of-hospital coronary heart disease (CHD) deaths in the WHO MONICA Project allows both views to be reconciled. The WHO MONICA Project provides the largest data set worldwide to explore the relationship between CHD CF and age, sex, coronary event rate, and first versus recurrent event.

Methods and Results
All 79 669 events of definite AMI or possible coronary death, occurring from 1985 to 90 among 5 725 762 people, 35 to 64 years of age, in 29 MONICA populations are the basis for CF calculations. Age-adjusted CF (percentage of CHD events that were fatal) was calculated across populations, stratified for different time periods, and related to age, sex, and CHD event rate. Median 28-day population CF was 49% (range, 35% to 60%) in men and 51% (range, 34% to 70%) in women and was particularly higher in women than men in populations in which CHD event rates were low. Median 28-day CF for hospitalized events was much lower: in men 22% (range, 15% to 36%) and in women 27% (range, 19% to 46%). Among hospitalized events CF was twice as high for recurrent as for first events.

Conclusions
Overall 28-day CF is halved for hospitalized events compared with all events and again nearly halved for hospitalized 24-hour survivors. Because approximately two thirds of 28-day CHD deaths in men and women occurred before reaching the hospital, opportunities for reducing CF through improved care in the acute event are limited. Major emphasis should be on primary and secondary prevention.
cis
-Acting Sequences That Mediate Induction of β-Myosin Heavy Chain Gene Expression During Left Ventricular Hypertrophy due to Aortic Constriction
Authors: Hasegawa Koji , Lee Soo Jin , Jobe Shawn M. , Markham Bruce E. , Kitsis Richard N.
Published: June 2012

Background
Marked alterations in the expression of specific genes occur during the development of cardiac hypertrophy in vivo. Little is known, however, about the
cis
-acting elements that mediate these changes in response to clinically relevant hypertrophic stimuli, such as hemodynamic overload, in intact adult animals.

Methods and Results
The left ventricular expression of a directly injected reporter gene driven by 3542 bp of rat β-myosin heavy chain (β-MHC) promoter was increased 3.0-fold by aortic constriction (
P
<.005), an increment similar to the 3.2-fold increase in the level of the endogenous β-MHC mRNA in the same left ventricles. Subsequent analysis identified a 107-bp β-MHC promoter sequence (−303/−197) sufficient to convert a heterologous neutral promoter to one that is activated by aortic constriction. These sequences contain two M-CAT elements, which have previously been demonstrated to mediate inducible expression during α
1
-adrenergic–stimulated hypertrophy in cultured neonatal cardiac myocytes, and a GATA element. Although simultaneous mutation of both M-CAT elements markedly decreased the basal transcriptional activity of an injected 333-bp β-MHC promoter, it had no effect on aortic constriction-stimulated transcription (3.5-fold increase,
P
<.005 for both wild type and mutant). In contrast, mutation of the GATA motif markedly attenuated aortic constriction-stimulated transcription (1.6-fold,
P
=NS) without affecting the basal transcriptional activity. This GATA site can interact with in vitro translated GATA-4 and compete with an established GATA site for GATA-4 binding activity in nuclear extracts from aortic constricted hearts.

Conclusions
Basal and aortic constriction-stimulated transcription of the β-MHC gene is mediated, at least in part, through different mechanisms. A GATA element within β-MHC sequences -303/-197 plays a role in the transcriptional activation of this gene by aortic constriction.
Intrapericardial Delivery of
l
-Arginine Reduces the Increased Severity of Ventricular Arrhythmias During Sympathetic Stimulation in Dogs With Acute Coronary Occlusion
Authors: Fei Lü , Baron Alain D. , Henry David P. , Zipes Douglas P.
Published: June 2012

Background
Nitric oxide (NO) modulates autonomic effects on myocardial contractility and sinus and atrioventricular nodal function of the heart. Whether NO influences autonomic actions on ventricular electrophysiological properties and arrhythmogenesis is not known.

Methods and Results
Four groups consisting of 43 autonomically denervated dogs were studied. To “superfuse” sympathetic nerves innervating the ventricles, test drugs were introduced into the pericardial sac for 30 minutes, and their effects on ventricular effective refractory period (ERP) and arrhythmia development were assessed before and during sympathetic stimulation (SS). In group 1 (n=12), ventricular ERPs showed no significant difference between control and superfusion with
l
-arginine, a NO precursor (222±20 versus 222±19 ms,
P
=.485). However,
l
-arginine significantly reduced SS-induced ERP shortening compared with control (9±7 versus 13±7 ms,
P
<.001). Simultaneous administration of
N
G
-monomethyl-
l
-arginine (2 mg/mL) abolished the inhibitory effects of
l
-arginine (13±7 versus 13±7 ms,
P
=.885). In group 2 (n=15), the severity of ventricular arrhythmias significantly increased during SS.
l
-Arginine reduced this increase caused by SS. In group 3 (n=8), plasma norepinephrine spillover measured from the coronary sinus significantly increased during SS and was reduced by pericardial superfusion with
l
-arginine compared with control (6005.2±1525.6 versus 8503.4±2044.5 pg/min,
P
=.012). In group 4 (n=8),
l
-arginine pericardial superfusion significantly increased NO overflow measured from the coronary sinus during SS (93.25±59.20 versus 114.82±74.92 nmol/min,
P
=.043).

Conclusions
Pericardial
l
-arginine reduces ERP shortening and increased severity of ischemic ventricular arrhythmias during SS in dogs. NO-induced reduction of norepinephrine release in the heart may be one of the underlying mechanisms.
Electrophysiological Effects of Acute Dilatation in the Isolated Rabbit Heart
Authors: Reiter Michael J. , Landers Mark , Zetelaki Zoltan , Kirchhof Charles J. H. , Allessie Maurits A.
Published: June 2012

Background
Acute ventricular dilatation has important electrophysiological effects: Dilatation shortens action potential duration and refractoriness without an apparent effect on conduction velocity. These effects have been implicated as a potential mechanism of arrhythmias in patients with congestive failure. Because the influence of cycle length on these phenomena has not been studied, we examined the effects of dilatation during ventricular pacing at cycle lengths from 1000 to 150 ms.

Methods and Results
Thin epicardial layers were created in isolated, perfused rabbit left ventricles (n=7). A fluid filled latex balloon was secured in the left ventricle to dilate the left ventricle. Mapping was performed with 248 epicardial electrodes. Longitudinal conduction velocity (76±1 cm/s; mean±SEM) and transverse conduction velocity (26±1 cm/s) were not influenced by dilatation at any cycle length. In contrast, the effects of dilatation in decreasing left ventricular effective refractory period (ERP) were significantly greater at shorter drive cycle lengths: The decrease in ERP was 2±2 ms (a 1% change) at a drive cycle length of 1000 ms and 18±4 ms (a 20% change) at a drive cycle length of 150 ms. In 10 additional intact, isolated perfused rabbit hearts, dilatation decreased ERP to a greater degree during 250 ms drive cycle length pacing than during pacing at 400 ms (25±4 versus 16±3 ms;
P
=.01).

Conclusions
Acute dilatation exaggerates the normal rate-dependent shortening of refractoriness but does not influence transverse or longitudinal conduction velocity. This observation suggests that the electrophysiological effects of acute dilatation may be greater during tachycardia than at slower cycle lengths. This may have implications for arrhythmias in patients with congestive heart failure.
A Genome-Based Resource for Molecular Cardiovascular Medicine
Authors: Hwang David M. , Dempsey Adam A. , Wang Ruo-Xiang , Rezvani Mojgan , Barrans J. David , MHSc  , Dai Ken-Shwo , Wang Hui-Yuan , Ma Hong , Cukerman Eva , Liu Yu-Qing , Gu Jian-Ren , Zhang Jing-Hui , Tsui Stephen K. W. , Waye Mary M. Y. , Fung Kwok-Pui , Lee Cheuk-Yu , Liew Choong-Chin
Published: June 2012

Background
Large-scale partial sequencing of cDNA libraries to generate expressed sequence tags (ESTs) is an effective means of discovering novel genes and characterizing transcription patterns in different tissues. To catalogue the identities and expression levels of genes in the cardiovascular system, we initiated large-scale sequencing and analysis of human cardiac cDNA libraries.

Methods and Results
Using automated DNA sequencing, we generated 43 285 ESTs from human heart cDNA libraries. An additional 41 619 ESTs were retrieved from public databases, for a total of 84 904 ESTs representing more than 26 million nucleotides of raw cDNA sequence data from 13 independent cardiovascular system–based cDNA libraries. Of these, 55% matched to known genes in the Genbank/EMBL/DDBJ databases, 33% matched only to other ESTs, and 12% did not match to any known sequences (designated cardiovascular system–based ESTs, or CVbESTs). ESTs that matched to known genes were classified according to function, allowing for detection of differences in general transcription patterns between various tissues and developmental stages of the cardiovascular system. In silico Northern analysis of known gene matches identified widely expressed cardiovascular genes as well as genes putatively exhibiting greater tissue specificity or developmental stage specificity. More detailed analysis identified 48 genes potentially overexpressed in cardiac hypertrophy, at least 10 of which were previously documented as differentially expressed. Computer-based chromosomal localizations of 1048 cardiac ESTs were performed to further assist in the search for disease-related genes.

Conclusions
These data represent the most extensive compilation of cardiovascular gene expression information to date. They further demonstrate the untapped potential of genome research for investigating questions related to cardiovascular biology and represent a first-generation genome-based resource for molecular cardiovascular medicine.
Cyclosporin A Inhibits Monocyte Tissue Factor Activation in Cardiac Transplant Recipients
Authors: Hölschermann Hans , Kohl Oliver , Maus Ulrich , Dürfeld Frank , Bierhaus Angelika , Nawroth Peter P. , Lohmeyer Jürgen , Tillmanns Harald , Haberbosch Werner
Published: June 2012

Background
Fibrin deposition and thrombosis have been implicated in both allograft rejection and vasculopathy after cardiac transplantation. Because monocytes play a pivotal role in the pathophysiology of intravascular coagulation activation through their ability to synthesize tissue factor (TF), we asked (1) whether monocyte TF activation occurs in cardiac transplant recipients and (2) whether monocyte TF expression is affected by treatment with cyclosporin A (CsA).

Methods and Results
We measured levels of TF activity in peripheral blood mononuclear cells and highly purified monocytes/macrophages from 10 consecutive cardiac transplant recipients and 10 healthy control subjects. TF activity generated by both unstimulated and endotoxin-stimulated cells was significantly higher in transplant recipients than in control subjects (
P
<.05). Increased monocyte TF expression in transplant recipients was shown to be adversely affected by treatment with CsA: TF induction was markedly reduced by CsA serum concentrations reaching peak CsA drug levels. Inhibition of TF induction in the presence of high CsA blood concentrations was also observed when stimulation of cells was performed with interferon-γ or interleukin-1β. As shown by reverse transcription–polymerase chain reaction and electrophoretic mobility shift assay, respectively, treatment with CsA leads to decreased TF mRNA expression and reduced activation of the NF-κB transcription factor, which is known to contribute to the induction of the TF promotor in human monocytes.

Conclusions
This study demonstrates that TF activation, occurring in mononuclear cells of cardiac transplant recipients, is inhibited by treatment with CsA. Inhibition of monocyte TF induction by CsA may contribute to its successful use in cardiac transplant medicine and might be useful in managing further settings of vascular pathology also known to involve TF expression and NF-κB activation.
Effect of the ACE Inhibitor Lisinopril on Mortality in Diabetic Patients With Acute Myocardial Infarction
Authors: Zuanetti Giulio , Latini Roberto , Maggioni Aldo P. , Franzosi MariaGrazia , Santoro Luigi , Tognoni Gianni
Published: June 2012

Background
Mortality of diabetic patients with acute myocardial infarction (MI) remains high despite recent improvement in their management. There is a need to evaluate efficacy and safety of novel treatments of MI in this high-risk population. We evaluated whether treatment with an ACE inhibitor begun within 24 hours from the onset of symptoms is able to decrease mortality and morbidity of diabetic patients with acute MI.

Methods and Results
A retrospective analysis of the data of the GISSI-3 study in patients with and without a history of diabetes was performed. Patients with suspected acute MI were randomized to treatment with lisinopril (2.5 to 5 up to 10 mg/d) with or without nitroglycerin (5 to 20 μg IV then 10 mg/d) begun within 24 hours and continued for 6 weeks. The main end point was mortality at 6 weeks, and the secondary end point was a combined evaluation of mortality and severe left ventricular dysfunction. Information on diabetic status was available for 18 131 patients (≈94% of the total population enrolled), of whom 2790 patients had a history of diabetes. Treatment with lisinopril was associated with a decreased 6-week mortality in diabetic patients (8.7% versus12.4%; OR, 0.68; 95% CI, 0.53 to 0.86; 37±12 lives saved per 1000 treated patients), an effect that was significantly (
P
<.025) higher than that observed in nondiabetic patients. The survival benefit in diabetics was mostly maintained at 6 months despite withdrawal from treatment at 6 weeks (12.9% versus 16.1%; OR, 0.77; 95% CI, 0.62 to 0.95).

Conclusions
Early treatment with the ACE inhibitor lisinopril in diabetic patients with acute MI is associated with a decreased 6-week mortality. This beneficial effect supports a widespread and early use of ACE inhibitors in diabetic patients with acute MI. The burden of mortality plus morbidity for ventricular dysfunction in diabetics remains clinically important and warrants further testing of novel therapeutic approaches.
Enhanced Myosin Light Chain Phosphorylations as a Central Mechanism for Coronary Artery Spasm in a Swine Model With Interleukin-1β
Authors: Katsumata Naoki , Shimokawa Hiroaki , Seto Minoru , Kozai Toshiyuki , Yamawaki Tohru , Kuwata Kouichi , Egashira Kensuke , Ikegaki Ichiro , Asano Toshio , Sasaki Yasuharu , Takeshita Akira
Published: June 2012

Background
Although coronary artery spasm plays an important role in a wide variety of ischemic heart diseases, the intracellular mechanism for the spasm remains to be clarified. We examined the role of myosin light chain (MLC) phosphorylations, a key mechanism for contraction of vascular smooth muscle, in our swine model with interleukin-1β (IL-1β).

Methods and Results
IL-1β was applied chronically to the porcine coronary arteries from the adventitia to induce an inflammatory/proliferative lesion. Two weeks after the operation, intracoronary serotonin repeatedly induced coronary hyperconstrictions at the IL-1β-treated site both in vivo and in vitro, which were markedly inhibited by fasudil, an inhibitor of protein kinases, including protein kinase C and MLC kinase. Western blot analysis showed that during serotonin-induced contractions, MLC monophosphorylation was significantly increased and sustained in the spastic segment compared with the control segment, whereas MLC diphosphorylation was noted only in the spastic segment. A significant correlation was noted between the serotonin-induced contractions and MLC phosphorylations. Both types of MLC phosphorylation were markedly inhibited by fasudil. In addition, MLC diphosphorylation was never induced by a simple endothelium removal in the normal coronary artery, whereas enhanced MLC phosphorylations in the spastic segment were noted regardless of the presence or absence of the endothelium.

Conclusions
These results indicate that enhanced MLC phosphorylations in the vascular smooth muscle play a central role in the pathogenesis of coronary spasm in our swine model.
Additional Lead Improves Defibrillation Efficacy With an Abdominal ‘Hot Can’ Electrode System
Authors: Yamanouchi Yoshio , Mowrey Kent A. , Niebauer Mark J. , Tchou Patrick J. , Wilkoff Bruce L.
Published: June 2012

Background
Although the left prepectoral site is preferred for “hot can” placement, this site is unavailable in some patients. We evaluated the influence of electrode location on defibrillation thresholds with alternative hot can and transvenous lead configurations.

Methods and Results
Three interrelated studies were performed. In group 1, the importance of hot can location was investigated by pairing a right ventricular lead to five different hot can placement sites in seven pigs. The defibrillation energies for right pectoral, left pectoral, left subaxillary, and right and left abdominal hot can sites were 20.3±2.7,* 15.9±3.8, 14.9±2.5, 32.0±3.4,* and 30.0±3.4 J,* respectively (*
P
<.005 versus left pectoral and left subaxillary sites). In group 2, the value of a three-electrode configuration with an abdominal hot can placement was investigated by adding a subclavian vein lead to the pectoral or abdominal hot can configurations in seven pigs. The defibrillation energies for left pectoral and abdominal sites were 18.6±4.2 and 29.0±5.8 J (
P
=.0001), respectively. The addition of a right or left subclavian vein lead with an abdominal hot can reduced the threshold to 19.3±4.2* or 18.8±3.2,* respectively (*
P
=.0001 versus abdominal site). In group 3, the contribution of the abdominal hot can electrode to the three-electrode configuration was tested by a comparison with two purely transvenous two-electrode configurations in six pigs. The defibrillation energy (19.9±3.2 J) for the abdominal hot can with a subclavian vein lead was lower than the transvenous lead configurations with a subclavian vein (29.0±2.5 J,
P
=.0001) or a superior vena cava lead (30.7±3.7 J,
P
=.0001). The right ventricular lead was the sole cathode during the first phase of the biphasic shock in all experiments.

Conclusions
Defibrillation energy depends on the hot can placement site. The addition of a subclavian vein lead with an abdominal hot can improves defibrillation efficacy to the level of the pectoral placement and is better than a purely transvenous lead configuration.
Regulation of Hepatic Vascular Volume
Authors: Kjekshus Harald , Risoe Cecilie , Scholz Tim , Smiseth Otto A.
Published: June 2012

Background
It is unclear how the liver contributes to regulation of cardiac filling. The aims of this study were to establish an animal model to quantify hepatic vascular capacitance and to determine the mechanisms whereby catecholamines and sodium nitroprusside modify hepatic blood volume.

Methods and Results
In 8 anesthetized pigs we measured hepatic and systemic pressures and flows. Liver vascular volume was measured by sonomicrometry calibrated against integrated hepatic inflow during outflow occlusion. Pressure-volume (P-V) curves were constructed during outflow occlusion. Sonomicrometry accurately reflected hepatic blood volume (
r
=.99±.001), and hepatic P-V curves were highly reproducible. Norepinephrine (0.3 and 0.7 μg · kg body weight (bwt)
−1
· min
−1
intraportally) significantly reduced hepatic blood volume by 3.3±1 and 4.3±1 mL · kg bwt
−1
, respectively. Nitroprusside (8 and 18 μg · kg bwt
−1
· min
−1
intraportally) increased hepatic blood volume by 1.1±0.2 and 1.9±0.3 mL · kg bwt
−1
, respectively. Norepinephrine and nitroprusside parallel shifted the hepatic P-V curves, indicating reduced and increased unstressed blood volume, respectively. These curve shifts accounted for more than 90% of the respective blood volume changes. Compliance was unchanged. Phenylephrine but not isoprenaline yielded similar results as norepinephrine.

Conclusions
The pig model used in this study, accurately quantified hepatic capacitance. α-Adrenergic stimulation decreased and nitroprusside increased capacitance by changing unstressed blood volume. These changes in capacitance correspond to expulsion of 300 mL and pooling of 130 mL of blood, respectively, in a 70-kg individual, reflecting that the liver is not only a passive blood reservoir but can respond actively and vigorously to pharmacological interventions.
Activation of Monocyte/Macrophage Functions Related to Acute Atheroma Complication by Ligation of CD40
Authors: Mach François , Schönbeck Uwe , Bonnefoy Jean-Yves , Pober Jordan S. , Libby Peter
Published: June 2012

Background
Plaque disruption with thrombosis commonly causes the acute coronary syndromes. Macrophages, abundant at sites of plaque rupture, release proteinases that weaken plaques and express tissue factor (TF), which initiates thrombosis. The signals that induce expression of these macrophage functions, particularly TF, remain obscure. Recent studies have localized the receptor CD40 and its ligand in human atheroma. This study tested the hypothesis that ligation of CD40 can activate key mononuclear phagocyte functions related to clinical manifestations of atheroma.

Methods and Results
Stimulation of human monocytes/macrophages through CD40 by either membranes from activated T cells or recombinant CD40L (rCD40L) induced expression of interstitial collagenase, stromelysin, and TF protein and activity. In contrast, the soluble cytokines interleukin-1 or tumor necrosis factor-α did not induce or weakly induced TF expression. Neutralization with anti-CD40L antibody markedly inhibited these actions of both T-cell membranes and rCD40L.

Conclusions
By inducing the expression of matrix-degrading proteinases and of TF procoagulant, CD40 signaling may contribute to the triggering of acute coronary events.
Colocalization of CPP-32 With Apoptotic Cells in Human Atherosclerotic Plaques
Authors: Mallat Ziad , Ohan Jeanny , Lesèche Guy , Tedgui Alain
Published: June 2012

Background
Apoptosis that has been reported in human atherosclerosis may contribute to the remodeling of atherosclerotic plaques. The identification of specific markers for apoptosis in these plaques would permit the development of specific therapeutic strategies to limit their progression. Cysteine protease CPP-32 is essential for apoptotic death in mammalian cells and appears to be an attractive candidate.

Methods and Results
We studied 12 atherosclerotic plaques from 12 patients who underwent carotid endarterectomy. Apoptosis was analyzed by in situ end labeling of fragmented DNA (TUNEL method) and corroborated by the presence of DNA fragmentation in agarose gel electrophoresis. CPP-32 was detected with the use of a specific monoclonal antibody, and its expression was compared with that of interleukin-1β–converting enzyme (ICE). We showed that CPP-32 was highly expressed in 10 of 12 atherosclerotic plaques and that it colocalized with apoptotic cells. Expression of ICE generally paralleled that of CPP-32, but ICE was also detected in plaques negative for CPP-32 and showing no apoptosis.

Conclusions
CPP-32 is highly expressed within human atherosclerotic plaques and is closely related to apoptosis. This finding suggests that CPP-32 may be the ICE-like enzyme responsible for apoptosis in human atherosclerosis and opens new perspectives for the development of therapeutic strategies to alter the progression of this disease.
Functional Evaluation of Lipid-Lowering Therapy by Pravastatin in the Regression Growth Evaluation Statin Study (REGRESS)
Authors: Aengevaeren Wim R. M. , Uijen Gerard J. H. , Jukema J. Wouter , Bruschke Albert V. G. , van der Werf Tjeerd
Published: June 2012

Background
Lipid-lowering therapy during 2 years in the Regression Growth Evaluation Statin Study (REGRESS) was associated with less progression of coronary atherosclerosis in the pravastatin group compared with the placebo group. The effect of lipid-lowering therapy on the functional state of the coronary circulation is less well known. The purpose of this study was to evaluate this effect.

Methods and Results
In a substudy of REGRESS, 69 patients were randomized to pravastatin or placebo. Thirty-seven of these patients were allocated to the medical management stratum. Quantitative coronary angiography, regional myocardial perfusion, exercise testing, and classification of angina pectoris were assessed at baseline and after 2 years of therapy. Regional myocardial perfusion was assessed by digital subtraction angiography after intracoronary papaverine with videodensitometric calculation of the hyperemic mean transit time (HMTT) of contrast. In the medical management stratum, regional myocardial perfusion was assessed in 31 regions in the pravastatin group and 25 regions in the placebo group. The change in HMTT in the pravastatin group was −0.18 seconds (−5%) and in the placebo group +0.52 seconds (+18%), a difference of 0.70 seconds (
P
=.004). The mean difference in change in classification of angina pectoris (scale, 1 to 4) between pravastatin and placebo was 0.7 (
P
=.03) in favor of the pravastatin-treated patients. The change in HMTT was correlated with the change in exercise time (
r
=−.65,
P
=.002).

Conclusions
In patients with symptomatic coronary artery disease, treatment with the HMG-coenzyme A reductase inhibitor pravastatin during 2 years resulted in a preserved regional myocardial perfusion, whereas patients on placebo deteriorated. The classification of angina pectoris improved only in patients receiving pravastatin. In lipid-lowering therapy, the evaluation of myocardial perfusion by assessment of the HMTT reveals a combined measure of functional and structural changes in the coronary circulation.
Intracoronary Doppler Assessment of Moderate Coronary Artery Disease
Authors: Heller Louis I. , Cates Christopher , Popma Jeffrey , Deckelbaum Lawrence I. , Joye James D. , Dahlberg Seth T. , Villegas Bernard J. , Arnold Anita , Kipperman Robert , Grinstead W. Carter , Balcom Sharon , Ma Yunsheng , Cleman Michael , Steingart Richard M. , Leppo Jeffrey A.
Published: June 2012

Background
Coronary angiography may not reliably predict whether a stenosis causes exercise-induced ischemia. Intracoronary Doppler ultrasound may enhance diagnostic accuracy by providing a physiological assessment of stenosis severity. The goal of this study was to compare intracoronary Doppler ultrasound with both
201
Tl imaging and coronary angiography.

Methods and Results
Fifty-five patients with 67 stenotic coronary arteries underwent coronary angiography with intracoronary Doppler ultrasound and had exercise
201
Tl testing within a 1-week period. Coronary flow reserve was measured, and analyses were performed by independent core laboratories. The mean stenosis was 59±12%; 51 of 67 stenoses were intermediate in severity (40% to 70%). A coronary flow reserve <1.7 predicted the presence of a stress
201
Tl defect in 56 of 67 stenoses (agreement=84%; κ=0.67; 95% CI=0.48 to 0.86). In the patients who achieved 75% of their predicted maximum heart rate, the Doppler and
201
Tl imaging data agreed in 46 of 52 stenoses (agreement=88%; κ=0.77; 95%CI=0.57 to 0.97). Scatter was evident when angiography was compared with coronary flow reserve (
r
=.43), and the angiogram did not reliably predict the results of the
201
Tl stress test (κ=0.21; agreement=57% to 63%).

Conclusions
Doppler-derived coronary flow reserve accurately predicts the presence of exercise-induced ischemia on stress
201
Tl imaging, and coronary angiography does not reliably assess the physiological significance of an intermediate coronary stenosis.
Cardiac Atrophy After Bed-Rest Deconditioning
Authors: Levine Benjamin D. , Zuckerman Julie H. , Pawelczyk James A.
Published: June 2012

Background
The cardiovascular adaptation to bed rest leads to orthostatic intolerance, characterized by an excessive fall in stroke volume (SV) in the upright position. We hypothesized that this large fall in SV is due to a change in cardiac mechanics.

Methods and Results
We measured pulmonary capillary wedge pressure (PCWP), SV, left ventricular end-diastolic volume (LVEDV), and left ventricular mass (by echocardiography) at rest, during lower-body negative pressure, and after saline infusion before and after 2 weeks of bed rest with −6° head-down tilt (n=12 subjects aged 24±5 years). Pressure (P)-volume (V) curves were modeled exponentially by P=
ae

k
V

+
b
and logarithmically by P=−
S
ln[(V
m
−V)/(V
m
−V
0
], where V
0
indicates volume at P=0, and the constants
k
and
S
were used as indices of normalized chamber stiffness. Dynamic stiffness (dP/dV) was calculated at baseline LVEDV. The slope of the line relating SV to PCWP during lower-body negative pressure characterized the steepness of the Starling curve. We also measured plasma volume (with Evans blue dye) and maximal orthostatic tolerance. Bed rest led to a reduction in plasma volume (17%), baseline PCWP (18%), SV (12%), LVEDV (16%), V
0
(33%), and orthostatic tolerance (24%) (all
P
<.05). The slope of the SV/PCWP curve increased from 4.6±0.4 to 8.8±0.9 mL/mm Hg (
P
<.01) owing to a parallel leftward shift in the P-V curve. Normalized chamber stiffness was unchanged, but dP/dV was reduced by 50% at baseline LVEDV, and cardiac mass tended to be reduced by 5% (
P
<.10).

Conclusions
Two weeks of head-down–tilt bed rest leads to a smaller, less distensible left ventricle but a shift to a more compliant portion of the P-V curve. This results in a steeper Starling relationship, which contributes to orthostatic intolerance by causing an excessive reduction in SV during orthostasis.
Noninvasive Measurement of Shortening in the Fiber and Cross-Fiber Directions in the Normal Human Left Ventricle and in Idiopathic Dilated Cardiomyopathy
Authors: MacGowan Guy A. , Shapiro Edward P. , Azhari Haim , Siu Cynthia O. , Hees Paul S. , Hutchins Grover M. , Weiss James L. , Rademakers Frank E.
Published: June 2012

Background
Studies in anesthetized dogs have shown that myocardial fibers shorten ≈8%. However, in the endocardium, shortening occurs to a much greater extent at 90° to the fiber orientation (“cross-fiber shortening”) than it does along the fiber direction. The purpose of this study was to estimate the extent of fiber and cross-fiber shortening in the normal human left ventricle and in patients with idiopathic dilated cardiomyopathy (IDC).

Methods and Results
Ten normal subjects and nine patients with IDC were imaged with magnetic resonance tissue tagging. Finite strain analysis was used to calculate endocardial and epicardial shortening in the fiber and cross-fiber directions using anatomic fiber angles from representative autopsy specimens as references. Anatomic fiber angles were not different between normal subjects and IDC patients. Epicardial fiber strain was −0.14±0.01 in normal subjects and −0.08±0.01 in IDC patients (
P
<.0001 versus normal subjects). Epicardial cross-fiber strain was −0.08±0.01 in normal subjects and −0.06±0.01 in IDC patients (
P
=NS). Endocardial fiber strain was −0.16±0.01 in normal subjects and −0.09±0.01 in IDC patients (
P
<.0001), and endocardial cross-fiber strain was −0.26±0.01 in normal subjects and −0.15±0.01 in IDC patients (
P
<.0001). Cross-fiber shortening was greater than fiber shortening at the endocardium in both normal subjects (
P
<.0001) and IDC patients (
P
<.05).

Conclusions
In normal humans, the direction of maximal deformation aligns with the fiber direction in the epicardium but is perpendicular to the fiber direction in the endocardium. When strain in a coordinate system aligned to the fibers is estimated, cross-fiber shortening is found to be the dominant shortening strain at the endocardium. Normal fiber shortening is ≈15%, and this is markedly reduced in IDC. The normal transition in fiber orientation through the wall is not altered in IDC, and cross-fiber shortening is still the dominant strain at the endocardium, suggesting that interactions between myocardial layers persist in these patients.
Inhibition of Tissue Factor–Mediated Coagulation Markedly Attenuates Stenosis After Balloon-Induced Arterial Injury in Minipigs
Authors: Oltrona Luigi , Speidel Christopher M. , Recchia Dino , Wickline Samuel A. , Eisenberg Paul R. , Abendschein Dana R.
Published: June 2012

Background
Exposure and upregulation of tissue factor in the wall of balloon-injured arteries may result in prolonged activation of coagulation contributing to restenosis. This study was designed to determine whether brief or more prolonged inhibition of tissue factor–mediated coagulation with tissue factor pathway inhibitor (TFPI) attenuates neointimal formation and luminal stenosis after balloon-induced arterial injury.

Methods and Results
The carotid artery of minipigs fed an atherogenic diet was injured by repetitive balloon hyperinflations, a procedure that rapidly yields complex, plaque-like neointimal lesions and high-grade luminal stenosis. Recombinant TFPI (rTFPI) was administered intravenously beginning 15 minutes before balloon injury as either a high dose (0.5 mg/kg bolus and 100 μg·kg
−1
·min
−1
) for 3 hours (n=7) or 24 hours (n=6) or as a low dose (0.5 mg/kg and 25 μg·kg
−1
·min
−1
) for 24 hours (n=6). Control animals received intravenous heparin (100 U·kg
−1
·h
−1
) for 3 hours (n=6) or 24 hours (n=7) or aspirin (5 mg/kg PO) followed by heparin for 24 hours (n=7). Luminal stenosis, assessed histologically 4 weeks after injury, was 73±17% and 76±18% (mean±SEM) in animals that received rTFPI or heparin for 3 hours, respectively. In contrast, luminal stenosis was only 11±12% and 6±3% in pigs given high and low doses, respectively, of rTFPI for 24 hours compared with 46±22% in pigs given heparin for 24 hours and 40±19% in those given both heparin and aspirin (
P
<.0002).

Conclusions
Inhibition of tissue factor–mediated coagulation during the first 24 hours after deep arterial injury appears to be particularly effective for attenuating subsequent neointimal formation and stenosis.
Myocardial Contrast Echocardiography Can Be Used to Quantify Intramyocardial Blood Volume
Authors: Wu Clarence C. , Feldman Marc D. , Mills James D. , Manaugh Christine A. , Fischer David , Jafar M. Zubair , Villanueva Flordeliza S.
Published: June 2012

Background
Changes in intramyocardial blood volume (IBV) mediate autoregulatory adaptations to coronary stenosis. This study investigated whether (1) myocardial contrast echocardiography (MCE) can quantify changes in IBV during coronary stenosis and (2) the relation between coronary resistance– and MCE-derived IBV could yield insight into structural mechanisms of IBV change.

Methods and Results
A circulating in vitro model with constant flow and varying volume was used to determine whether indicator dilution theory could be applied to MCE. Contrast echo was performed with albumin microbubbles, and time-intensity data were fit to a gamma-variate function. With six different volumes, bubble transit time was linearly related to volume (
r
=.91). To determine whether changes in IBV could be quantified in vivo, the left anterior descending coronary artery in 12 dogs was instrumented with a flow probe, occluder, and intracoronary pressure catheter, and non–flow-limiting stenoses were created. IBV was derived by use of coronary resistance measurements applied to models that assumed autoregulation to occur via vasodilatation or microvascular recruitment. MCE-IBV was calculated from microbubble transit rates. At constant flow, MCE and resistance IBV increased with stenosis. Although MCE and resistance IBV were linearly related, MCE overestimated IBV derived from the vasodilatation model and underestimated IBV calculated from the recruitment model.

Conclusions
MCE can quantify autoregulatory increases in IBV that maintain resting myocardial perfusion. These data suggest that both microvessel vasodilatation and recruitment are dual mechanisms of IBV change. MCE thus may be a clinically useful technique for the detection and quantification of coronary artery disease at rest.
Lipoprotein Lipase Variants D9N and N291S Are Associated With Increased Plasma Triglyceride and Lower High-Density Lipoprotein Cholesterol Concentrations
Authors: Gerdes Christian , Fisher Rachel M. , Nicaud Viviane , Boer Jolanda , Humphries Steve E. , Talmud Philippa J. , Faergeman Ole
Published: June 2012

Background
Variations at the DNA level with moderate effects on biochemical variables may be important for the occurrence of disease at the population level, if they are common. Two mutations in the LPL gene, N9 and S291, are associated with variation in fasting plasma concentrations of HDL cholesterol (HDL-C) and triglycerides (TG). We investigated whether these mutants were more frequent in offspring of cases with premature coronary disease and analyzed the effects on fasting plasma lipids and postprandial TG.

Methods and Results
Students with and without paternal history of myocardial infarction (cases and control subjects [controls]) were studied in the European Atherosclerosis Research Studies I and II (EARS-I and -II). Allelic frequencies for the N9 and S291 mutations did not differ between cases and control subjects. The N9 mutation was identified in 4.2% of all subjects in EARS-I, and carriers had higher fasting TG levels (
P
<.001) than noncarriers. In an oral fat tolerance test, there were no differences in postprandial TG between carriers and noncarriers of the N9 allele. The S291 mutation was identified in 3.1% of all subjects in EARS-I, and carriers had lower fasting HDL-C levels (
P
<.005) than noncarriers. There was a significant interaction between S291 genotype and body mass index on fasting TG levels (
P
<.01). In the cases, carriers of the S291 allele had higher TG levels 6 hours postprandially (
P
<.04) than did noncarriers.

Conclusions
The two LPL mutations are common and may predispose to elevated TG and decreased HDL-C concentrations, even in young subjects. In the case of the S291 mutation, this effect appears to be mediated via delayed postprandial TG clearance. Moreover, even moderate obesity potentiates the TG-raising and HDL-lowering effects associated with the S291 allele.
Danish Multicenter Randomized Study of Invasive Versus Conservative Treatment in Patients With Inducible Ischemia After Thrombolysis in Acute Myocardial Infarction (DANAMI)
Authors: Madsen Jan K. , Grande Peer , Saunamäki Kari , Thayssen Per , Kassis Eli , Eriksen Ulrik , Rasmussen Klaus , Haunsø Stig , Nielsen Torsten T. , Haghfelt Torben , Fritz-Hansen Per , Hjelms Erik , Paulsen Peter K. , Alstrup Poul , Arendrup Henrik , Niebuhr-Jørgensen Uffe , Andersen Lars I.
Published: June 2012

Background
The aim of the DANish trial in Acute Myocardial Infarction (DANAMI) study was to compare an invasive strategy of percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass grafting (CABG) with a conservative strategy in patients with inducible myocardial ischemia who received thrombolytic treatment for a first acute myocardial infarction (AMI).

Methods and Results
Of the 503 patients randomized to an invasive strategy, PTCA was performed in 266 (52.9%) and CABG in 147 (29.2%) from 2 to 10 weeks after the AMI. Of the 505 patients in the conservative treatment group, only 8 (1.6%) had been revascularized 2 months after the AMI. The patients were followed up from 1 to 4.5 years. The primary end points were mortality, reinfarction, and admission with unstable angina. At 2.4 years’ follow-up (median), mortality was 3.6% in the invasive treatment group and 4.4% in the conservative treatment group (not significant). Invasive treatment was associated with a lower incidence of AMI (5.6% versus 10.5%;
P
=.0038) and a lower incidence of admission for unstable angina (17.9% versus 29.5%;
P
<.00001). The percentages of patients with a primary end point were 15.4% and 29.5% at 1 year, 23.5% and 36.6% at 2 years, and 31.7% versus 44.0% at 4 years (
P
=<.00001) in the invasive and conservative treatment groups, respectively. At 12 months, stable angina pectoris was present in 21% of patients in the invasive treatment group and 43% in the conservative treatment group.

Conclusions
Invasive treatment in post-AMI patients with inducible ischemia results in a reduction in the incidence of reinfarction, fewer admissions due to unstable angina, and lower prevalence of stable angina. We conclude that patients with inducible ischemia before discharge who have received treatment with thrombolytic drugs for their first AMI should be referred to coronary arteriography and revascularized accordingly.
Clearance of Tissue Plasminogen Activator (TPA) and TPA/Plasminogen Activator Inhibitor Type 1 (PAI-1) Complex
Authors: Chandler W. L. , Alessi M. C. , Aillaud M. F. , Henderson P. , Vague P. , Juhan-Vague I.
Published: June 2012

Background
To evaluate the effect of plasminogen activator inhibitor type 1 (PAI-1) levels on the clearance of total tissue plasminogen activator (TPA) antigen, we studied the clearance of active TPA and TPA/PAI-1 complex in subjects with low (181±109 pmol/L; n=7) and high (1166±322 pmol/L; n=4) baseline active PAI-1.

Methods and Results
A 5-μg/kg bolus of TPA was infused over a 15-second period followed by measurement of TPA activity, TPA antigen, TPA/PAI-1, TPA/C1 inhibitor, PAI-1 activity, and PAI-1 antigen over a 4-hour period. α-Phase clearance of total TPA antigen was faster in subjects with low PAI-1 (t
1/2
of 3.5±0.7 minutes) versus high PAI-1 (t
1/2
of 5.3±0.9 minutes) (
P
=.006). Clearance of all factors was best fit by a two-compartment pharmacokinetic model based on a computer-simulated human circulatory system. The average hepatic clearance fraction in the two-compartment model was greater for active TPA (89±10%, t
1/2
of 2.4±0.3 minutes) than for TPA/PAI-1 complex (48±17%, t
1/2
of 5.0±1.8 minutes) (
P
=.0006).

Conclusions
Plasma clearance of active TPA was faster than clearance of TPA/PAI-1 complex. High levels of active PAI-1 converted more TPA into TPA/PAI-1 complex, effectively slowing the clearance of total TPA antigen and explaining in part why high levels of PAI-1 activity are associated with increases in total TPA antigen.
Increase in Angiotensin II Type 1 Receptor Expression Immediately After Ischemia-Reperfusion in Isolated Rat Hearts
Authors: Yang B. C. , Phillips M. I. , Ambuehl P. E. J. , Shen L. P. , Mehta P. , Mehta J. L.
Published: June 2012

Background
Myocardial ischemia is known to upregulate the systemic renin-angiotensin system, which influences myocardial ischemic events by affecting hemodynamics and hemostatic activity. This study was designed to examine whether angiotensin II (Ang II) receptor expression in the myocardium is altered immediately after ischemia-reperfusion.

Methods and Results
Isolated buffer-perfused Sprague-Dawley rat hearts were subjected to continuous perfusion (control, n=5) or to 25 minutes of global ischemia followed by 30 minutes of reperfusion (n=10). Autoradiographic analysis for Ang II receptors of multiple myocardial sections was performed. Whereas continuous perfusion of hearts resulted in minor changes in coronary perfusion pressure (CPP), left ventricular end-diastolic pressure (LVEDP), and developed left ventricular pressure (dLVP=LVSP−LVEDP), ischemia-reperfusion caused a marked increase in CPP and LVEDP and a decrease in dLVP, indicating severe cardiac dysfunction. Concurrently, total myocardial Ang II receptor expression was greater (
P
<.05) in hearts subjected to ischemia-reperfusion than in the continuously perfused control hearts. Most of the increase in Ang II receptor expression was due to an increase in type 1 receptor (AT
1
) expression (34.6±6.5 versus 18.2±4.4 fmol/g,
P
<.05), because Ang II type 2 receptor expression was unaffected. To examine the importance of AT
1
receptor expression, another group of isolated rat hearts (n=5) was perfused with buffer containing losartan (10
−5
mol/L) and subjected to ischemia followed by reperfusion. Perfusion of hearts with losartan attenuated the ischemia-reperfusion–induced cardiac dysfunction. Perfusion of hearts with losartan also blocked the ischemia-reperfusion–induced increase in myocardial AT
1
binding.

Conclusions
These observations indicate that myocardial AT
1
expression increases immediately after ischemia-reperfusion and contributes to cardiac dysfunction.