bluuebunny/crossref_metadata_2025 huggingface dataset:
Predictors of Outcome in Patients With Acute Coronary Syndromes Without Persistent ST-Segment Elevation
Authors: Boersma Eric , Pieper Karen S. , Steyerberg Ewout W. , Wilcox Robert G. , Chang Wei-Ching , Lee Kerry L. , Akkerhuis K. Martijn , Harrington Robert A. , Deckers Jaap W. , Armstrong Paul W. , Lincoff A. Michael , Califf Robert M. , Topol Eric J. , Simoons Maarten L.
Published: June 2012

Background
—Appropriate treatment policies should include an accurate estimate of a patient’s baseline risk. Risk modeling to date has been underutilized in patients with acute coronary syndromes without persistent ST-segment elevation.

Methods and Results
—We analyzed the relation between baseline characteristics and the 30-day incidence of death and the composite of death or myocardial (re)infarction in 9461 patients with acute coronary syndromes without persistent ST-segment elevation enrolled in the PURSUIT trial [Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin (eptifibatide) Therapy]. Variables examined included demographics, history, hemodynamic condition, and symptom duration. Risk models were created with multivariable logistic regression and validated by bootstrapping techniques. There was a 3.6% mortality rate and 11.4% infarction rate by 30 days. More than 20 significant predictors for mortality and for the composite end point were identified. The most important baseline determinants of death were age (adjusted χ
2
=95), heart rate (χ
2
=32), systolic blood pressure (χ
2
=20), ST-segment depression (χ
2
=20), signs of heart failure (χ
2
=18), and cardiac enzymes (χ
2
=15). Determinants of mortality were generally also predictive of death or myocardial (re)infarction. Differences were observed, however, in the relative prognostic importance of predictive variables for mortality alone or the composite end point; for example, sex was a more important determinant of the composite end point (χ
2
=21) than of death alone (χ
2
=10). The accuracy of the prediction of the composite end point was less than that of mortality (C-index 0.67 versus 0.81).

Conclusions
—The occurrence of adverse events after presentation with acute coronary syndromes is affected by multiple factors. These factors should be considered in the clinical decision-making process.
Relationship of
Chlamydia pneumoniae
Infection to Severity of Human Coronary Atherosclerosis
Authors: Ericson Katharina , Saldeen Tom G. P. , Lindquist Olle , Påhlson Carl , Mehta Jawahar L.
Published: June 2012

Background
—Infection with
Chlamydia pneumoniae
has been postulated to play a pathogenic role in atherosclerosis. We examined the role of infection with
C pneumoniae
in relation to the extent of coronary atherosclerosis.

Methods and Results
—Coronary atherosclerosis was graded microscopically on a postmortem basis in a blinded fashion in 60 subjects as mild (n=18) or severe (n=42) atherosclerosis. Serum antibodies to
C pneumoniae
were measured by microimmunofluorescence test. Paraffin-embedded coronary artery specimens were examined for the presence of chlamydia by use of a genus-specific direct immunofluorescence monoclonal antibody. Frozen coronary artery specimens were examined by immunoperoxidase for the presence of
C pneumoniae
by use of a specific monoclonal antibody RR-402. Direct immunofluorescence was reactive in 86% of cases with severe atherosclerosis but in only 6% of cases with mild atherosclerosis (
P
<0.01), whereas immunoperoxidase staining was reactive in 80% and 38% of cases with severe and mild atherosclerosis, respectively (
P
<0.01). Elevated IgG and IgA levels against
C pneumoniae
were not different in cases with severe and mild atherosclerosis (61% and 30% for severe atherosclerosis and 67% and 42% for mild atherosclerosis, respectively).

Conclusions
—This study supports the hypothesis that intracellular infection with
C pneumoniae
may relate to the severity of atherosclerosis in some subjects. Serum antibody titers against
C pneumoniae
do not differentiate between severe and mild atherosclerosis.
Extent of Cardiac Sympathetic Neuronal Damage Is Determined by the Area of Ischemia in Patients With Acute Coronary Syndromes
Authors: Matsunari Ichiro , Schricke Ullrich , Bengel Frank M. , Haase Hans-Ullrich , Barthel Petra , Schmidt Georg , Nekolla Stephan G. , Schoemig Albert , Schwaiger Markus
Published: June 2012

Background
—Prior studies have demonstrated that acute ischemic injury causes sympathetic neuronal damage exceeding the area of necrosis. The aim of this study was to test the hypothesis that sympathetic neuronal damage measured by
123
I-metaiodobenzylguanidine (MIBG) imaging would be determined by the area of ischemia as reflected by area at risk in patients undergoing reperfusion therapy for acute coronary syndromes.

Methods and Results
—In 12 patients, the myocardium at risk was assessed by
99m
Tc-sestamibi SPECT before reperfusion, and infarct size was measured by follow-up
99m
Tc-sestamibi SPECT 1 week later. All patients also underwent
123
I-MIBG SPECT within a mean of 11 days after onset. The SPECT image analysis was based on a semiquantitative polar map approach. Defect size on the
123
I-MIBG or
99m
Tc-sestamibi SPECT was measured for the left ventricle (LV) with the use of a threshold of −2.5 SD from the mean value of a normal database and was expressed as %LV. The
123
I-MIBG defect size (47±18%LV) was larger than the infarct size (27±23%LV,
P
<0.001) but was similar to the risk area (49±18%LV,
P
=NS). Furthermore, the
123
I-MIBG defect size was closely correlated with the risk area (
r
=0.905,
P
<0.001).

Conclusions
—Sympathetic neuronal damage measured by
123
I-MIBG SPECT is larger than infarct size and is closely related to risk area, suggesting high sensitivity of neuronal structures to ischemia compared with myocardial cells.
Distinct Patterns of Dystrophin Organization in Myocyte Sarcolemma and Transverse Tubules of Normal and Diseased Human Myocardium
Authors: Kaprielian R. R. , Stevenson S. , Rothery S. M. , Cullen M. J. , Severs N. J.
Published: June 2012

Background
—Genetic mutations of dystrophin and associated glycoproteins underlie cell degeneration in several inherited cardiomyopathies, although the precise physiological role of these proteins remains under discussion. We studied the distribution of dystrophin in relation to the force-transducing vinculin-rich costameres in left ventricular cardiomyocytes from normal and failing human hearts to further elucidate the function of this protein complex.

Methods and Results
—Single- and double-label immunoconfocal microscopy and parallel high-resolution immunogold fracture-label electron microscopy were used to localize dystrophin and vinculin in human left ventricular myocytes from normal (n=6) and failing hearts (idiopathic dilated cardiomyopathy, n=7, or ischemic heart disease, n=5). In control cardiomyocytes, dystrophin had a continuous distribution at the peripheral sarcolemma, with concentrated bands corresponding to the vinculin-rich costameres. Intracellular labeling extended along transverse (T) tubule membranes. Fracture-label confirmed this distribution, showing significantly greater label on plasma membrane fractures overlying I-bands (I-band 4.1±0.3 gold particles/μm; A-band 3.3±0.2 gold particles/μm: mean±SE,
P
=0.02). Hypertrophied myocytes from failing hearts showed maintenance of this surface distribution except in degenerating cells; there was a clear increase in intracellular dystrophin label reflecting T-tubule hypertrophy.

Conclusions
—Dystrophin partially colocalizes with costameric vinculin in normal and hypertrophied myocytes, a distribution lost in degenerating cells. This suggests a primarily mechanical role for dystrophin in maintenance of cell membrane integrity in normal and hypertrophied myocytes. The presence of dystrophin in the cardiac T-tubule membrane, in contrast to its known absence in skeletal muscle T-tubules, implies additional roles for dystrophin in membrane domain organization.
Local Pulse Pressure and Regression of Arterial Wall Hypertrophy During Long-Term Antihypertensive Treatment
Authors: Boutouyrie Pierre , Bussy Caroline , Hayoz Daniel , Hengstler Jurg , Dartois Nathalie , Laloux Brigitte , Brunner Hans , Laurent Stéphane
Published: June 2012

Background
—Local pulse pressure (PP) is an independent determinant of carotid artery wall thickness, stronger than mean blood pressure (BP). The present study was designed to assess whether a β-adrenoceptor antagonist–based or an ACE inhibitor–based treatment was able to reduce carotid artery wall hypertrophy through a reduction in carotid PP rather than by lowering mean BP and whether the influence of local PP reduction could also be detected at the site of a muscular artery, the radial artery.

Methods and Results
—Ninety-eight essential hypertensive patients were randomized to 9 months of double-blind treatment with either celiprolol or enalapril. Arterial parameters were determined with high-resolution echo-tracking systems. PP was measured locally with applanation tonometry and independently of mean BP. After 9 months of treatment, mean BP, carotid PP, and intimal-medial thickness (IMT) decreased significantly, with no difference between the 2 groups. The reduction in carotid PP but not in mean BP was a major independent determinant of the reduction in carotid IMT. Radial artery IMT and PP decreased significantly with both treatments. However, the reduction in radial artery IMT was not related to the changes in radial artery PP.

Conclusions
—The regression of carotid artery wall hypertrophy during long-term antihypertensive treatment was dependent on the reduction in local PP rather than on the lowering of mean BP. The effect of PP lowering on IMT reduction was observed at the site of an elastic artery but not at the site of a muscular artery.
Effects of the Maze Operation on Health-Related Quality of Life in Patients With Atrial Fibrillation
Authors: Lönnerholm Stefan , Blomström P. , Nilsson L. , Oxelbark S. , Jideus L. , Blomström-Lundqvist C.
Published: June 2012

Background
—Maze surgery for atrial fibrillation (AF) is a curative therapy, but its effect on health-related quality of life has not been studied.

Methods and Results
—Maze operations were performed in 48 patients with drug-refractory AF. The majority of patients (80%) had lone AF, and the primary indication for surgery in all patients was AF. The SF-36 Health Survey was used to assess quality of life before operation and at 6 months and 1 year after surgery. Twenty-five patients were available for the 1-year follow-up and completed all questionnaires. Before maze surgery, the SF-36 scores were significantly lower than in the general Swedish population, reflecting significant impairment in well-being, physical and social functioning, and mental health. After maze surgery, the quality of life was significantly improved at 6 months and at 1 year on all scales except for bodily pain, which, however, was not significantly decreased before surgery. At both 6 months and 1 year after maze surgery, quality of life, measured by the SF-36, reached the levels of the general Swedish population.

Conclusions
—The maze operation can significantly improve the health-related quality of life in selected groups of patients with both paroxysmal and chronic AF refractory to antiarrhythmic therapy.
Orally Administered Unfractionated Heparin With Carrier Agent Is Therapeutic for Deep Venous Thrombosis
Authors: Gonze Mark D. , Salartash Khashayar , Sternbergh W. Charles , Baughman Robert A. , Leone-Bay Andrea , Money Samuel R.
Published: June 2012

Background
—Orally administered heparin (OHEP) is unreliable because of poor absorption. Sodium
N-
(8[2-hydroxybenzoyl]amino) caprylate (SNAC) is an amido acid that facilitates the gastrointestinal absorption of heparin. We evaluated the effectiveness of OHEP combined with SNAC (OHEP/SNAC) in the treatment of deep-vein thrombosis (DVT).

Methods and Results
—An internal jugular DVT was produced in 54 male Sprague-Dawley rats. Animals were assigned to 6 different groups for 7 days of treatment: untreated control, subcutaneous heparin (SC HEP) (300 U/kg SC TID), SNAC only (300 mg/kg PO TID), OHEP only (30 mg/kg PO TID), low-molecular-weight heparin (LMWH) (enoxaparin 5 mg/kg SC QD), and OHEP/SNAC (30 mg/kg:300 mg/kg PO TID). The activated partial thromboplastin time (aPTT) and anti–factor X (anti-Xa) levels were measured. The incidence of residual DVT after 1 week of treatment was 100% (9 of 9) in the control group versus 10% (1 of 10) in the OHEP/SNAC and 10% (1 of 10) in the LMWH groups (
P
<0.001). There was also a significant reduction in clot weights between these groups. Compared with controls, there were no significant differences in the residual DVT in the SNAC-only (6 of 6), OHEP-only (9 of 9), or SC HEP (8 of 10) groups. Combination OHEP/SNAC was as effective in the resolution of the clot and reducing clot weight as LMWH. The aPTT levels in the OHEP/SNAC group peaked at 30 minutes and were significantly higher than in all other groups (
P
<0.01). Anti-Xa levels were elevated at 15 minutes after dosing in the OHEP/SNAC group and remained significantly elevated at 4 hours (
P
<0.001).

Conclusions
—OHEP combined with a novel carrier agent (SNAC) successfully treated DVT in this rat model.
Luigi Luciani and the Earliest Graphic Demonstration of Wenckebach Periodicity
Authors: Upshaw Charles B. , Silverman Mark E.
Published: June 2012

Abstract
—Using an isolated frog heart preparation with ligatures around the atria, Luigi Luciani, an Italian physiologist working in 1873 in Carl Ludwig’s famous laboratory in Leipzig, was the first to demonstrate cardiac group beating, which he named periodic rhythm. He attributed this to increased resistance to impulse propagation between the atria and the ventricle. Karel F. Wenckebach, in his 1899 landmark report of group beating in a patient in which he also used pulse tracings, credited Luciani with this discovery. Wenckebach referred to the phenomena as “Luciani periods.” With the advent of electrocardiography in the early 20th century, this form of group beating became known as Wenckebach periodicity and then as Mobitz type I atrioventricular block. We reanalyzed Luciani’s original paper and pulse tracings, and we show that periodic rhythm does indeed meet the criteria of second-degree atrioventricular block as established by Wenckebach. We also reviewed the career of Luciani, who was an important investigator, outstanding teacher and mentor, and distinguished leader of 19th-century physiology. We conclude that Wenckebach still deserves to have his name eponymously attached to this type of atrioventricular block because he was the first to unravel the complicated relationship between atrial and ventricular conduction.
Regulation of Angiotensin II Receptor Subtypes During Atrial Fibrillation in Humans
Authors: Goette Andreas , Arndt Marco , Röcken Christoph , Spiess Antje , Staack Thorsten , Geller J. Christoph , Huth Christof , Ansorge Siegfried , Klein Helmut U. , Lendeckel Uwe
Published: June 2012

Background
—Previous studies have suggested that atrial fibrillation (AF) is associated with the activation of the atrial angiotensin system. However, it is not known whether the expression of angiotensin II receptors changes during AF. The purpose of this study was to determine the atrial expression of angiotensin II type 1 and type 2 receptors (AT
1
-R and AT
2
-R) in patients with AF.

Methods and Results
—Atrial tissue samples from 30 patients undergoing open heart surgery were examined. Eleven patients had chronic persistent AF (≥6 months; cAF), 8 patients had paroxysmal AF (pAF), and 11 patients were in sinus rhythm. AT
1
-R and AT
2
-R were localized in the atrial tissue by immunohistochemistry and quantified at the protein and mRNA level by Western blotting and quantitative polymerase chain reaction. Both types of AT-R were predominantly expressed in atrial myocytes in all groups. The amount of AT
1
-R was reduced to 34.9% during cAF (
P
<0.01) and to 51.7% during pAF (
P
<0.05) compared with patients in sinus rhythm. In contrast, AT
2
-R was increased during cAF (246%;
P
=NS) and pAF (505%;
P
<0.01). AT
1
-R/AT
2
-R mRNA content was similar in all groups.

Conclusions
—AF is associated with the down-regulation of atrial AT
1
-R and the up-regulation of AT
2
-R proteins. These findings may help define the pathophysiological role of the angiotensin system in the structural remodeling of the fibrillating atria.
Microvascular Obstruction and Left Ventricular Remodeling Early After Acute Myocardial Infarction
Authors: Gerber Bernhard L. , Rochitte Carlos E. , Melin Jacques A. , McVeigh Elliot R. , Bluemke David A. , Wu Katherine C. , Becker Lewis C. , Lima João A. C.
Published: June 2012

Background
—The presence of microvascular obstruction (MO) within infarcted regions may adversely influence left ventricular (LV) remodeling after acute myocardial infarction. This study examined whether the extent of MO directly alters the mechanical properties of the infarcted myocardium.

Methods and Results
—Seventeen dogs underwent 90 minutes of balloon occlusion of the left anterior descending coronary artery, followed by reperfusion. Gadolinium-enhanced perfusion MRI and 3D-tagging were performed 4 to 6 and 48 hours (8 animals) and 10 days (9 animals) after reperfusion. Early increase in LV end-diastolic volume (from 42±9 to 54±14 mL,
P
<0.05) between 4 to 6 and 48 hours after reperfusion was predicted by both extent of MO (
r
=0.89,
P
<0.01) and infarct size (
r
=0.83,
P
<0.01), defined as MRI hypoenhanced and hyperenhanced regions, respectively. Multivariate analysis demonstrated that extent of MO had better and independent value to predict LV volume than overall infarct size. A strong inverse relationship existed between magnitude of first principal strain (
r
=−0.80,
P
<0.001) and relative extent of MO within infarcted myocardium. Also, infarcted myocardium involved by extensive areas of MO demonstrated reductions of circumferential (
r
=−0.61,
P
<0.01) and longitudinal (
r
=−0.53,
P
<0.05) stretching. Furthermore, significant reductions of radial thickening (9±6% versus 14±3%,
P
<0.01) occurred in noninfarcted regions adjacent to infarcts that had increased (>35%) amounts of MO.

Conclusions
—In the early healing phase of acute myocardial infarction, the extent of MO in infarcted tissue relates to reduced local myocardial deformation and dysfunction of noninfarcted adjacent myocardium. Such strain alterations might explain the increased remodeling observed in patients with large regions of MO.
Cardiovascular Disease Mortality in Familial Forms of Hypertriglyceridemia: A 20-Year Prospective Study
Authors: Austin Melissa A. , McKnight Barbara , Edwards Karen L. , Bradley Cynthia M. , McNeely Marguerite J. , Psaty Bruce M. , Brunzell John D. , Motulsky Arno G.
Published: June 2012

Background
—Familial combined hyperlipidemia (FCHL) and familial hypertriglyceridemia (FHTG) are 2 of the most common familial forms of hyperlipidemia. There is a paucity of prospective data concerning the risk of cardiovascular disease (CVD) in such families. The purposes of this study were to estimate 20-year total and CVD mortality risk among relatives in these families and to evaluate plasma triglyceride as a predictor of death.

Methods and Results
—The study was based on lipid and medical history data from 101 families ascertained in 2 studies conducted in the early 1970s. Vital status and cause of death was determined during 1993 to 1997 for 685 family members, including first-degree relatives of the probands and spouse control subjects. Compared with spouse control subjects, 20-year CVD mortality risk was increased among siblings and offspring in FCHL (relative risk 1.7,
P
=0.02) after adjustment for baseline covariates. In FHTG families, the relative risk was also 1.7 but was not statistically significant (
P
=0.39). Baseline triglyceride was associated with increased CVD mortality risk independent of total cholesterol among relatives in FHTG families (relative risk 2.7,
P
=0.02) but not in FCHL families (relative risk 1.5,
P
=0.16) after adjustment for baseline covariates.

Conclusions
—This prospective study establishes that relatives in FCHL families are at increased risk for CVD mortality and illustrates the need for effective prevention strategies in this group. Baseline triglyceride level predicted subsequent CVD mortality among relatives in FHTG families, adding to the growing evidence for the importance of hypertriglyceridemia as a risk factor for CVD.
Impairment of Ventilatory Efficiency in Heart Failure
Authors: Kleber F. X. , Vietzke G. , Wernecke K. D. , Bauer U. , Opitz C. , Wensel R. , Sperfeld A. , Gläser S.
Published: June 2012

Background
—Impairment of ventilatory efficiency in congestive heart failure (CHF) correlates well with symptomatology and contributes importantly to dyspnea.

Methods and Results
—We investigated 142 CHF patients (mean NYHA class, 2.6; mean maximum oxygen consumption [V̇
o
2
max], 15.3 mL O
2
· kg
−1
· min
−1
; mean left ventricular ejection fraction [LVEF], 27%). Patients were compared with 101 healthy control subjects. Cardiopulmonary exercise testing was performed, and ventilatory efficiency was defined as the slope of the linear relationship of V̇
co
2
and ventilation (VE). Results are presented in percent of age- and sex-adjusted mean values. Forty-four events (37 deaths and 7 instances of heart transplantation, cardiomyoplasty, or left ventricular assist device implantation) occurred. Among V̇
o
2
max, NYHA class, LVEF, total lung capacity, and age, the most powerful predictor of event-free survival was the VE versus V̇
co
2
slope; patients with a slope ≤130% of age- and sex-adjusted normal values had a significantly better 1-year event-free survival (88.3%) than patients with a slope >130% (54.7%;
P
<0.001).

Conclusions
—The VE versus V̇
co
2
slope is an excellent prognostic parameter. It is easier to obtain than parameters of maximal exercise capacity and is of higher prognostic importance than V̇
o
2
max.
Monoclonal T-Cell Proliferation and Plaque Instability in Acute Coronary Syndromes
Authors: Liuzzo Giovanna , Goronzy Jörg J. , Yang Hongyu , Kopecky Stephen L. , Holmes David R. , Frye Robert L. , Weyand Cornelia M.
Published: June 2012

Background
—Unstable angina (UA) is associated with systemic inflammation and with expansion of interferon-γ–producing T lymphocytes. The cause of T-cell activation and the precise role of activated T cells in plaque instability are not understood.

Methods and Results
—Peripheral blood T cells from 34 patients with stable angina and 34 patients with UA were compared for the distribution of functional T-cell subsets by flow cytometric analysis. Clonality within the T-cell compartment was identified by T-cell receptor spectrotyping and subsequent sequencing. Tissue-infiltrating T cells were examined in extracts from coronary arteries containing stable or unstable plaque. The subset of CD4
+
CD28
null
T cells was expanded in patients with UA and infrequent in patients with stable angina (median frequencies: 10.8% versus 1.5%,
P
<0.001). CD4
+
CD28
null
T cells included a large monoclonal population, with 59 clonotypes isolated from 20 UA patients. T-cell clonotypes from different UA patients used antigen receptors with similar sequences. T-cell receptor sequences derived from monoclonal T-cell populations were detected in the culprit but not in the nonculprit lesion of a patient with fatal myocardial infarction.

Conclusions
—UA is associated with the emergence of monoclonal T-cell populations, analogous to monoclonal gammopathy of unknown significance. Shared T-cell receptor sequences in clonotypes of different patients implicate chronic stimulation by a common antigen, for example, persistent infection. The unstable plaque but not the stable plaque is invaded by clonally expanded T cells, suggesting a direct involvement of these lymphocytes in plaque disruption.
Physical Activity Prevents Age-Related Impairment in Nitric Oxide Availability in Elderly Athletes
Authors: Taddei Stefano , Galetta Fabio , Virdis Agostino , Ghiadoni Lorenzo , Salvetti Guido , Franzoni Ferdinando , Giusti Costantino , Salvetti Antonio
Published: June 2012

Background
—Aging is associated with increased cardiovascular risk and endothelial dysfunction. Since exercise can improve endothelium-dependent vasodilation, in the present study we tested whether long-term physical activity could prevent aging-related endothelial dysfunction.

Methods and Results
—In 12 young and elderly (age 26.9±2.3 and 62.9±5.8 years, respectively) healthy sedentary subjects and 11 young and 14 elderly matched athletes (age 27.5±1.9 and 66.4±6.1 years, respectively), we studied (with strain-gauge plethysmography) forearm blood flow modifications induced by intrabrachial acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 μg/100 mL per minute), an endothelium-dependent vasodilator, at baseline, during infusion of
N
G
-monomethyl-
l
-arginine (L-NMMA) (100 μg/100 mL forearm tissue per minute), a nitric oxide–synthase inhibitor, vitamin C (8 mg/100 mL forearm tissue per minute), an antioxidant, and finally under simultaneous infusion of L-NMMA and vitamin C. The response to sodium nitroprusside (1, 2, and 4 μg/100 mL forearm tissue per minute) was also evaluated. In young athletes and sedentary subgroups, vasodilation to acetylcholine was inhibited by L-NMMA and was not changed by vitamin C. In elderly subjects, vasodilation to acetylcholine was blunted as compared with young subjects in both control subjects and athletes, whereas the response to sodium nitroprusside was similar. Moreover, in elderly athletes, vitamin C did not change the vasodilation to acetylcholine. In contrast, in elderly sedentary subjects, the response to acetylcholine was resistant to L-NMMA. In this subgroup, vitamin C increased the vasodilation to acetylcholine and restored the inhibiting effect of L-NMMA.

Conclusions
—These results suggest that regular physical activity can at least in part prevent the age-induced endothelial dysfunction, probably the restoration of nitric oxide availability consequent to prevention of production of oxidative stress.
Cardioprotective Effects of the Na
+
/H
+
Exchange Inhibitor Cariporide in Patients With Acute Anterior Myocardial Infarction Undergoing Direct PTCA
Authors: Rupprecht Hans-Jürgen , Dahl Jürgen vom , Terres Wolfram , Seyfarth Karl Melchior , Richardt Gert , Schultheiß Heinz-Peter , Buerke Michael , Sheehan Florence H. , Drexler Helmut
Published: June 2012

Background
—Activation of Na
+
/H
+
exchange in myocardial ischemia and/or reperfusion leads to calcium overload and myocardial injury. Experimental studies have shown that Na
+
/H
+
exchange inhibitors can attenuate Ca
2+
influx into cardiomyocytes. We therefore performed a multicenter, randomized, placebo-controlled clinical trial to test the hypothesis that inhibition of Na
+
/H
+
exchange limits infarct size and improves myocardial function in patients with acute anterior myocardial infarction (MI) treated with direct PTCA.

Methods and Results
—One hundred patients were randomized to receive placebo (n=51) or a 40-mg intravenous bolus of the Na
+
/H
+
exchange inhibitor cariporide (HOE 642) (n=49) before reperfusion. Global and regional left ventricular functions were analyzed by use of paired contrast left ventriculograms performed before and 21 days after PTCA and myocardial enzymes (ie, creatine kinase [CK], CK-MB, and LDH) as markers for myocardial tissue injury were evaluated. At follow-up, the ejection fraction was higher (50% versus 40%;
P
<0.05) and the end-systolic volume was lower (69.0 versus 97.0 mL;
P
<0.05) in the cariporide group. Significant improvements in some indices of regional wall motion abnormalities were observed, such as the percentage of chords with hypokinesis < −2 SD (
P
=0.045) and the severity of hypokinesis in the border zone of the infarct region (
P
=0.052). In addition, CK, CK-MB, or LDH release was significantly reduced in the cariporide patients.

Conclusions
—Our findings suggest that inhibition of Na
+
/H
+
exchange by cariporide may attenuate reperfusion injury and thereby improve the recovery from left ventricular dysfunction after MI.
Infections, Inflammation, and the Risk of Coronary Heart Disease
Authors: Roivainen Merja , Viik-Kajander Maarit , Palosuo Timo , Toivanen Petri , Leinonen Maija , Saikku Pekka , Tenkanen Leena , Manninen Vesa , Hovi Tapani , Mänttäri Matti
Published: June 2012

Background
—The role of infections and inflammation in the pathophysiology of coronary heart disease is emerging. We studied the independent and joint effects of these 2 components on coronary risk.

Methods and Results
—We measured baseline levels of C-reactive protein (CRP) and antibodies to adenovirus, enterovirus, cytomegalovirus, and herpes simplex virus as well as to
Chlamydia pneumoniae
(
Cpn
) and
Helicobacter pylori
in 241 subjects who suffered either myocardial infarction or coronary death during the 8.5-year trial in the Helsinki Heart Study, a coronary primary prevention trial. The 241 controls in this nested case-control study were subjects who completed the study without coronary events. Antibody levels to herpes simplex type I (HSV-1) and to
Cpn
were higher in cases than in controls, whereas the distributions of antibodies to other infectious agents were similar. Mean CRP was higher in cases (4.4 versus 2.0 mg/L;
P
<0.001), and high CRP increased the risks associated with smoking and with high antimicrobial antibody levels. The odds ratios in subjects with high antibody and high CRP levels were 25.4 (95% CI 2.9–220.3) for HSV-1 and 5.4 (95% CI 2.4–12.4) for
Cpn
compared with subjects with low antibody levels and low CRP. High antibody levels to either HSV-1 or to
Cpn
increased the risk independently of the other, and their joint effect was close to additive.

Conclusions
—Two chronic infections, HSV-1 and
Cpn
, increase the risk of coronary heart disease. The effect is emphasized in subjects with ongoing inflammation, denoted by increased CRP levels.
Thromboresistance of Balloon-Injured Porcine Carotid Arteries After Local Gene Transfer of Human Tissue Factor Pathway Inhibitor
Authors: Zoldhelyi Pierre , McNatt Janice , Shelat Harnath S. , Yamamoto Yasutaka , Chen Zhi-Qiang , Willerson James T.
Published: June 2012

Background
—Tissue factor pathway inhibitor (TFPI) is an endogenous inhibitor of factor Xa and the coagulant initiator complex tissue factor/factor VIIa.

Methods and Results
—To study the effects of TFPI gene transfer on thrombus formation, balloon-injured porcine carotid arteries were treated locally with an adenovirus encoding human TFPI (Ad-TFPI) or control virus. Gene transfer of TFPI was confirmed by detection of human TFPI in the conditioned medium of porcine carotid arteries kept in culture after in vivo transduction. When carotid flow was measured with Doppler probe 5 days after surgery, cyclic flow variations (CFVs) developed in 7 of 8 control pigs after constriction of the injured carotid artery by 40%, and all control-treated arteries occluded after 70% constriction. In contrast, CFVs were observed in only 1 of 8 Ad-TFPI–treated pigs after 40% constriction, and only 3 of 8 occluded after constriction by 70% (
P
=0.0027 and
P
=0.007, respectively). None of the 5 TFPI-transduced arteries open after 70% constriction developed CFVs during an incremental epinephrine infusion.

Conclusions
—Compared with baseline, systemic hemostatic variables and platelet aggregation were unimpaired, suggesting that TFPI gene transfer can prevent arterial thrombosis in the presence of severe shear stress and without detectable hemostatic impairment.
Important Role of Local Angiotensin II Activity Mediated via Type 1 Receptor in the Pathogenesis of Cardiovascular Inflammatory Changes Induced by Chronic Blockade of Nitric Oxide Synthesis in Rats
Authors: Usui Makoto , Egashira Kensuke , Tomita Hideharu , Koyanagi Masamichi , Katoh Makoto , Shimokawa Hiroaki , Takeya Motohiro , Yoshimura Teizo , Matsushima Kouji , Takeshita Akira
Published: June 2012

Background
—The chronic inhibition of NO synthesis by
N
ω
-nitro-
l
-arginine methyl ester (L-NAME) upregulates the cardiovascular tissue angiotensin II (Ang II)–generating system and induces cardiovascular inflammatory changes in rats.

Methods and Results
—We used a rat model to investigate the role of local Ang II activity in the pathogenesis of such inflammatory changes. Marked increases in monocyte infiltration into coronary vessels and myocardial interstitial areas, monocyte chemoattractant protein-1 (MCP-1) expression, and nuclear factor-κB (NF-κB, an important redox-sensitive transcriptional factor that induces MCP-1) activity were observed on day 3 of L-NAME administration. Along with these changes, vascular superoxide anion production was also increased. Treatment with an Ang II type 1 receptor antagonist or with a thiol-containing antioxidant,
N
-acetylcysteine, prevented all of these changes.

Conclusions
—Increased Ang II activity mediated via the type 1 receptor may thus be important in the pathogenesis of early cardiovascular inflammatory changes in this model. Endothelium-derived NO may decrease MCP-1 production and oxidative stress–sensitive signals by suppressing localized activity of Ang II.
First Clinical Experience With the DeBakey VAD Continuous-Axial-Flow Pump for Bridge to Transplantation
Authors: Wieselthaler Georg M. , Schima Heinrich , Hiesmayr Michael , Pacher Richard , Laufer Günther , Noon George P. , DeBakey Michael , Wolner Ernst
Published: June 2012

Background
—A shortage of donor organs and increased numbers of deaths of patients on the waiting list for cardiac transplantation make mechanical circulatory support for a bridge to transplantation a standard clinical procedure. Continuous-flow rotary blood pumps offer exciting new perspectives.

Methods and Results
—Two male patients (ages 44 and 65 years) suffering from end-stage left heart failure were implanted with a DeBakey VAD axial-flow pump for use as a bridge to transplant. In the initial postoperative period, the mean pump flow was 3.9±0.5 L/min, which equals a mean cardiac index (CI) of 2.3±0.2 L · min
−1
· m
−2
. In both patients, the early postoperative phase was characterized by a completely nonpulsatile flow profile. However, with the recovery of heart function 8 to 12 days after implantation, increasing pulse pressures became evident, and net flow rose to 4.5±0.6 L/min, causing an increase of mean CI up to 2.7±0.2 L · min
−1
· m
−2
. Patients were mobilized and put through regular physical training. Hemolysis stayed in the physiological range and increased only slightly from 2.1±0.8 mg/dL before surgery to 3.3±1.8 mg/dL 6 weeks after implantation.

Conclusions
—The first clinical implants of the DeBakey VAD axial-flow pump have demonstrated the device to be a promising measure of bridge-to-transplant mechanical support.
Cost-Effectiveness of Platelet Glycoprotein IIb/IIIa Inhibition With Eptifibatide in Patients With Non–ST-Elevation Acute Coronary Syndromes
Authors: Mark Daniel B. , Harrington Robert A. , Lincoff A. Michael , Califf Robert M. , Nelson Charlotte L. , Tsiatis Anastasios A. , Buell Hope , Mahaffey Kenneth W. , Davidson-Ray Linda , Topol Eric J.
Published: June 2012

Background
—In the PURSUIT trial, eptifibatide significantly reduced the 30-day incidence of death and myocardial infarction relative to placebo in 9461 patients with an acute coronary syndrome (unstable angina or non–Q-wave myocardial infarction).

Methods and Results
—We conducted a 2-part prospective economic substudy of the 3522 US patients enrolled in PURSUIT: (1) an empirical intention-to-treat comparison of medical costs (hospital plus physician) up to 6 months after hospitalization and (2) a lifetime cost-effectiveness analysis. The base-case cost-effectiveness ratio was expressed as the 1996 US dollars required to add 1 life-year with eptifibatide therapy. The 2 treatment arms had equivalent resource consumption and medical costs (exclusive of the cost of the eptifibatide regimen) during the index (enrollment) hospitalization (
P
=0.78) and up to 6 months afterward (
P
=0.60). The average wholesale price of the eptifibatide regimen was $1217, but a typical hospital discounted price was $1014. The estimated life expectancy from randomization in the US patients was 15.96 years for eptifibatide and 15.85 years for placebo, an incremental difference of 0.111. The incremental cost-effectiveness ratio for eptifibatide therapy in US PURSUIT patients was $16 491 per year of life saved. This result was robust through a wide range of sensitivity analyses. The cost-utility ratio for eptifibatide (using time trade-off defined utilities) was $19 693 per added quality-adjusted life-year.

Conclusions
—Based on the results observed in the US PURSUIT patients, the routine addition of eptifibatide to standard care for non–ST-elevation acute coronary syndrome patients is economically attractive by conventional standards.
Relationships Between Homocysteine, Factor VIIa, and Thrombin Generation in Acute Coronary Syndromes
Authors: Al-Obaidi Mohamed K. , Philippou Helen , Stubbs Peter J. , Adami Antonella , Amersey Rajiv , Noble Mark M. , Lane David A.
Published: June 2012

Background
—It has been suggested by clinical, epidemiological, and experimental in vitro studies that homocysteine potentiates thrombin generation. This prothrombotic effect however has not previously been demonstrated in patients presenting with acute coronary syndromes (ACS).

Methods and Results
—Patients with ACS (n =117) presenting with confirmed acute myocardial infarction (MI) (n =57) or unstable angina pectoris (UAP) (n =60) were consecutively recruited together with patients (n =18) in whom the presenting chest pain was not of cardiac origin (NCP), included as controls. Plasma samples were collected on admission and before clinical intervention. Homocysteine was assayed by high performance liquid chromatography, and both Factor VIIa and prothrombin fragment F1+2 were analyzed by ELISA. There were significant elevations in F1+2 in MI (
P
<0.001) and UAP (
P
=0.003), and modest elevations in Factor VIIa in UAP (
P
<0.05) compared with NCP but no differences in homocysteine levels among those groups. On dividing patients with ACS into quartiles of homocysteine, there was a stepwise increase in F1+2 (
P
<0.0001) and of Factor VIIa (
P
<0.05). There were significant correlations in ACS between homocysteine and F1+2 (
r
=0.46,
P
<0.0001), homocysteine and Factor VIIa (
r
=0.24,
P
<0.01), and F1+2 and Factor VIIa (
r
=0.41,
P
<0.0001). There was no correlation between homocysteine and either F1+2 (
r
=−0.15,
P
=0.57) or Factor VIIa (
r
=0.22,
P
=0.37) in the NCP patients.

Conclusions
—Elevated plasma homocysteine is associated with and may cause elevated Factor VIIa and thrombin generation in patients presenting with ACS. These findings suggest an explanation for the prothrombotic effect of homocysteine in ACS.
Effects of Methionine-Induced Hyperhomocysteinemia on Endothelium-Dependent Vasodilation and Oxidative Status in Healthy Adults
Authors: Chao Chia-Lun , Kuo Tsung-Li , Lee Yuan-Teh
Published: June 2012

Background
—Homocysteine-mediated endothelial dysfunction has been proposed to occur via oxidative stress mechanisms in humans. However, there is controversy regarding the effects of homocysteine on endothelial function and oxidative status, which may in part result from age discrepancy across the studies. The present study was designed to investigate the aging effect on the relationship between endothelium-dependent vasodilation and oxidative status in methionine-induced hyperhomocysteinemia.

Methods and Results
—Plasma homocysteine, phosphatidylcholine hydroperoxide (PCOOH), P-selectin levels, and brachial artery flow-mediated vasodilation were measured at baseline and 4 hours after an oral methionine load (0.1 g/kg) in 15 younger (21 to 40 years) and 15 older (55 to 70 years) healthy adults. Homocysteine increased from 7.3±1.3 μmol/L at baseline to 22.7±5.2 μmol/L at 4 hours in younger (
P
<0.001) and from 7.4±1.4 to 24.3±4.5 μmol/L in older adults (
P
<0.001). PCOOH levels were not significantly different between baseline and 4 hours in both groups (
P
=0.10 in young;
P
=0.14 in old). P-selectin, which is expected to increase during oxidative stress, was not changed in older (
P
=0.08) but decreased in younger adults (
P
=0.037) at 4 hours. Flow-mediated vasodilation was preserved from 13.1±2.1% at baseline to 13.5±2.8% at 4 hours in younger (
P
=0.49) and decreased from 12.8±2.4% to 8.5±2.8% in older adults (
P
<0.001).

Conclusions
—The present study demonstrates that endothelial dysfunction caused by methionine-induced hyperhomocysteinemia is age-related and is mediated through impaired nitric oxide activity without change of oxidative status. Our data do not support previous hypotheses that endothelial damage by homocysteine is via oxidative stress mechanism in humans.
Hemodynamic, Renal, and Hormonal Effects of Adrenomedullin Infusion in Patients With Congestive Heart Failure
Authors: Nagaya Noritoshi , Satoh Toru , Nishikimi Toshio , Uematsu Masaaki , Furuichi Shinichi , Sakamaki Fumio , Oya Hideo , Kyotani Shingo , Nakanishi Norifumi , Goto Yoichi , Masuda Yoshiaki , Miyatake Kunio , Kangawa Kenji
Published: June 2012

Background
—Experimental studies have shown that adrenomedullin (AM) causes vasodilatation, diuresis, and a positive inotropic effect. In humans, however, whether infusion of AM has beneficial effects in congestive heart failure (CHF) remains unknown.

Methods and Results
—Hemodynamic, renal, and hormonal responses to intravenous infusion of human AM (0.05 μg · kg
−1
· min
−1
) were examined in 7 patients with CHF and 7 normal healthy subjects (NL). In NL group, AM significantly decreased mean arterial pressure (−16 mm Hg,
P
<0.05) and increased heart rate (+12 bpm,
P
<0.05). In CHF group, AM also decreased mean arterial pressure (−8 mm Hg,
P
<0.05) and increased heart rate (+5 bpm,
P
<0.05), but to a much lesser degree (
P
<0.05 versus NL). AM markedly increased cardiac index (CHF, +49%; NL, +39%,
P
<0.05) while decreasing pulmonary capillary wedge pressure (CHF, −4 mm Hg; NL, −2 mm Hg,
P
<0.05). AM significantly decreased mean pulmonary arterial pressure only in CHF (−4 mm Hg,
P
<0.05). AM increased urine volume (CHF, +48%; NL, +62%,
P
<0.05) and urinary sodium excretion (CHF, +42%; NL, +75%,
P
<0.05). Only in CHF, plasma aldosterone significantly decreased during (−28%,
P
<0.05) and after (−36%,
P
<0.05) AM infusion. These parameters remained unchanged in 7 patients with CHF and 6 healthy subjects who received placebo.

Conclusions
—Intravenous infusion of AM has beneficial hemodynamic and renal effects in patients with CHF.
Spironolactone Increases Nitric Oxide Bioactivity, Improves Endothelial Vasodilator Dysfunction, and Suppresses Vascular Angiotensin I/Angiotensin II Conversion in Patients With Chronic Heart Failure
Authors: Farquharson Colin A. J. , Struthers Allan D.
Published: June 2012

Background
—The RALES study showed that spironolactone, added to conventional therapy for chronic heart failure, dramatically reduced mortality. We tested the hypothesis that this benefit was partially due to improvement in endothelial function and/or to amplified suppression of the vascular renin-angiotensin axis.

Methods and Results
—We performed a randomized, placebo-controlled, double-blind crossover study on 10 patients with NYHA class II to III chronic heart failure on standard diuretic/ACE inhibitor therapy, comparing 50 mg/d spironolactone (1 month) versus placebo. Forearm vasculature endothelial function was assessed by bilateral forearm venous occlusion plethysmography using acetylcholine and
N
-monomethyl-
l
-arginine (L-NMMA), with sodium nitroprusside as a control vasodilator. Also, vascular ACE activity was assessed by use of angiotensin (Ang) I, with Ang II as a control vasoconstrictor. Spironolactone significantly increased the forearm blood flow response to acetylcholine (percentage change in forearm blood flow [mean±SEM], 177±29% versus 95±20%, spironolactone versus placebo;
P
<0.001), with an associated increase in vasoconstriction due to L-NMMA (−35±6% versus −18±4%;
P
<0.05). The Ang I response was also significantly reduced with spironolactone (
P
<0.05), with Ang II responses unaltered.

Conclusions
—Spironolactone improves endothelial dysfunction, increases NO bioactivity, and inhibits vascular Ang I/Ang II conversion in patients with heart failure, providing novel mechanisms for its beneficial effect on cardiovascular mortality.
Extent and Direction of Arterial Remodeling in Stable Versus Unstable Coronary Syndromes
Authors: Schoenhagen Paul , Ziada Khaled M. , Kapadia Samir R. , Crowe Timothy D. , Nissen Steven E. , Tuzcu E. Murat
Published: June 2012

Background
—The morphological characteristics of coronary plaques in patients with stable versus unstable coronary syndromes have been described in vivo with intravascular ultrasound, but the relationship between arterial remodeling and clinical presentation is not well known.

Methods and Results
—We studied 85 patients with unstable and 46 patients with stable coronary syndromes using intravascular ultrasound before coronary intervention. The lesion site and a proximal reference site were analyzed. The remodeling ratio (RR) was defined as the ratio of the external elastic membrane (EEM) area at the lesion to that at the proximal reference site. Positive remodeling was defined as an RR >1.05 and negative remodeling as an RR <0.95. Plaque area (13.9±5.5 versus 11.1±4.8 mm
2
;
P
=0.005), EEM area (16.1±6.2 versus 13.0±4.8 mm
2
;
P
=0.004), and the RR (1.06±0.2 versus 0.94±0.2;
P
=0.008) were significantly greater at target lesions in patients with unstable syndromes than in patients with stable syndromes. Positive remodeling was more frequent in unstable than in stable lesions (51.8% versus 19.6%), whereas negative remodeling was more frequent in stable lesions (56.5% versus 31.8%) (
P
=0.001).

Conclusions
—Positive remodeling and larger plaque areas were associated with unstable clinical presentation, whereas negative remodeling was more common in patients with stable clinical presentation. This association between the extent of remodeling and clinical presentation may reflect a greater tendency of plaques with positive remodeling to cause unstable coronary syndromes.
The Anatomic Basis of Connections Between the Coronary Sinus Musculature and the Left Atrium in Humans
Authors: Chauvin Michel , Shah Dipen C. , Haïssaguerre Michel , Marcellin Luc , Brechenmacher Claude
Published: June 2012

Background
—This study determined the histological features of the atrial myocardium connecting the coronary sinus and the left atrium in humans.

Methods and Results
—Ten necropsied hearts were studied by performing serial longitudinal sections parallel to the long axis of the coronary sinus that extended its full length using a large microtome. In all specimens, the venous wall of the coronary sinus was surrounded by a cuff of striated muscle extending 40±8 mm from the ostium. Striated myocardial connections of varying number and morphology left this coronary muscle cuff and connected to the left atrium; they ranged from 1 to 2 fascicles to a widely intermingled continuum (thickness, 2.79±2 mm; width, 2.91±3.5 mm). These connections originated 8.8±5.7 mm from the coronary sinus ostium and inserted 18±11 mm distally into the left atrium. The insulating compartment in which the connections traversed between the left atrium and the coronary sinus was mostly formed of adipose tissue. The valve of Vieussens was found in 6 hearts at a mean distance of 3.4±3.2 mm from the distal extremity of the coronary sinus muscle cuff.

Conclusions
—In the human heart, a consistent but morphologically variable left atrial coronary sinus myocardial connection was found. This emphasizes the need for surgical dissection or catheter ablation in or around the coronary sinus to eliminate these connections.