bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic Influence of Elevated Values of Cardiac Troponin I in Patients With Unstable Angina
Authors: Galvani Marcello , Ottani Filippo , Ferrini Donatella , Ladenson Jack H. , Destro Antonio , Baccos Daniele , Rusticali Franco , Jaffe Allan S.
Published: June 2012

Background
Elevations of the MB isoform of creatine kinase (CK) and cardiac troponin T seem to confer an adverse prognosis in unstable angina. We examined whether this prognostic influence is also present for cardiac troponin I (cTnI), a new and even more specific marker of myocardial injury.

Methods and Results
We studied 106 patients with the clinical diagnosis of unstable angina showing chest discomfort at rest within 48 hours of admission, ECG evidence of myocardial ischemia, and normal values of total CK over the initial 16 hours of observation. The primary end point was death or nonfatal myocardial infarction (MI) at 30 days; the secondary end point was the incidence of cardiac events at 1 year. Blood was drawn every 8 hours for 3 days. Thirteen patients were excluded because of increased CK-MB mass concentrations within 16 hours of admission (non–Q-wave MI) and 2 because of inadequate blood sampling. Of the remaining 91 patients, 22 had cTnI elevations on admission (n=7) or after 8 hours (n=15). At 30 days, no deaths (0%) and 4 MIs (5.8%) occurred in the 69 patients with normal cTnI compared with 2 deaths (9.1%) and 4 MIs (18.2%) in the 22 patients with elevated cTnI. The combined incidence of death and nonfatal MI was 5.8% and 27.3%, respectively (
P
=.02). At 1 year, only 68% of patients with elevated cTnI were free of cardiac events, compared with 90% of those without elevations (
P
=.01).

Conclusions
These data indicate that cTnI is an important prognostic variable in patients with unstable angina. Elevations of cTnI predict an adverse short- and long-term prognosis.
Effect of Exercise Training on Myocardial Remodeling in Patients With Reduced Left Ventricular Function After Myocardial Infarction
Authors: Dubach Paul , Myers Jonathan , Dziekan Gerald , Goebbels Ute , Reinhart Walter , Vogt Paul , Ratti Reto , Muller Peter , Miettunen Risto , Buser Peter
Published: June 2012

Background
There are conflicting reports on the effects of training on the remodeling process in post–myocardial infarction patients with ventricular damage.

Methods and Results
Twenty-five patients with reduced ventricular function (mean ejection fraction, 32.3±6%) after an anteroseptal or inferolateral myocardial infarction were randomized to an exercise group (n=12) or a control group (n=13). Patients in the exercise group resided in a rehabilitation center for 2 months and underwent a training program consisting of two 1-hour sessions of walking daily, along with four monitored 45-minute sessions of stationary cycling weekly. Before and after the study period, maximal exercise testing and cardiac MRI were performed. Oxygen uptake increased 26% at maximal exercise (19.7±3 to 23.9±5,
P
<.05) and 39% at the lactate threshold (
P
<.01) in the exercise group, whereas control values did not change. No differences were observed within or between groups in MRI measures of end-diastolic (187±47 pre versus 196±35 mL post in the exercise group and 179±52 pre versus 180±51 mL post in the control group), end-systolic volume (118±41 pre versus 121±33 mL post in the exercise group and 119±54 pre versus 116±56 mL post in the control group), or ejection fraction (38.0±9 pre versus 38.2±10% post in the exercise group and 37.0±10 pre versus 38.3±13% post in the control group). Myocardial wall thickness measurements at end diastole and end systole and their difference in 80 myocardial segments determined by MRI yielded no significant interactions between groups. When myocardial wall thickness measurements were classified by infarct or noninfarct areas, no differences were observed between groups over the study period.

Conclusions
A high-intensity, 2-month residential cardiac rehabilitation program resulted in substantial increases in exercise capacity among patients with reduced left ventricular function. In contrast to some recent reports, the training program had no deleterious effects on left ventricular volume, function, or wall thickness regardless of infarct area.
Segmental Analysis of Color Kinesis Images
Authors: Mor-Avi Victor , Vignon Philippe , Koch Rick , Weinert Lynn , Garcia Maria J. , Spencer Kirk T. , Lang Roberto M.
Published: June 2012

Background
We describe a method for objective assessment of left ventricular (LV) endocardial wall motion based on Color Kinesis, a new echocardiographic technique that color-encodes pixel transitions between blood and myocardial tissue.

Methods and Results
We developed a software that analyzes Color Kinesis images and provides quantitative indices of magnitude and timing of regional endocardial motion. Images obtained in 12 normal subjects were used to evaluate the variability in each index. Esmolol, dobutamine, and atropine were used to track variations in LV function in 14 subjects. Objective evaluation of wall motion was tested in 20 patients undergoing dobutamine stress testing. Regional fractional area change, displacement, and radial shortening were displayed as histograms and time curves. Global function was assessed by calculating magnitude and timing of peak ejection or filling rates and mean time of ejection or filling. Patterns of endocardial motion were consistent between normal subjects. Fractional area change and peak ejection rate decreased with esmolol and increased with dobutamine. Time to peak ejection and mean time of contraction were prolonged with esmolol and shortened with dobutamine. Using atropine, we proved that our findings with dobutamine were not secondary to its chronotropic effects. Dobutamine induced regional wall motion abnormalities in 10 patients in 38 segments diagnosed conventionally. Segmental analysis detected abnormalities in 36 of these 38 segments and in an additional 5 of 322 segments.

Conclusions
Analysis of Color Kinesis images allows fast, objective, and automated evaluation of regional wall motion sensitively enough to evaluate clinical dobutamine stress data. This method has significant potential in the diagnosis of myocardial ischemia.
High-Dose Heparin Decreases Nitric Oxide Production by Cultured Bovine Endothelial Cells
Authors: Upchurch Gilbert R. , Welch George N. , Freedman Jane E. , Fabian Attila J. , Pigazzi Alessio , Scribner Anne M. , Alpert Caroline S. , Keaney John F. , Loscalzo Joseph
Published: June 2012

Background
Abrupt cessation of heparin therapy can lead to a recrudescence of thrombosis and acute ischemia. Endothelial NO is an important endogenous inhibitor of platelet-mediated thrombosis, yet biochemical studies examining the effect of heparin on NO production by the endothelium have heretofore been lacking.

Methods and Results
In an attempt to address the effect of heparin on endothelial cell production of NO, confluent bovine aortic endothelial cells (BAECs) on microcarrier beads were incubated in the presence or absence of heparin. Results indicate that BAECs incubated with heparin were less able to inhibit platelet aggregation than control cells (
P
<.005 by ANOVA) and that this effect correlated with a decrease in NO production (36% decrease for heparin compared with control,
P
<.05). Dextran sulfate evoked the same response (67% decrease,
P
<.0001 compared with control), suggesting that the decrease in NO after heparin treatment is secondary to its negative charge rather than to a specific polysaccharide sequence. The decrease in NO production by heparin was accompanied by a 72% decrease in steady-state
Nos 3
mRNA as well as a 49% decrease in immunodetectable endothelial NO synthase (eNOS) protein.

Conclusions
These data show that high-dose heparin at concentrations achieved in some acute cardiovascular settings increases in vitro platelet aggregation in media conditioned by endothelial cells by decreasing endothelial NO production through a mechanism that involves a decrease in steady-state
Nos 3
mRNA and eNOS protein. These observations suggest a possible mechanism by which to explain in part the prothrombotic effects of heparin.
Negative Inotropic Effect of Adrenomedullin in Isolated Adult Rabbit Cardiac Ventricular Myocytes
Authors: Ikenouchi Hiroshi , Kangawa Kenji , Matsuo Hisayuki , Hirata Yasunobu
Published: June 2012

Background
Adrenomedullin (AM) is a potent vasodilator peptide. AM-induced vasodilatation is mediated by an increase of NO as well as cAMP. Both AM and binding sites for this peptide have been found in cardiac tissue, indicating the possible existence of an autocrine or paracrine system of AM in the heart.

Methods and Results
Myocytes were isolated by use of retrograde coronary perfusion with physiological solution containing collagenase and hyaluronidase from adult rabbit ventricles. Contraction of cardiac myocytes was traced with a video motion detector, and [Ca
2+
]
i
was measured with indo 1 at 37°C. The
I
Ca
was measured with a whole-cell patch clamp at 23°C. AM and calcitonin gene–related peptide (CGRP), another member of the same peptide family, showed a concentration-dependent negative inotropic effect (10
−7
mol/L AM: contraction amplitude, 64±7% of control; [Ca
2+
]
i
, 52±5% of control; n=10; 10
−6
mol/L CGRP: contraction amplitude, 64±25%; [Ca
2+
]
i
, 70±3%; n=5; mean±SD).
I
Ca
was decreased to 60±39% by superfusion with AM after the cessation of
N
G
-monomethyl-
l
-arginine (L-NMMA), an NO synthase inhibitor. Pretreatment with L-NMMA (10 μmol/L) abolished the negative inotropic effect of AM, whereas switching from AM+L-NMMA to AM+
l
-arginine (1 mmol/L) restored it. Superfusion with 8-bromo-cGMP also showed a negative inotropic effect. AM significantly increased the intracellular content of cGMP, a second messenger of NO, but not that of cAMP. AM (10 nmol/L) blunted the effect of 1 μmol/L forskolin.

Conclusions
AM has a negative inotropic effect and decreased both [Ca
2+
]
i
and
I
Ca
, with these effects being at least partly mediated via the
l
-arginine–NO pathway in adult rabbit ventricular myocytes.
Site-Specific Intracoronary Heparin Delivery in Humans After Balloon Angioplasty
Authors: Camenzind Edoardo , Bakker Willem H. , Reijs Ambroos , van Geijlswijk Ingeborg M. , Boersma Eric , Kutryk Michael J. B. , Krenning Eric P. , Roelandt Jos R. T. C. , Serruys Patrick W.
Published: June 2012

Background
Demonstration and quantification of site-specific intracoronary administration of compounds has been confined thus far to the experimental animal laboratory. The aim of this study was to describe a scintigraphic method to demonstrate site-specific intracoronary drug delivery in humans. The methods allow on-line visualization and off-line quantification of site-specifically infused γ-emitting compounds.

Methods and Results
In 12 patients after balloon angioplasty,
99m
Tc-labeled heparin was administered at the site of dilatation by use of a coil balloon. Both the infusion period and the washout period after the end of infusion were monitored with a γ-camera. A curve of counts per pixel as a function of time was derived that showed an accumulation phase during infusion followed by a washout phase after the end of infusion. Both phases were fitted by regression analysis and showed a linear accumulation pattern and a biexponential washout pattern. After correction for background counts,
99m
Tc decay, and body attenuation, peak heparin amount and regional bioavailability were calculated. Peak amount was defined as the initial point of the slow washout component of the biexponential curve (elimination component), and regional bioavailability was defined as the area under the curve of accumulation and washout phase. Half-life and retention time, defined as seven half-lives, were obtained by use of the elimination component after correction for
99m
Tc decay. Mean peak delivered amount was 45±44 IU (236±228 μg), corresponding to an efficiency of delivery ranging from 1% to 8% of the totally infused dose. Total regionally bioavailable heparin reached 244±194 IU·h (1.28±1.01 mg·h). Retention time varied from 12 to 90 hours (mean, 50:33±22:50 hours:minutes).

Conclusions
Site-specific intracoronary heparin delivery after angioplasty by means of the coil balloon was demonstrated in humans, and regional pharmacokinetics was quantified by use of a radioisotopic technique.
Diagnostic Value of Electrocardiography and Echocardiography for Familial Hypertrophic Cardiomyopathy in a Genotyped Adult Population
Authors: Charron Philippe , Dubourg Olivier , Desnos Michel , Isnard Richard , Hagege Albert , Millaire Alain , Carrier Lucie , Bonne Gisele , Tesson Frédérique , Richard Pascale , Bouhour Jean-Brieuc , Schwartz Ketty , Komajda Michel
Published: June 2012

Background
The diagnostic value of ECG and echocardiography for familial hypertrophic cardiomyopathy (FHC) has not been reassessed since the development of molecular genetics. The aim of the study was to evaluate it in adults, with the genetic status used as the criterion of reference.

Methods and Results
Ten families with previously identified mutations were studied (9 mutations in 3 genes). ECG and echocardiography were analyzed in 155 adults, of whom 77 were genetically affected and 78 unaffected. The major diagnostic criteria were, for echocardiography, a left ventricular wall thickness >13 mm and, for ECG, abnormal Q waves, left ventricular hypertrophy, and marked ST-T changes. Minor ECG and echographic abnormalities were also analyzed. (1) Sensitivity and specificity of major criteria were 61% and 97% for ECG and 62% and 100% for echocardiography. (2) Sensitivity but not specificity was age related (from 50% at <30 years to 94% at >50 years old,
P
<.01) and sex related (83% in men versus 57% in women,
P
=.01). (3) Sensitivity was improved by the addition of minor criteria and by the association of ECG and echocardiography. The negative predictive value was therefore very good (95%) at >30 years of age. (4) Healthy carriers without any ECG or echocardiographic abnormality represented 17% of genetically affected adults.

Conclusions
ECG and echocardiography have similar diagnostic values for FHC in adults, with an excellent specificity and a lower sensitivity. The association of the two techniques allows a better evaluation of the risk of being genetically affected in families with hypertrophic cardiomyopathy.
Effect of Sympathoinhibition on Exercise Performance in Patients With Heart Failure
Authors: Lang Chim C. , Rayos Glenn H. , Chomsky Don B. , Wood Alastair J. J. , Wilson John R.
Published: June 2012

Background
In patients with heart failure, excessive sympathetic activation during exercise could interfere with exercise performance by impairing arteriolar dilation in working muscle and by adversely altering skeletal muscle metabolic behavior. To test this hypothesis, we examined the effect of sympathoinhibition with clonidine, a central sympatholytic agent, on skeletal muscle blood flow and metabolism in patients with heart failure.

Methods and Results
Swan-Ganz and femoral venous catheters were inserted in 20 patients with chronic heart failure and exercise intolerance (peak exercise V̇
o
2
=9.3±1.4 [SEM] mL·min
−1
·kg
−1
). Central hemodynamic measurements, leg blood flow determined by thermodilution, and systemic and leg metabolic parameters were measured during maximal treadmill exercise before and 2 hours after clonidine 2 μg/kg IV (n=15) or 0.9% normal saline (n=5). During control exercise before the administration of clonidine, leg blood flow increased from 0.3±0.1 to 1.8±0.2 L/min and plasma norepinephrine increased from 485±61 to 2155±186 pg/mL (both
P
<.01). Treatment with clonidine markedly suppressed norepinephrine levels during exercise (matched peak exercise workload: control, 2137±187 versus clonidine, 1430±161 pg/mL), increased leg blood flow (control, 1.8±0.2 versus clonidine, 2.3±0.4 L/min), reduced systemic oxygen consumption (control, 1002±70 versus clonidine, 966±68 mL/min), reduced pulmonary artery lactate concentration (control, 3.2±0.3 versus clonidine, 2.6±0.2 mEq/L), and decreased minute ventilation (control, 39.7±2.1 versus clonidine, 34.9±2.4 L/min) (all
P
<.05).

Conclusions
These findings suggest that sympathetic activation during exercise reduces leg blood flow, increases muscle glycolysis, and decreases muscle efficiency in patients with heart failure.
Effects of Permanent Pacemaker and Oral Theophylline in Sick Sinus Syndrome
Authors: Alboni Paolo , Menozzi Carlo , Brignole Michele , Paparella Nelly , Gaggioli Germano , Lolli Gino , Cappato Riccardo
Published: June 2012

Background
Pacemakers and theophylline are currently being used to relieve symptoms in patients with sick sinus syndrome (SSS). However, the impact of either therapy on the natural course of the disease is unknown. We conducted a randomized controlled trial to prospectively assess the effects of pacemakers and theophylline in patients with SSS.

Methods and Results
One hundred seven patients with symptomatic SSS (age, 73±11 years) were randomized to no treatment (control group, n=35), oral theophylline (n=36), or dual-chamber rate-responsive pacemaker therapy (n=36). They were followed for up to 48 months (mean, 19±14 months). During follow-up, the occurrence of syncope was lower in the pacemaker group than in the control group (
P
=.02) and tended to be lower than in the theophylline group (
P
=.07). Heart failure occurred less often in patients assigned to pacemaker therapy and theophylline than in control patients (both,
P
=.05), whereas the incidence of sustained paroxysmal tachyarrhythmias, permanent atrial fibrillation, and thromboembolic events did not show any apparent difference among the three groups. Heart rate was higher in the theophylline group than in the control group. Both pacemaker therapy and theophylline improved symptom scores after 3 months of treatment; however, a similar improvement was observed in the control group.

Conclusions
In patients with symptomatic SSS, therapy with theophylline or dual-chamber pacemaker is associated with a lower incidence of heart failure; pacemaker therapy is also associated with a lower incidence of syncope. The therapeutic benefits of pacemakers and theophylline on symptoms are partly a result of spontaneous improvement of the disease.
Oral Sulfonylurea Hypoglycemic Agents Prevent Ischemic Preconditioning in Human Myocardium
Authors: Cleveland Joseph C. , Meldrum Daniel R. , Cain Brian S. , Banerjee Anirban , Harken Alden H.
Published: June 2012

Background
Patients receiving oral hypoglycemic agents for diabetes mellitus are at increased risk of cardiovascular mortality. Oral hypoglycemic agents are inhibitors of the ATP-sensitive potassium (K
ATP
) channel. Ischemic preconditioning is mediated by K
ATP
channel activation. We therefore hypothesized that myocardium from patients taking long-term oral hypoglycemic agents would be resistant to the protection by ischemic preconditioning.

Methods and Results
Isolated human right atrial trabeculae were suspended in an organ bath at 37°C, with field stimulation at 1 Hz. Control trabeculae were then subjected to 45 minutes of simulated ischemia (hypoxic, glucose-free buffer with pacing at 3 Hz) and 120 minutes of reperfusion. Ischemic preconditioned (IPC) trabeculae from patients without oral hypoglycemic therapy and from patients taking insulin (Ins+IPC) were given 5 minutes of simulated ischemia before this injury. Trabeculae (Oral Hypo+IPC) were obtained from patients taking long-term oral hypoglycemic agents and were also exposed to 5 minutes of simulated ischemia before this injury. Developed force (DF) was recorded. Recovery of DF relative to preischemic values was 28±4% in control trabeculae, whereas IPC trabeculae showed 52±5% recovery (
P
<.05 versus control). In patients receiving long-term oral hypoglycemic agents (Oral Hypo+IPC), recovery of DF was 27±3%, but in trabeculae from insulin-treated patients (Ins+IPC), it was 45±6%.

Conclusions
Human myocardium from patients without long-term exposure to oral hypoglycemic agents is functionally protected by preconditioning. Long-term oral hypoglycemic intake blocks the protection by preconditioning. These data suggest that ischemic preconditioning in human myocardium relies on K
ATP
channels, and long-term inhibition of K
ATP
channels with oral hypoglycemic agents may explain the excess cardiovascular mortality in these patients.
Workplace Demands, Economic Reward, and Progression of Carotid Atherosclerosis
Authors: Lynch John , Krause Niklas , Kaplan George A. , Salonen Riitta , Salonen Jukka T.
Published: June 2012

Background
Characteristics of the work environment have been associated with cardiovascular morbidity and mortality, but it is unclear whether these factors are associated with preclinical manifestations of disease.

Methods and Results
We investigated the association between job demands, economic reward, and the 4-year progression of carotid atherosclerosis in a population-based sample of 940 Finnish men. Data from the Kuopio Ischemic Heart Disease Risk Factor Study were used to estimate changes in plaque height, maximum and mean intima-media thicknesses across combinations of job demands, and income. Associations were examined in relation to atherosclerotic risk factors and were stratified by baseline levels of atherosclerosis and prevalent ischemic heart disease. Men who had jobs with high demands and low economic rewards had significantly greater 4-year progression of plaque height (0.33 mm,
P
=.008) and maximum intima-media thickness (0.32,
P
=.03) than men with low-demand, high-income jobs. The magnitude of these differences was not greatly attenuated by risk factor adjustment and did not differ when examined by the level of workplace resources, social support, or employment status. Larger differences were observed in a subsample of men who had more advanced atherosclerosis at baseline.

Conclusions
These results show that men with demanding work that produces little economic reward have significantly greater progression of carotid atherosclerosis than more advantaged men. The relationship between job demands and health should be understood in a broad framework of interacting economic conditions, social circumstances, and behaviors that cascade over the life course and may ultimately contribute to socioeconomic inequalities in morbidity and mortality.
Comparison of Human Tissues and Mechanical Prostheses for Aortic Valve Replacement in Children
Authors: Lupinetti Flavian M. , Warner Joanie , Jones Thomas K. , Herndon S. Paul
Published: June 2012

Background
Aortic valve replacement in children is problematic because of complications of mechanical valves and uncertain outcomes associated with human valves. The results of pediatric aortic valve replacements over 5 years were reviewed.

Methods and Results
Mechanical valves were used exclusively during the first part of this series (n=26). Thereafter, 25 consecutive aortic valve replacements were performed with autografts (n=19) or allografts (n=6). Allografts were used for Marfan’s syndrome patients or those with unusable pulmonary valves. Among autograft/allograft recipients, 16 patients underwent 27 prior operations. In the mechanical group, 18 patients underwent 19 previous operations. Three patients in each group underwent a previous mechanical aortic valve replacement. Operative complications included two mild strokes and one pacemaker in the autograft/allograft group and three deaths and two pacemakers in the mechanical group. One autograft recipient required reoperation for pulmonary allograft stenosis. In the mechanical group, late complications included six cases of nonstructural degeneration and two cases of endocarditis, with three reoperations. Reoperation-free survival was 96% at 2 years in the autograft/allograft group and 80% at 2 years and 75% at 3 years in the mechanical group. Event-free survival was 96% at 2 years in the autograft/allograft group compared with 67% at 2 years and 49% at 3 years in the mechanical group (
P
<.05).

Conclusions
The frequency of reoperations for mechanical aortic valve replacement has been surprisingly high. Aortic valve replacement in children with only autografts or allografts achieves good early results.
Transient Triglyceridemia Decreases Vascular Reactivity in Young, Healthy Men Without Risk Factors for Coronary Heart Disease
Authors: Lundman Pia , Eriksson Maria , Schenck-Gustafsson Karin , Karpe Fredrik , Tornvall Per
Published: June 2012

Background
Hypertriglyceridemia is now accepted as a risk factor for coronary heart disease, although the mechanism behind the increased risk is not well understood. The present study was undertaken to investigate the effects of triglyceridemia on endothelial function, because impaired endothelial function is considered a marker of atherogenesis.

Methods and Results
Flow- and nitroglycerin-induced dilatation of the brachial artery was investigated noninvasively by high-resolution ultrasound technique in seven young, healthy men without risk factors for coronary heart disease. Transient triglyceridemia was induced by infusion of a triglyceride emulsion, Intralipid, which raised free fatty acid concentrations twofold and triglyceride levels fourfold. Flow-induced vasodilatation decreased from 7.1±3.0% to 1.6±2.6% (
P
<.0002), whereas nitroglycerin-induced vasodilatation decreased from 20.5±5.8% to 11.5±3.2% (
P
<.002) before and after 1 hour of infusion of Intralipid, respectively.

Conclusions
Transient triglyceridemia decreases vascular reactivity, presumably by both endothelium-dependent and endothelium-independent mechanisms.
Cardiovascular Death and Left Ventricular Remodeling Two Years After Myocardial Infarction
Authors: Sutton Martin St. John , Pfeffer Marc A. , Moye Lemuel , Plappert Ted , Rouleau Jean L. , Lamas Gervasio , Rouleau Jacques , Parker John O. , Arnold Malcolm O. , Sussex Bruce , Braunwald Eugene
Published: June 2012

Background
We quantified cardiovascular death and/or left ventricular (LV) dilatation in patients from the SAVE trial to determine whether dilatation continued beyond 1 year, whether ACE inhibitor therapy attenuated late LV dilatation, and whether any baseline descriptors predicted late dilatation.

Methods and Results
Two-dimensional echocardiograms were obtained in 512 patients at 11±3 days and 1 and 2 years postinfarction to assess LV size, percentage of the LV that was akinetic/dyskinetic (%AD), and LV shape index. LV function was assessed by radionuclide ejection fraction. Two hundred sixty-three patients (51.4%) sustained cardiovascular death and/or LV diastolic dilatation; 279 (54.5%) had cardiovascular death and/or systolic dilatation. In 373 patients with serial echocardiograms, LV end-diastolic and end-systolic sizes increased progressively from baseline to 2 years (both
P
<.01). More patients with LV dilatation had a decrease in ejection fraction: 24.8% versus 6.8% (
P
<.001) (diastole) and 25.7% versus 5.3% (
P
<.001) (systole). Captopril attenuated diastolic LV dilatation at 2 years (
P
=.048), but this effect was carried over from the first year of therapy because changes in LV size with captopril beyond 1 year were similar to those with placebo. Predictors of cardiovascular death and/or dilatation were age (
P
=.023), prior infarction (
P
<.001), lower ejection fraction (
P
<.001), angina (
P
=.007), heart failure (
P
=.002), LV size (
P
<.001), and infarct size (%AD) (
P
<.001).

Conclusions
Cardiovascular death and/or LV dilatation occurred in >50% of patients by 2 years. LV dilatation is progressive, associated with chamber distortion and deteriorating function that is unaffected by captopril beyond 1 year.
Body Iron Stores and the Risk of Carotid Atherosclerosis
Authors: Kiechl Stefan , Willeit Johann , Egger Georg , Poewe Werner , Oberhollenzer Friedrich
Published: June 2012

Background
Fe
2+
released from tissue iron stores may accelerate lipid peroxidation by virtue of its pro-oxidant properties and thus promote early atherogenesis.

Methods and Results
The present prospective survey addresses the potential association between serum ferritin concentrations and the 5-year progression of carotid atherosclerosis as assessed by ultrasonographic follow-up evaluations. The study population comprises a random sample of 826 men and women 40 to 79 years old. Serum ferritin was one of the strongest risk predictors of overall progression of atherosclerosis. The main part of this association appeared to act through modification of the atherogenic potential of LDL cholesterol (OR [95% CI] for a 1–SD unit increase in ferritin at LDL levels of 2.5, 3.6, and 4.9 mmol/L: 1.55 [1.30 to 1.85], 1.77 [1.40 to 2.24], and 2.05 [1.50 to 2.80];
P
=.0012 for effect modification). Changes in iron stores during the follow-up period modified atherosclerosis risk, in that a lowering was beneficial and further iron accumulation exerted unfavorable effects. All these findings applied equally to incident atherosclerosis and the extension of preexisting atherosclerotic lesions. The significance of prominent iron stores in the development of carotid stenosis was clearly less pronounced. Finally, ferritin and LDL cholesterol showed a synergistic association with incident cardiovascular disease and death (n=59).

Conclusions
The present study provided strong epidemiological evidence for a role of iron stores in early atherogenesis and suggests promotion of lipid peroxidation as the main underlying pathomechanism. This hypothesis could in part explain the sex difference in atherosclerotic vascular disease.
Nonuniform Nighttime Distribution of Acute Cardiac Events
Authors: Lavery Cynthia E. , Mittleman Murray A. , Cohen Mylan C. , Muller James E. , Verrier Richard L.
Published: June 2012

Background
Although 250 000 myocardial infarctions and 38 000 sudden cardiac deaths occur at night annually, this public health problem is underappreciated and poorly understood. We examined whether the incidence of myocardial infarction, sudden cardiac death, and automatic implantable cardioverter-defibrillator (AICD) discharge was nonuniform, a result that may implicate physiological triggers such as sleep-state dependent changes in autonomic nervous system activity.

Methods and Results
We conducted a review of the circadian pattern of the onset of myocardial infarction (n=19), sudden cardiac death (n=12), and AICD discharge (n=7). The nighttime period was chosen a priori as midnight to 5:59
am.
These reports documented 11 633 nocturnal myocardial infarctions (20% of the total myocardial infarctions), 1981 nocturnal sudden cardiac deaths (14.6% of the total sudden cardiac deaths), and 1200 nocturnal AICD discharges (15.0% of the total discharges). The distributions of myocardial infarction, sudden cardiac death, and AICD discharge were each significantly nonuniform (
P
<.001). The peak incidence of myocardial infarction and AICD discharge occurred between midnight and 0:59
am
, whereas the peak incidence of sudden cardiac death was between 1:00 and 1:59
am.
The trough in incidence occurred between 4:00 and 4:59
am
for sudden cardiac death and between 3:00 and 3:59
am
for myocardial infarction and AICD discharge.

Conclusions
Nocturnal myocardial infarction, sudden cardiac death, and AICD discharge exhibit nonuniform distributions. This finding is consistent with the hypothesis that sleep-state dependent fluctuations in autonomic nervous system activity may trigger the onset of major cardiovascular events and provides further impetus for more directly testing this hypothesis at population, individual, and mechanistic levels. A better understanding of nocturnal triggers may make it possible to reduce the incidence of myocardial infarction, ventricular tachyarrhythmias, and sudden cardiac death during the nocturnal period.
Topographic Analysis of Proliferative Activity in Carotid Endarterectomy Specimens by Immunocytochemical Detection of the Cell Cycle–Related Antigen Ki-67
Authors: Brandl Richard , Richter Thomas , Haug Klaus , Wilhelm Manfred G. , Maurer Peter C. , Nathrath Walter
Published: June 2012

Background
On the basis of contradictory results found in animal experiments and coronary atherectomy tissue, there is an ongoing debate about the significance of cellular proliferation in human atherosclerosis. In the present prospective study, the cell cycle–related antigen Ki-67 was detected for topographic determination of cell turnover in distinct regions of human carotid endarterectomy specimens harvested en bloc by surgical biopsy.

Methods and Results
After en bloc resection, serial sections of 26 consecutive carotid lesions were analyzed by histomorphological examination and immunohistochemistry. Thereby, 319 high-power fields were attributed to separate plaque regions defined as follows: distal boundary of the lesion with normal intima, plaque shoulder, core region, and diffuse intimal thickening. Endothelial cells, smooth muscle cells, T cells, and macrophages were identified by immunostaining of factor VIII–related protein, α-actin, CD68, and CD45R0. An overall proliferation index of 0.49±1.05% was yielded by positive anti–Ki-67 immunolabeling, predominantly in macrophage-rich areas characterized by high cell density (>1000 cells/mm
2
) as well as in reparative sites in the perimeter of atheroma, intramural thrombosis, plaque hemorrhage, and neovascularization (P<.01). Few or no signs of proliferation activity were found in normal intima, in areas of dense α-actin positivity, or adjacent media. As shown by double immunostaining, macrophages and unspecified mesenchymal cells represented the prevailing proliferating cell type.

Conclusions
Our results suggest that proliferation in advanced human carotid lesions is confined to the intima and focally concentrated in central plaque regions negative for α-actin. Furthermore, it apparently occurs primarily as part of inflammatory processes and structural repair predominantly involving macrophages, as well as unspecific mesenchymal cells.
Prognostic Value of Intracoronary Flow Velocity and Diameter Stenosis in Assessing the Short- and Long-term Outcomes of Coronary Balloon Angioplasty
Authors: Serruys Patrick W. , di Mario Carlo , Piek Jan , Schroeder Erwin , Vrints Christian , Probst Peter , de Bruyne Bernard , Hanet Claude , Fleck Eckart , Haude Michael , Verna Edoardo , Voudris Vasilis , Geschwind Herbert , Emanuelsson Håkan , Mühlberger V. , Danzi Giambattista , Peels Hans O. , Ford Andrew J. , Boersma Eric
Published: June 2012

Background
The aim of this prospective, multicenter study was the identification of Doppler flow velocity measurements predictive of clinical outcome of patients undergoing single-vessel balloon angioplasty with no previous Q-wave myocardial infarction.

Methods and Results
In 297 patients, a Doppler guidewire was used to measure basal and maximal hyperemic flow velocities proximal and distal to the stenosis before and after angioplasty. In 225 patients with an angiographically successful percutaneous transluminal coronary angioplasty (PTCA), postprocedural distal coronary flow reserve (CFR) and percent diameter stenosis (DS%) were correlated with symptoms and/or ischemia at 1 and 6 months, with the need for target lesion revascularization, and with angiographic restenosis (defined as DS ≥50% at follow-up). Logistic regression and receiver operator characteristic curve analyses were applied to determine the prognostic cutoff value of CFR and DS separately and in combination. Optimal cutoff criteria for predictors of these clinical events were DS, 35%; CFR, 2.5. A distal CFR after angioplasty >2.5 with a residual DS ≤35% identified lesions with a low incidence of recurrence of symptoms at 1 month (10% versus 19%,
P
=.149) and at 6 months (23% versus 47%,
P
=.005), a low need for reintervention (16% versus 34%,
P
=.024), and a low restenosis rate (16% versus 41%,
P
=.002) compared with patients who did not meet these criteria.

Conclusions
Measurements of distal CFR after PTCA, in combination with DS%, have a predictive value, albeit modest for the short- and long-term outcomes after PTCA, and thus may be used to identify patients who will or will not benefit from additional therapy such as stent implantation.
Grading of Mitral Regurgitation by Quantitative Doppler Echocardiography
Authors: Dujardin Karl S. , Enriquez-Sarano Maurice , Bailey Kent R. , Nishimura Rick A. , Seward James B. , Tajik A. Jamil
Published: June 2012

Background
Quantitative Doppler echocardiography and proximal flow convergence methods are validated techniques for quantifying mitral regurgitation. However, the clinical interpretation of the values calculated is hindered by the absence of calibration of ranges of severity in large numbers of patients.

Methods and Results
In 180 consecutive patients (men, 62%; mean age±SD, 66±11 years), the results of Doppler quantification of isolated mitral regurgitation were calibrated by use of left ventricular angiographic grading performed within 3 months in routine practice and without intervening events. The thresholds of the quantitative variables corresponding to the angiographic grades were identified by maximizing the sum of sensitivity and specificity and minimizing their difference. The mitral regurgitation grade by angiography was 2.7±1.3. The mean value and correlation with angiographic grades for effective regurgitant orifice were 43±37 mm and
r
=.79 (
P
<.0001); for regurgitant volume, 62±45 mL and
r
=.80 (
P
<.0001); and for regurgitant fraction, 45±17% and
r
=.78 (
P
<.0001). Despite some overlap, differences between mitral regurgitation grades were all significant (all
P
<.05). The thresholds for severe mitral regurgitation (grade 4) were 60 mL, 50%, and 40 mm
2
for regurgitant volume, regurgitant fraction, and orifice, respectively.

Conclusions
In routine practice in large numbers of patients in a clinical laboratory, Doppler echocardiographic quantification of mitral regurgitation shows highly significant correlation with qualitative angiographic grades. Despite an expected overlap between classes, the calibration by angiography of grading ranges for the quantitative variables provides a framework for their interpretation and allows the definition in clinical practice of thresholds for severe mitral regurgitation.
Increased Myocardial Muscarinic Receptor Density in Idiopathic Dilated Cardiomyopathy
Authors: Le Guludec Dominique , Cohen-Solal Alain , Delforge Jacques , Delahaye Nicolas , Syrota André , Merlet Pascal
Published: June 2012

Background
Congestive heart failure is associated with decreased stimulated myocardial adenylate cyclase activity, increased G
i
-binding protein, attenuated parasympathetic tone, and increased modulation of β-adrenergic inotropic left ventricular stimulation by parasympathetic agonists. Despite these abnormalities, changes in the density or affinity of ventricular muscarinic receptors have not been demonstrated in patients.

Methods and Results
The density and affinity constants of myocardial muscarinic receptors were evaluated noninvasively by means of positron emission tomography with
11
C-MQNB (methylquinuclidinyl benzilate), a specific hydrophilic antagonist, in 20 patients with congestive heart failure due to idiopathic dilated cardiomyopathy (mean left ventricular ejection fraction, 22±9%) and compared with values in 12 normal subjects. The mean receptor concentration was significantly higher in patients than in control subjects (
B′

max

, 34.5±8.9 versus 25±7.7 pmol/mL,
P
<.005), with no changes in affinity constants. The change in heart rate after injection of 0.6 mg of cold MQNB was lower in patients than in control subjects (34±20% versus 55±36%,
P
<.05), and receptor density correlated negatively with maximal heart rate in the patients (
r
=.45,
P
<.05).

Conclusions
Congestive heart failure is associated with an upregulation of myocardial muscarinic receptors. This may be an adaptive mechanism to β-agonist stimulation and should increase the number of potential targets for pharmacological intervention.
Relationship Between Atrial Fibrillation and Typical Atrial Flutter in Humans
Authors: Roithinger Franz X. , Karch Martin R. , Steiner Paul R. , SippensGroenewegen Arne , Lesh Michael D.
Published: June 2012

Background
A transitional rhythm precedes the spontaneous onset of atrial flutter in an animal model, but few data are available in man.

Methods and Results
In 10 patients, 16 episodes of atrial fibrillation (166±236 seconds) converting into atrial flutter during electrophysiological evaluation were analyzed. A 20-pole catheter was used for mapping the right atrial free wall. Preceding the conversion was a characteristic sequence of events: (1) a gradual increase in atrial fibrillation cycle length (150±25 ms after onset, 166±28 ms before conversion,
P
<.01); (2) an electrically silent period (267±45 ms); (3) “organized atrial fibrillation” (cycle length, 184±24 ms) with the same right atrial free wall activation direction as during atrial flutter; (4) another delay on the lateral right atrium (283±52 ms); and (5) typical atrial flutter (cycle length, 245±38 ms). The coronary sinus generally had a different rate than the right atrial free wall until the beat that initiated flutter, when right atrium and coronary sinus were activated in sequence.

During 1313 seconds of fibrillation, there were 171 episodes of “organized atrial fibrillation.” An additional activation delay at least 30 ms longer than the mean organized atrial fibrillation cycle length was sensitive (100%) and specific (99%) for impending organization into atrial flutter. During organized atrial fibrillation, right atrial free wall activation was craniocaudal in 70% and caudocranial in 30%, which may explain why counterclockwise flutter is a more common clinical rhythm than clockwise flutter. Atrial flutter never degenerated into fibrillation, even after adenosine infusion.

Conclusions
Anatomic barriers, along with statistical properties of conduction and refractoriness during atrial fibrillation, may explain the remarkably stereotypical pattern of endocardial activation during the initiation of atrial flutter via fibrillation and the rarity of degeneration of flutter to fibrillation once it stabilizes.
Gap Junction Uncoupler Heptanol Prevents Cell-to-Cell Progression of Hypercontracture and Limits Necrosis During Myocardial Reperfusion
Authors: Garcia-Dorado David , Inserte Javier , Ruiz-Meana Marisol , González Miguel A. , Solares Julia , Juliá Margarita , Barrabés José A. , Soler-Soler J.
Published: June 2012

Background
The objective of this study was to test the hypothesis that chemical interaction through gap junctions may result in cell-to-cell progression of hypercontracture and that this phenomenon contributes to the final extent of reperfused infarcts.

Methods and Results
Cell-to-cell transmission of hypercontracture was studied in pairs of freshly isolated adult rat cardiomyocytes. Hypercontracture induced by microinjection of a solution containing 1 mmol/L Ca
2+
and 2% lucifer yellow (LY) was transmitted to the adjacent cell (11 of 11 pairs), and the gap junction uncoupler heptanol (2 mmol/L) prevented transmission in 6 of 8 pairs (
P
=.003), with a perfect association between passage of the LY and transmission of hypercontracture. In the isolated, perfused rat heart submitted to 30 minutes of hypoxia, addition of heptanol to the perfusion media during the first 15 minutes of reoxygenation had a dose-related protective effect against the oxygen paradox, as demonstrated by a reduction of diastolic pressure and marked recovery of developed pressure (
P
<.001), as well as less lactate dehydrogenase release during reoxygenation (
P
<.001) and less contraction band necrosis (
P
<.001) than controls. In the in situ pig heart submitted to 48 minutes of coronary occlusion, the intracoronary infusion of heptanol during the first 15 minutes of reperfusion at a final concentration of 1 mmol/L limited myocardial shrinkage, reflecting hypercontracture (
P
<.05), reduced infarct size after 5 hours of reperfusion by 54% (
P
=.04), and modified infarct geometry with a characteristic fragmentation of the area of necrosis. Heptanol at 1 mmol/L had no significant effect on contractility of nonischemic myocardium.

Conclusions
These results demonstrate that hypercontracture may be transmitted to adjacent myocytes through gap junctions and that heptanol may interfere with this transmission and reduce the final extent of myocardial necrosis during reoxygenation or reperfusion. These findings are consistent with the hypothesis tested and open a new approach to limitation of infarct size by pharmacological control of gap junction conductance.
Ca
2+
Release From Intracellular Stores Is an Initial Step in Hypoxic Pulmonary Vasoconstriction of Rat Pulmonary Artery Resistance Vessels
Authors: Gelband Craig H. , Gelband Henry
Published: June 2012

Background
A reduction in oxygen tension in the lungs is believed to inhibit a voltage-dependent K
+
(Kv) current, which is thought to result in membrane depolarization leading to hypoxic pulmonary vasoconstriction (HPV). However, the direct mechanism by which hypoxia inhibits Kv current is not understood.

Methods and Results
Experiments were performed on rat pulmonary artery resistance vessels and single smooth muscle cells isolated from these vessels to examine the role of Ca
2+
release from intracellular stores in initiating HPV. In contractile experiments, hypoxic challenge of endothelium-denuded rat pulmonary artery resistance vessels caused either a sustained or transient contraction in Ca
2+
-containing or Ca
2+
-free solution, respectively (n=44 vessels from 11 animals). When the ring segments were treated with either thapsigargin (5 μmol/L), ryanodine (5 μmol/L), or cyclopiazonic acid (5 μmol/L) in Ca
2+
-containing or Ca
2+
-free solution, a significant increase in pulmonary arterial tone was observed (n=44 vessels from 11 animals). Subsequent hypoxic challenge in the presence of each agent produced no further increase in tone (n=44 vessels from 11 animals). In isolated pulmonary resistance artery cells loaded with fura 2, hypoxic challenge, thapsigargin, ryanodine, and cyclopiazonic acid resulted in a significant increase in [Ca
2+
]
i
(n=18 cells from 6 animals) and depolarization of the resting membrane potential (n=22 cells from 6 animals). However, with prior application of thapsigargin, ryanodine, or cyclopiazonic acid, a hypoxic challenge produced no further change in [Ca
2+
]
i
(n=18 from 6 animals) or membrane potential (n=22 from 6 animals). Finally, application of an anti-Kv1.5 antibody increased [Ca
2+
]
i
and caused membrane depolarization. Subsequent hypoxic challenge resulted in a further increase in [Ca
2+
]
i
with no effect on membrane potential (n=16 cells from 4 animals).

Conclusions
In rat pulmonary artery resistance vessels, an initial event in HPV is a release of Ca
2+
from intracellular stores. This rise in [Ca
2+
]
i
causes inhibition of voltage-dependent K
+
channels (possibly Kv1.5), membrane depolarization, and an increase in pulmonary artery tone.