bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk Factors for Sudden Cardiac Death in Middle-Aged British Men
Authors: Wannamethee Goya , Shaper A. G. , Macfarlane P. W. , Walker Mary
Published: June 2012

Background
Risk factors specific to sudden cardiac death (SCD), ie, death within 1 hour after onset of symptoms, have been poorly identified, although recent findings from the present study incriminate heavy drinking and elevated heart rate. This paper examines the relations between a wide range of established and potential risk factors for ischemic heart disease (IHD) and SCD to identify independent risk factors for SCD and factors that might particularly or specifically relate to SCD.

Methods and Results
We present a prospective study of a cohort that was drawn from general practices in 24 British towns of 7735 middle-aged men who were followed up for 8 years. During 8 years of follow-up, the men experienced 488 major IHD events (nonfatal and fatal), of which 117 (24%) were classified as SCD. Age, preexisting IHD, arrhythmia, systolic blood pressure, blood cholesterol, elevated heart rate (≥90 beats per minute), physical activity (all,
P
<.05), and, to a lesser extent, smoking (
P
=.06), HDL cholesterol (
P
<.07), and elevated hematocrit (≥46%,
P
<.09) emerged as independent risk factors for SCD after adjustment for a wide range of factors. Diabetes was not found to be associated with SCD, and forced expiratory volume in 1 second, body mass index, white blood cell count, and antihypertensive drugs were not associated with risk of SCD after adjustment. When examined in relation to non–sudden IHD deaths and nonfatal myocardial infarction, elevated heart rate, heavy drinking, and arrhythmia emerged as factors that appear to be specific or particular to SCD. These three factors and age and blood cholesterol were associated with an increased risk of SCD in men both with and without preexisting IHD. Physical activity, systolic blood pressure, and current smoking were associated with SCD only in men without preexisting IHD. HDL cholesterol and hematocrit were strong predictors of SCD only in men with preexisting IHD.

Conclusions
Three risk factors appear to be specific or particular to the risk of SCD, and these and other risk factors operate differently in patients with versus those without preexisting IHD. These findings have implications for the causes and prevention of SCD.
Characterization of Right Ventricular Diastolic Performance After Complete Repair of Tetralogy of Fallot
Authors: Cullen Seamus , Shore Darryl , Redington Andrew
Published: June 2012

Background
Prolonged postoperative recovery caused by a low cardiac output state occurs in some patients after complete repair of tetralogy of Fallot. Biventricular systolic function is usually well preserved in these patients. The contribution of impaired diastolic function, particularly of the right ventricle, has not been studied in detail; therefore, we performed a prospective study of right ventricular diastolic function in this patient group.

Methods and Results
We studied biventricular systolic and diastolic function using Doppler echocardiographic examination. Tricuspid valve, superior vena caval, pulmonary arterial, and mitral valve Doppler spectrals were obtained during the first postoperative day in 35 patients aged 6 months to 45 years who underwent complete repair of tetralogy of Fallot. Biventricular systolic function was grossly normal in all patients. Isolated restrictive right ventricular physiology characterized by pulmonary arterial antegrade flow coincident with atrial systole and associated with prominent retrograde superior vena caval flow was seen in 17 of the 35 patients (group 1). This flow was augmented during the expiratory phase of positive pressure ventilation and abolished or greatly diminished during the inspiratory phase (
P
<.001). An increase in the duration of pulmonary regurgitation occurred during the inspiratory phase of positive pressure ventilation in these patients (
P
<.01). All patients with right ventricular restriction had a clinical picture compatible with a low cardiac output state, requiring prolonged stays in intensive care and the hospital. Clinical improvement was mirrored by resolution of the Doppler markers of right ventricular restriction in most of the patients.

Conclusions
Isolated right ventricular restriction is characterized by antegrade diastolic pulmonary arterial flow on Doppler echocardiography and is responsible for the slower postoperative course and clinical evidence of low cardiac output state in some patients after complete repair of tetralogy of Fallot.
Ibutilide, a Methanesulfonanilide Antiarrhythmic, Is a Potent Blocker of the Rapidly Activating Delayed Rectifier K
+
Current (I
Kr
) in AT-1 Cells
Authors: Yang Tao , Snyders Dirk J. , Roden Dan M.
Published: June 2012

Background
Ibutilide is an action potential–prolonging antiarrhythmic currently in clinical trials. The drug shares structural similarities with E-4031 and dofetilide, specific blockers of the rapidly activating delayed rectifier K
+
current (I
Kr
). However, previous in vitro studies in guinea pig myocytes have indicated that ibutilide does not block I
Kr
but rather increases a slow inward sodium current.

Methods and Results
In this study, we compared the effects of ibutilide with those of dofetilide on outward current in mouse atrial tumor myocytes (AT-1 cells), a preparation in which, unlike guinea pig, a typical I
Kr
is the major delayed rectifier and can be readily recorded in isolation from other currents. In AT-1 cells, ibutilide and dofetilide were both potent I
Kr
blockers, with EC
50
values of 20 (n=12) and 12 (n=8) nmol/L, respectively, at +20 mV. The time and voltage dependence of I
Kr
inhibition by the two compounds were virtually identical. The following characteristics were most consistent with open channel block: (1) block increased with depolarizing pulses; (2) block increased with longer pulses; (3) currents deactivated more slowly in the presence of drug, resulting in a “crossover” typical of open channel block; and (4) with repetitive pulsing after drug wash-in, use-dependent block was observed.

Conclusions
These data suggest that the clinical actions of ibutilide are mediated at least in part by block of I
Kr
; an effect on inward currents is not excluded. AT-1 cells are a useful model system for the study of drug block of this important repolarizing current.
Role of Nitric Oxide in the Coronary Microvascular Responses to Adenosine and Increased Metabolic Demand
Authors: Jones Christopher J. H. , Kuo Lih , Davis Michael J. , DeFily David V. , Chilian William M.
Published: June 2012

Background
The purpose of this study was to test the hypothesis that endothelium-derived nitric oxide (NO) participates in coronary microvascular responses to adenosine and pacing-induced increases in metabolic demand by maintaining an optimal distribution of coronary resistance.

Methods and Results
Coronary microvascular diameters were measured by stroboscopic epi-illumination and intravital microscopy in open-chest dogs (n=20). Epicardial coronary blood velocity (CBV) was measured by Doppler flowmetry. Responses to adenosine (1 and 10 μg · kg
−1
· min
−1
IC) and left atrial pacing (180 beats per minute) were recorded before and after inhibition of NO synthesis by
N
G
-nitro-
l
-arginine methyl ester (L-NAME, 30 μg · kg
−1
· min
−1
IC). At baseline, adenosine dilated arterioles (<100 μm) (11±4% and 25±3% diameter changes,
P
<.05) more than small arteries (>100 μm) (−4±6% and 7±3%,
P
<.05 for the higher dose) and increased CBV (43±31% and 118±25%,
P
<.05). Left atrial pacing dilated arterioles (12±2%,
P
<.05) and small arteries (8±3%,
P
<.05) and also increased CBV (68±9%,
P
<.05). L-NAME abolished CBV increases caused by acetylcholine (10 and 100 ng · kg
−1
· min
−1
IC; 53±33% and 168±82% versus −12±15% and −1±14%,
P
<.05) but not papaverine. Small arteries were constricted by L-NAME (−8±2%,
P
<.05), arterioles were dilated (10±4%,
P
<.05), and CBV was unchanged. After L-NAME, adenosine failed to dilate arterioles further (3±3% and 2±2%;
P
<.05 versus prior responses), and CBV changes were attenuated (14±16% and 8±13%;
P
<.05 versus prior responses). Pacing also failed to dilate arterioles (−4±2%,
P
<.05 versus prior response), resulting in an attenuated CBV change (34±13%,
P
<.05 versus prior response). The possibility that adenosine stimulates NO release in canine coronary arterioles was investigated in isolated arterioles (diameters, 81±4 μm; n=8). Adenosine caused dose-dependent dilation to maximal diameter, which was unaffected by inhibition of NO synthesis by L-NAME.

Conclusions
Inhibition of NO synthesis attenuates coronary dilation during adenosine infusions and during pacing-induced increases in metabolic demand. Inhibition of NO synthesis may shift the major site of coronary resistance into small arteries through autoregulatory adjustments in arterioles. These data therefore suggest that NO, by dilating predominantly small coronary arteries, promotes metabolic coronary dilation by preserving the tone and vasodilator reserve of arterioles.
Heart Rate Variability During Specific Sleep Stages
Authors: Vanoli Emilio , Adamson Philip B. , Ba-Lin  , Pinna Gian D. , Lazzara Ralph , Orr William C.
Published: June 2012

Background
Heart rate variability (HRV) is typically higher during nighttime. This evidence supports the concept that overall, sleep is a condition during which vagal activity is dominant. Myocardial infarction (MI) results in a loss in the overall nocturnal HRV increase. However, the characteristics of HRV during specific sleep stages in normal subjects and, more importantly, after MI, are unknown. This study describes HRV during sleep stages in normal subjects and in patients with a recent MI.

Methods and Results
HRV was measured from 5 minutes of continuous ECG recording in 8 subjects with no clinical evidence of coronary artery disease (age, 47±4 years) and in 8 patients with a recent MI (age, 51±2 years; NS versus control subjects) in the awake state, non–rapid eye movement (REM), and REM sleep. In normal subjects, the low- to high-frequency ratio (LF/HF) derived from power spectral analysis of HRV decreased significantly from the awake state to non-REM sleep (from 4±1.4 to 1.22±0.33,
P
<.01). During REM sleep, the LF/HF increased to 3±0.74 (
P
<.01 versus non-REM, NS versus awake). In post-MI patients, the LF/HF showed an opposite trend toward an increase from 2.4±0.7 to 5.11±1.4 (NS,
P
<.01 versus the control subjects). REM sleep produced a further increase in the LF/HF up to 8.9±1.6 (
P
<.01 versus awake and versus REM in control subjects).

Conclusions
Myocardial infarction causes a loss in the capability of the vagus to physiologically activate during sleep. This results in a condition of relative sympathetic dominance even in a situation such as sleep, normally described as a condition of vagal dominance and, consequently, low risk for lethal events. The evidence that the sleep-related vagal activation is lost after MI may provide new insights to understanding the nocturnal occurrence of sudden death.
Natural History of Focal Moderate Cardiac Allograft Rejection
Authors: Winters Gayle L. , Loh Evan , Schoen Frederick J.
Published: June 2012

Background
The rate of progression and potential long-term consequences of isolated foci of moderate acute rejection (FMR) on endomyocardial biopsy (EMB) have not been defined; therefore, whether FMR necessitates augmented immunosuppression remains controversial.

Methods and Results
At our institution, recipients with EMBs having FMR, defined as one or two isolated foci of cellular infiltrates with associated myocyte damage (International Society for Heart and Lung Transplantation [ISHLT] grade 2 and a subset of grade 3A), do not routinely receive intensified immunosuppression. Accordingly, to determine the outcome of untreated FMR, we reviewed 4398 EMBs (mean, 4.4 samples each) obtained after orthotopic heart transplantation in 208 consecutive recipients maintained on triple immunosuppressive therapy. The incidence of progression versus resolution of FMR, the time interval after transplantation when FMR was detected, and the relation of untreated FMR to recipient survival were analyzed. FMR categorized as one (n=312) or two (n=89) foci was present in 401 EMBs (9% of total) obtained 10 days to 7.5 years after transplantation from 149 recipients (72%). EMBs with FMR resolved without treatment in 341 of 401 (85%), and only 60 of 401 (15%) progressed to higher grade rejection. EMBs that progressed occurred 7.5±7.9 months (mean±SD) after transplantation compared with 14.0±16.5 months after transplantation for those that resolved (
P
<.005). Of the 60 EMBs that progressed, 55% occurred within the first 6 months, 78% within the first year, and 97% within the first 2 years after transplantation. EMBs with two foci of FMR were no more likely to progress than those with one focus. Thirty-nine recipients experienced one (n=25), two (n=9), three (n=3), or four (n=2) episodes of FMR that progressed. One or more episodes of FMR that did not progress occurred in 110 recipients. By Kaplan-Meier analysis, survival at 1 and 5 years was similar in recipients with and those without FMR progression.

Conclusions
First, untreated FMR consisting of either one or two foci has a low rate of progression. Second, progression of FMR decreases with increasing postoperative interval and becomes rare after 2 years. Last, FMR progression did not identify recipients with decreased survival.
Atrial Arrhythmias in Adults After Repair of Tetralogy of Fallot
Authors: Roos-Hesselink Jolien , Perlroth Mark G. , McGhie Jacky , Spitaels Silja
Published: June 2012

Background
The long-term success of intracardiac repair of tetralogy of Fallot is hampered by the occurrence of arrhythmias. Numerous studies have stressed the potential role of ventricular arrhythmias. However, the importance of other arrhythmias in the morbidity of these patients appears to be underestimated. Furthermore, most follow-up studies have been limited to children or adolescents, whereas many patients have reached adulthood after earlier repair of tetralogy of Fallot. The aim of the present study was to determine the incidence of atrial fibrillation, atrial flutter, and other supraventricular arrhythmias in adult patients after intracardiac repair for tetralogy of Fallot and their correlation with surgical and clinical findings.

Methods and Results
The study group consisted of 53 consecutive patients referred to the Thoraxcenter adult congenital heart disease clinic. They underwent repair at a mean age of 9.1 years (range, 0.7 to 55 years). The median age at the time of study was 23.2 years (range, 15 to 57 years; mean age, 26.6 years), and the mean duration of follow-up of 17.5 years (range, 1.4 to 32 years) after surgery. Records were reviewed extensively for evidence of arrhythmias. The follow-up study included routine 12-lead ECG, 24-hour continuous ambulatory monitoring, and echocardiography, and 46 patients underwent exercise testing. Sinus node dysfunction was recorded in 19 patients (36%), of whom 4 required a permanent pacemaker. Atrial fibrillation or flutter was found in 12 patients, and other supraventricular tachycardias were found in 6. The former were more frequently of older age at follow-up. Antiarrhythmic therapy and cardioversion were typically directed at control of atrial (and not ventricular) tachyarrhythmias. Ten patients (19%) showed nonsustained ventricular tachycardia; they were older at initial surgery and older at follow-up and had more intracardiac repairs and longer cardiopulmonary bypass times.

Conclusions
Despite an emphasis on ventricular ectopy in past series, the main sources of morbidity in adult patients after surgical correction of tetralogy of Fallot emanated from atrial arrhythmias, which were present in one third of the patients.
α
1
-Adrenoceptor Activation Increases Ecto-5′-Nucleotidase Activity and Adenosine Release in Rat Cardiomyocytes by Activating Protein Kinase C
Authors: Kitakaze Masafumi , Hori Masatsugu , Morioka Toshikazu , Minamino Tetsuo , Takashima Seiji , Okazaki Yasushi , Node Koichi , Komamura Kazuo , Iwakura Katsuomi , Itoh Takahito , Inoue Michitoshi , Kamada Takenobu
Published: June 2012

Background
Adenosine is an important regulator of many cardiac functions and is synthesized primarily by ecto- and cytosolic 5′-nucleotidase. We have previously reported that α
1
-adrenoceptor blockade attenuates adenosine release from ischemic myocardium, raising the possibility that α
1
-adrenoceptor activation activates 5′-nucleotidase. This study tested whether activation of protein kinase C by α
1
-adrenoceptor activation increases 5′-nucleotidase activity and augments adenosine release.

Methods and Results
Cardiomyocytes were isolated from adult male Wistar rats and suspended in modified HEPES-Tyrode’s buffer solution. After stabilization, the cardiomyocytes were incubated with and without an exposure to norepinephrine (10
−9
to 10
−5
mol/L) while being treated with propranolol and yohimbine or with and without an exposure to methoxamine (10
−9
to 10
−5
mol/L). Ecto-5′-nucleotidase activity was increased by norepinephrine and methoxamine during 30 minutes in a dose-dependent manner, whereas cytosolic 5′-nucleotidase was not activated. These increases in ecto-5′-nucleotidase activity were inhibited by GF109203X, an inhibitor of protein kinase C, and mimicked by phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C. The increase in ecto-5′-nucleotidase was not prevented by cycloheximide. When ecto-5′-nucleotidase activity increased, adenosine release was augmented in methoxamine- and PMA-treated cardiomyocytes (1299±252% and 1372±149%, respectively) compared with the untreated group (578±26%). The increase in adenosine release was blunted by GF109203X and α,β-methyleneadenosine 5′-diphosphate, an inhibitor of ecto-5′-nucleotidase.

Conclusions
Thus, we conclude that α
1
-adrenoceptor–mediated increases in ecto-5′-nucleotidase activity are attributed to activation of protein kinase C in rat cardiomyocytes.
Cholesterol Reduction Yields Clinical Benefit
Authors: Gould A. Lawrence , Rossouw Jacques E. , Santanello Nancy C. , Heyse Joseph F. , Furberg Curt D.
Published: June 2012

Background
There has been a continuing debate about the overall benefit of cholesterol lowering. We performed a novel meta-analysis of all randomized trials of more than 2 years’ duration (n=35 trials) to describe how coronary-heart-disease (CHD), non-CHD, and total mortality are related to cholesterol lowering and to type of intervention.

Methods and Results
The analytic approach was designed to separate the effects of cholesterol lowering itself from the other effects of the different types of intervention used. For every 10 percentage points of cholesterol lowering, CHD mortality was reduced by 13% (
P
<.002) and total mortality by 10% (
P
<.03). Cholesterol lowering had no effect on non-CHD mortality. Certain types of intervention had specific effects independent of cholesterol lowering. Fibrates (clofibrates, 7 trials; gemfibrozil, 2 trials) increased non-CHD mortality by about 30% (
P
<.01) and total mortality by about 17% (
P
<.02). Hormones (estrogen, 2 trials; dextrothyroxin, 2 trials) increased CHD mortality in men by about 27% (
P
<.04), non-CHD mortality by about 55% (
P
<.03), and total mortality by about 33% (
P
<.01). No specific effects independent of cholesterol lowering were found due to diet (n=11) or other interventions (resins, 5; niacin, 3; statins, 2; partial ileal bypass, 1).

Conclusions
The results suggest that cholesterol lowering itself is beneficial but that specific adverse effects of fibrates and hormones increase the risk of CHD (hormones only), non-CHD, and total mortality.
A De Novo Mutation in α-Tropomyosin That Causes Hypertrophic Cardiomyopathy
Authors: Watkins Hugh , Anan Ryuichiro , Coviello Domenico A. , Spirito Paolo , Seidman J.G. , Seidman Christine E.
Published: June 2012

Background
Two missense mutations in the gene for α-tropomyosin have been described that segregate with hypertrophic cardiomyopathy in single families. To confirm that these mutations are the cause of the disease, we have investigated the origins of one of these mutations, Asp175Asn, in a third and unrelated family.

Methods and Results
The presence or absence of an α-tropomyosin mutation and the haplotypes of the flanking chromosomal regions were determined for members of a family with hypertrophic cardiomyopathy. Haplotypes were constructed by use of an intragenic polymorphism and 10 flanking polymorphisms spanning a region of 35 centimorgans. The Asp175Asn missense mutation was present in the proband and his two affected offspring but not in any of the proband’s three siblings. Although both parents were deceased, the haplotypes of the four parental chromosomes could be reconstructed. One parental chromosome was transmitted to two offspring: one bearing the Asp175Asn mutation (the affected proband) and one clinically unaffected sibling who lacked the α-tropomyosin mutation. Thus, the Asp175Asn mutation must have arisen de novo.

Conclusions
De novo mutations in the α-tropomyosin gene can result in hypertrophic cardiomyopathy that may appear to be sporadic but in subsequent generations gives rise to familial disease. Individuals with sporadic hypertrophic cardiomyopathy should be advised of the risk of transmission to offspring. In addition, these findings provide the strongest genetic evidence that mutations in the α-tropomyosin gene are directly responsible for hypertrophic cardiomyopathy.
Genetic Approaches to Cardiovascular Disease
Authors: Keating Mark T.
Published: June 2012

Background
Although family history can be an important risk factor for cardiovascular disease, relatively little is known about the nature of specific genetic risk factors. One approach to this problem is to identify and characterize genes responsible for inherited disorders in the hope that this information will also provide mechanistic insight into common forms of cardiovascular disease.

Methods and Results
Over the last decade, it has become possible to identify genes that cause human disease by use of the techniques of molecular genetics, specifically genetic linkage analysis, positional cloning, and mutational analyses. We have used these techniques to study three inherited cardiovascular disorders: supravalvular aortic stenosis, Williams syndrome, and long-QT syndrome. We have discovered that the vascular pathology of supravalvular aortic stenosis and Williams syndrome results from mutations involving the elastin gene on chromosome 7q11.23. These mutations include intragenic deletions, translocations, and complete deletion of the elastin gene, suggesting that a quantitative reduction in elastin during vascular development is pathogenically important. To date, only the elastin gene has proved important for supravalvular aortic stenosis. By contrast, genetic linkage analyses in families with long-QT syndrome indicate that at least four distinct genes can cause this disorder. We have identified three LQT loci:
LQT1
on chromosome 11p15.5,
LQT2
on 7q35-36, and
LQT3
on 3p21-24. Recently, we demonstrated that mutations in a putative cardiac potassium channel gene,
HERG
, are responsible for the chromosome 7–linked form of long-QT syndrome, whereas mutations in the cardiac sodium channel gene
SCN5A
cause the chromosome 3–linked form of this disorder.
HERG
mutations and potassium channel biophysics suggest a dominant-negative molecular mechanism and reduced repolarization currents. By contrast,
SCN5A
mutations probably cause subtle alterations of cardiac sodium channel function and prolonged depolarizing currents.

Conclusions
Molecular genetic analyses of long-QT syndrome, supravalvular aortic stenosis, and Williams syndrome have begun to unravel the mechanisms underlying these inherited disorders. Rapid genetic testing for Williams syndrome is now available using a simple cytogenetic test, fluorescence in situ hybridization, but additional work will be required for long-QT syndrome and autosomal-dominant supravalvular aortic stenosis. Improved diagnosis and mechanistic understanding of these disorders should lead to rational treatment and prevention.
Relation Between Myocardial Fractional Flow Reserve Calculated From Coronary Pressure Measurements and Exercise-Induced Myocardial Ischemia
Authors: De Bruyne Bernard , Bartunek Jozef , Sys Stanislas U. , Heyndrickx Guy R.
Published: June 2012

Background
Myocardial fractional flow reserve (FFR
myo
) is a functional index of stenosis severity that can be derived from intracoronary pressure measurements performed during maximal vasodilatation. It is defined as the maximal myocardial perfusion during hyperemia in the presence of a stenosis in the epicardial artery expressed as a fraction of its normal maximal expected value. To determine threshold values of FFR
myo
, of hyperemic translesional pressure gradient (ΔP
max
), and of resting translesional pressure gradient (ΔP
rest
) that are uniformly associated with exercise-induced ischemia, we studied the relation between these pressure-derived indexes and the results of exercise ECG.

Methods and Results
We studied 60 patients with an isolated lesion in one major epicardial coronary artery, normal left ventricular function, and no left ventricular hypertrophy. Maximal exercise ECG (off anti-ischemic medication) was performed within 6 hours before catheterization. Intracoronary pressure measurements were taken at rest and during hyperemia with a pressure monitoring guide wire. ST-segment depressions at peak exercise (considered abnormal when ≥0.1 mV) were compared with FFR
myo
, ΔP
max
, and ΔP
rest
. Thirty-seven patients had an abnormal and 23 patients a normal exercise ECG. A significant linear correlation was found between the magnitude of ST-segment depressions and both FFR
myo
and ΔP
max
(
r
=−.75, SEE=0.53;
r
=.71, SEE=0.56). A weaker correlation was noted between ST-segment depressions and ΔP
rest
(
r
=.53, SEE=0.67). Sensitivity and specificity curves were constructed for the prediction of an abnormal exercise ECG for the three pressure-derived indexes. The values that most accurately predicted an abnormal exercise ECG were 66% for FFR
myo
, 31 mm Hg for ΔP
max
, and 12 mm Hg for ΔP
rest
. No patient with a FFR
myo
value >72% showed an abnormal exercise ECG. In addition, receiver operating characteristic curves demonstrated a greater accuracy of FFR
myo
and of ΔP
max
than of ΔP
rest
for predicting the results of the exercise ECG.

Conclusions
In the present study, cutoff values of FFR
myo
and translesional pressure gradients are established from the relation between intracoronary pressure–derived indexes and ECG signs of myocardial ischemia during maximal exercise. These values can be helpful for clinical decision making in cases with dubious angiographic results. Furthermore, our data support the concept that stenosis physiology is better reflected by hyperemic than by basal measurements.
Results of the International Study of the Implantable Pacemaker Cardioverter-Defibrillator
Authors: Zipes Douglas P. , Roberts Diana
Published: June 2012

Background
The purpose of the present report was to document clinical experience derived from the implantation of 2834 epicardial and endocardial cardioverter-defibrillators (ICDs) in 2807 patients who were followed for almost 1 year and to compare the results obtained with the two systems.

Methods and Results
Patients in the two groups had similar clinical characteristics. More than half of the patients had a total of almost 50 000 spontaneous ventricular tachyarrhythmias that were terminated with equal success (≈98%) by epicardial and endocardial ICDs. Lead dislodgement and pocket infection occurred more often with the endocardial than with the epicardial ICD, whereas perioperative mortality was higher with the epicardial ICD than with the endocardial ICD. Mortality from sudden cardiac death was 1.4% in the epicardial ICD group and 0.6% in the endocardial ICD group at 1 year (
P
=.069). Overall mortality at 1 year was 12.2% and 6.9% for the epicardial and endocardial groups, respectively (
P
<.001), reflecting the higher surgical mortality for the epicardial system.

Conclusions
The endocardial ICD is as effective as the epicardial ICD but incurs lower perioperative mortality.
Prolonged Antithrombin Activity of Low-Molecular-Weight Heparins
Authors: Agnelli Giancarlo , Iorio Alfonso , Renga Cinzia , Boschetti Enrico , Nenci Giuseppe G. , Ofosu Frederick A. , Hirsh Jack
Published: June 2012

Background
The mechanism for the efficacy of once- or twice-daily subcutaneous injections of low-molecular-weight heparins (LMWHs) for the treatment of venous thromboembolism has been difficult to explain. The confusion exists because the observation from experimental studies that the antithrombin activity of LMWHs is necessary for their antithrombotic effect is inconsistent with the reported short half-life of the antithrombin activity of LMWHs. Previous pharmacokinetic studies were performed with lower doses of LMWHs than have been used in contemporary trials, and antithrombin activity was assessed with the barely sensitive chromogenic assay.

Methods and Results
We performed a pharmacokinetic study to compare the relative half-lives of prophylactic and therapeutic doses of LMWHs assessing antithrombin activity with both the chromogenic and a more sensitive assay (plasma thrombin neutralization assay). An eight-way cross-over randomized study in healthy volunteers was performed. Enoxaparin (20 and 40 mg and 1 and 2 mg/kg) and nadroparin (7500 and 10 000 ICU and 225 and 450 ICU/kg) were administered subcutaneously. The maximal peak activity for aPTT ratio was 1.7. A dose-dependent peak activity was found for both antifactor Xa and antithrombin activities. Disappearance time of these activities after the highest dose of both LMWHs was longer than 16 hours. Overall mean antifactor Xa activity half-life was 4.6 hours. Overall mean antithrombin activity half-life was longer than 4 hours.

Conclusions
Our results provide an explanation for the effectiveness of LMWHs administered either once or twice daily. High and sustained plasma antithrombin activity is achieved when LMWHs are administered in therapeutic doses used in contemporary trials with only a moderate prolongation of the aPTT.
Effect of Insulin on Acetylcholine-Induced Vasodilation in Normotensive Subjects and Patients With Essential Hypertension
Authors: Taddei Stefano , Virdis Agostino , Mattei Paola , Natali Andrea , Ferrannini Ele , Salvetti Antonio
Published: June 2012

Background
The present study was designed to directly test the vasodilation action of insulin and its relation to endothelium-dependent mechanisms.

Methods and Results
In 18 normotensive subjects and 27 patients with untreated mild to moderate essential hypertension, we studied the effect of intrabrachial insulin on the changes in forearm blood flow (strain-gauge plethysmography) induced by intrabrachial acetylcholine (at doses of 0.15, 0.45, 1.5, 4.5, and 15 μg · min
−1
· dL
−1
), an endothelium-dependent vasodilator, or sodium nitroprusside (at doses of 1, 2, and 4 μg · min
−1
· dL
−1
), an endothelium-independent vasodilator. Local hyperinsulinemia (deep venous plasma insulin, 48±6 and 51±5 μU/mL in control subjects and hypertensive patients, respectively) did not affect basal forearm blood flow and stimulated forearm glucose extraction (control subjects, 3±1% to 11±2%,
P
<.001; hypertensive patients, 3±1% to 6±1%,
P
<.001;
P
<.01 for the between-group difference). In both normotensive and hypertensive subjects, insulin significantly potentiated acetylcholine-induced vasodilation, whereas it did not alter the vasodilatory response to sodium nitroprusside.
N
G
-monomethyl-
l
-arginine, an inhibitor of endothelial nitric oxide synthesis, blunted insulin-induced facilitation of acetylcholine vasodilation in normotensive but not in hypertensive subjects. In contrast, in hypertensive patients but not in normotensive control subjects, the potentiation of the vascular response to acetylcholine induced by local hyperinsulinemia was abolished by intrabrachial ouabain, an inhibitor of Na
+
-K
+
pump.

Conclusions
In healthy humans and essential hypertensive patients alike, local physiological hyperinsulinemia per se does not increase forearm blood flow but potentiates the vasodilation induced by acetylcholine regardless of metabolic insulin resistance. This effect is endothelium-dependent because it is not seen with nitroprusside and is related to the
l
-arginine–nitric oxide pathway in normotensive subjects and to smooth muscle cell hyperpolarization in essential hypertensive patients.
Intracoronary Low-Dose β-Irradiation Inhibits Neointima Formation After Coronary Artery Balloon Injury in the Swine Restenosis Model
Authors: Waksman Ron , Robinson Keith A. , Crocker Ian R. , Wang Chris , Gravanis Michael B. , Cipolla Gustavo D. , Hillstead Richard A. , King Spencer B.
Published: June 2012

Background
Neointima formation contributing to recurrent stenosis remains a major limitation of percutaneous transluminal angioplasty. Endovascular low-dose γ-irradiation has been shown to reduce intimal thickening (hyperplasia) after balloon overstretch injury in pig coronary arteries, a model of restenosis. The objective of this study was to determine whether the use of a β-emitting radioisotope for this application would have similar effects and to examine the dose-response relations with this approach.

Methods and Results
Normal domestic pigs underwent balloon overstretch injury in the left anterior descending and left circumflex and coronary arteries. A flexible catheter was introduced by random assignment into one of these arteries and was afterloaded with a 2.5-cm ribbon of encapsulated
90
Strontium/
90
Yttrium sources (
90
Sr/Y, a pure β-emitter). It was left in place for a period of time sufficient to deliver one of four doses: 7, 14, 28, or 56 Gy, to a depth of 2 mm. Animals were killed 14 days after balloon injury, the coronary vasculature was pressure-perfusion fixed, and histomorphometric analysis of arterial cross sections was performed. All arteries treated with radiation demonstrated significantly decreased neointima formation compared with control arteries. The ratio of intimal area to medial fracture length was inversely correlated with increasing radiation dose: control (no radiation), 0.47; 7 Gy, 0.34; 14 Gy, 0.20; 28 Gy, 0.08; and 56 Gy, 0.02 (
r
=−.78,
P
<.000001). Scanning electron microscopy demonstrated a confluent layer of endothelium-like cells both in control and in 14 Gy–irradiated arteries. There was neither evidence of significant necrosis nor excess fibrosis in the media, adventitia, or perivascular space of the coronary arteries or adjacent myocardium in the irradiated groups. Furthermore, the exposure to the staff and the total body exposure to the pig with the β source was a small fraction of the dose previously measured and calculated with
192
Ir, a γ-emitting radioisotope.

Conclusions
Administration of endovascular β-radiation to the site of coronary arterial overstretch balloon injury in pigs with
90
Sr/Y is technically feasible and safe. Radiation doses between 7 and 56 Gy showed evidence of inhibition of neointima formation. A dose-response relation was demonstrated, but no further inhibitory effect was seen beyond 28 Gy. These data suggest that intracoronary β-irradiation is practical and feasible and may aid in preventing clinical restenosis.
Effects of Anterior Communicating Artery Diameter on Cerebral Hemodynamics in Internal Carotid Artery Disease
Authors: Cassot Francis , Vergeur Valérie , Bossuet Philippe , Hillen Berend , Zagzoule Mokhtar , Marc-Vergnes Jean-Pierre
Published: June 2012

Background
Collateral circulatory pathways are considered the primary determinant of cerebral hemodynamics in patients with obstructive lesions of the internal carotid arteries (ICaAs). However, the hemodynamic effects of the diameter of the anterior communicating artery (ACoA) have never been assessed quantitatively in humans.

Methods and Results
Two different mathematical models were used to simulate changes affecting blood pressures and flows in cerebral arteries as a function of ACoA diameter and ICaA stenoses or occlusions. Small changes in ACoA diameter were found to have marked hemodynamic effects when they occurred within the range of 0.4 to 1.6 mm, a situation observed in 80% of the cases. Outside this range, changes in ACoA diameter had no effect. Simulated pressure drops through a stenotic ICaA were consistent with those observed. They were found to depend on the degrees of the stenoses in both ICaAs and on ACoA diameter according to a simple equation. Pressure reserve in the middle and anterior cerebral arteries decreased to below the lower limit of autoregulation, despite a normal mean arterial blood pressure, when the arteries were distal to a unique 70% ICaA stenosis associated with a small-diameter ACoA or to a 50% ICaA stenosis associated with a contralateral ICaA occlusion and a large-diameter ACoA. Above these thresholds, the circle of Willis allowed for an almost complete global cerebral blood flow compensation that involved all the afferent and communicating vessels.

Conclusions
ACoA diameter strongly modulates the effects of ICaA lesions on cerebral hemodynamics. Some proposals for endarterectomy indications can be derived from our study.
Magnetic Resonance Angiography of Anomalous Coronary Arteries
Authors: Post Johannes C. , van Rossum Albert C. , Bronzwaer Jean G.F. , de Cock Carel C. , Hofman Mark B.M. , Valk Jacob , Visser Cees A.
Published: June 2012

Background
The clinical significance of anomalously originating coronary arteries depends on their proximal course. Diagnosis of this course by conventional x-ray coronary angiography alone may be equivocal. We postulated that with fast magnetic resonance (MR) angiography, accurate detection of anomalous coronary arteries and unambiguous delineation of their proximal course is feasible.

Methods and Results
In a selected group of 38 patients, 19 of them having an anomalously originating coronary artery, a fast MR angiographic technique was used to study the proximal coronary anatomy. Blinded analysis of randomly ordered MR studies was performed independently by two observers. Both origin and proximal course of the coronary arteries were defined. Two cardiologists reviewed all x-ray coronary angiograms. After the separate analyses, a final consensus result was defined for each patient. In 37 patients, successful MR coronary angiography could be performed. Interobserver agreement for determining both origin and proximal course was 100%. An x-ray coronary angiogram was available in 36 patients. In 3 patients (all with an anomalous left main coronary artery originating from the right aortic sinus), there was disagreement about the proximal course between the results of MR and x-ray coronary angiography. Review of these cases demonstrated that MR angiography had unambiguously visualized the proximal coronary artery course, whereas the results of x-ray angiography had been equivocal. Thus, sensitivity and specificity for detecting anomalous coronary arteries and delineating their proximal course were 100%.

Conclusions
These data suggest that fast MR angiography is highly accurate in determining the origin and delineating the proximal course of anomalous coronary arteries, even in those cases in which x-ray coronary angiographic diagnosis is difficult or even erroneous.
Vascular Smooth Muscle Cells of H-2K
b
-tsA58 Transgenic Mice
Authors: Ehler Elisabeth , Jat Parmjit S. , Noble Mark D. , Citi Sandra , Draeger Annette
Published: June 2012

Background
The vascular wall is composed of at least two different populations of smooth muscle cells that are distinct in their structure and protein composition. According to the developmental stage of tissue taken for culture, the ratio between cells of epithelioid phenotype and spindle-shaped cells is variable. In particular, the epithelioid cells display characteristic features associated with immaturity. Because their increased appearance can be observed in endothelial denudation, they represent a dedifferentiated, proliferative smooth muscle cell type with a repair function in vascular injury.

Methods and Results
To investigate this cellular heterogeneity, we established vascular smooth muscle cell lines from H-2K
b
-tsA58 transgenic mice. Due to temperature-sensitive expression of the SV 40 large T-antigen in cells derived from this mouse strain, our smooth muscle lines were conditionally immortalized from the onset of their life in culture. Thus, we were able to clone cell lines representing the two different phenotypes described so far. Epithelioid cells derived from newborn animals are characterized by their expression of cytokeratins and the development of tight junctional complexes. Spindle-shaped cells, which could be isolated from newborn or adult animals, corresponded in phenotype and protein expression to smooth muscle cell lines established previously.

Conclusions
The special properties of vascular smooth muscle cells of the epithelioid phenotype suggest an endothelial replacement function in the course of injury to the vascular wall.
Clinical Misconceptions Dispelled by Epidemiological Research
Authors: Kannel William B.
Published: June 2012

Abstract
The epidemiological approach to investigation of cardiovascular disease was innovated in 1948 by Ancel Keys’ Seven Countries Study and T.R. Dawber’s Framingham Heart Study. Conducted in representative samples of the general population, these investigations provided an undistorted perception of the clinical spectrum of cardiovascular disease, its incidence and prognosis, the lifestyles and personal attributes that predispose to cardiovascular disease, and clues to pathogenesis. The many insights gained corrected numerous widely held misconceptions derived from clinical studies. It was learned, for example, that the adverse consequences of hypertension do not derive chiefly from the diastolic pressure, left ventricular hypertrophy was not an incidental compensatory phenomenon, and small amounts of proteinuria were more than orthostatic trivia. Exercise was considered dangerous for cardiovascular disease candidates; smoking, cholesterol, and a fatty diet were regarded as questionable promoters of atherosclerosis. The entities of sudden death and unrecognized myocardial infarction were not widely appreciated as prominent features of coronary disease, and the disabling and lethal nature of cardiac failure and atrial fibrillation was underestimated. It took epidemiological research to coin the term “risk factor” and dispel the notion that cardiovascular disease must have a single origin. Epidemiological investigation provided health professionals with multifactorial risk profiles to more efficiently target candidates for cardiovascular disease for preventive measures. Clinicians now look to epidemiological research to provide definitive information about possible predisposing factors for cardiovascular disease and preventive measures that are justified. As a result, clinicians are less inclined to regard usual or average values as acceptable and are more inclined to regard optimal values as “normal.” Cardiovascular events are coming to be regarded as a medical failure rather than the first indication of treatment.
Value of Myoglobin, Troponin T, and CK-MB
mass
in Ruling Out an Acute Myocardial Infarction in the Emergency Room
Authors: de Winter Robbert J. , Koster Rudolph W. , Sturk Augueste , Sanders Gerard T.
Published: June 2012

Background
Ruling out acute myocardial infarction (AMI) on the basis of rapid assays for cardiac markers will allow early triage of patients and cost-effective use of available coronary care facilities.

Methods and Results
We studied the value of myoglobin, creatine kinase (CK)–MB
mass
, and troponin T in ruling out an AMI in the emergency room in 309 consecutive patients presenting with chest pain. The gold standard for AMI was the combination of history, ECG, and a typical curve of the CK-MB activity (CK-MB
act
). Myoglobin was the earliest marker, and its negative predictive value (NPV) was significantly higher than for CK-MB
mass
and troponin T from 3 to 6 hours after the onset of symptoms (myoglobin versus CK-MB
mass
,
P
<.03; myoglobin versus troponin T,
P
<.01). The NPV of myoglobin reached 89% 4 hours after the onset of symptoms. The NPV of CK-MB
mass
reached 95% 7 hours after the onset of symptoms. Troponin T was not an early marker for ruling out AMI, and NPV changed over time, together with CK-MB
act
. The early NPV was higher in a subgroup of patients with a low probability of the presence of AMI for the three markers. Cardiac markers rise earlier in patients with large infarcts than in patients with small infarcts as indicated by the cumulative proportion of the marker above the upper reference limit at each time point (myoglobin,
P
=.04; CK-MB
mass
,
P
=.013; troponin T,
P
=.016).

Conclusions
For ruling out AMI in the emergency room, myoglobin is a better marker than CK-MB
mass
or troponin T from 3 until 6 hours after the onset of symptoms, but the maximal NPV reaches only 89%. At 7 hours, the NPV of CK-MB
mass
is 95%. The test characteristics are influenced by the probability of the presence of AMI in the patients studied and by the size of their AMI. Infarct size of AMI patients should be reported in studies evaluating cardiac markers.
Evaluation of Importance of Central Effects of Atenolol and Metoprolol Measured by Heart Rate Variability During Mental Performance Tasks, Physical Exercise, and Daily Life in Stable Postinfarct Patients
Authors: Tuininga Ype S. , Crijns Harry J.G.M. , Brouwer Jan , van den Berg Maarten P. , Man in’t Veld Arie J. , Mulder G. , Lie K.I.
Published: June 2012

Background
Physical exercise and mental work cause alterations in cardiac autonomic control. β-Blockers protect the heart against stress, and this effect may be in part centrally mediated. In this context, the lipophilicity of the drug would be clinically relevant.

Methods and Results
Thirty postinfarct patients were randomized to receive 100 mg atenolol or 200 mg metoprolol CR in a double-blind, crossover manner, each for a 6-week period. Heart rate (HR) variability was used to study autonomic effects during mental and physical stress and to study circadian variations. Mean 24-hour HR decreased from 77±7 to 60±6 beats per minute after atenolol and to 62±6 beats per minute after metoprolol (
P
=.046). At baseline, mental performance tasks did not affect HR, but decreased HR variability (SDNN index from 51±26 to 30±13 milliseconds [ms],
P
<.001; high-frequency power from 130±143 to 110±125 ms
2
,
P
=.046; and low-frequency power from 538±447 to 290±275 ms
2
,
P
<.001). Both β-blockers decreased HR during mental performance tasks (
P
<.001) and increased SDNN index and high-frequency power. Before treatment, bicycle exercise decreased HR variability; root-mean-square of successive difference decreased from 21±8 to 15±10 ms (
P
=.004). β-Blockade could not prevent this decrease. No differences between atenolol and metoprolol were observed for absolute high- and low-frequency power or after adjustment for HR. Vagal blockade with methylatropine during chronic β-blocker treatment nearly abolished all components of spectral power. HR was found to be the parameter most strongly affected by β-blockade but not by an influence on vagal tone. No differences were found between atenolol and metoprolol.

Conclusions
In stable postinfarct patients, chronic treatment with metoprolol and atenolol attenuates the reduction in HR variability induced by mental performance tasks, but the effects during exercise are limited. β-Blockers do not appear to increase vagal tone in this stable patient group. The point of action in these patients is mainly a reduction in HR, probably due to a reduction in stress-induced sympathetic activation. Clinically significant differences between atenolol and metoprolol were absent, indicating that the degree of lipophilicity does not distinguish among the β-blockers what their salutary effects are on HR variability during the specific challenges used.