bluuebunny/crossref_metadata_2025 huggingface dataset:
Selective Uptake of Radiolabeled Annexin V on Acute Porcine Left Atrial Thrombi
Authors: Stratton John R. , Dewhurst Timothy A. , Kasina Sudhakar , Reno John M. , Cerqueira Manuel D. , Baskin Dennis G. , Tait Jonathan F.
Published: June 2012

Background
Annexin V is a human phospholipid binding protein that binds to activated platelets in vitro. We sought to determine the potential of this agent for imaging intracardiac thrombi in swine.

Methods and Results
Left atrial thrombi were formed by crush injury. In initial nonimaging experiments using intravenous
125
I-labeled human annexin V, the mean thrombus/whole blood ratio was 13.4±4.8 for the entire thrombus using well counting of resected specimens (n=8). Using intravenously injected
99m
Tc-labeled human annexin V, the left atrial thrombus/blood ratio by well counting was similar (14.2±10.6 for the entire thrombus and 26.2±14.9 for the peak section) (n=12). The ratio for a control protein,
125
I-ovalbumin, was only 1.0±0.2.
99m
Tc tomographic imaging was positive (n=10) or equivocal (n=2) in all experiments with but negative in 10 controls without left atrial thrombi. By region-of-interest analysis of the tomographic images, the mean left atrial appendage/blood ratio at 2 hours in animals with a thrombus was 3.90±1.12 compared with 0.84±0.10 in closed chest controls and 1.01±0.23 in open chest controls (
P
<.001).

Conclusions
We conclude that
99m
Tc-labeled human annexin V detects acute left atrial thrombi in vivo in swine. The combination of a new thrombus detection agent, annexin V, with a
99m
Tc label may allow in vivo imaging of thrombi in humans.
Prospective Study of Shift Work and Risk of Coronary Heart Disease in Women
Authors: Kawachi Ichiro , Colditz Graham A. , Stampfer Meir J. , Willett Walter C. , Manson JoAnn E. , Speizer Frank E. , Hennekens Charles H.
Published: June 2012

Background
The purpose of this study was to examine prospectively the relation of shift work to risk of coronary heart disease (CHD) in a cohort of women.

Methods and Results
An ongoing prospective cohort of US female nurses, in whom we assessed (in 1988) the total number of years during which they worked rotating night shifts (at least three nights per month in addition to day and evening shifts), included 79 109 women, 42 to 67 years old in 1988, who were free of diagnosed CHD and stroke. Incident CHD was defined as nonfatal myocardial infarction and fatal CHD. During 4 years of follow-up (1988 to 1992), 292 cases of incident CHD (248 nonfatal myocardial infarction and 44 fatal CHD) occurred. The age-adjusted relative risk of CHD was 1.38 (95% CI, 1.08 to 1.76) in women who reported ever doing shift work compared with those who had never done so. The excess risk persisted after adjustment for cigarette smoking and a variety of other cardiovascular risk factors. Compared with women who had never done shift work, the multivariate adjusted relative risks of CHD were 1.21 (95% CI, 0.92 to 1.59) among women reporting less than 6 years and 1.51 (95% CI, 1.12 to 2.03) among those reporting 6 or more years of rotating night shifts.

Conclusions
These data are compatible with the possibility that 6 or more years of shift work may increase the risk of CHD in women.
Sympathetic Activation and Loss of Reflex Sympathetic Control in Mild Congestive Heart Failure
Authors: Grassi Guido , Seravalle Gino , Cattaneo Bianca M. , Lanfranchi Antonio , Vailati Sabrina , Giannattasio Cristina , Del Bo Alberto , Sala Carla , Bolla Giovanni B. , Pozzi Massimo , Mancia Giuseppe
Published: June 2012

Background
Baroreflex control of sympathetic activity is impaired in severe congestive heart failure (CHF), probably causing the marked sympathetic activation typical of this condition. Little information exists, however, as to whether baroreflex impairment and related sympathetic activation also occur in mild CHF.

Methods and Results
We studied 19 patients (age, 57.5±2.2 years, mean±SEM) with CHF in New York Heart Association (NYHA) class III or IV and with a marked reduction in left ventricular ejection fraction (LVEF, 30.1±1.5% from echocardiography) and 17 age-matched patients with CHF in NYHA class I or II and with an only slightly reduced LVEF (44.9±3.3%) that never was <40%. Seventeen age-matched healthy subjects served as control subjects. Primary measurements included beat-to-beat arterial blood pressure (with the Finapres technique), heart rate (from ECG), and postganglionic muscle sympathetic nerve activity (MSNA, from microneurography at the peroneal nerve). Measurements were performed at baseline and during baroreceptor stimulation (intravenous phenylephrine infusion), baroreceptor deactivation (intravenous nitroprusside infusion), and cold-pressor test. Baseline blood pressure was similar in the three groups, whereas heart rate was progressively greater from control subjects to patients with mild and severe CHF. MSNA (bursts per 100 heart beats) increased significantly and markedly from control subjects to patients with mild and severe CHF (47.1±2.9 versus 64.4±6.2 and 82.1±3.4,
P
<.05 and
P
<.01, respectively). Heart rate and MSNA were progressively reduced by phenylephrine infusion and progressively increased by nitroprusside infusion. Compared with control subjects, the responses were strikingly impaired in severe CHF patients, but a marked impairment also was seen in mild CHF patients. On average, baroreflex sensitivity in mild CHF patients was reduced by 59.1±5.5% (MSNA) and 64.8±4.8% (heart rate). In contrast, reflex responses to the cold-pressor test were similar in the three groups.

Conclusions
These results demonstrate that in mild CHF patients the baroreceptor inhibitory influence on heart rate and MSNA is already markedly impaired. This impairment may be responsible for the early sympathetic activation that occurs in the course of CHF.
Randomized, Double-Blind Comparison of Intravenous Amiodarone and Bretylium in the Treatment of Patients With Recurrent, Hemodynamically Destabilizing Ventricular Tachycardia or Fibrillation
Authors: Kowey Peter R. , Levine Joseph H. , Herre John M. , Pacifico Antonio , Lindsay Bruce D. , Plumb Vance J. , Janosik Denise L. , Kopelman Harry A. , Scheinman Melvin M.
Published: June 2012

Background
After several days of loading, oral amiodarone, a class III antiarrhythmic, is highly effective in controlling ventricular tachyarrhythmias; however, the delay in onset of activity is not acceptable in patients with immediately life-threatening arrhythmias. Therefore, an intravenous form of therapy is advantageous. This study was designed to compare the safety and efficacy of a high and a low dose of intravenous amiodarone with bretylium, the only approved class III antiarrhythmic agent.

Methods and Results
A total of 302 patients with refractory, hemodynamically destabilizing ventricular tachycardia or ventricular fibrillation were enrolled in this double-blind trial at 82 medical centers in the United States. They were randomly assigned to therapy with intravenous bretylium (4.7 g) or intravenous amiodarone administered in a high dose (1.8 g) or a low dose (0.2 g). The primary analysis, arrhythmia event rate during the first 48 hours of therapy, showed comparable efficacy between the bretylium group and the high-dose (1000 mg/24 h) amiodarone group that was greater than that of the low-dose (125 mg/24 h) amiodarone group. Similar results were obtained in the secondary analyses of time to first event and the proportion of patients requiring supplemental infusions. Overall mortality in the 48-hour double-blind period was 13.6% and was not significantly different among the three treatment groups. Significantly more patients treated with bretylium had hypotension compared with the two amiodarone groups. More patients remained on the 1000-mg amiodarone regimen than on the other regimens.

Conclusions
Bretylium and amiodarone appear to have comparable efficacies for the treatment of highly malignant ventricular arrhythmias. Bretylium use, however, may be limited by a high incidence of hypotension.
Dose-Ranging Study of Intravenous Amiodarone in Patients With Life-Threatening Ventricular Tachyarrhythmias
Authors: Scheinman Melvin M. , Levine Joseph H. , Cannom David S. , Friehling Ted , Kopelman Harry A. , Chilson Donald A. , Platia Edward V. , Wilber David J. , Kowey Peter R.
Published: June 2012

Background
Oral amiodarone effectively suppresses ventricular arrhythmias; however, full activity may take days or weeks. In patients with frequent, life-threatening ventricular arrhythmias, this delay is not acceptable. Thus, in these patients, the speed and dosing accuracy of an intravenous formulation would be beneficial. The goal of this study was to demonstrate the efficacy of intravenous amiodarone in patients with refractory, recurrent hemodynamically destabilizing ventricular tachycardia or ventricular fibrillation by determining a dose response among three regimens.

Methods and Results
A total of 342 patients were enrolled at 46 medical centers in the United States. Patients received one of three randomized, double-blind dose regimens delivering 125, 500, or 1000 mg during the first 24 hours. Supplemental infusions (150 mg) of intravenous amiodarone could be given to treat breakthrough ventricular arrhythmias. The key efficacy end points were the arrhythmia event rate, time to first arrhythmic event, and number of supplemental infusions administered. The event rate decreased with increasing doses: median values were 0.07, 0.04, and 0.02 events per hour for the 125-, 500-, and 1000-mg dose groups, respectively, representing a significant decrease from baseline event rates (
P
=.043), and approached significance in the overall test for trend (
P
=.067). There was a significant dose-related increase in the time to first event (trend test
P
=.025) and a significant dose-related decrease in the number of supplemental boluses per hour (trend test
P
=.043). Hypotension was the most common (26%) treatment-emergent adverse event during intravenous amiodarone therapy; there was no dose-response relationship. Seventy-eight percent of the patients survived to at least 48 hours.

Conclusions
Intravenous amiodarone is effective for the treatment of recurrent, life-threatening ventricular tachyarrhythmias.
Long QT Syndrome Patients With Mutations of the
SCN5A
and
HERG
Genes Have Differential Responses to Na
+
Channel Blockade and to Increases in Heart Rate
Authors: Schwartz Peter J. , Priori Silvia G. , Locati Emanuela H. , Napolitano Carlo , Cantù Francesco , Towbin Jeffrey A. , Keating Mark T. , Hammoude Hicham , Brown Arthur M. , Chen Ling-Sing K. , Colatsky Thomas J.
Published: June 2012

Background
The genes for the long QT syndrome (LQTS) linked to chromosomes 3 (LQT3) and 7 (LQT2) were identified as
SCN5A
, the cardiac Na
+
channel gene, and as
HERG
, a K
+
channel gene. These findings opened the possibility of attempting gene-specific control of ventricular repolarization. We tested the hypothesis that the QT interval would shorten more in LQT3 than in LQT2 patients in response to mexiletine and also in response to increases in heart rate.

Methods and Results
Fifteen LQTS patients were studied. Six LQT3 and 7 LQT2 patients were treated with mexiletine, and its effects on QT and QT
c
were measured. Mexiletine significantly shortened the QT interval among LQT3 patients (QT
c
from 535±32 to 445±31 ms,
P
<.005) but not among LQT2 patients (QT
c
from 530±79 to 503±60 ms,
P
=NS). LQT3 patients (n=7) shortened their QT interval in response to increases in heart rate much more than LQT2 patients (n=4) and also more than 18 healthy control subjects (9.45±3.3 versus 3.95±1.97 and 2.83±1.33,
P
<.05; data expressed as percent reduction in QT per 100-ms shortening in RR). Among these patients, there is also a trend for LQT2 patients to have syncope or cardiac arrest under emotional or physical stress and for LQT3 patients to have cardiac events either at rest or during sleep.

Conclusions
This is the first study to demonstrate differential responses of LQTS patients to interventions targeted to their specific genetic defect. These findings also suggest that LQT3 patients may be more likely to benefit from Na
+
channel blockers and from cardiac pacing because they would be at higher risk of arrhythmia at slow heart rates. Conversely, LQT2 patients may be at higher risk to develop syncope under stressful conditions because of the combined arrhythmogenic effect of catecholamines with the insufficient adaptation of their QT interval when heart rate increases.
Localization of a Gene Responsible for Familial Dilated Cardiomyopathy to Chromosome 1q32
Authors: Durand Jean-Bernard , Bachinski Linda L. , Bieling Lisa C. , Czernuszewicz Grazyna Z. , Abchee Antoine B. , Tao Yu Qun , Tapscott Terry , Hill Rita , Ifegwu Jonah , Marian A.J. , Brugada Ramon , Daiger Steven , Gregoritch Jane M. , Anderson Jeffrey L. , Quiñones Miguel , Towbin Jeffrey A. , Roberts Robert
Published: June 2012

Background
Dilated cardiomyopathy, characterized by ventricular dilatation and decreased systolic contraction, is twofold to threefold more common as a cause of heart failure than hypertrophic cardiomyopathy and costs several billion dollars annually. The idiopathic form occurring early in life, with a 75% mortality in 5 years, is a common reason for transplantation. It is estimated that at least 20% of cases are familial.

Methods and Results
A family of 46 members spanning four generations underwent history and physical examinations, echocardiographic analysis, and blood sampling for genotyping. Diagnostic criteria, detected by echocardiography, consisted of ventricular dimension of ≥2.7 cm/m
2
with an ejection fraction ≤50% in the absence of other potential causes. DNA from all members was analyzed by polymerase chain reaction for amplification of short tandem-repeat polymorphic markers located every 10 cM throughout the human genome. Assuming a penetrance of 90%, linkage analysis was performed to map the responsible chromosomal locus. Linkage analysis, after 412 markers were analyzed, indicated the locus to be on chromosome 1q32, with a peak multipoint logarithm of the odds score at D1S414 of 6.37.

Conclusions
The locus identified in this study for familial dilated cardiomyopathy, 1q32, is rich in candidate genes, such as MEF-2, renin, and helix loop helix DNA binding protein MYF-4. Identification of the genetic defect could provide insight into the molecular basis for the cardiac dilatory response in both familial and acquired disorders.
Chlamydia pneumoniae
(TWAR) in Atherosclerosis of the Carotid Artery
Authors: Grayston J. Thomas , Kuo Cho-chou , Coulson Alan S. , Campbell Lee Ann , Lawrence Robert D. , Lee Ming Jong , Strandness Eugene D. , Wang San-pin
Published: June 2012

Background Chlamydia pneumoniae
has been demonstrated in atherosclerotic lesions of coronary arteries and aorta. A seroepidemiological study found
C pneumoniae
–specific antibody more frequently in persons with significant carotid artery wall thickening than in matched control subjects.

Methods and Results
Fresh-frozen or formalin-fixed tissue obtained at carotid endarterectomy was examined by immunocytochemistry (ICC) and the polymerase chain reaction (PCR) for the presence of
C pneumoniae.
Five of five fresh-frozen and formalin-fixed carotid endarterectomy specimens were positive for
C pneumoniae
by ICC (three of five by PCR). A total of 56 archival formalin-fixed, paraffin-embedded carotid endarterectomy tissues from three hospitals were examined by ICC. Thirty-two were positive. Thirteen normal carotid artery tissue sections from six patients were negative for
C pneumoniae
.

Conclusions
C pneumoniae
organisms are frequently found in the advanced carotid atherosclerotic lesions of persons undergoing endarterectomy. Although these findings do not establish causality for
C pneumoniae
in carotid artery atherosclerosis, they should stimulate investigation of a possible causal or pathogenic role for the organism in the disease.
Prediction of Atrioventricular Block During Radiofrequency Ablation of the Slow Pathway of the Atrioventricular Node
Authors: Hintringer Florian , Hartikainen Juha , Davies D. Wyn , Heald Spencer C. , Gill Jaswinder S. , Ward David E. , Rowland Edward
Published: June 2012

Background
Selective radiofrequency (RF) ablation of the slow pathway is an effective treatment for atrioventricular (AV) nodal reentry tachycardia. A previous report showed that rapid junctional tachycardia (JT) caused by RF associated with loss of ventriculoatrial (VA) conduction is related to increased risk for AV block. However, this can be difficult to detect during energy delivery, and more importantly, it cannot be measured before the onset of RF energy delivery. The aim of our study was to determine whether measurements made from electrograms could be used to predict the risk of AV block before RF energy is delivered.

Methods and Results
Fifty-eight patients underwent 63 selective slow pathway RF ablation procedures. In 46 (26.9%) of 172 JTs caused by RF, VA block was observed, and in 11 this was followed by AV block of various degrees. Electrograms before each application of RF were analyzed for the interval between the atrial signals in the His bundle catheter and in the distal mapping catheter [A(H)-A(Md)], the interval between the atrial signals in the His bundle catheter and in the proximal coronary sinus catheter [A(H)-A(CS)], the AV ratio, and the presence of a slow pathway potential or a fractionated atrial signal in the distal mapping catheter. Mean cycle length (CL) of JT was calculated if it consisted of at least 10 beats. These parameters were compared between patients with JT who developed VA block and subsequent AV block (group 1), patients with JT and VA block but without subsequent AV block (group 2), and patients with JT without VA block (group 3). The A(H)-A(Md) interval was significantly shorter in group 1 (17±8 ms) than in groups 2 (33±8 ms,
P
<.001) and 3 (32±10 ms,
P
<.001), whereas the A(H)-A(Md) intervals of groups 2 and 3 did not differ from each other. CL of JT, A(H)-A(CS) interval, AV ratio, presence of a slow pathway potential, or a fractionated atrial electrogram were not related to the occurrence of AV block.

Conclusions
The A(H)-A(Md) interval provides an electrophysiological marker that can be used in addition to the radiological catheter position to assess the risk for AV block before onset of RF delivery. CL of JT and occurrence of VA block are not related to the risk of AV block.
Exposure to Shear Stress Alters Endothelial Adhesiveness
Authors: Tsao Philip S. , Lewis Neil P. , Alpert Susan , Cooke John P.
Published: June 2012

Background
Shear stress increases the release of nitric oxide (NO) by endothelial cells (ECs). We and others have provided evidence that endothelium-derived NO inhibits monocyte adhesion to the vessel wall. We therefore hypothesized that previous exposure to shear stress would inhibit endothelial adhesiveness for monocytes by virtue of its effect to increase NO release.

Methods and Results
Confluent monolayers of bovine aortic endothelial cells, human aortic endothelial cells, or human venous endothelial cells were exposed to laminar fluid flow. Culture media were collected for measurement of NO (by chemiluminescence) and the prostacyclin metabolite 6-keto-prostaglandin F
1α
. NO
x
and 6-keto-prostaglandin F
1α
accumulated in the conditioned medium during laminar fluid flow from 30 minutes to 24 hours in a time-dependent fashion. In another set of studies, ECs previously exposed to flow or to static conditions were washed with Hanks’ buffer and exposed to THP-1 cells for 30 minutes. Adherent cells were counted by microscopy. Previous exposure to flow reduced endothelial adhesiveness for monocytes by 50% (
P
<.05). The effect of flow on endothelial adhesiveness occurred within 30 minutes. This effect was abrogated by nitro-
l
-arginine (an antagonist of NO synthesis), as well as by tetraethylammonium ion (an antagonist of the flow-activated potassium channel); the effects of these inhibitors were reversed by the NO donor SPM-5185. Although the cyclo-oxygenase inhibitor indomethacin totally inhibited the flow-induced production of prostacyclin by ECs, it minimally affected adherence of THP-1 cells. The early effect of flow on endothelial adhesiveness was not mediated by alterations in the expression of the endothelial adhesion molecules VCAM-1 or ICAM-1 as assessed by fluorescent activated cell sorting.

Conclusions
Shear stress alters endothelial adhesiveness for monocytes; at early time points, this effect is largely due to flow-stimulated release of NO and, to a lesser extent, prostacyclin. This effect of flow occurs within 30 minutes and is probably due to alterations in the signal transduction or activation state (rather than the expression) of endothelial adhesion molecules.
Selection and Treatment of Candidates for Heart Transplantation
Authors: Costanzo Maria Rosa , Augustine Sharon , Bourge Robert , Bristow Michael , O’Connell John B. , Driscoll David , Rose Eric
Published: June 2012

Improved outcome of heart failure in response to medical therapy, coupled with a critical shortage of donor organs, makes it imperative to restrict heart transplantation to patients who are most disabled by heart failure and who are likely to derive the maximum benefit from transplantation. Hemodynamic and functional indexes of prognosis are helpful in identifying these patients.

Stratification of ambulatory heart failure patients by objective criteria, such as peak exercise oxygen consumption, has improved ability to select appropriate adult patients for heart transplantation. Such patients will have a poor prognosis despite optimal medical therapy. When determining the impact of individual comorbid conditions on a patient’s candidacy for heart transplantation, the detrimental effects of each condition on posttransplantation outcome should be weighed.

Evaluation of patients with severe heart failure should be done by a multidisciplinary team that is expert in management of heart failure, performance of cardiac surgery in patients with low left ventricular ejection fraction, and transplantation. Potential heart transplant candidates should be reevaluated on a regular basis to assess continued need for transplantation.

Long-term management of heart failure should include continuity of care by an experienced physician, optimal dosing in conventional therapy, and periodic reevaluation of left ventricular function and exercise capacity. The outcome of high-risk conventional cardiovascular surgery should be weighed against that of transplantation in patients with ischemic and valvular heart disease.

Establishment of regional specialized heart failure centers may improve access to optimal medical therapy and new promising medical and surgical treatments for these patients as well as stimulate investigative efforts to accelerate progress in this critical area.
Effect of Short-term Cardiovascular Conditioning and Low-Fat Diet on Myocardial Blood Flow and Flow Reserve
Authors: Czernin Johannes , Barnard R. James , Sun Karl T. , Krivokapich Janine , Nitzsche Egbert , Dorsey Deborah , Phelps Michael E. , Schelbert Heinrich R.
Published: June 2012

Background
Cardiovascular conditioning reduces resting myocardial oxygen demand by lowering systolic blood pressure and heart rate. Lower myocardial oxygen demand at rest would be expected to be associated with a decrease in resting myocardial blood flow and, consequently, an increase in myocardial flow reserve as the ratio of hyperemic to resting blood flow. However, the effect of controlled exercise together with a low-lipid diet on myocardial blood flow and flow reserve has not been examined in humans.

Methods and Results
Myocardial blood flow at rest and after dipyridamole-induced hyperemia (0.56 mg/kg IV) was quantified with [
13
N]ammonia and positron emission tomography in 13 volunteers before and upon completion of a 6-week program of cardiovascular conditioning and a low-fat diet. Exercise capacity and serum lipid profiles were also assessed at the start and finish of the program. Eight normal volunteers of similar age not participating in the conditioning program served as a control group. Cardiovascular conditioning lowered the resting rate-pressure product (8859±2128 versus 7450±1496,
P
<.001), serum cholesterol (217±36 versus 181±26 mg/dL), LDL cholesterol (140±32 versus 114±24 mg/dL), and triglycerides (145±53 versus 116±33 mg/dL, all
P
<.05). Exercise tolerance (metabolic equivalent of the task, METs) improved significantly from 10.0±3.0 to 14.4±3.6 (
P
<.01). Resting blood flow decreased (0.78±0.18 versus 0.69±0.14 mL · g
−1
· min
−1
,
P
<.05), whereas hyperemic blood flow increased (2.06±0.35 versus 2.25±0.40 mL · g
−1
· min
−1
,
P
<.05), resulting in an improved myocardial flow reserve (2.82±1.07 versus 3.39±0.91,
P
<.05). Overall, the myocardial flow reserve was significantly related to exercise performance (METs). In the control group, no changes in resting rate-pressure product, serum cholesterol levels, exercise performance, resting or hyperemic myocardial blood flow, or flow reserve were observed.

Conclusions
Short-term cardiovascular conditioning together with a low-fat diet results in an improved myocardial flow reserve by lowering resting blood flow and increasing coronary vasodilatory capacity. These changes are associated with an improved exercise capacity and may offer a protective effect in patients with coronary artery disease.
Coronary Artery Disease in Heterozygous Familial Hypercholesterolemia Patients With the Same LDL Receptor Gene Mutation
Authors: Ferrières J. , Lambert J. , Lussier-Cacan S. , Davignon J.
Published: June 2012

Background
Familial hypercholesterolemia (FH), an autosomal codominant disease, is characterized by high levels of LDL cholesterol and a high incidence of coronary artery disease (CAD). To date, genetic heterogeneity has hindered the proper assessment of the relation between risk factors and CAD in FH patients.

Methods and Results
We studied the association between CAD and common risk factors in a sample of 263 French Canadian FH patients (147 women, 116 men) carrying the same >10-kb deletion of the LDL receptor gene. Thirty-five women and 54 men had CAD. The mean age of onset of CAD was 45.6±12.7 years in women and 38.8±9.4 years in men. Multiple logistic regression analyses were performed to test the association between CAD and age, tendon xanthomas, cigarette smoking, hypertension, diabetes mellitus, apolipoprotein E polymorphism, total plasma cholesterol, triglycerides, VLDL cholesterol, LDL cholesterol, HDL cholesterol, and lipoprotein(a) [Lp(a)]. In FH women, significant multivariate predictors were age (odds ratio, 1.10 for 1 year;
P
<.0001), VLDL cholesterol (odds ratio, 3.85 for 1 natural log unit;
P
<.002), and LDL cholesterol (odds ratio, 1.42 for 1 mmol/L;
P
<.02). In FH men, age (odds ratio, 1.08 for 1 year;
P
<.0001) and HDL cholesterol (odds ratio, 0.14 for 1 mmol/L;
P
=.05) were significant predictors of disease. Lp(a) was not a significant predictor in univariate or multivariate analyses.

Conclusions
This study suggests that increased risk of CAD in FH is not solely due to elevated LDL cholesterol levels and demonstrates a sex-specific lipoprotein influence on CAD in a large sample of FH patients carrying the same LDL receptor gene defect.
Circulating Cardiac Troponin T in Potential Heart Transplant Donors
Authors: Riou Bruno , Dreux Sophie , Roche Sabine , Arthaud Martine , Goarin Jean-Pierre , Léger Philippe , Saada Michel , Viars Pierre
Published: June 2012

Background
Brain death may induce myocardial dysfunction, the mechanisms of which are not yet fully understood. Circulating cardiac troponin T is considered a highly sensitive and specific marker of myocardial cell injury.

Methods and Results
We prospectively measured circulating cardiac troponin T in 100 brain-dead patients and measured the left ventricular ejection fraction area (LVEFa), using transesophageal echocardiography. Sixty-one patients had normal LVEFa, 25 had moderate decrease in LVEFa (30% to 50%), and 14 had severe decrease in LVEFa (≤30%). Circulating cardiac troponin T concentrations were significantly higher (1.68±1.03 μg/L
−1
,
P
<.01) in patients with a severe decrease in LVEFa than in the two other groups (0.42±0.43 and 0.12±0.16 μg/L
−1
, respectively), and there was a significant correlation between LVEFa and cardiac troponin T concentration (ρ=−0.59,
P
<.0001). An elevated circulating cardiac troponin T concentration (≥0.5 μg/L
−1
) was more accurate (sensitivity, 1.00; specificity, 0.84) in predicting a severe decrease in LVEFa than an elevated CKMB value or an increased CKMB/CK ratio.

Conclusions
An elevated circulating cardiac troponin T was associated with a severe decrease in LVEFa in brain-dead patients, suggesting that severe and potentially irreversible myocardial cell damage occurred. In contrast, CKMB determination was not useful. Since the quality of the donor’s heart is considered an important prognosis factor in heart transplantation, the determination of circulating cardiac troponin T concentration could be useful to the heart transplantation team.
Vascular Cell Adhesion Molecule–1 Is Induced on Vascular Endothelia and Medial Smooth Muscle Cells in Experimental Cardiac Allograft Vasculopathy
Authors: Ardehali Abbas , Laks Hillel , Drinkwater Davis C. , Ziv Eli , Drake Thomas A.
Published: June 2012

Background
Cardiac allograft vasculopathy (CAV) is the major cause of late death among heart transplant recipients. The pathogenesis of CAV is poorly understood.

Methods and Results
To better characterize CAV, we performed immunohistochemical analysis of vascular lesions in a previously described murine model of CAV. The B10.A strain hearts were transplanted heterotopically into B10.BR strain recipients. The cardiac allografts were harvested from 1 to 2 months after implantation. The majority of epicardial and intramyocardial coronary arteries in explanted hearts had developed intimal thickening. The cellular infiltrate of the intimal thickening, major histocompatibility (MHC) antigens, intracellular adhesion molecule–1 (ICAM-1), and vascular cell adhesion molecule–1 (VCAM-1) expression were studied with the use of immunohistochemistry. In experimental CAV in mice, the cellular infiltrate of expanded intima consisted of macrophages, T lymphocytes, and smooth muscle cells. A substantial number of macrophages and T lymphocytes within the expanded intima expressed MHC class II antigen, a marker of cellular activation. The vessel wall cells also appeared to be activated due to their expression of endothelium-leukocyte adhesion molecules. The vascular endothelium of cardiac allografts displayed ICAM-1, VCAM-1, and unmatched MHC antigen (MHC class I in this model) upregulation. The medial smooth muscle cells also expressed VCAM-1 and unmatched MHC antigen.

Conclusions
These findings suggest that (1) the cellular infiltrate of the expanded intima in experimental CAV is similar to that of human CAV, (2) experimental CAV is a local immune-mediated process requiring active participation of donor vessel wall cells and recipient mononuclear cells, and (3) coexpression of adhesion molecules and unmatched MHC antigen identifies endothelial cells as immune targets for activated host mononuclear cells. Furthermore, the presence of both VCAM-1 and unmatched MHC antigen supports a central role for medial smooth muscle cells as allogeneic immune stimulator.
Deleterious Effects of a Systemic Lytic State on Reperfused Myocardium
Authors: Ohnishi Yoshio , Butterfield Michelle C. , Saffitz Jeffrey E. , Sobel Burton E. , Corr Peter B. , Goldstein James A.
Published: June 2012

Background
The beneficial effects of flow restoration and the deleterious impact of reperfusion injury on ischemic myocardium are well known. However, most experimental studies have induced reperfusion by mechanical release of nonthrombotic occlusions, only occasionally in the presence of a systemic lytic state. Conditions differ markedly in patients undergoing pharmacological or mechanical recanalization of thrombotically occluded coronary arteries. Accordingly, this study was designed to determine whether the method of coronary occlusion and mode of recanalization influence the response of the heart to reperfusion.

Methods and Results
The acute effects of reperfusion on right ventricular (RV) function and histology were studied in open-chest dogs subjected to right coronary artery (RCA) balloon occlusion and deflation alone (group 1), pharmacological lysis of thrombotic occlusions (group 2), balloon occlusion with reperfusion induced by balloon deflation in the presence of a systemic lytic state (group 3), and recanalization of thrombotically occluded vessels by direct angioplasty (group 4). In all groups, 1 hour of RCA occlusion led to RV free wall (FW) dyskinesis. In group 1, reperfusion promptly improved RVFW function, with normal RVFW thickness and only minimal edema by microscopy. In contrast, in group 2, clot lysis led to acute RVFW swelling and impaired recovery of RVFW contraction associated with striking interstitial edema, contraction band necrosis, and hemorrhage by microscopy. In group 3, balloon deflation in the presence of a lytic state led to a similar but less severe pattern of abrupt RVFW swelling and impaired recovery of RVFW function but lesser histological alterations than in group 2. However, mechanical recanalization of thrombotically occluded vessels (group 4) led to prompt recovery of RVFW function without significant RVFW swelling or histological abnormalities.

Conclusions
Our observations indicate that the responses of ischemic myocardium to reperfusion are influenced by factors beyond those effects attributable to ischemia and reperfusion per se. Pharmacological lysis of coronary thrombi results in alterations characteristic of reperfusion injury and associated with impaired functional recovery. Such changes are also evident, although to a lesser extent, when reperfusion of nonthrombotic occlusions is induced by mechanical recanalization in the presence of a systemic lytic state but not in its absence. However, such effects were not seen with direct mechanical recanalization of thrombotically occluded vessels. In aggregate, these findings indicate that induction of a systemic lytic state, together with products released by lysis of intracoronary thrombi, generates an injurious milieu that exerts adverse effects on reperfused myocardium.
Prevalence of Hypertrophic Cardiomyopathy in a General Population of Young Adults
Authors: Maron Barry J. , Gardin Julius M. , Flack John M. , Gidding Samuel S. , Kurosaki Tom T. , Bild Diane E.
Published: June 2012

Background
Hypertrophic cardiomyopathy (HCM) is a genetically transmitted disease and an important cause of morbidity and sudden cardiac death in young people, including competitive athletes. At present, however, few data exist to estimate the prevalence of this disease in large populations.

Methods and Results
As part of the Coronary Artery Risk Development in (Young) Adults (CARDIA) Study, an epidemiological study of coronary risk factors, 4111 men and women 23 to 35 years of age selected from the general population of four urban centers had technically satisfactory echocardiographic studies during 1987 through 1988. Probable or definite echocardiographic evidence of HCM was present in 7 subjects (0.17%) on the basis of identification of a hypertrophied, nondilated left ventricle and maximal wall thickness ≥15 mm that were not associated with systemic hypertension. Prevalence in men and women was 0.26:0.09%; in blacks and whites, 0.24:0.10%. Ventricular septal thickness was 15 to 21 mm (mean, 17 mm) in the 7 subjects. Only 1 of the 7 subjects had ever experienced important cardiac symptoms attributable to HCM, had previously been suspected of having cardiovascular disease, or had obstruction to left ventricular outflow; 4 other subjects had relatively mild systolic anterior motion of the mitral valve that was insufficient to produce dynamic basal outflow obstruction. ECGs were abnormal in 5 of the 7 subjects. Five other study subjects had left ventricular wall thicknesses of 15 to 21 mm that were a consequence of systemic hypertension.

Conclusions
HCM was present in about 2 of 1000 young adults. These unique population-based data will aid in assessments of the impact of HCM-related mortality and morbidity in the general population and the practicality of screening large populations for HCM, including those comprising competitive athletes.
Myocardial Blood Flow Response to Pacing Tachycardia and to Dipyridamole Infusion in Patients With Dilated Cardiomyopathy Without Overt Heart Failure
Authors: Neglia Danilo , Parodi Oberdan , Gallopin Michela , Sambuceti Gianmario , Giorgetti Assuero , Pratali Lorenza , Salvadori Piero , Michelassi Claudio , Lunardi Maurizio , Pelosi Gualtiero , Marzilli Mario , L’Abbate Antonio
Published: June 2012

Background
Myocardial blood flow (MBF) impairment has been documented in advanced dilated cardiomyopathy (DCM) in which hemodynamic factors, secondary to severe ventricular dysfunction, may limit myocardial perfusion. To assess whether MBF impairment in DCM may also be present independent of hemodynamic factors, the present study was designed to quantify myocardial perfusion in patients with mild disease without overt heart failure.

Methods and Results
Absolute regional MBF (milliliters per minute per gram) was measured by positron emission tomography and
13
N-ammonia in resting conditions, during pacing-induced tachycardia, and after dipyridamole infusion (0.56 mg/kg over 4 minutes) in 22 DCM patients and in 13 healthy subjects. Patients were in New York Heart Association functional class I-II and showed depressed left ventricular (LV) ejection fraction by radionuclide angiography (35±8%; range, 21% to 48%), normal coronary angiography, and normal or moderately increased LV end-diastolic pressure (9.2±5.5 mm Hg; range, 2 to 20 mm Hg). There were no differences in arterial blood pressure, heart rate, and rate-pressure product between patients and control subjects in the three study conditions. Compared with control subjects, DCM patients had lower mean MBF at rest (0.80±0.25 versus 1.08±0.20 mL · min
−1
· g
−1
,
P
<.01), during atrial pacing tachycardia (1.21±0.59 versus 2.03±0.64 mL · min
−1
· g
−1
,
P
<.01), and after dipyridamole infusion (1.91±0.76 versus 3.78±0.86 mL · min
−1
· g
−1
,
P
<.01). LV MBF values were related to baseline LV end-diastolic pressure at rest (
r
=−.57,
P
<.01) and during pacing (
r
=−.67,
P
<.01) but not after dipyridamole infusion (
r
=.19,
P
=.40). Five patients had LV end-diastolic pressure >12 mm Hg; in 4, myocardial perfusion was severely depressed both at baseline and in response to stress.

Conclusions
In patients with DCM without overt heart failure, myocardial perfusion is impaired both at rest and in response to vasodilating stimuli. The abnormalities in vasodilating capability can be present despite normal hemodynamics; progression of the disease is associated with more depressed myocardial perfusion.
Left Ventricular Hypertrophy Has a Greater Impact on Survival in Women Than in Men
Authors: Liao Youlian , Cooper Richard S. , Mensah George A. , McGee Daniel L.
Published: June 2012

Background
Echocardiographically determined left ventricular hypertrophy (LVH) has a well-demonstrated association with cardiovascular morbidity and mortality. However, whether or not there is a sex differential in the impact of LVH on mortality has never been systematically explored.

Methods and Results
This study enrolled 436 consecutive black patients (163 men and 273 women) free of angiographic coronary artery disease from a hospital registry. LVH (left ventricular [LV] mass/body surface area ≥117 g/m
2
in men and ≥104 g/m
2
in women) was present in 84 men (52%) and 119 women (44%). During a mean of 5 years’ follow-up (range, 0 to 9), 49 patients (26 men and 23 women) died. The mortality rate was 5.40 per 100 patient-years in men with LVH and 2.58 in men without LVH (crude relative risk [RR]=2.09) and 3.21 and 0.66, respectively, in women (RR=4.87). In Cox regression analysis, adjusting for age, hypertension, and ejection fraction, the RR of total death for LVH versus non-LVH was 2.0 (95% confidence interval [CI], 0.8 to 5.0) in men and 4.3 (95% CI, 1.6 to 11.7) in women. For cardiac death, RR was 1.3 (95% CI, 0.4 to 3.7) and 7.5 (95% CI, 1.6 to 33.8) in men and women, respectively. Analyses using LV mass indexed by height or height
2.7
with the use of different LVH cut points, comparing patients in the highest sex-specific tertile of mass index to those in the lower two tertiles, and the use of LV mass indexes as continuous variables similarly demonstrated a greater increase in risk of either fatal end point among women than men.

Conclusions
These findings indicate a sex difference in the contribution of LV mass and hypertrophy to mortality in the absence of coronary artery disease.
Effects of Valve Surgery on Left Ventricular Contractile Function in Patients With Long-term Mitral Regurgitation
Authors: Starling Mark R.
Published: June 2012

Background
Patients with long-term mitral regurgitation were studied both before and 1 year after successful valve surgery to test the hypothesis that impaired left ventricular contractile function improves after surgery for long-term mitral regurgitation in humans.

Methods and Results
Fifteen patients with long-term mitral regurgitation were studied. Micromanometer left ventricular pressures and radionuclide angiograms for left ventricular volumes were acquired over a range of loading conditions both before and 1 year after successful valve surgery for long-term mitral regurgitation. To assess both left ventricular contractility and pump efficiency, we used left ventriculoarterial coupling to evaluate the interaction of the left ventricle with the arterial system with the use of the left ventricular contractile index, E
es
, and effective arterial elastance, E
a
. Left ventricular pump efficiency was expressed as the ratio of forward left ventricular stroke work to the corresponding pressure–volume area. All patients had successful mitral valve surgery as manifest by no or only trivial residual mitral regurgitation on physical examination and Doppler echocardiography. The average radionuclide regurgitant index of 1.28±0.56 was also less than the preoperative value of 2.70±0.80 (
P
<.0001). The mean left ventricular end-diastolic volume index decreased from 137±37 to 90±31 mL/m
2
(
P
<.001), and the average left ventricular end-systolic volume index also decreased (59±29 to 45±27 mL/m
2
,
P
<.01), although individual variation was observed. The average left ventricular ejection fraction fell from 0.58±0.12 to 0.53±0.16, which was not significant. In contrast, E
es
increased from a mean value of 0.95±0.66 mm Hg/mL during the preoperative study to 2.62±2.16 mm Hg/mL at the 1-year postsurgical study (
P
<.01). This improvement in left ventricular contractility was observed in patients with long-term mitral regurgitation, who before surgery had preserved left ventricular ejection fraction (
P
<.001), less left ventricular dilation at end diastole (
P
<.01) and end systole (
P
<.001), and less impaired left ventricular contractility. Because effective arterial elastance was unchanged, left ventriculoarterial coupling also improved from an average of 0.47±0.39 to 1.81±1.63 (
P
<.01). Consequently, left ventricular pump efficiency improved from a mean preoperative value of 0.23±0.10 to 0.55±0.22 at the 1-year postsurgical study (
P
<.0001).

Conclusions
The results indicate that left ventricular contractile impairment is reversible in many patients with long-term mitral regurgitation. In fact, these data indicate that mitral valve surgery can be recommended to preserve left ventricular contractility in patients with long-term mitral regurgitation, particularly in those patients who before surgery have normal left ventricular ejection fractions and less left ventricular dilation and contractile impairment.
Left Atrial Size and the Risk of Stroke and Death
Authors: Benjamin Emelia J. , D’Agostino Ralph B. , Belanger Albert J. , Wolf Philip A. , Levy Daniel
Published: June 2012

Background
The medical literature contains conflicting reports on the association of left atrial (LA) enlargement with risk of stroke. The relation of LA size to risk of stroke and death in the general population remains largely unexplored.

Methods and Results
Subjects 50 years of age and older from the Framingham Heart Study were studied to assess the relations between echocardiographic LA size and risk of stroke and death. During 8 years of follow-up, 64 of 1371 (4.7%) men and 73 of 1728 (4.2%) women sustained a stroke, and 296 (21.6%) men and 271 (15.7%) women died. Sex-specific Cox proportional-hazards models were adjusted for age, hypertension, diabetes, atrial fibrillation, smoking, ECG left ventricular (LV) hypertrophy, and congestive heart failure or myocardial infarction. After multivariable adjustment, for every 10-mm increase in LA size, the relative risk of stroke was 2.4 in men (95% CI, 1.6 to 3.7) and 1.4 in women (95% CI, 0.9 to 2.1); the relative risk of death was 1.3 in men (95% CI, 1.0 to 1.5) and 1.4 in women (95% CI, 1.1 to 1.7). Adjusting for ECG LV mass/height attenuated the relation of LA size to stroke and death.

Conclusions
After multivariable adjustment, LA enlargement remained a significant predictor of stroke in men and death in both sexes. The relation of LA enlargement to stroke and death appears to be partially mediated by LV mass.