bluuebunny/crossref_metadata_2025 huggingface dataset:
Concordance of Preoperative Clinical Risk With Angiographic Severity of Coronary Artery Disease in Patients Undergoing Vascular Surgery
Authors: Paul Sumita D. , Eagle Kim A. , Kuntz Karen M. , Young Jess R. , Hertzer Norman R.
Published: June 2012

Background
Preoperative clinical indexes to stratify cardiac risk have not been validated angiographically. Our aims were to determine the concordance of clinical risk with severity of coronary stenosis and to develop and validate a preoperative clinical index to exclude the presence of significant coronary stenosis.

Methods and Results
We carried out a prospective study of 878 consecutive patients (including the derivation and validation sets). “Severe” stenosis was defined as three-vessel (≥50% stenosis in each), two-vessel (≥50% stenosis in one when the other is ≥70% stenosis of the left anterior descending), or left main disease (≥50%); “critical” stenosis was three-vessel (≥70% stenosis in each) and/or left main stenosis ≥70%. A preoperative clinical index (diabetes mellitus, prior myocardial infarction, angina, age >70 years, congestive heart failure) was used to stratify patients. A gradient of risk for severe stenosis was seen with increasing numbers of clinical markers. The following prediction rules were developed: The absence of severe coronary stenoses can be predicted with a positive predictive value of 96% for patients who have no (1) history of diabetes, (2) prior angina, (3) previous myocardial infarction, or (4) history of congestive heart failure. The absence of critical coronary stenoses can be predicted with a positive predictive value of 94% for those who have no (1) prior angina, (2) previous myocardial infarction, or (3) history of congestive heart failure.

Conclusions
By reliably identifying a large proportion of patients with a low likelihood of significant stenoses, these prediction rules can help to substantially reduce healthcare costs associated with preoperative cardiac risk assessment for noncardiac surgery.
Circadian Variation in Defibrillation Energy Requirements
Authors: Venditti Ferdinand J. , John Roy M. , Hull Michael , Tofler Geoffrey H. , Shahian David M. , Martin David T.
Published: June 2012

Background
Reports have demonstrated a circadian variation in the incidence of acute myocardial infarction, ventricular arrhythmias, and sudden cardiac death. We tested the hypothesis that a similar circadian variation exists for defibrillation energy requirements in humans.

Methods and Results
We reviewed the time of defibrillation threshold (DFT) measurements in 134 patients with implantable cardioverter-defibrillators (ICDs) who underwent 345 DFT measurements. The DFT was determined in 130 patients at implantation, in 121 at a 2 months, and in 94 at 6 months. All patients had nonthoracotomy systems. The morning DFT (8
am
to 12 noon) was 15.1±1.2 J compared with 13.1±0.9 J in the midafternoon (12 noon to 4
pm
) and 13.0±0.7 J in the late afternoon (4 to 8
pm
),
P
<.02. In a separate group of 930 patients implanted with an ICD system with date and time stamps for each therapy, we reviewed 1238 episodes of ventricular tachyarrhythmias treated with shock therapy. To corroborate the hypothesis that energy requirements for arrhythmia termination vary during the course of the day, we plotted the failed first shock frequency for all episodes per hour. There was a significant peak in failed first shocks in the morning compared with other time intervals (
P
=.02).

Conclusions
There is a morning peak in DFT and a corresponding morning peak in failed first shock frequency. This morning peak resembles the peaks seen in other cardiac events, specifically sudden cardiac death. These findings have important implications for appropriate ICD function, particularly in patients with marginal DFTs.
Adventitial Myofibroblasts Contribute to Neointimal Formation in Injured Porcine Coronary Arteries
Authors: Shi Yi , O'Brien James E. , Fard Ali , Mannion John D. , Wang Dian , Zalewski Andrew
Published: June 2012

Background
The adventitia undergoes remodeling changes after a deep medial coronary injury. Because this process is associated with the formation of adventitial myofibroblasts, which resemble medial smooth muscle (SM) cells, we have examined myofibroblast involvement in the development of neointima.

Methods and Results
In a porcine model, severe endoluminal coronary injury resulted in fibroblast proliferation and adventitial remodeling. Significant adventitial responses were associated with increased neointimal formation (
P
<.01). To examine the contribution of adventitial cells to the development of neointima, proliferating cells were labeled with bromodeoxyuridine (BrdU) at 12 and 24 hours after injury, and their subsequent localization was determined by immunohistochemistry (n=24). At 2 to 3 days after severe injury, the adventitia contained numerous BrdU-labeled cells (37±4%), whereas the media demonstrated infrequent labeled cells (4±1%). Adventitial cells lacked α-SM actin and desmin, which distinguished them from medial SM cells. At 7 to 8 days, some labeled cells acquired characteristics of myofibroblasts expressing α-SM actin. They were found to translocate to the gap between dissected media and contributed to the formation of neointima (76±19%). At 18 to 35 days, labeled cells were abundant in the neointima (86±5%). They showed uniform immunostaining for α-SM actin but not for desmin, thereby differing from medial SM cells and blood-borne cells.

Conclusions
This study demonstrates translocation of adventitial fibroblasts to neointima, their phenotypic modulation to myofibroblasts, and distinct characteristics of myofibroblasts within neointima after severe endoluminal coronary injury. These findings suggest the significance of vascular fibroblasts in the process of arterial repair.
Subacute Thrombosis and Vascular Injury Resulting From Slotted-Tube Nitinol and Stainless Steel Stents in a Rabbit Carotid Artery Model
Authors: Sheth Sushil , Litvack Frank , Dev Vishva , Fishbein Michael C. , Forrester James S. , Eigler Neal
Published: June 2012

Background
Our objectives were to quantify the thrombogenicity and extent of vascular injury created by slotted-tube geometry stainless steel and nitinol coronary stents in a rabbit carotid artery model.

Methods and Results
Stents were implanted in rabbit right carotid arteries without antiplatelet therapy. Stainless steel stents were implanted for 4 days while nitinol stents were placed for 4 and 14 days (n=8, 8, and 6, respectively). Stent thrombosis was assessed by thrombus weight, grading thrombus encroachment of the lumen, and by blood flow in the stented and contralateral arteries. Stainless steel stents at 4 days contained more thrombus than 4- and 14-day nitinol stents (20.0±5.9 versus 2.5±0.6 and 2.7±0.3 mg, respectively;
P
<.000001). Stainless steel stents were more often occluded by thrombus (6 of 8) or contained more subocclusive thrombus (2 of 8) than nitinol stents (0 of 14,
P
<.002). Resting blood flow was reduced in arteries with stainless steel stents compared with 4- and 14-day nitinol stents (1.5±2.8 versus 24.0±2.0 and 25.5±1.9 mL/min, respectively,
P
<.000001). Stainless steel stents were less uniformly expanded, had deeper strut penetration into the vascular wall, and were associated with more extensive medial smooth muscle cell necrosis. There were strong correlations (
r
=.77 to .95) between variables of thrombosis extent (thrombus weight and grade) and histologically determined vascular injury (strut penetration and medial necrosis).

Conclusions
Slotted-tube stainless steel stents were more thrombogenic and created more extensive vascular injury than nitinol stents in a rabbit carotid artery model. The mechanisms underlying these differences probably are related to metallurgic and design geometry properties of the two stent types.
Thrombogenic Properties of Murine Anti-Cardiolipin Antibodies Induced by β
2
Glycoprotein 1 and Human Immunoglobulin G Antiphospholipid Antibodies
Authors: Pierangeli Silvia S. , Liu Xiao Wei , Anderson G. , Barker J.H. , Harris E.N.
Published: June 2012

Background
Recurrent arterial thrombosis and venous thrombosis are frequent complications of the antiphospholipid syndrome (APS). Patients produce anti-cardiolipin antibodies, but the role of these antibodies in thrombus formation is uncertain. This study used a unique CD-1 mouse model of thrombosis to determine whether anti-cardiolipin and anti-β
2
glycoprotein 1 (β
2
GP1) antibodies induced immunologically in these animals are thrombogenic.

Methods and Results
The CD-1 mouse model enables measurement of the kinetics of a thrombus induced in the femoral vein of the animal. Animals are first anesthetized, then one femoral vein is exposed and subjected to a standardized, nonpenetrating “pinch” injury that induces a thrombus. The vein is transilluminated, and the growing thrombus is visualized on a television screen. The rate of formation and disappearance of the thrombus as well as its area can be measured by a computer attached to the television. Three groups of CD-1 mice (each group comprising seven animals) were studied. Group 1 mice were actively immunized with β
2
GP1, resulting in production of anti-β
2
GP1 and anti-cardiolipin antibodies. Group 2 mice were actively immunized with human immunoglobulin G (IgG) anti-cardiolipin antibodies and produced anti-human IgG as well as anti-cardiolipin antibodies (the latter by an idiotype–anti-idiotype reaction). These animals did not produce anti-β
2
GP1 antibodies. Group 3 mice were immunized with human serum albumin (HSA) and produced anti-HSA but not anti-cardiolipin antibodies. The kinetics of thrombus formation induced in the femoral veins of the experimental mice were compared. Results showed that the mean thrombus area as well as mean time during which thrombi persisted were significantly greater in group 1 and group 2 mice compared with group 3. There was no statistical difference between group 1 or group 2.

Conclusions
Demonstration of a thrombogenic effect of murine anti-cardiolipin antibodies suggests that these antibodies may be pathogenic in humans with APS.
Contribution to Heart Rate Variability by Mechanoelectric Feedback
Authors: Horner S.M. , Murphy C.F. , Coen B. , Dick D.J. , Harrison F.G. , Vespalcova Z. , Lab M.J.
Published: June 2012

Background
Heart rate variability is an important prognostic indicator for sudden death. An increased risk of sudden death and arrhythmia is associated with reduced heart rate variability in heart failure. In heart failure, there is also dilatation of the atria, which raises the prospect that there could be some physiological basis to possibly link heart rate variability with atrial dilatation. We therefore investigated whether sustained atrial stretch could modulate heart rate variability directly.

Methods and Results
Pigs were anesthetized and their hearts exposed. A specially built device stretched the sinoatrial node before and after vagal section and then after administration of propranolol. Stretch of the sinoatrial node decreases heart rate variability in the following ways: The standard deviation of the beat-to-beat interval decreases (4.2 to 2.6 ms;
P
=.004), and the high-frequency components are reduced (control, 6.5±2.2 ms
2
; during stretch, 1.4±0.3 ms
2
;
P
=.003). After section of both vagi, the high-frequency components are reduced by stretch of the sinoatrial node (2.8±0.9 ms
2
for control versus 1.2±0.3 ms
2
during stretch;
P
=.05). Similarly, after both vagal section and β-blockade, stretch of the sinoatrial node reduces the high-frequency components (10.6±3.5 ms
2
for control versus 3.0±1.5 ms
2
during stretch;
P
=.01).

Conclusions
We conclude that stretch of the sinoatrial node reduces high-frequency heart rate variability. This may account in part for the reduced heart rate variability seen in clinical conditions in which the right atrium is dilated, such as congestive cardiac failure.
Preconditioning by Transient Myocardial Ischemia Confers Protection Against Ischemia-Induced Ventricular Arrhythmias in Variant Angina
Authors: Pasceri Vincenzo , Lanza Gaetano A. , Patti Giuseppe , Pedrotti Patrizia , Crea Filippo , Maseri Attilio
Published: June 2012

Background
In experimental models, ischemic preconditioning of the heart protects against ischemic damage and ventricular arrhythmias during subsequent coronary occlusion. In this study, we investigated whether protection against ischemic suffering and ischemia-induced arrhythmias may occur after spontaneous transmural ischemia in humans.

Methods and Results
We performed 24-hour Holter monitoring in 10 patients with variant angina who developed complex ventricular arrhythmias (CVAs, more than five premature ventricular beats per minute or repetitive ventricular arrhythmias) during episodes of ST-segment elevation. A total of 150 episodes of ST-segment elevation were detected on Holter monitoring, 21 (14%) of which showed CVAs. Episodes separated from the previous one by a time interval of ≤30 minutes or by a time interval of >30 minutes did not differ in either magnitude or duration of ST-segment elevation, but CVAs occurred more frequently in the second group (3% versus 29%,
P
<.0001). The time interval from the preceding ischemic episode was longer for the episodes with compared with those without CVAs (197±275 versus 57±87 minutes,
P
<.001), but these two groups of episodes also had similar severities and durations of ST-segment elevation. Finally, when we analyzed 13 clusters of two to six ischemic episodes, CVAs were found much more frequently in the first (92%) than in the last (23%,
P
=.009) episode of the clusters, while ST-segment elevations were similar (2.1±1.6 versus 2.2±1.1 mm) and ischemia durations shorter in the first than in the last episode (3.9±3.6 versus 6.1±1.7 minutes,
P
=.03).

Conclusions
Our data indicate that preconditioning by transient ischemia induces a significant protection against ischemia-induced CVAs in patients with variant angina. This beneficial effect was not related to a reduction in either severity or duration of ischemia, suggesting that arrhythmic protection was a direct consequence of preconditioning rather than an epiphenomenon of ischemic protection.
Creatine Kinase System in Failing and Nonfailing Human Myocardium
Authors: Nascimben Luigino , Ingwall Joanne S. , Pauletto Paolo , Friedrich Jan , Gwathmey Judith K. , Saks Valdur , Pessina Achille Cesare , Allen P.D.
Published: June 2012

Background
The creatine kinase (CK) reaction is important for rapid resynthesis of ATP when the heart increases its work. Studies defining the CK system in human failing and nonfailing myocardium are limited and in conflict. To resolve this conflict, we measured the activities of CK and its isoenzymes and the contents of creatine and CK-B in homogenates of human myocardium.

Methods and Results
Myocardium was sampled from 23 subjects who underwent heart transplant, 36 subjects maintained in an intensive care unit before heart harvesting, 13 accident victims, and 2 patients undergoing heart surgery. Since the characteristics of myocardium of potential organ donors differed from those of myocardium of accident victims, data are presented for three groups: failing, donor, and control. CK activity was 7.7±1.9 and 6.0±1.4 IU/mg protein in left (LV) and right (RV) ventricles of failing, 9.4±2.5 and 10.7±2 IU/mg protein in LV and RV of donor, and 11.6±2.4 IU/mg protein in LV of control hearts. CK-MM and the mitochondrial isoenzyme activities were lower in failing and donor LV, and CK-MB activity and CK-B content were higher in failing and donor hearts. Creatine contents were 64±25 and 56±18.6 nmol/mg protein in LV and RV of failing, 96±30 and 110±24 nmol/mg protein in LV and RV of donor, and 131±28 nmol/mg protein in LV of control hearts.

Conclusions
In failing and nonfailing donor human myocardium, there is a combined decrease of CK activity and creatine that may impair the ability to deliver ATP to energy-consuming systems.
Multiple Mechanisms in the Long-QT Syndrome
Authors: Roden Dan M. , Lazzara Ralph , Rosen Michael , Schwartz Peter J. , Towbin Jeffry , Vincent G. Michael
Published: June 2012

Abstract
The congenital long-QT syndrome (LQTS) is characterized by prolonged QT intervals, QT interval lability, and polymorphic ventricular tachycardia. The manifestations of the disease vary, with a high incidence of sudden death in some affected families but not in others. Mutations causing LQTS have been identified in three genes, each encoding a cardiac ion channel. In families linked to chromosome 3, mutations in
SCN5A
, the gene encoding the human cardiac sodium channel, cause the disease. Mutations in the human ether-a`-go-go–related gene (
HERG
), which encodes a delayed-rectifier potassium channel, cause the disease in families linked to chromosome 7. Among affected individuals in families linked to chromosome 11, mutations have been identified in
KVLQT1
, a newly cloned gene that appears to encode a potassium channel. The
SCN5A
mutations result in defective sodium channel inactivation, whereas
HERG
mutations result in decreased outward potassium current. Either mutation would decrease net outward current during repolarization and would thereby account for prolonged QT intervals on the surface ECG. Preliminary data suggest that the clinical presentation in LQTS may be determined in part by the gene affected and possibly even by the specific mutation. The identification of disease genes in LQTS not only represents a major milestone in understanding the mechanisms underlying this disease but also presents new opportunities for combined research at the molecular, cellular, and clinical levels to understand issues such as adrenergic regulation of cardiac electrophysiology and mechanisms of susceptibility to arrhythmias in LQTS and other settings.
Increased Immunoreactive Endothelin-1 in Human Transplant Coronary Artery Disease
Authors: Ravalli Stefano , Szabolcs Matthias , Albala Arline , Michler Robert E. , Cannon Paul J.
Published: June 2012

Background
The pathogenesis of transplant coronary artery disease (TCAD) is unknown, but it is thought to derive from an interaction between immune and nonimmune factors, leading to smooth muscle cell proliferation and accumulation in the expanded neointima. Endothelin-1 (ET-1), a potent vasoconstrictor with mitogenic properties for vascular smooth muscle cells, has recently been demonstrated in native vessel atherosclerosis. The present study used immunohistochemistry to investigate the role of ET-1 in TCAD.

Methods and Results
ET-1 immunoreactivity and cellular localization were assessed in human coronary arteries with TCAD (n=13) and in normal coronary arteries (n=10) with single- and double-label immunohistochemistry. The intensity of immunostaining was determined by a semiquantitative method. Diffuse and intense ET-1 immunoreactivity was found in 11 of 13 patients with TCAD (85%), mainly in myointimal cells and, in lesser amounts, in macrophages and endothelial cells. In contrast, normal coronary arteries had only faint immunostaining localized to the endothelial layer. Mean semiquantitative grade was significantly higher in TCAD than in normal arteries (1.8 versus 0.7;
P
<.05). ET-1 was more frequently present in lipid-rich, atheromatous lesions than in lipid-poor, proliferative ones. Intimal neovessels consistently immunostained for ET-1.

Conclusions
Immunoreactivity for ET-1 is significantly increased in TCAD, possibly as a result of stimulatory cytokines and growth factors that are upregulated in the posttransplant state. The results suggest a role for this mitogenic peptide in the pathogenesis of graft arteriosclerosis.
Importance of Subvalvular Preservation and Early Operation in Mitral Valve Surgery
Authors: Lee Evelyn M. , Shapiro Leonard M. , Wells Francis C.
Published: June 2012

Background
Mitral valve replacement (MVR) has a high mortality and morbidity. It has been suggested that preservation of the subvalvular apparatus and more optimal timing of surgery might improve outcome.

Methods and Results
We performed a retrospective study of 612 consecutive patients who underwent mitral valve repair or replacement: 226 patients had repair, 68 had replacement with subvalvular preservation (MVR/SVP), and 318 had replacement without subvalvular preservation (MVR/NoSVP). Baseline characteristics were most unfavorable in the repair group with respect to age (
P
=.002) and in the repair and MVR/SVP groups with respect to NYHA functional class and left ventricular function (
P
=.044). Thirty-day mortality was lower in the repair (1.8%,
P
=.046) and MVR/SVP (1.5%,
P
=NS) groups than the MVR/NoSVP group (5.0%). Overall survival at 7 years was better in the repair (71.2±5.6%,
P
=.022) and MVR/SVP (66.2±12.4%,
P
=.017) groups than the MVR/NoSVP group (63.5±3.4%). Myocardial failure caused 66 of 107 complication-related deaths. Multivariate analysis confirmed independent beneficial effects of repair on 30-day mortality (odds ratio, 0.27,
P
<.05) and of repair and MVR/SVP on overall mortality (hazard ratios, 0.43,
P
<.001 and 0.40,
P
<.05, respectively) and complication-related death (hazard ratios, 0.38,
P
<.001 and 0.35,
P
<.05, respectively). Preoperative NYHA class III or IV symptoms and left ventricular impairment were independent risk factors for death and myocardial failure.

Conclusions
Mitral valve repair is superior to replacement. If repair is not feasible, the subvalvular apparatus should be preserved. Early surgery before the development of severe symptoms and demonstrable left ventricular impairment is also needed to optimize outcome.
Predominance of Dense Low-Density Lipoprotein Particles Predicts Angiographic Benefit of Therapy in the Stanford Coronary Risk Intervention Project
Authors: Miller Bonnie D. , Alderman Edwin L. , Haskell William L. , Fair Joan M. , Krauss Ronald M.
Published: June 2012

Background
LDL particles differ in size and density. Individuals with LDL profiles that peak in relatively small, dense particles have been reported to be at increased risk of coronary artery disease. We hypothesized that response to coronary disease therapy in such individuals might differ from response in individuals whose profiles peak in larger, more buoyant LDL. We examined this hypothesis in the Stanford Coronary Risk Intervention Project, an angiographic trial that compared multifactorial risk-reduction intervention with the usual care of physicians.

Methods and Results
For 213 men, a bimodal frequency distribution of peak LDL density (g/mL) determined by analytical ultracentrifugation was used to classify baseline LDL profiles as “buoyant mode” (density ≤1.0378) or “dense mode” (density >1.0378). Coronary disease progression after 4 years was assessed by rates of change (mm/y, negative when arteries narrow) of minimum artery diameter. Rates for buoyant-mode subjects were −0.038±0.007 (mean±SEM) in usual care (n=65) and −0.039±0.010 in intervention (n=56;
P
=.6). Rates for dense-mode subjects were −0.054±0.012 in usual care (n=51) and −0.008±0.009 in intervention (n=41,
P
=.007). Lipid changes did not account for this difference in angiographic response.

Conclusions
Different types of LDL profile may predict different responses to specific therapies, perhaps because metabolic processes determine both LDL profiles and responses to therapies.
Circulating Levels of Factor VII, Fibrinogen, and von Willebrand Factor and Features of Insulin Resistance in First-Degree Relatives of Patients With NIDDM
Authors: Mansfield Michael W. , Heywood Daniella M. , Grant Peter J.
Published: June 2012

Background
First-degree relatives of patients with non–insulin-dependent diabetes mellitus (NIDDM) have an increased risk of coronary artery disease partly attributable to clustering of risk factors in association with insulin resistance. Circulating levels of some hemostatic factors predict coronary events, and there is growing evidence that insulin resistance is also associated with abnormalities of coagulation and fibrinolysis. This study examined the hypotheses that elevated levels of factor VII coagulant activity (FVII:C), fibrinogen, and von Willebrand factor (vWF) occur (1) in first-degree relatives of NIDDM patients and (2) in association with recognized features of insulin resistance.

Methods and Results
Fasting blood samples were taken from 132 first-degree relatives of NIDDM patients and 151 age-matched control subjects for measurement of FVII:C, fibrinogen, vWF, insulin, total and HDL cholesterol, triglyceride, glucose, and HbA
1C
. Levels of FVII:C (130% versus 122%,
P
<.02) and fibrinogen (3.0 versus 2.7 g/L,
P
=.002) were higher in relatives than in control subjects, and there was no significant difference in levels of vWF (0.98 versus 0.95 IU/mL). There was a graded association with features of insulin resistance, which was strongest for FVII:C, weaker for fibrinogen, and weakest for vWF.

Conclusions
FVII:C and fibrinogen levels are increased in relatives of patients with NIDDM. Levels of FVII:C and, to a lesser extent, fibrinogen and vWF cluster with other risk factors associated with insulin resistance. Abnormalities of circulating hemostatic factors, possibly in relation to insulin resistance, may contribute to cardiovascular risk in relatives of patients with NIDDM.
Regional Deficits of Myocardial Blood Flow and Function in Left Ventricular Pacing–Induced Heart Failure
Authors: Helmer Gregory A. , McKirnan M. Dan , Shabetai Ralph , Boss Gerry R. , Ross John , Hammond H. Kirk
Published: June 2012

Background
Pacing-induced congestive heart failure has become a preferred model for the study of the pathogenesis of dilated cardiomyopathy. However, little is known regarding regional myocardial blood flow and function during the development of heart failure in this model.

Methods and Results
To determine whether regional differences in myocardial blood flow are associated with regional dysfunction in ventricular pacing–induced heart failure, regional myocardial blood flow (radioactive microspheres) and regional wall thickening (transthoracic echocardiography) were measured in pigs studied at weekly intervals during the progression of heart failure induced by rapid pacing from the lateral wall of the left ventricle (220±9 bpm for 26±4 days). Echocardiography and hemodynamic measurements with the pacemaker off showed progressive, severe global left ventricular dysfunction. During pacing over the 3- to 4-week period, a progressive decrease in systolic wall thickening in the lateral wall occurred compared with the interventricular septum (IVS;
P
=.001); at 21 to 28 days, the difference was 50% (lateral wall, 14±6%; IVS, 28±6%;
P
=.0001). A difference in subendocardial blood flow per beat between the left ventricular lateral wall (the site of stimulation) and the IVS was found immediately on the initiation of pacing (IVS, 0.009±0.002 mL · min
−1
· g
−1
· beat
−1
; lateral wall, 0.005±0.001 mL · min
−1
· g
−1
· beat
−1
;
P
=.001), a difference that was sustained during pacing throughout the study. Subendocardial blood flow per beat was normal in both regions with the pacemaker off throughout the study.

Conclusions
These data indicate that regional myocardial ischemia is associated with the development of contractile dysfunction of the paced wall during prolonged rapid left ventricular pacing and that regional stunning contributes to persistent global left ventricular dysfunction when pacing is discontinued.
Medical Therapy Can Improve the Biological Properties of the Chronically Failing Heart
Authors: Eichhorn Eric J. , Bristow Michael R.
Published: June 2012

Abstract
Myocardial failure has been considered to be an irreversible and progressive process characterized by ventricular enlargement, chamber geometric alterations, and diminished pump performance. However, more recent evidence has suggested that certain types of medical therapy may lead to retardation and even reversal of the cardiomyopathic process. In the failing heart, long-term neurohormonal/autocrine-paracrine activation results in abnormalities in myocyte growth, energy production and utilization, calcium flux, and receptor regulation that produce a progressively dysfunctional, mechanically inefficient heart. Interventions such as ACE inhibition and β-blockade result in a reduction in the harmful long-term consequences of neurohormonal/autocrine-paracrine effects and retard the progression of left ventricular dysfunction or ventricular remodeling. Furthermore, in subjects with idiopathic dilated or ischemic cardiomyopathy, antiadrenergic therapy with β-blocking agents appears to be able to partially reverse systolic dysfunction and ventricular remodeling. Although the precise mechanisms underlying this latter effect have not yet been elucidated, the general mechanism appears to be via improvement in the biological function of the cardiac myocyte. Such an improvement in the intrinsic defect(s) responsible for myocardial failure will likely translate into important clinical benefits.
Recognition of Acute Cardiac Allograft Rejection From Serial Integrated Backscatter Analyses in Human Orthotopic Heart Transplant Recipients
Authors: Angermann Christiane E. , Nassau Kirsten , Stempfle Hans-Ulrich , Kru¨ger Thomas M. , Drewello Ralph , Junge Reinhard , U¨berfuhr Peter , Weiß Max , Theisen Karl
Published: June 2012

Background
Previous studies showed that moderate and severe acute cardiac rejection (AR) but not mild AR is associated with significant myocardial acoustic changes. This study examines whether serial measurements of end-diastolic two-dimensional integrated backscatter (2D-IB) enhance the diagnostic potential of ultrasonic tissue analysis in AR.

Methods and Results
Serial endomyocardial biopsies, conventional echocardiograms, and parasternal long-axis radiofrequency signals for determination of posterior wall and septal 2D-IB were performed in 52 transplant patients. Histology showed no AR in 155 biopsy samples, AR grade 1A in 25, AR grade 1B/2 in 27, and AR grade 3A/3B in 13. Whereas no significant 2D-IB changes occurred between AR-free studies and during AR grade 1A, posterior wall and septal 2D-IB increased during AR grade 1B/2 from −47.80±4.36 to −42.97±5.11 dB and from −36.72±7.45 to −32.52±7.98 dB (
P
<.001 and
P
<.05, respectively) and during AR grade 3A/3B from −47.96±4.74 to −38.25±5.32 dB and from −37.92±5.87 to −31.01±4.62 dB (
P
<.001 and
P
<.01, respectively). Changes in posterior wall and septal 2D-IB were greater during AR grade 3A/3B than during AR grade 1B/2 (
P
<.01 and
P
<.05). Increases of 1.5 dB in posterior wall or septal 2D-IB indicated AR grades ≥1B with sensitivities of 88% and 83% and specificities of 89% and 85%; posterior wall and septal 2D-IB increases of 5.5 and 3.8 dB identified AR grades ≥3A with sensitivities of 92% and 79% and specificities of 90% and 84%. Although a weak inverse correlation between posterior wall and septal 2D-IB changes and posterior wall and septal thickening (
r
=.41 and
r
=.39, both
P
<.001) and fractional diameter shortening (
r
=.35,
P
<.001) was found, significant 2D-IB increases also occurred in some rejecting patients with unaltered contraction.

Conclusions
Increases in end-diastolic posterior wall and septal 2D-IB in serial studies permit reliable identification not only of moderate and severe AR but also of mild AR. Because 2D-IB increases significantly more in AR with myocyte damage than without such damage, an estimate of AR severity appears feasible. Significant myocardial acoustic changes during AR may occur independently of changes in contractile performance.
Elevations of Cardiac Troponin I Associated With Myocarditis
Authors: Smith Stacy C. , Ladenson Jack H. , Mason Jay W. , Jaffe Allan S.
Published: June 2012

Background
Endomyocardial biopsy is currently the standard method used to diagnose myocarditis. However, it is invasive and has a low diagnostic yield. Because the histological diagnosis of myocarditis requires the presence of myocyte injury, we sought to determine whether measurement of cardiac troponin I (cTnI), which is a serum marker with high sensitivity and specificity for cardiac myocyte injury, could aid in the diagnosis of myocarditis.

Methods and Results
To validate this approach, cTnI values were first measured in mice with autoimmune myocarditis. cTnI values were elevated in 24 of 26 mice with myocarditis but were not elevated in any of the control animals (
P
<.001). Next, cTnI values were measured in the sera from 88 patients referred to the Myocarditis Treatment Trial and were compared with creatine kinase–MB (CK-MB) values measured in the same patients. cTnI values were elevated in 18 (34%) of 53 patients with myocarditis and in only 4 (11%) of 35 patients without myocarditis (
P
=.01). In contrast, CK-MB values were elevated in only 3 (5.7%) of 53 patients with myocarditis and 0 of 35 patients without myocarditis (
P
=.27). Thus, elevations of cTnI occurred more frequently than did elevations of CK-MB in patients with biopsy-proven myocarditis (
P
=.001). Importantly, elevations of cTnI in patients with myocarditis were significantly correlated with ≤1 month duration of heart failure symptoms (
P
=.02), suggesting that the majority of myocyte necrosis occurs early, and thus the window for diagnosis and treatment may be relatively brief.

Conclusions
cTnI was superior to CK-MB for detection of myocyte injury in myocarditis, and cTnI elevations were substantially more common in the first month after the onset of heart failure symptoms.
Dilated Cardiomyopathy Associated With Deficiency of the Cytoskeletal Protein Metavinculin
Authors: Maeda Masato , Holder Emma , Lowes Brian , Valent Scott , Bies Roger D.
Published: June 2012

Background
The cytoskeleton plays an important role in maintaining cell structure and integrity. Defects in cytoskeletal proteins can cripple cell strength and may cause cardiomyopathy. We analyzed heart tissues from subjects with dilated cardiomyopathy for abnormalities in the cardiac cytoskeleton. Metavinculin, a cardiac isoform of the cytoskeletal protein vinculin, connects actin microfilaments to the intercalated disk and membrane costameres of the heart.

Methods and Results
Metavinculin and vinculin transcripts and protein were analyzed by polymerase chain reaction (PCR) and Western blotting. Thirty-three human heart specimens were studied, including 5 normal controls, 4 subjects with ischemic cardiomyopathy, 1 with X-linked cardiomyopathy, and 23 with idiopathic dilated cardiomyopathy (IDC). PCR of cardiac cDNA detected absence of the metavinculin transcript in cardiac tissue from a subject with IDC. PCR of genomic DNA showed that the metavinculin exon was present but not utilized in the cardiac transcript. Western blot analysis demonstrated absence of metavinculin protein in the heart from this subject. Immunostaining of cardiac vinculin in this heart showed disorganized intercalated disk structures. Metavinculin deficiency was associated with normal cardiac expression of the cytoskeletal proteins vinculin, α-actinin, and dystrophin. Normal metavinculin expression in the other heart specimens suggests that the defect is specific in the IDC subject identified.

Conclusions
These results demonstrate an association between metavinculin deficiency and dilated cardiomyopathy due to a defect in alternative mRNA splicing.
Protective Role of Nerve Growth Factor Against Postischemic Dysfunction of Sympathetic Coronary Innervation
Authors: Abe Toyohiko , Morgan Donald A. , Gutterman David D.
Published: June 2012

Background
Nerve growth factor (NGF) is produced rapidly in myocardium after brief myocardial ischemia. It contributes to the maintenance of neural integrity in several tissues. We examined the effect of exogenous and endogenous NGF on ischemia-induced dysfunction of cardiac sympathetic nerves.

Methods and Results
In anesthetized dogs, bilateral stellate stimulation was performed, measuring changes in coronary vascular resistance (%ΔCVR) before and after release of either a 7- or 15-minute occlusion of the left anterior descending coronary artery (LAD). NGF (10 ng·kg
−1
·min
−1
, n=5) or vehicle (n=6) was infused into the LAD in dogs during a 15-minute LAD occlusion. In separate experiments, antibody to NGF (anti-NGF, 2 ng·kg
−1
·min
−1
, n=5) or vehicle (n=6) was infused into dogs during a 7-minute LAD occlusion. After release of a 15-minute LAD occlusion, attenuation of the coronary constriction to stellate stimulation was seen in the vehicle group (30±3% to 15±1% increase in CVR,
P
<.05); however, no such reduction was seen in the group receiving NGF. A 7-minute LAD occlusion with reperfusion did not alter %ΔCVR in the vehicle group (36±6% versus 37±7%,
P
=NS) but attenuated %ΔCVR in the anti-NGF group (39±8% to 17±2%,
P
<.05).

Conclusions
We conclude that exogenously infused and endogenously released NGF protects against postischemic neural stunning of sympathetic cardiac innervation.
Arterial and Venous Thrombosis Is Not Associated With the 4G/5G Polymorphism in the Promoter of the Plasminogen Activator Inhibitor Gene in a Large Cohort of US Men
Authors: Ridker Paul M. , Hennekens Charles H. , Lindpaintner Klaus , Stampfer Meir J. , Miletich Joseph P.
Published: June 2012

Background
The 4G allele of the 4G/5G polymorphism in the promoter of the plasminogen activator inhibitor (PAI-1) gene is associated with increased PAI-1 activity. In a small group of young Swedish men, this allele has been reported to predict risk of myocardial infarction. Whether this polymorphism increases risk of arterial and venous thrombosis among middle-aged men is unknown.

Methods and Results
Among 14 916 men 40 to 84 years old participating in the Physicians' Health Study who provided baseline blood samples for DNA analysis, 374 suffered first myocardial infarction and 121 had venous thromboembolism during 8.6 years of follow-up. Distributions of the 4G/5G polymorphism in the PAI-1 gene promoter were assessed in these men as well as in a sample of study participants matched on age and smoking who did not develop vascular occlusion during the prospective follow-up period. The distributions of the 4G/4G, 4G/5G, and 5G/5G genotypes among men who developed myocardial infarction (0.27, 0.51, 0.22;
P
=.7) or venous thromboembolism (0.30, 0.49, 0.21;
P
=.5) were virtually identical to those of men who remained free of vascular disease (0.27, 0.50, 0.23). Thus, the relative risk of future thrombosis among those with the 4G/4G genotype compared with those without the 4G/4G genotype was 1.02 (95% CI, 0.8 to 1.3). There was no effect modification by age, smoking status, family history of premature thrombosis, history of hypertension, hypercholesterolemia, or aspirin use.

Conclusions
These data indicate that the 4G/5G polymorphism in the promoter of the PAI-1 gene is not a major pathogenetic risk factor for arterial or venous thrombosis among middle-aged men.
Effect of the Direct Nitric Oxide Donors Linsidomine and Molsidomine on Angiographic Restenosis After Coronary Balloon Angioplasty
Authors: Lablanche Jean-Marc , Grollier Gilles , Lusson Jean-Rene´ , Bassand Jean-Pierre , Drobinski Ge´rard , Bertrand Bernard , Battaglia Salvatore , Desveaux Bernard , Juillie`re Yves , Juliard Jean-Michel , Metzger Jean-Philippe , Coste Pierre , Quiret Jean-Claude , Dubois-Rande´ Jean-Luc , Crochet Pierre Dominique , Letac Brice , Boschat Jacques , Virot Patrice , Finet Ge´rard , Le Breton Herve´ , Livarek Bernard , Leclercq Florence , Be´ard Thierry , Giraud Thierry , McFadden Euge`ne P. , Bertrand Michel E.
Published: June 2012

Background
Nitric oxide (NO) donors, in addition to their vasodilator effect, decrease platelet aggregation and inhibit vascular smooth muscle cell proliferation. These actions could have beneficial effects on restenosis after coronary balloon angioplasty.

Methods and Results
In a prospective multicenter, randomized trial, 700 stable coronary patients scheduled for angioplasty received direct NO donors (infusion of linsidomine followed by oral molsidomine) or oral diltiazem. Treatment was started before angioplasty and continued until 12 to 24 hours before follow-up angiography at 6 months. The primary study end point was minimal lumen diameter, assessed by quantitative coronary angiography, 6 months after balloon angioplasty. Clinical variables were well matched in both groups. However, despite intracoronary administration of isosorbide dinitrate, the reference diameter in the NO donor group was significantly greater than in the diltiazem group on the preangioplasty, postangioplasty, and follow-up angiograms. Pretreatment with an NO donor was associated with a modest improvement in the immediate angiographic result compared with pretreatment with diltiazem (minimum luminal diameter, 1.94 versus 1.81 mm;
P
=.001); this improvement was maintained at the 6-month angiographic follow-up (minimal lumen diameter, 1.54 versus 1.38 mm;
P
=.007). The extent of late luminal narrowing did not differ significantly between groups (loss index in the NO donor and diltiazam groups, 0.35±0.78 and 0.46±0.74, respectively;
P
=.103). Restenosis, defined as a binary variable (≥50% stenosis), occurred less often in the NO donor group (38.0% versus 46.5%;
P
=.026). Combined major clinical events (death, nonfatal myocardial infarction, and coronary revascularization) were similar in the two groups (32.2% versus 32.4%).

Conclusions
Treatment with linsidomine and molsidomine was associated with a modest improvement in the long-term angiographic result after angioplasty but had no effect on clinical outcome. The improved angiographic result related predominantly to a better immediate procedural result, because late luminal loss did not differ significantly between groups.
Aortic Root Dilatation in Patients With Spontaneous Cervical Artery Dissection
Authors: Tzourio Christophe , Cohen Ariel , Lamisse Nathalie , Biousse Valérie , Bousser Marie-Germaine
Published: June 2012

Background
Spontaneous cervical artery dissections are a relatively common cause of ischemic stroke in young adults. Their mechanism is unknown, though it is generally assumed that an underlying minor form of extracellular matrix defect could exist. The present study tested the hypothesis that aortic and cardiac morphological abnormalities usually seen in patients with heritable connective diseases are more frequent in patients with spontaneous cervical artery dissections than in patients without such dissections.

Methods and Results
We performed a case-control study of 28 case patients with spontaneous cervical artery dissection and 84 control subjects with an ischemic stroke not due to cervical artery dissection. Control subjects were matched to case patients for age (±5 years), sex, and year of hospitalization. The aortic root was more frequently enlarged (ie, diameter >34 mm) in case patients (56%) than in control subjects (15%). Mitral valve prolapse, mitral valve dystrophy, and aortic valve dystrophy were more frequent in case patients than in control subjects. In multivariate analyses, aortic diameter >34 mm was the only variable associated with an increased risk of spontaneous cervical artery dissection (odds ratio, 14.2; 95% CI, 3.2 to 63.6;
P
<.001).

Conclusions
These results suggest that aortic root diameter enlargement is associated with an increased risk of spontaneous cervical artery dissection. This finding is consistent with the idea that a generalized defect of the extracellular matrix is present in patients with spontaneous cervical artery dissection.
ACE Gene Polymorphism: Ischemic Heart Disease and Longevity in 10 150 Individuals
Authors: Agerholm-Larsen Birgit , Nordestgaard Børge G. , Steffensen Rolf , Sørensen Thorkild I.A. , Jensen Gorm , Tybjærg-Hansen Anne
Published: June 2012

Background
Homozygosity for the deletion allele (
D
) of the angiotensin-converting enzyme (
ACE
) gene insertion-deletion polymorphism has been suggested to be a potent risk factor for myocardial infarction. With one exception, the samples studied so far have been small and/or ethnically heterogeneous, and most investigators have studied men only.

Methods and Results
We investigated the association between
ACE
genotype and myocardial infarction as well as other manifestations of ischemic heart disease for both women and men in a case-referent study (n=10 150) as well as in a retrospective cohort study (n=7263). The cohort was from the ethnically homogeneous Danish population. Case subjects were from the same geographic area and had ischemic heart disease. Irrespective of the assumed degree of relative penetrance of the
D
allele, the odds ratios were not significantly different from 1.0 (
P
>.05) for ischemic heart disease, severe stenosis on coronary angiography, or myocardial infarction. There was also no association between
ACE
genotype and phenotypic variation in recognized risk factors for ischemic heart disease. Finally, the relative frequency of the
D
allele did not change as a function of age in subjects aged from 20 to ≥80 years.

Conclusions
In two large studies, a case-referent study and a retrospective cohort study in an ethnically homogeneous white population, there was no evidence for a statistically significant difference in the development of myocardial infarction or any other manifestations of ischemic heart disease between genotype classes of the
ACE
gene polymorphism in either women or men.
A Prospective Study of Passive Smoking and Coronary Heart Disease
Authors: Kawachi Ichiro , Colditz Graham A. , Speizer Frank E. , Manson JoAnn E. , Stampfer Meir J. , Willett Walter C. , Hennekens Charles H.
Published: June 2012

Background
Several epidemiological studies have suggested an association of passive smoking with coronary heart disease (CHD). However, few studies have taken account of exposure to passive smoking in the workplace. Additionally, several studies have been unable to control for the full range of potential confounding factors. We examined prospectively the relationship of passive smoking with risk of CHD in a cohort of women.

Methods and Results
The study was carried out in an ongoing prospective cohort of US female nurses, in whom we assessed exposure to passive smoking at home and at work as well as duration of years spent living with someone who smoked regularly. We studied 32 046 women 36 to 61 years of age in 1982 who had never smoked and were free of diagnosed CHD, stroke, and cancer. During 10 years of follow-up (1982 to 1992), 152 incident cases of CHD (127 nonfatal myocardial infarction and 25 fatal CHD) occurred. Compared with women not exposed to passive smoking, the relative risks of total CHD—adjusted for a broad range of cardiovascular risk factors—were 1.58 (95% CI, 0.93 to 2.68) among those reporting occasional exposure and 1.91 (95% CI, 1.11 to 3.28) among women reporting regular exposure to passive smoking at home or work. There was no relation apparent between duration of living with a smoker and risk of CHD.

Conclusions
Despite the fact that exposure to passive smoking was assessed by self-report and only at baseline (as well as other limitations), these data suggest that regular exposure to passive smoking at home or work increases the risk of CHD among nonsmoking women.