- The First Evaluation of a Novel Vitamin K Antagonist, Tecarfarin (ATI-5923), in Patients With Atrial Fibrillation
- Antiarrhythmics After Ablation of Atrial Fibrillation (5A Study)
- Metabolic Syndrome, Inflammation, and Risk of Symptomatic Peripheral Artery Disease in Women: A Prospective Study
- Pathophysiological Changes in Calf Muscle Predict Mobility Loss at 2-Year Follow-Up in Men and Women With Peripheral Arterial Disease
- A Prospective Study of Bone Lead Concentration and Death From All Causes, Cardiovascular Diseases, and Cancer in the Department of Veterans Affairs Normative Aging Study
- Cardiomyocyte-Specific Overexpression of Human Stem Cell Factor Improves Cardiac Function and Survival After Myocardial Infarction in Mice
- Engraftment, Differentiation, and Functional Benefits of Autologous Cardiosphere-Derived Cells in Porcine Ischemic Cardiomyopathy
- Baseline Values but Not Treatment-Induced Changes in Carotid Intima-Media Thickness Predict Incident Cardiovascular Events in Treated Hypertensive Patients: Findings in the European Lacidipine Study on Atherosclerosis (ELSA)
- Real-Time 3-Dimensional Echocardiography Provides New Insight Into Mechanisms of Tricuspid Valve Regurgitation in Patients With Hypoplastic Left Heart Syndrome
- Novel Small Interfering RNA–Containing Solution Protecting Donor Organs in Heart Transplantation
- Accelerated Infusion of Streptokinase for the Treatment of Left-Sided Prosthetic Valve Thrombosis: A Randomized Controlled Trial
- Improved Oral Anticoagulation After a Dietary Vitamin K–Guided Strategy: A Randomized Controlled Trial
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The First Evaluation of a Novel Vitamin K Antagonist, Tecarfarin (ATI-5923), in Patients With Atrial Fibrillation
This is the first evaluation of a novel vitamin K antagonist, tecarfarin (ATI-5923), in patients with atrial fibrillation. Tecarfarin is a structural analogue of warfarin that was designed to provide more uniform and stable anticoagulation. It is metabolized by carboxylesterases in the hepatic microsome and, unlike warfarin, circumvents the cytochrome P450 system isoenzyme CYP2C9, which is shared and influenced by many foods and drugs. The objective of this study is to prove that tecarfarin safely leads to a larger proportion of patients with a time in therapeutic international normalized ratio range of 2.0 to 3.0. Earlier studies have suggested that a greater time in therapeutic range with warfarin results in improved thromboembolic and hemorrhagic outcomes. This study finds that tecarfarin, by virtue of more stable metabolism, may be an easily regulated and efficacious anticoagulant. This study sets the stage for future direct comparisons between tecarfarin and warfarin with the use of time in therapeutic range as well as other end points. If tecarfarin is found to have greater time in therapeutic range than conventional warfarin therapy, it may prove to be an equally efficient and more easily regulated anticoagulant than warfarin. See p 1029.
Antiarrhythmics After Ablation of Atrial Fibrillation (5A Study)
Early recurrence of atrial fibrillation after pulmonary vein isolation, although not necessarily indicating failure of the procedure, can be associated with bothersome symptoms and lead to the need for cardioversion or hospital visits. Antiarrhythmic drugs are commonly used during the early period after ablation in order to prevent early arrhythmia recurrences, but the benefits of this approach have never been formally studied. The Antiarrhythmics After Ablation of Atrial Fibrillation (5A) Study randomized patients with paroxysmal atrial fibrillation to empirical use of antiarrhythmic drugs or no antiarrhythmic drugs for the first 6 weeks after pulmonary vein isolation. In the 5A Study, antiarrhythmic therapy significantly reduced the risk of early recurrence of atrial arrhythmias and the need for hospitalization or cardioversion. There was no difference in the length of hospitalization, and only 3 patients had an adverse reaction to drug therapy. This demonstrates that use of antiarrhythmic therapy for the initial 6 weeks after ablation is likely to result in fewer symptoms and reduced cost of care. See p 1036.
Metabolic Syndrome, Inflammation, and Risk of Symptomatic Peripheral Artery Disease in Women: A Prospective Study
The metabolic syndrome (MetS) is associated with myocardial infarction and stroke and is linked with subclinical inflammation. We conducted a prospective cohort study among 27 111 women free of baseline cardiovascular disease to evaluate the relationship between MetS, inflammation, and incident peripheral artery disease. We found that MetS was associated with a significantly increased risk of peripheral artery disease after multivariable adjustment (hazard ratio 1.48, 95% confidence interval 1.01 to 2.18), similar to previously documented associations between MetS and coronary disease or stroke; however, when inflammatory biomarkers were added to multivariable models, risk associated with MetS was attenuated and was no longer significant. Our findings were comparable in women who were nondiabetic at baseline. Taken together, our data provide evidence that MetS confers an increased risk of incident peripheral artery disease among initially healthy women and that this increased risk is largely mediated through the effects of inflammation and endothelial activation. See p 1041.
Pathophysiological Changes in Calf Muscle Predict Mobility Loss at 2-Year Follow-Up in Men and Women With Peripheral Arterial Disease
Men and women with lower extremity peripheral arterial disease (PAD) have smaller calf muscle area, lower calf muscle density, and increased calf muscle percent fat compared with people without PAD. However, the prognostic significance of these calf muscle changes in PAD is unclear. This observational, prospective study measured calf muscle area, calf muscle density, and calf muscle percent fat with the use of computed tomography in 370 participants with PAD. At 2-year follow-up, participants with lower baseline calf muscle area, lower baseline calf muscle density, and higher baseline calf muscle percent fat had higher rates of mobility loss. These findings also suggest that interventions to prevent mobility loss in PAD should focus on reversing pathophysiological findings in calf muscle. See p 1048.
A Prospective Study of Bone Lead Concentration and Death From All Causes, Cardiovascular Diseases, and Cancer in the Department of Veterans Affairs Normative Aging Study
Genetics is well known to play only a limited role in the pathogenesis of cardiovascular disease. It is now known that in addition to diet, exercise, and other lifestyle and behavioral factors, certain environmental risk factors play a significant role in the general population. Much attention has been paid recently to particulate air pollution and secondhand cigarette smoke as such risk factors, for example. This study builds on another body of research recently indicating that cumulative environmental lead exposure (from decades of exposures to lead in combusted gasoline, paint, water, and food cans) is a risk factor for hypertension and myocardial infarction and goes even farther by linking such exposure directly to increased prospective cardiovascular mortality. Like a number of other recent studies, this investigation also shows that the risk to individuals posed by lead exposure cannot be captured adequately by measuring blood lead levels, which primarily signifies recent, rather than cumulative, exposure. From a clinical perspective, this research highlights the importance of incorporating at least a brief environmental/occupational assessment in the conduct of preventive cardiology and medicine and of advocating for the elimination or minimization of activities that are associated with lead exposure. It also underscores the anticipation surrounding an ongoing National Institutes of Health–funded multicenter trial testing the potential value of chelation in reducing cardiovascular risks, the results of which remain pending. See p 1056.
Cardiomyocyte-Specific Overexpression of Human Stem Cell Factor Improves Cardiac Function and Survival After Myocardial Infarction in Mice
Myocardial infarction (MI) is a major cause of death in coronary heart disease. Loss of myocardium after MI leads to scar formation and subsequent cardiac remodeling characterized by hypertrophy of noninfarct myocardium, left ventricular dilatation, and heart failure. Despite current available treatments, the outcome of MI remains poor. Stem cell factor (SCF) has been shown to promote survival and mobilization of bone marrow stem cells and endothelial progenitor cells. The present study investigated the effects of cardiomyocyte-specific overexpression of the membrane-associated isoform of human SCF (hSCF) on cardiac function after MI. We hypothesized that inducible cardiomyocyte-specific overexpression of membrane-associated hSCF improves cardiac repair, myocardial function, and survival after MI. To test this hypothesis, we generated a novel transgenic mouse that overexpresses membrane-associated hSCF in cardiomyocytes under the control of a Tet-off system. We demonstrated that cardiomyocyte-specific hSCF overexpression increased stem cell and endothelial progenitor cell retention in the infarct myocardium, promoted myocardial angiogenesis, increased capillary density, decreased myocardial apoptosis, and reduced left ventricular hypertrophy after MI. These beneficial effects led to significant improvements in cardiac function and survival in hSCF-overexpressing mice after MI and are likely due to the enhanced recruitment of endothelial progenitor cells to the infarct myocardium and improved cardiac repair. Our study suggests that hSCF may have therapeutic potential in the treatment of heart failure after MI. See p 1065.
Engraftment, Differentiation, and Functional Benefits of Autologous Cardiosphere-Derived Cells in Porcine Ischemic Cardiomyopathy
Every year, more than 1 million Americans suffer a myocardial infarction; nearly one third will go on to develop heart failure. This burden of ischemic cardiomyopathy has driven interest in stem cell therapy, in the hope that damaged myocardium might be repaired. Cardiosphere-derived cells (CDCs) are cardiac-derived stem cells and supporting cells that can be isolated from minimally invasive percutaneous endomyocardial biopsies and grown to large numbers (millions) in a few weeks. CDCs have the advantage of being preprogrammed to differentiate into cardiac and vascular lineages, but not into cell types that are alien to the heart. In mice, human CDCs delivered postinfarction engraft, reduce infarct size, and preserve left ventricular function compared with placebo. To further translate these findings, we studied CDCs in a porcine model of anterior myocardial infarction and resultant ischemic cardiomyopathy. We found that endomyocardial biopsy after myocardial infarction is safe, and CDC isolation from these biopsies is highly successful. After optimization of the delivery solution, autologous CDCs may be safely delivered via intracoronary infusion at doses that result in engraftment and formation of new cardiac myocytes and vascular cells. As compared with placebo infusion, animals receiving CDCs had decreased infarct size, less postinfarct ventricular remodeling, and improved hemodynamic function. No neoplastic or proarrhythmic side effects were observed. Together, these results indicate that CDCs are a novel, safe, and potentially effective therapy for ischemic cardiomyopathy. Recently, the National Institutes of Health–sponsored phase I CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction trial was initiated to study intracoronary delivery of autologous CDCs in patients with mild-to-moderate ischemic cardiomyopathy. See p 1075.
Baseline Values but Not Treatment-Induced Changes in Carotid Intima-Media Thickness Predict Incident Cardiovascular Events in Treated Hypertensive Patients: Findings in the European Lacidipine Study on Atherosclerosis (ELSA)
Carotid intima-media thickness (IMT) is recommended for stratifying cardiovascular risk because a number of observational studies have shown its value in predicting cardiovascular events. Whether this predictive value is independent of high blood pressure and is preserved when hypertension is treated effectively was unknown but has now been shown to be true. In the hypertensive patients of the European Lacidipine Study on Atherosclerosis (ELSA), baseline IMT strongly predicted cardiovascular events occurring during a 4-year follow-up under antihypertensive treatment, even after adjustment for all major baseline risk factors. Carotid IMT also has been used as an end point of several intervention trials, including ELSA. Whether treatment-induced IMT changes have a predictive role on cardiovascular outcomes also was unknown. New analyses from the ELSA database have failed to prove a significant predictive role of treatment-induced changes for any type of cardiovascular outcome. Although this failure may be due in part to the smallness of the IMT changes with respect to the large intersubject variability of baseline IMT, it weakens the relevance of IMT changes as an intermediate end point of intervention studies. See p 1084.
Real-Time 3-Dimensional Echocardiography Provides New Insight Into Mechanisms of Tricuspid Valve Regurgitation in Patients With Hypoplastic Left Heart Syndrome
Significant tricuspid valve regurgitation is a major risk factor in hypoplastic left heart syndrome. Thus far, our understanding of the mechanisms responsible for tricuspid valve regurgitation is limited. In addition, surgical treatment of tricuspid regurgitation tends to be nonspecific, usually involving bicuspidization of the valve. Real-time 3-dimensional echocardiography may provide insight into the mechanisms of tricuspid valve regurgitation. This technique permits an evaluation of the spatial relationships between the tricuspid annulus, leaflets, and their supporting apparatus. Real-time 3-dimensional color Doppler also permits accurate evaluation of the severity of regurgitation. This cross-sectional study addressed the mechanisms of tricuspid valve regurgitation in a group of 35 patients with hypoplastic left heart syndrome, all of whom were at various stages after first-stage palliation. All had no more than mild regurgitation at the time of initial presentation. Real-time 3-dimensional echocardiography was used to extract spatial coordinates of the tricuspid annulus, leaflets, and supporting papillary muscles. Three-dimensional color Doppler was used to determine the severity of regurgitation. Analysis of the data revealed that moderate tricuspid regurgitation was associated with tethering and prolapse of the leaflets. Those with tethering had lateral displacement of the anterior papillary muscle and a more planar tricuspid annulus. On the other hand, prolapse was associated with a smaller septal leaflet area, older age, and annular dilatation. This study allows an improved understanding of the mechanisms of tricuspid valve regurgitation in hypoplastic left heart syndrome, with the potential to assist surgeons in targeting specific mechanisms. See p 1091.
Novel Small Interfering RNA–Containing Solution Protecting Donor Organs in Heart Transplantation
The present study provides a framework for development of a clinically applicable ex vivo method of modifying organ grafts to decrease immunogenicity. These findings support further investigation into the feasibility of large-organ manipulation through the perfusion method. Current organ storage solutions have the limitation of providing physical protection from hypothermia-associated changes but do nothing to inhibit ischemia/reperfusion injury or the ensuing rise in immunogenicity. By demonstrating that gene silencing can be induced in the context of this clinically applicable scenario, we can develop new targets and approaches to improve graft quality before replantation, which would expand the use of marginal donors and increase organ transportation time. See p 1099.
Accelerated Infusion of Streptokinase for the Treatment of Left-Sided Prosthetic Valve Thrombosis: A Randomized Controlled Trial
Left-sided prosthetic valve thrombosis is frequently seen in developing countries and is most often treated with prolonged infusions of streptokinase. Treatment is often associated with a high rate of serious embolic and bleeding complications. In a single-center randomized controlled trial, we compared an accelerated infusion of streptokinase with the standard prolonged infusion in 120 patients presenting with a first episode of left-sided prosthetic valve thrombosis, in the belief that the accelerated regimen may expedite valve opening and reduce the rate of complications. The primary outcome was the occurrence of a complete clinical response, defined as complete restoration of valve function in the absence of major complications. The secondary outcome was a composite of death, major bleeding, embolic stroke, or non–central nervous system systemic embolism. We were unable to demonstrate a statistically significant difference in the occurrence of the primary or secondary outcomes between the treatment and control groups. This was because of the loss in power that resulted from an unexpectedly low response rate (59%) with streptokinase. In particular, the subgroup of patients in New York Heart Association class III/IV responded very poorly. This is in contrast to previous retrospective series that suggested overall response rates in excess of 80%. These results, derived from the only large prospective study of patients with prosthetic valve thrombosis, call into question the current practice of offering fibrinolysis as first-line therapy. In addition, the large number of patients recruited over a relatively short period of time from a single center in India highlights the huge burden of prosthetic valve thrombosis in developing countries. See p 1108.
Improved Oral Anticoagulation After a Dietary Vitamin K–Guided Strategy: A Randomized Controlled Trial
Dietary vitamin K has been recognized recently as a key factor that might interfere with long-term oral anticoagulation stability because of solid biochemical evidence that associates the vitamin K regenerative cycle with the net clinical effect of several anticoagulant drugs. The potential clinical applicability of this interaction, however, has not been explored adequately in prospective randomized clinical trials. In the present protocol, we hypothesized that a simple vitamin K–guided management strategy to adjust oral anticoagulation would be feasible and safe and could result in improved long-term oral anticoagulation compared with the traditional adjustment strategy based on changes in dosage of anticoagulants. Our results demonstrate that patients allocated to the dietary vitamin K–guided group reached a prespecified international normalized ratio target progressively more frequently than those allocated to the conventional approach. On the basis of these findings, we now have solid prospective clinical evidence that modulation of dietary vitamin K is an adequate approach to reach anticoagulation stability. This strategy is self-educational, is based on individual anticoagulation status, and depends on a simple semiquantitative assessment of the patient’s own dietary habits. As such, our data might change substantially the way physicians understand and manage anticoagulated patients, focusing on a factor that might be central to explain the intraindividual instability of coagulation parameters. See p 1115.
- Antiarrhythmics After Ablation of Atrial Fibrillation (5A Study)
- Novel Small Interfering RNA–Containing Solution Protecting Donor Organs in Heart Transplantation
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