- Role of Microvolt T-Wave Alternans in Assessment of Arrhythmia Vulnerability Among Patients With Heart Failure and Systolic Dysfunction: Primary Results From the T-Wave Alternans Sudden Cardiac Death in Heart Failure Trial Substudy
- Benefit of Oral Anticoagulant Over Antiplatelet Therapy in Atrial Fibrillation Depends on the Quality of International Normalized Ratio Control Achieved by Centers and Countries as Measured by Time in Therapeutic Range
- Antithrombotic Therapy With Fondaparinux in Relation to Interventional Management Strategy in Patients With ST- and Non–ST-Segment Elevation Acute Coronary Syndromes: An Individual Patient–Level Combined Analysis of the Fifth and Sixth Organization to Assess Strategies in Ischemic Syndromes (OASIS 5 and 6) Randomized Trials
- Fasting and Nonfasting Lipid Levels: Influence of Normal Food Intake on Lipids, Lipoproteins, Apolipoproteins, and Cardiovascular Risk Prediction
- Long-Term Trends in the Incidence of Heart Failure After Myocardial Infarction
- Identification of Cardiac Troponin I Sequence Motifs Leading to Heart Failure by Induction of Myocardial Inflammation and Fibrosis
- c-Jun N-Terminal Kinase 2 Deficiency Protects Against Hypercholesterolemia-Induced Endothelial Dysfunction and Oxidative Stress
- Combined Tyrosine and Serine/Threonine Kinase Inhibition by Sorafenib Prevents Progression of Experimental Pulmonary Hypertension and Myocardial Remodeling
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Role of Microvolt T-Wave Alternans in Assessment of Arrhythmia Vulnerability Among Patients With Heart Failure and Systolic Dysfunction: Primary Results From the T-Wave Alternans Sudden Cardiac Death in Heart Failure Trial Substudy
Sudden cardiac death remains a leading cause of mortality despite advances in medical treatment for the prevention of ischemic heart disease and heart failure. Studies of the implantable cardioverter defibrillator (ICD) showed significant reductions in mortality among certain high-risk cohorts of patients. Recently, there has been a dramatic increase in ICD use for primary prevention, largely because of the results of 2 studies: the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) and the second Multicenter Automatic Defibrillator Implantation Trial (MADIT II). However, both studies showed that shocks for ventricular tachyarrhythmias occurred in only 25% to 35% of subjects during 4 to 5 years of follow-up. This suggests that many ICD patients may not benefit from this invasive therapy and that better risk stratification is needed to optimize patient selection. In this regard, microvolt T-wave alternans (TWA) is a noninvasive test of arrhythmia vulnerability. Previous observational studies showed that TWA predicted ICD shocks or arrhythmic events in diverse patient populations. This has led some to propose using TWA to identify patients most likely to benefit from ICD implantation; however, the value of TWA for risk stratification had not been evaluated previously in a randomized trial of ICD therapy. In the present study, 490 patients enrolled in SCD-HeFT underwent TWA testing and were followed up prospectively. TWA testing did not predict arrhythmic events or mortality in the cohort as a whole or in subgroups with ischemic or nonischemic cardiomyopathy. Accordingly, these results suggest that TWA is not useful as an aid in clinical decision making about ICD therapy among patients with heart failure and left ventricular dysfunction. See p 2022.
Benefit of Oral Anticoagulant Over Antiplatelet Therapy in Atrial Fibrillation Depends on the Quality of International Normalized Ratio Control Achieved by Centers and Countries as Measured by Time in Therapeutic Range
Oral anticoagulation (OAC) has proved to be beneficial for the reduction of stroke and vascular events in atrial fibrillation. Previous studies have clearly shown that OAC therapy needs to be controlled carefully so that the international normalized ratio of the prothrombin time remains in the therapeutic range, between 2 and 3. However, this target is not always achieved. Previous studies have shown that the time in the therapeutic range (TTR) varies between patients and that a high TTR is associated with increased risk of stroke and bleeding. No previous study has indicated the minimum TTR needed to achieve a beneficial response from OAC. The Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE W) study data have been used to develop an estimate of the minimal TTR needed to confidently achieve a benefit compared with therapy with clopidogrel and aspirin. This estimate is based on comparing the outcomes of patients in ACTIVE W randomized to either OAC or clopidogrel plus aspirin. The analysis used stratification according to the TTR achieved by each clinical center in its OAC patients. Only patients at centers with TTR above the study median of 65% benefited from OAC compared with clopidogrel plus aspirin. An analysis by country has also been carried out, and a strong relationship has been found between the TTR achieved by a country and the benefit of OAC. The estimate of the minimum TTR needed to achieve a benefit from OAC therapy is between 58% and 65%. Centers that achieve below this level cannot be confident that their patients are benefiting from OAC compared with antiplatelet therapy. An even higher TTR (ie >70%) is associated with even greater benefit from OAC and was achieved in some countries. These data indicate that providers of OAC therapy need to evaluate how well they deliver OAC to patients with atrial fibrillation, with the intent of achieving a minimum TTR of 58% to 65% and an optimal control of >70% TTR. See p 2029.
Antithrombotic Therapy With Fondaparinux in Relation to Interventional Management Strategy in Patients With ST- and Non–ST-Segment Elevation Acute Coronary Syndromes: An Individual Patient–Level Combined Analysis of the Fifth and Sixth Organization to Assess Strategies in Ischemic Syndromes (OASIS 5 and 6) Randomized Trials
The Fifth and Sixth Organization to Assess Strategies in Ischemic Syndromes (OASIS 5 and 6) trials evaluated fondaparinux, a synthetic factor Xa inhibitor, in patients with non–ST- and ST-segment elevation acute coronary syndromes, respectively. Combined results for these 2 trials on major efficacy and safety outcomes and data on the effects of fondaparinux in relation to interventional management strategy have not been previously reported. This report describes an individual patient–level combined analysis of 26 512 patients from the OASIS 5 and 6 trials who were randomized in a double-blind fashion to fondaparinux 2.5 mg daily or a heparin-based strategy (dose-adjusted unfractionated heparin or enoxaparin). The results were then stratified according to whether an early invasive, a delayed invasive, or an initial conservative management strategy was performed. Fondaparinux was found to be superior to heparin in reducing the composite of death, myocardial infarction, or stroke (8.0% versus 7.2%; hazard ratio [HR], 0.91; P=0.03) and death alone (4.3% versus 3.8%; HR, 0.89; P=0.05). Fondaparinux also was safer; it reduced major bleeding by 41% (3.4% versus 2.1%; HR, 0.59; P<0.00001) and had a more favorable net clinical outcome than heparin (11.1% versus 9.3%; HR, 0.83; P<0.0001). In 19 085 patients treated with an invasive strategy, fondaparinux suppressed ischemic events to an extent similar to heparin and reduced major bleeding by more than one-half, resulting in a superior net clinical outcome (10.8% versus 9.4%; HR, 0.87; P=0.008). A similar benefit also was observed in those treated with a conservative strategy (HR, 0.74; 95% confidence interval, 0.64 to 0.85; P<0.001). Therefore, compared with a heparin-based strategy, fondaparinux reduces mortality, ischemic events, and major bleeding across the full spectrum of acute coronary syndromes and is associated with a more favorable net clinical outcome in patients undergoing either an invasive or a conservative management strategy. These data underscore the wide therapeutic potential of fondaparinux in patients with acute coronary syndromes. See p 2038.
Fasting and Nonfasting Lipid Levels: Influence of Normal Food Intake on Lipids, Lipoproteins, Apolipoproteins, and Cardiovascular Risk Prediction
Lipid profiles are usually measured after fasting; however, it would be much simpler for patients if a random nonfasting sample could be used. We tested the hypotheses that lipid profiles change only minimally in response to normal food intake and that random nonfasting levels predict cardiovascular events. We cross-sectionally studied 33 391 adults from the Copenhagen General Population Study and 9319 adults from the Copenhagen City Heart Study, of whom 1166 developed cardiovascular events during 14 years of follow-up. After normal food intake, individuals in the general population had a maximum mean change from fasting levels of −0.2 mmol/L (−8 mg/dL) for total cholesterol at 0 to 2 hours after the last meal, −0.2 mmol/L (−8 mg/dL) for low-density lipoprotein cholesterol at 0 to 2 hours, −0.1 mmol/L (−4 mg/dL) for high-density lipoprotein cholesterol at 0 to 5 hours, and 0.3 mmol/L (26 mg/dL) for triglycerides at 1 to 4 hours after the last meal. Highest versus lowest tertile of nonfasting total cholesterol, non–high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, triglycerides, ratio of total to high-density lipoprotein cholesterol, and ratio of apolipoprotein B to apolipoprotein A1 and lowest versus highest tertile of nonfasting high-density lipoprotein cholesterol and apolipoprotein A1 predicted 1.7- to 2.4-fold increased risk of cardiovascular events. Because we detected only minimal changes in levels of lipids, lipoproteins, and apolipoproteins in response to normal food intake in the general population, changes that are clinically unimportant, and because nonfasting levels predict cardiovascular events, our data challenge the necessity for asking patients to fast before measurement of lipid profiles for cardiovascular risk prediction. See p 2047.
Long-Term Trends in the Incidence of Heart Failure After Myocardial Infarction
Mortality due to myocardial infarction (MI) has decreased in recent decades; however, few community-based epidemiological investigations have addressed the long-term trends in the incidence of heart failure after MI. We evaluated trends in the incidence of heart failure after MI in the time period 1970 to 1999 in the Framingham Heart Study cohort. We related the decade of MI incidence to the occurrence of heart failure in the early (within 30 days of MI) and late (after 30 days and up to 5 years) post-MI periods and to the incidence of death free of heart failure. We observed a striking increase in the incidence of heart failure after MI in the decade 1990 to 1999 (compared with the decade 1970 to 1979), accompanied by a decrease in the incidence of death without heart failure after MI over the same time period. We conclude that the increase in heart failure incidence after MI in recent decades was explained primarily by increases in the early post-MI period, in part due to a major decrease in mortality during this period in recent decades. The present data are consistent with the notion that a greater salvage of high-risk patients in recent time periods may have contributed to the observed trends in post-MI heart failure. See p 2057.
Identification of Cardiac Troponin I Sequence Motifs Leading to Heart Failure by Induction of Myocardial Inflammation and Fibrosis
Despite the widespread use of cardiac troponin I (cTnI) for diagnosis of myocyte injury and risk stratification in acute cardiac disorders, little is known about the precise role of an autoimmune response to the troponins on cardiac function. Recently, investigators made the surprising discovery that mice treated with monoclonal anti-cTnI antibodies developed myocardial dysfunction. Shortly afterward, it was reported that autoantibodies to cTnI are also present in patients with acute coronary syndrome. These findings indicate that induction of an autoimmune response to cTnI is not a rare event in patients. Recently, we demonstrated that the prevalence of cTnI antibodies in patients with acute coronary syndrome has an impact on improvement in left ventricular ejection fraction. Furthermore, the role of autoantibodies in heart failure has been supported by clinical studies demonstrating that the removal of immunoglobulins by immunoadsorption can improve ejection fraction in patients with dilated cardiomyopathy. Recently, we showed that inducing an autoimmune response to cTnI leads to severe inflammation in the myocardium followed by fibrosis and heart failure with increased mortality in mice. Now, we demonstrate that this disease is primarily a CD4+ T-cell–dependent disease with a Th2/Th17 phenotype, and we identify the antigenic determinants of cTnI that are responsible. We believe that these findings can fundamentally change the understanding of the pathophysiology of inflammatory cardiovascular diseases and postinfarct remodeling. See p 2063.
c-Jun N-Terminal Kinase 2 Deficiency Protects Against Hypercholesterolemia-Induced Endothelial Dysfunction and Oxidative Stress
Atherosclerosis is a systemic immunoinflammatory disease that develops in response to endothelial injury. Hypercholesterolemia, a crucial risk factor for cardiovascular disease, leads to accumulation and oxidation of low-density lipoprotein cholesterol within the intima of the arterial wall. Thereby, hypercholesterolemia triggers endothelial dysfunction and creates a proinflammatory milieu, both critical initial steps of atherogenesis. The c-Jun N-terminal kinases (JNKs) play a fundamental role in inflammation, stress responses, cell survival, and apoptosis. Three distinct JNK genes have been described, JNK1, JNK2, and JNK3, encoding for different isoforms. We recently reported that genetic JNK2 deletion decreases progression of atherosclerosis by inhibiting foam cell formation. However, the role of JNK2 in early atherogenesis related to hypercholesterolemia-induced endothelial dysfunction remains unknown. In the present study, we compared JNK2-deficient mice with wild-type mice exposed long term to a high-cholesterol or a normal diet. Our results show that genetic JNK2 deletion inhibits hypercholesterolemia-induced and oxidative stress–mediated endothelial dysfunction, suggesting a critical role of endogenous JNK2 in this context. Thus, the concept of JNK inhibition with proven protective effects in atherogenesis, abdominal aneurysm formation, myocardial infarction, and cerebral ischemia may be extended to endothelial dysfunction as the initial step of vascular disease. Given the additional beneficial effects of pharmacological JNK inhibition in mouse models of obesity and diabetes, JNK blockade may represent an attractive therapeutic target for both cardiovascular and metabolic disease. See p 2073.
Combined Tyrosine and Serine/Threonine Kinase Inhibition by Sorafenib Prevents Progression of Experimental Pulmonary Hypertension and Myocardial Remodeling
Pulmonary arterial hypertension is a life-threatening disease that is characterized by a variety of remodeling processes in the pulmonary vasculature and the right ventricle, including migration of pulmonary endothelial and vascular smooth muscle cells as well as hypertrophy, fibrosis, and dysregulation of extracellular matrix in the right ventricular myocardium. Current vasodilatory therapy does not causally address the underlying deviations in intracellular signal transduction leading to pulmonary vascular and myocardial remodeling. Interestingly, dysregulation of kinase signaling pathways is a key characteristic of many cancer tissues as well as in pulmonary hypertension. Overactivation of receptor tyrosine kinases has been linked to endothelial and pulmonary vascular smooth muscle cell proliferation, whereas serine/threonine kinases are connected to smooth muscle and myocardial hypertrophy and remodeling. In the present study, we demonstrate that the combined tyrosine and serine/threonine kinase inhibitor sorafenib can prevent pulmonary and myocardial remodeling in a rat model of pulmonary arterial hypertension. As a result of its dual pulmonary and myocardial action, combined kinase inhibition may represent a promising and more causal approach to treat pulmonary arterial hypertension. See p 2081.
- Long-Term Trends in the Incidence of Heart Failure After Myocardial Infarction
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