Circulation: Clinical Summaries
Original Research Put Into Perspective for the Practicing Clinician
- Mechanisms Underlying the Lack of Effect of Implantable Cardioverter-Defibrillator Therapy on Mortality in High-Risk Patients With Recent Myocardial Infarction: Insights from the Defibrillation in Acute Myocardial Infarction Trial (DINAMIT)
- Autonomic Denervation With Magnetic Nanoparticles
- Primary Results From the SmartDelay Determined AV Optimization: A Comparison to Other AV Delay Methods Used in Cardiac Resynchronization Therapy (SMART-AV) Trial : A Randomized Trial Comparing Empirical, Echocardiography-Guided, and Algorithmic Atrioventricular Delay Programming in Cardiac Resynchronization Therapy
- Ryanodine Receptor Phosphorylation by Calcium/Calmodulin-Dependent Protein Kinase II Promotes Life-Threatening Ventricular Arrhythmias in Mice With Heart Failure
- Aspirin Plus Clopidogrel Versus Aspirin Alone After Coronary Artery Bypass Grafting : The Clopidogrel After Surgery for Coronary Artery Disease (CASCADE) Trial
- Matricellular Signaling Molecule CCN1 Attenuates Experimental Autoimmune Myocarditis by Acting as a Novel Immune Cell Migration Modulator
- β3 Adrenergic Stimulation of the Cardiac Na+-K+ Pump by Reversal of an Inhibitory Oxidative Modification
- Intracoronary Versus Intravenous Administration of Abciximab in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention With Thrombus Aspiration : The Comparison of Intracoronary Versus Intravenous Abciximab Administration During Emergency Reperfusion of ST-Segment Elevation Myocardial Infarction (CICERO) Trial
- Total Anomalous Pulmonary Venous Connection : Morphology and Outcome From an International Population-Based Study
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Mechanisms Underlying the Lack of Effect of Implantable Cardioverter-Defibrillator Therapy on Mortality in High-Risk Patients With Recent Myocardial Infarction: Insights from the Defibrillation in Acute Myocardial Infarction Trial (DINAMIT)
In the Defibrillation in Acute Myocardial Infarction Trial (DINAMIT) study, implanted defibrillators did not reduce mortality in high-risk patients if implanted early after myocardial infarction. In patients randomized to an implantable cardioverter-defibrillator (ICD), sudden deaths were reduced but nonarrhythmic mortality was increased. In an analysis of the potential causes of this finding, patients who are destined to receive therapy from their ICD (compared with those destined not to receive therapy) have clinical features that also increase their risk of nonsudden death, including risks related to heart failure and recurrent ischemic events. During follow-up, patients who receive therapy from their ICD are more likely to have intercurrent cardiac clinical adverse events both before and after ICD therapy compared with patients who receive no therapy or do not have an ICD. In an early post–myocardial infarction setting, the same clinical circumstances that increase the risk of ventricular arrhythmias also increase the risk of nonsudden death; in addition, ICD therapies themselves may increase the risk of subsequent death. These findings underscore the limitations of a strategy of ICD implantation in certain high-risk groups, especially early after acute myocardial infarction. See p 2645.
Autonomic Denervation With Magnetic Nanoparticles
The intrinsic cardiac autonomic nervous system, composed of ganglionated plexi and interconnecting nerves, is involved in the initiation of atrial fibrillation. Injury of ganglionated plexi (GP) may be important for the success of atrial fibrillation ablation in some patients but with present catheter methods, success is achieved with substantial ablation to atrial myocardium. In this animal investigation, we show the feasibility of a targeted drug delivery system for GP ablation. Superparamagnetic nanoparticles containing magnetite, a hydrogel matrix, and a neurotoxin were synthesized. When injected into a ganglia, the neurotoxin is released and suppresses GP function. When a magnet is placed over a GP, superparamagnetic nanoparticles injected into a coronary artery concentrate in the GP beneath the magnet and suppress GP function. With the advances in stereotactic localization, it may be possible to use externally applied magnetic fields to target GP for ablation with superparamagnetic nanoparticles. See p 2653.
Primary Results From the SmartDelay Determined AV Optimization: A Comparison to Other AV Delay Methods Used in Cardiac Resynchronization Therapy (SMART-AV) Trial : A Randomized Trial Comparing Empirical, Echocardiography-Guided, and Algorithmic Atrioventricular Delay Programming in Cardiac Resynchronization Therapy
The clinical benefit of cardiac resynchronization therapy for patients with moderate to severe symptomatic heart failure, severe left ventricular systolic dysfunction, and intraventricular conduction delay is firmly established. Nonetheless, a significant number of patients derive limited benefit from cardiac resynchronization therapy. One possibility is that systematic optimization of the programmed atrioventricular (AV) delay might improve overall outcomes. A variety of methods are used clinically for programming the AV delay, with no current consensus on the best practice. The SmartDelay Determined AV Optimization: A Comparison to Other AV Delay Methods Used in Cardiac Resynchronization Therapy (SMART-AV) delay trial prospectively randomized patients to a fixed empirical AV delay (120 milliseconds), echocardiographically optimized AV delay, or AV delay optimized with SmartDelay, an empirically derived electrogram-based algorithm. A total of 980 patients were randomized and followed up for 6 months. At the end of the trial, there was no difference in the primary end point, left ventricular end-systolic volume, or any of the secondary end points: left ventricular end-diastolic volume, ejection fraction, New York Heart Association class, quality of life, and 6-minute walk distance. The routine use of echocardiographic optimization and algorithm-based AV interval optimization is not clinically warranted. However, these data do not exclude possible utility in selected patients who do not respond to cardiac resynchronization therapy. See p 2660.
Ryanodine Receptor Phosphorylation by Calcium/Calmodulin-Dependent Protein Kinase II Promotes Life-Threatening Ventricular Arrhythmias in Mice With Heart Failure
Despite recent therapeutic advances including β-adrenergic blockers and implantable cardioverter-defibrillators, ventricular arrhythmias remain a prominent cause of death in patients with heart failure. Diastolic Ca2+ leak from the sarcoplasmic reticulum is believed to contribute to arrhythmia initiation in failing hearts, although the underlying mechanisms remain poorly understood. The expression and activity of the enzyme Ca2+/calmodulin-dependent protein kinase II (CaMKII) are upregulated in heart failure. Although increased CaMKII activity has been implicated in arrhythmogenesis, the specific CaMKII targets contributing to arrhythmia susceptibility have remained elusive. Our data revealed that mice in which the CaMKII phosphorylation site on the cardiac ryanodine receptor is constitutively activated exhibit an increased likelihood of intracellular Ca2+ releases. This diastolic Ca2+ “leak” leads to an increased susceptibility to ventricular tachycardia in mice. Moreover, constitutive CaMKII phosphorylation of ryanodine receptor caused an increase in arrhythmogenic sudden cardiac deaths after induction of experimental heart failure. Conversely, mice with genetic ablation of the CaMKII site on ryanodine receptor exhibited protection from induced ventricular arrhythmias due to heart failure. Taken together, our studies suggest that CaMKII phosphorylation of ryanodine receptor is an important downstream target of CaMKII that could be exploited therapeutically to minimize arrhythmia susceptibility in heart failure. Future studies utilizing pharmacological inhibition of this signaling event, once tested, may be a new avenue for reducing risk of sudden death in patients with heart failure. See p 2669.
Aspirin Plus Clopidogrel Versus Aspirin Alone After Coronary Artery Bypass Grafting : The Clopidogrel After Surgery for Coronary Artery Disease (CASCADE) Trial
Coronary artery bypass grafting (CABG) is an effective treatment for ischemic heart disease, but its long-term results are compromised by the development of saphenous vein graft (SVG) disease. After surgery, a platelet-mediated thickening of the SVG wall occurs, with smooth muscle cell proliferation and extracellular matrix protein synthesis. This process, termed intimal hyperplasia, forms a template for the development of SVG atherosclerosis and eventual occlusion. Clopidogrel has been shown to inhibit intimal hyperplasia in animal studies and therefore may reduce SVG intimal hyperplasia after coronary artery bypass grafting. In the Clopidogrel After Surgery for Coronary Artery DiseasE (CASCADE) study, we conducted a double-blind, placebo-controlled trial to evaluate whether the addition of clopidogrel to aspirin inhibits the development of SVG disease. A total of 113 patients undergoing coronary artery bypass grafting with SVGs were randomized to receive either aspirin 162 mg plus clopidogrel 75 mg daily or aspirin 162 mg plus placebo daily for 1 year, followed by SVG intravascular ultrasound and coronary angiography. The primary outcome, SVG intimal area at 1 year, did not differ significantly between the 2 groups (4.1±2.0 versus 4.5±2.1 mm2, aspirin-clopidogrel versus aspirin-placebo, P=0.44). Graft patency and freedom from major adverse cardiovascular events also did not significantly differ between the 2 groups. In summary, CASCADE indicated that compared with aspirin monotherapy, the combination of aspirin plus clopidogrel did not significantly reduce SVG intimal hyperplasia 1 year after coronary artery bypass grafting. Newer antiplatelet agents with purported advantages over clopidogrel may constitute important areas for future research to target the inhibition of SVG disease after CABG. See p 2680.
Matricellular Signaling Molecule CCN1 Attenuates Experimental Autoimmune Myocarditis by Acting as a Novel Immune Cell Migration Modulator
CCN1 is an evolutionary ancient matricellular protein that modulates biological processes associated with tissue repair. Here, we provide evidence of a novel function of CCN1 as a modulator of immune cell migration, with therapeutic potential in diseases associated with chronic pathogenic inflammation. In the current proof-of-concept study, we used CCN1 gene transfer to evaluate its therapeutic potential in animal models of human inflammatory cardiomyopathy and myocardial infarction. CCN1 therapy significantly reduced immune cell infiltration in both models. CCN1 exposure resulted in strongly suppressed migration of immune cells both in vivo and in vitro and abrogated their chemotactic response to various chemokines. These data suggest that CCN1 has potential as a new broad-spectrum immune cell migration inhibitor, in contrast to specific chemokine- or chemokine receptor–blocking agents with their known limitations arising from the fact that in most inflammatory diseases, multiple chemokines and chemokine receptors are involved and no single target of outstanding pathogenic importance exists. From a clinical translational perspective, it is of interest that the effects of the endogenous protein CCN1 on immune cell chemotaxis and migration are partially mimicked by cyclic RGD peptides that are currently being evaluated in clinical trials, although as yet for cancer therapy only. Our proof-of-concept study suggests further investigation of CCN1 as a new parent compound for immune cell migration modulation and of cyclic RGD peptides as CCN1 mimetics with immediate potential for clinical evaluation in cardiac diseases associated with chronic pathogenic inflammation. See p 2688.
β3 Adrenergic Stimulation of the Cardiac Na+-K+ Pump by Reversal of an Inhibitory Oxidative Modification
The β3 adrenergic receptor differs from the β1 and β2 types in its structure, ligand affinities, and coupling to intracellular signaling pathways. Its expression in the myocardium is upregulated in heart failure, and because it mediates a negative inotropic effect in the normal heart, this upregulation has been thought to be maladaptive. This has led to the suggestion that β3 adrenergic receptor antagonists might be useful. The β receptor antagonists of proven efficacy target β1-\ and β2 receptors, and we have reported that the downstream cAMP-dependent pathways coupled to these receptors induce an oxidative modification on a subunit of the membrane Na+-K+ pump that inhibits pump activity. Because raised intracellular Na+ levels and increased myocardial oxidative stress contribute adversely to the phenotype of contractile abnormalities and cardiac arrhythmias in heart failure, the “β-blockers” may limit the oxidative Na+-K+ pump inhibition and hence reduce myocyte Na+ overload. Here, we show that selective β3 adrenergic receptor agonists reverse the oxidative molecular modification that inhibits the cardiac Na+-K+ pump and hence stimulate pump activity. Activation of upregulated β3 adrenergic receptors with the increase in catecholamine levels typically seen in heart failure may be a useful compensatory mechanism, consistent with a recent report of β3 adrenergic receptor knockout mice suffering an accentuated cardiac phenotype in an aortic constriction model. It may also explain the adverse outcome in a previous large human heart failure trial when raised catecholamine levels were specifically targeted in heart failure with the use of a centrally acting sympatholytic drug. See p 2699.
Intracoronary Versus Intravenous Administration of Abciximab in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention With Thrombus Aspiration : The Comparison of Intracoronary Versus Intravenous Abciximab Administration During Emergency Reperfusion of ST-Segment Elevation Myocardial Infarction (CICERO) Trial
Administration of the glycoprotein IIb/IIIa inhibitor abciximab is an effective adjunctive antiplatelet strategy during primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. Experimental studies have reported that higher local concentrations of abciximab exert additional effects, including disaggregation of newly formed thrombus, and can be achieved by intracoronary administration. Recently, small-scale studies have suggested beneficial clinical effects of intracoronary over intravenous administration. In the present Comparison of Intracoronary Versus Intravenous Abciximab Administration During Emergency Reperfusion of ST-Segment Elevation Myocardial Infarction (CICERO) trial, 534 ST-segment elevation myocardial infarction patients were randomized within 12 hours of symptom onset to either an intracoronary or an intravenous bolus of abciximab during primary percutaneous coronary intervention with thrombus aspiration. Patients were pretreated with aspirin, heparin, and high-dose clopidogrel. Intracoronary administration of abciximab compared with intravenous administration did not improve the rate of successful myocardial reperfusion as assessed by ST-segment resolution. In contrast, intracoronary administration was associated with a significantly higher rate of successful myocardial reperfusion as assessed by myocardial blush grade and a smaller enzymatic infarct size. In addition, bleeding complications occurred at similar frequencies between both treatment groups. Although intracoronary administration did not improve the primary end point of ST-segment resolution, the beneficial effects on secondary end points may translate into improved clinical outcome. Larger randomized multicenter trials are required to investigate whether intracoronary administration of abciximab reduces major adverse cardiac events. See p 2709.
Total Anomalous Pulmonary Venous Connection : Morphology and Outcome From an International Population-Based Study
Totally anomalous pulmonary venous connection is a cyanotic congenital heart disease with ongoing morbidity and mortality particularly related to pulmonary venous obstruction. Our study is the largest population-based study of the disease to date and reports on the incidence, morphology, outcome, and factors predictive of poor outcome for all babies born with this anomaly in a fixed geographic area (United Kingdom, Ireland, and Sweden). Importantly, our report represents an exhaustive collaborative effort of all pediatric cardiac centers in the United Kingdom, Ireland, and Sweden. Unlike other studies, the population-based nature of our data reflects the entire spectrum of morphology, as well as contemporary practice. We have identified a cohort of patients with pulmonary venous obstruction after surgical repair and identified risk factors for this. After reading the article, the clinician should be aware of the wide spectrum of complexity in this condition, should be better able to predict outcome for an individual patient with total anomalous pulmonary venous connection, and should understand which patients are particularly at risk of developing postoperative pulmonary venous obstruction. See p 2718.
- © 2010 American Heart Association, Inc.
- Autonomic Denervation With Magnetic Nanoparticles
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