Circulation: Clinical Summaries
Original Research Put Into Perspective for the Practicing Clinician
- Long-Term Prognosis of Patients With Kawasaki Disease Complicated by Giant Coronary Aneurysms: A Single-Institution Experience
- Safety and Tolerability of Atopaxar in the Treatment of Patients With Acute Coronary Syndromes: The Lessons From Antagonizing the Cellular Effects of Thrombin–Acute Coronary Syndromes Trial
- Randomized Trial of Atopaxar in the Treatment of Patients With Coronary Artery Disease: The Lessons From Antagonizing the Cellular Effect of Thrombin–Coronary Artery Disease Trial
- Genetic Predictors of Fibrin D-Dimer Levels in Healthy Adults
- Impact of Remote Telemedical Management on Mortality and Hospitalizations in Ambulatory Patients With Chronic Heart Failure: The Telemedical Interventional Monitoring in Heart Failure Study
- Transmural Heterogeneity and Remodeling of Ventricular Excitation-Contraction Coupling in Human Heart Failure
- Novel Antiplatelet Drug Revacept (Dimeric Glycoprotein VI-Fc) Specifically and Efficiently Inhibited Collagen-Induced Platelet Aggregation Without Affecting General Hemostasis in Humans
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Long-Term Prognosis of Patients With Kawasaki Disease Complicated by Giant Coronary Aneurysms: A Single-Institution Experience
Kawasaki disease, a systemic vasculitis with unknown origin, is the most frequent acquired cardiovascular disease in children in developed countries. Despite appropriate treatment, including high-dose intravenous immunoglobulin infusion and aspirin, a certain number of patients develop giant coronary aneurysms (≥8 mm) that could undergo remodeling, leading to ischemic heart disease. In the last 15 years, we have developed catheter and surgical interventions for this ischemic heart disease and proposed indications of these treatments. As a result, the long-term survival of patients with giant coronary aneurysms is moderately good, ie, 90% at 20 years and 87% at 30 years after onset. However, the result of catheter and surgical coronary intervention may not be satisfactory in this setting because many patients require repeat procedures. In addition, it is still difficult to treat small children with ischemic heart disease caused by Kawasaki disease. Further research should focus on medical treatment to prevent coronary vascular remodeling and the indications for and effectiveness of catheter and surgical coronary interventions. See p 1836.
Safety and Tolerability of Atopaxar in the Treatment of Patients With Acute Coronary Syndromes: The Lessons From Antagonizing the Cellular Effects of Thrombin–Acute Coronary Syndromes Trial
Atopaxar (E5555) is a reversible protease-activated receptor-1 thrombin receptor antagonist that interferes with platelet signaling. The primary objective of the phase II Lessons From Antagonizing the Cellular Effects of Thrombin–Acute Coronary Syndromes (LANCELOT—ACS) trial was to evaluate the safety and tolerability of atopaxar in patients with an acute coronary syndrome. A total of 603 subjects were randomly assigned to 1 of 3 doses of atopaxar (400-mg loading dose followed by 50, 100, or 200 mg daily) or matching placebo for 12 weeks. At the end of the follow-up, the incidence of bleeding (according to the Clopidogrel in Unstable Angina to Prevent Recurrent Events and Thrombolysis in Myocardial Infarction bleeding definitions) did not differ significantly between the combined atopaxar and placebo groups. Atopaxar significantly reduced ischemia on continuous ECG monitoring (Holter) at 48 hours compared with placebo. Transient dose-dependent transaminase elevation and relative QTc prolongation were observed with the highest doses of atopaxar. Overall, the study demonstrated that atopaxar was generally well tolerated, especially at the 50-mg treatment dose. Potential signals of efficacy without a clear increase in bleeding support the concept of the protease-activated receptor-1 receptor as a possible key target for inhibition. Larger trials are required to fully establish the efficacy and safety of atopaxar. See p 1843.
Randomized Trial of Atopaxar in the Treatment of Patients With Coronary Artery Disease: The Lessons From Antagonizing the Cellular Effect of Thrombin–Coronary Artery Disease Trial
Thrombin is a key mediator of platelet activation in acute coronary syndromes. Atopaxar is a reversible protease-activated receptor antagonist that interferes with thrombin mediated platelet effects. The phase II Lessons From Antagonizing the Cellular Effect of Thrombin–Coronary Artery Disease (LANCELOT–CAD) trial examined the safety and tolerability of prolonged therapy with atopaxar in subjects with CAD. Seven hundred and twenty subjects were randomized in a double-blind fashion to 1 of 3 dosing regimens of atopaxar (50, 100, or 200 mg daily) or matching placebo for 24 weeks and followed up for an additional 4 weeks. Overall bleeding rates tended to be higher with atopaxar compared with placebo by Clopidogrel in Unstable Angina to Prevent Recurrent Events and Thrombolysis in Myocardial Infarction criteria without a difference in major bleeding by either category. All atopaxar regimens achieved high levels of platelet inhibition with dose-dependent rapid onset and offset. Major adverse cardiac events tended to be less frequent with atopaxar, but the trial was not powered for clinical events, and statistically significant differences were not observed. Atopaxar was generally well tolerated, but QTc prolongations and liver transaminase elevations without clinical sequelae were observed with higher-dose atopaxar. Although these data are encouraging, larger-scale trials are needed to determine the clinical efficacy and safety of protease-activated receptor-1 antagonism in patients with atherosclerotic vascular disease. See p 1854.
Genetic Predictors of Fibrin D-Dimer Levels in Healthy Adults
Activation of blood coagulation plays a key role in hemostasis and in arterial and venous thrombosis. Fibrin D-dimer is the most widely used clinical marker of activated blood coagulation. Epidemiological and clinical studies over the last 20 years have established its associations with risk of arterial and venous thromboembolic events and with other pathologies. This article reports a novel association of plasma D-dimer levels with variation upstream from F3, the gene for tissue factor. The manuscript also confirms a previous report that D-dimer levels are associated with the factor V Leiden F5 R506Q variant (rs6025) and the FGA Ala331Thr variant (rs6050) variant, which are also associated with risk of arterial and venous thrombosis. Our demonstration that a genetic variant upstream from F3 is associated with variation in D-dimer levels in generally healthy populations supports the concept that F3 might be a potential therapeutic target to reduce thrombotic risk. See p 1864.
Impact of Remote Telemedical Management on Mortality and Hospitalizations in Ambulatory Patients With Chronic Heart Failure: The Telemedical Interventional Monitoring in Heart Failure Study
The Telemedical Interventional Monitoring in Heart Failure (TIM-HF) trial was designed to determine whether physician-led remote telemedical management (RTM) compared with usual care would positively affect total mortality in ambulatory, stable chronic heart failure patients. Eligible patients were in New York Heart Association class II or III, with a left ventricular ejection fraction ≤35% who had a history of heart failure decompensation within the previous 2 years or with a left ventricular ejection fraction ≤25%. Patients were randomly assigned (1:1) to RTM (n=354) or usual care (n=356). Remote telemedical management used portable devices for ECG, blood pressure, and body weight measurements. Data were transferred daily via a personal digital assistant to physician-led telemedical centers that were active on a 24 hours per day, 7 days per week basis. Of the patients assigned to RTM, 81% were ≥70% compliant with daily data transfers and no break for >30 days (except during hospitalizations). Over a median follow-up of 26 months, compared with usual care, RTM had no significant effect on total mortality (hazard ratio, 0.97; 95% confidence interval, 0.67 to 1.41; P=0.87) or on cardiovascular death or heart failure hospitalization (hazard ratio, 0.89; 95% confidence interval, 0.67 to 1.19; P=0.44), the first secondary outcome. In conclusion, in stable ambulatory patients with chronic heart failure, RTM compared with usual care was not associated with a reduction in all-cause mortality. Our results do not concur with the recently published meta-analysis. However, the latter need to be interpreted with caution, because not all telemedical approaches are the same. Telemedicine may not be appropriate for all heart failure patients. Future research needs to document which patients with chronic heart failure could benefit from certain types of telemedical support/management. See p 1873.
Transmural Heterogeneity and Remodeling of Ventricular Excitation-Contraction Coupling in Human Heart Failure
Excitation-contraction coupling is a complex process mediated by a network of proteins that control ionic currents, cell signaling, calcium handling, and sarcomeric mechanics. The 2 hallmarks of excitation-contraction coupling preceding mechanical contraction are the transmembrane action potential and intracellular calcium transient. Numerous studies in animal models have significantly advanced our understanding of the fundamental mechanisms of excitation-contraction coupling at the molecular, cellular, and whole-heart levels. However, the extrapolation of these findings to clinical practice is limited by the lack of functional human data. Our study provides, for the first time in medical history, such functional data: simultaneous recordings of action potentials and calcium transients from the human left ventricular tissue of nonfailing and failing hearts. We found that the nonfailing human left ventricle has a transmural gradient of calcium transient kinetics, with the calcium transient being longer at the endocardial than at the epicardial layers of the ventricular wall. A decrease in this gradient in the failing heart reversed the normal sequence of relaxation. We also found that heart failure leads to significant changes in calcium dynamics, manifesting as a biphasic calcium entry into the cytosol. Downregulation of sarcoplasmic reticulum Ca2+-ATPase 2a depends on the origin and anatomic location, which might explain the inconsistency in the literature on the subject. Transmural heterogeneity indicates that the anatomic location must be considered in studies of molecular remodeling of excitation-contraction coupling. Our study confirms some of the earlier findings in animal models but contradicts others. Thus, extrapolation of findings from animal models to humans should be done with caution. See p 1881.
Novel Antiplatelet Drug Revacept (Dimeric Glycoprotein VI-Fc) Specifically and Efficiently Inhibited Collagen-Induced Platelet Aggregation Without Affecting General Hemostasis in Humans
Treating atherothrombosis with Revacept in patients with acute cerebral arterial syndromes or acute coronary syndromes is a novel concept. This study drug is a soluble form of the platelet glycoprotein VI receptor, and binds specifically to collagen structures of ruptured plaques. Therefore, the first steps of platelet adhesion and the consecutive platelet aggregation are prevented without affecting the general platelet function and hemostasis. Revacept would be the first drug to potently block platelet function without increasing bleeding complications in patients. Preclinical and phase I studies in healthy volunteers have proved the mode of action and safety of this study drug. Despite tremendous progress in the treatment of patients with acute coronary or cerebral syndromes, decreased thrombus formation and reduction of ischemic complications are often achieved at the expense of increased bleeding. Therefore, a potent drug that inhibits platelet activation but would not affect general hemostasis would pose a significant improvement for the treatment of patients with acute arterial syndromes. The problem of increased bleeding has often hampered therapeutic benefits in the prevention or reduction of ischemia by antiplatelet or other antithrombotic drugs, especially in patients with ischemic strokes. Efficacy studies in patients must prove that the expectations will hold true in the future to develop a safe and potent platelet inhibitory drug. See p 1891.
- © 2011 American Heart Association, Inc.
- Genetic Predictors of Fibrin D-Dimer Levels in Healthy Adults
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