Circulation: Clinical Summaries
Original Research Put Into Perspective for the Practicing Clinician
- Off-Pump Coronary Artery Bypass Surgery Is Associated With Worse Arterial and Saphenous Vein Graft Patency and Less Effective Revascularization: Results From the Veterans Affairs Randomized On/Off Bypass (ROOBY) Trial
- Relations of Exercise Blood Pressure Response to Cardiovascular Risk Factors and Vascular Function in the Framingham Heart Study
- Ventricular Assist Device Implantation Corrects Myocardial Lipotoxicity, Reverses Insulin Resistance, and Normalizes Cardiac Metabolism in Patients With Advanced Heart Failure
- Multisite Randomized Trial of a Single-Session Versus Multisession Literacy-Sensitive Self-Care Intervention for Patients With Heart Failure
- Improving Blood Pressure Control Through a Clinical Pharmacist Outreach Program in Patients With Diabetes Mellitus in 2 High-Performing Health Systems: The Adherence and Intensification of Medications Cluster Randomized, Controlled Pragmatic Trial
- Short- and Long-Term Outcomes With Drug-Eluting and Bare-Metal Coronary Stents: A Mixed-Treatment Comparison Analysis of 117 762 Patient-Years of Follow-Up From Randomized Trials
- A Novel Regulator of Macrophage Activation: miR-223 in Obesity-Associated Adipose Tissue Inflammation
- Lack of Microsomal Prostaglandin E2 Synthase-1 in Bone Marrow–Derived Myeloid Cells Impairs Left Ventricular Function and Increases Mortality After Acute Myocardial Infarction
- Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes and a History of Stroke or Transient Ischemic Attack
- Dietary Nitrate Ameliorates Pulmonary Hypertension: Cytoprotective Role for Endothelial Nitric Oxide Synthase and Xanthine Oxidoreductase
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Off-Pump Coronary Artery Bypass Surgery Is Associated With Worse Arterial and Saphenous Vein Graft Patency and Less Effective Revascularization: Results From the Veterans Affairs Randomized On/Off Bypass (ROOBY) Trial
The Department of Veterans Affairs Randomized On/Off Bypass (ROOBY) trial is the largest trial to date to compare angiographic outcomes in off-pump versus on-pump coronary artery bypass graft (CABG) surgery. One-year follow-up angiography was obtained in 685 off-pump and 685 on-pump patients. Angiograms were analyzed in a blinded manner by intention to treat. Grafts were classified as patent (open versus closed) and were assessed for quality with the FitzGibbon classification system. Every patient was also assessed for effective revascularization, which was defined as follows: All 3 major coronary territories with significant disease were revascularized by a FitzGibbon A-quality graft to the major diseased artery, the graft was placed in proper position relative to native disease, and there were no new postanastomotic lesions. Effective revascularization has not been reported previously in a study of post-CABG graft patency. This study is the first randomized study of off-pump versus on-pump CABG to indicate that both graft patency and effective revascularization are clearly worse with off-pump CABG. FitzGibbon graft patency was worse for arterial, left internal mammary artery pedicle, and vein graft conduits. In addition, every coronary territory was revascularized less effectively with off-pump CABG. At the 1-year follow-up angiography, ≈50% of off-pump CABG patients had at least 1 coronary territory that was at risk for ischemia. Those patients with less effective revascularization had significantly more adverse cardiac events by 1 year after CABG. See p 2827.
Relations of Exercise Blood Pressure Response to Cardiovascular Risk Factors and Vascular Function in the Framingham Heart Study
Exercise blood pressure is an important marker of cardiovascular disease risk that is associated with incident hypertension, myocardial infarction, and cardiovascular mortality in individuals without overt coronary artery disease. It has been hypothesized that individuals with a hypertensive response to exercise may have abnormalities in vascular function that limit the compensatory mechanisms necessary to dampen the rise in blood pressure with exercise. Using data from >2000 individuals from the Framingham Offspring Study, we demonstrate that increases in blood pressure during low-intensity exercise (ie, walking) are associated with both endothelial dysfunction and increased aortic stiffness. Our findings suggest that impaired vascular function may contribute to exaggerated blood pressure responses during activities of daily living, resulting in repetitive increments in load on the heart and vessels and increased cardiovascular disease risk. Our results provide an important mechanistic link between the hypertensive response to exercise, left ventricular hypertrophy, and the associated increased risk of cardiovascular events. See p 2836.
Ventricular Assist Device Implantation Corrects Myocardial Lipotoxicity, Reverses Insulin Resistance, and Normalizes Cardiac Metabolism in Patients With Advanced Heart Failure
The failing human heart develops metabolic derangements characterized by a shift from fatty acids to glucose use for ATP generation. These metabolic changes are accompanied by transcriptional changes typically seen during embryogenesis. The aim of our study was to investigate myocardial levels of toxic lipid intermediates in samples from patients with advanced heart failure compared with control subjects. Furthermore, we analyzed whether mechanical unloading of the failing myocardium corrects impaired cardiac metabolism. For this purpose, we analyzed myocardium and serum of patients with advanced heart failure obtained during left ventricular assist device implantation and at explantation and from control subjects. Systemic insulin resistance in heart failure was accompanied by decreased myocardial triglyceride and overall fatty acid content but increased toxic lipid intermediates, diacylglycerol, and ceramide. Several downstream signaling molecules known to regulate insulin signaling (Akt, Foxo, and protein kinase C) were also found to be dysregulated in the failing myocardium, favoring an insulin-resistant state compared with control subjects. Left ventricular assist device implantation improved insulin resistance and decreased myocardial levels of the toxic lipid intermediates diacylglycerol and ceramide, whereas triglyceride and free fatty acid content remained unchanged. Therefore, abnormal myocardial metabolism, insulin resistance, and lipotoxicity develop in human heart failure. Mechanical unloading through left ventricular assist device implantation corrects systemic and local metabolic derangements in advanced heart failure. This study characterizes metabolic changes in human heart failure with the development of cardiac lipotoxicity. Furthermore, these findings suggest potential therapeutic implications of mechanical unloading of the failing myocardium for the correction of metabolic derangements in advanced human heart failure. See p 2844.
Multisite Randomized Trial of a Single-Session Versus Multisession Literacy-Sensitive Self-Care Intervention for Patients With Heart Failure
This manuscript describes the comparative effectiveness of 2 types of a heart failure self-care training program: single-session training versus multisession training. In a diverse population across 4 clinical sites, there was no difference in rate of hospitalization or death between the interventions. However, patient literacy was an important factor in the effect of the intervention. Patients with low literacy appeared to benefit from the multisession intervention compared with the single-session intervention, but patients with higher literacy did not benefit. Although self-care training for heart failure is an important component of guideline-based care for all patients, it may be important to focus our most intensive resources via ongoing training for patients with low literacy skills. See p 2854.
Improving Blood Pressure Control Through a Clinical Pharmacist Outreach Program in Patients With Diabetes Mellitus in 2 High-Performing Health Systems: The Adherence and Intensification of Medications Cluster Randomized, Controlled Pragmatic Trial
We studied the implementation and clinical outcomes of a state-of-the-art, intensive pharmacist-led intervention seeking to improve blood pressure control in a high-risk population (patients with diabetes mellitus, persistent hypertension, and documented medication adherence or management problems) in 2 high-performing healthcare systems (Kaiser Permanente and the Veterans Affairs Health System). In the short term, the program improved blood pressure control in comparison with usual care, but, by 6 months after the program's completion, patients receiving usual care had on average achieved similar systolic blood pressure improvements (mean of 10 mm Hg decrease). In such high-performing healthcare systems, the programs already put into place to achieve the impressive 80% rates of blood pressure control in these systems may be demonstrating best achievable practices. Clinical inertia alone may not be preventing the achievement of optimal control in high-risk patients. Clinicians should continue to work on improving medication management for these patients and on assisting patients with barriers to medication adherence. However, even with these strategies, it is likely that some patients with persistent hypertension will remain with poor blood pressure control. See p 2863.
Short- and Long-Term Outcomes With Drug-Eluting and Bare-Metal Coronary Stents: A Mixed-Treatment Comparison Analysis of 117 762 Patient-Years of Follow-Up From Randomized Trials
With the Food and Drug Administration's approval of more drug-eluting stents (DES), the relative short- and long-term efficacy and safety of DES compared with bare-metal stents and among the DES types are less well defined. Although each of the DES has had claims of superior efficacy or safety, direct comparisons have been limited. Our analyses from 76 randomized clinical trials with 117 762 patient-years of follow-up showed that DES are highly efficacious at reducing the risk of target-vessel revascularization without causing an increase in any safety outcomes, including stent thrombosis. However, among the DES types, there were considerable differences, such that the everolimus-eluting stent, sirolimus-eluting stent, and zotarolimus-eluting Resolute stent were the most efficacious and the everolimus-eluting stent was the safest stent. See p 2873.
A Novel Regulator of Macrophage Activation: miR-223 in Obesity-Associated Adipose Tissue Inflammation
Macrophage-mediated adipose tissue inflammation is a major contributor to the pathogenesis of obesity-associated chronic diseases, including the 2 types of most prevailing diseases, namely type 2 diabetes mellitus and cardiovascular diseases. The activation status of macrophages is a key determinant for the onset of these diseases, and despite extensive research in this area, major questions about macrophages function and their interactions with host tissues remain unanswered. The discovery of microRNAs (miRNAs) has opened a new window for understanding the regulatory networks related to homeostasis and disease. MiRNAs are a family of small noncoding RNAs that have been demonstrated to be crucial regulators in multiple physiological processes and disease pathogenesis. Altered expression patterns of miRNAs are tightly associated with chronic inflammatory diseases. However, miRNA-mediated regulatory networks in modulating macrophage polarization in adipose tissue inflammation have not been previously investigated. In this study, we demonstrated that miR-223 is a novel and crucial regulator of macrophage polarization and is indicated for suppressing proinflammatory and enhancing antiinflammatory responses. Our results identify a new miRNA-based paradigm for the regulation of insulin sensitivity and provide the basis for using miRNA analogs to treat insulin resistance–related diseases. See p 2892.
Lack of Microsomal Prostaglandin E2 Synthase-1 in Bone Marrow–Derived Myeloid Cells Impairs Left Ventricular Function and Increases Mortality After Acute Myocardial Infarction
Millions of patients use nonsteroidal anti-inflammatory drugs (NSAIDS) to treat pain and inflammatory disorders. NSAIDS block the activity of cyclooxygenase-2 (COX-2), an enzyme that catalyzes the second of three steps in prostaglandin biosynthesis. Unfortunately, some COX-2 inhibitors are associated with an increased risk of myocardial infarction (MI) and stroke, possibly because of decreased production of antithrombotic eicosanoids, such as PGI2, combined with simultaneous unopposed production of prothrombotic thromboxane A2, an eicosanoid catalyzed via COX-1 in platelets. Microsomal prostaglandin E 2 synthase-1 (mPGES-1) is downstream from COX-2 in the inducible PGE2 biosynthetic pathway. Inhibition or deletion of mPGES-1 decreases pain, fever and inflammation without increasing the propensity for thrombosis. Therefore, pharmacologic inhibitors of mPGES-1 may be a viable replacement for COX-2 inhibitors, and may not be associated with an increased risk of thrombotic cardiovascular events. We show that targeted deletion of mPGES-1 in bone marrow derived leukocytes that are recruited to the heart leads to left ventricular (LV) dilation, impaired LV systolic and diastolic function, adverse LV remodelling, and increased mortality after MI. These finding increase our understanding of the molecular events that control LV remodeling after MI, and demonstrate the importance of eicosanoid biosynthesis by inflammatory leukocytes in this process. However, caution is warranted in extrapolating the results of targeted deletion of mPGES-1 in bone marrow derived leukocytes in mice to the possible outcome of pharmacologic inhibition of mPGES-1 in clinical practice. Further studies, of mice and humans, are warranted to define the role of mPGES-1 in LV remodeling after MI. See p 2904.
Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes and a History of Stroke or Transient Ischemic Attack
Patients with acute coronary syndromes and a history of prior stroke are at a high risk of ischemic and bleeding events and constitute a treatment challenge. Therefore, novel and more potent antithrombotic agents need to be evaluated with regard to the balance between efficacy and safety, particularly in the most vulnerable patients. Ticagrelor provides faster, greater, and more consistent platelet inhibition than clopidogrel. The PLATelet inhibition and patient Outcomes (PLATO) trial showed that ticagrelor was superior to clopidogrel in a broad population of patients with acute coronary syndromes for the prevention of cardiovascular death, myocardial infarction, or stroke but with an increase in overall major bleeding events not associated with coronary artery bypass surgery. Among the 18 624 patients randomized in the PLATO study, 1152 (6.2%) were reported as having a history of stroke or transient ischemic attack. These patients presented higher rates of the primary composite end point (myocardial infarction, CV death, and stroke) at 1 year compared with those patients without prior stroke or transient ischemic attack. The reduction of the primary composite outcome and total mortality at 1 year with ticagrelor versus clopidogrel was consistent with the overall trial results. The rates of overall PLATO-defined major bleeding events associated with coronary artery bypass graft surgery, as well as major bleeding events, were similar, and intracranial bleeding occurred infrequently in the randomized groups. In light of a favorable clinical net benefit and associated impact on mortality, the results of the present study suggest that treatment with ticagrelor should not be withheld in acute coronary syndrome patients with a history of ischemic stroke or transient ischemic attack for safety concerns if otherwise indicated. See p 2914.
Dietary Nitrate Ameliorates Pulmonary Hypertension: Cytoprotective Role for Endothelial Nitric Oxide Synthase and Xanthine Oxidoreductase
Loss of nitric oxide (NO) bioactivity underpins many of the hemodynamic and morphological changes in the cardiopulmonary circulation that characterize pulmonary hypertension, particularly the pulmonary arterial hypertension subclass. Recent evidence suggests that the NO metabolites nitrite (NO2−) and nitrate (NO3−) can be chemically reduced in vivo to biologically active NO, a phenomenon that occurs optimally under conditions of hypoxia and acidosis. This nitrate-nitrite-NO pathway has been shown to exert a number of beneficial effects, including lowering of systemic blood pressure and protection against ischemia-reperfusion injury. Herein, we have used 2 etiologically distinct experimental models of pulmonary hypertension to demonstrate that dietary nitrate (and, to a lesser extent, nitrite) can prevent and reverse the pathogenesis of this debilitating disease. In addition, we have identified the principal enzymatic routes (ie, endothelial NO synthase and xanthine oxidoreductase) by which endogenous NO generation occurs. These data provide convincing evidence that supplementation of dietary nitrate is likely to represent a novel means by which to slow, halt, or actually reverse the development of pulmonary hypertension. Exploitation of this mechanism represents a viable, orally active therapy for pulmonary hypertension that warrants evaluation in this patient population and, if efficacious, could be implemented rapidly and cost-effectively. See p 2922.
- © 2012 American Heart Association, Inc.
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