- Impact of Proteinuria and Glomerular Filtration Rate on Risk of Thromboembolism in Atrial Fibrillation: The Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study
- Effects of Regional Dysfunction and Late Gadolinium Enhancement on Global Right Ventricular Function and Exercise Capacity in Patients With Repaired Tetralogy of Fallot
- Diagnostic Ultrasound Combined With Glycoprotein IIb/IIIa–Targeted Microbubbles Improves Microvascular Recovery After Acute Coronary Thrombotic Occlusions
- Divergent Tumor Necrosis Factor Receptor–Related Remodeling Responses in Heart Failure: Role of Nuclear Factor-κB and Inflammatory Activation
- Resolution of Established Cardiac Hypertrophy and Fibrosis and Prevention of Systolic Dysfunction in a Transgenic Rabbit Model of Human Cardiomyopathy Through Thiol-Sensitive Mechanisms
- Frequency of Myocardial Bridges and Dynamic Compression of Epicardial Coronary Arteries: A Comparison Between Computed Tomography and Invasive Coronary Angiography
- Predictors of Cerebral Arteriopathy in Children With Arterial Ischemic Stroke: Results of the International Pediatric Stroke Study
- Interleukin-17 and Interferon-γ Are Produced Concomitantly by Human Coronary Artery–Infiltrating T Cells and Act Synergistically on Vascular Smooth Muscle Cells
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Impact of Proteinuria and Glomerular Filtration Rate on Risk of Thromboembolism in Atrial Fibrillation: The Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study
Atrial fibrillation is a potent risk factor for ischemic stroke, but accurately determining a patient’s individual risk is challenging because current stroke risk classification methods have only modest prognostic ability. Chronic kidney disease (reduced glomerular filtration rate and/or proteinuria) is a major cardiovascular risk factor that is especially common among older persons, but whether it independently increases the risk for ischemic stroke in atrial fibrillation is poorly understood. Among 13 535 adults with atrial fibrillation, we examined the risk of thromboembolic events (ischemic stroke and other arterial embolism) associated with the level of estimated glomerular filtration rate and the presence of proteinuria. During 33 165 person-years off warfarin, we confirmed 676 thromboembolic events. After adjustment for known stroke risk factors (prior stroke, age, hypertension, diabetes, and heart failure) and other confounders, proteinuria increased the risk of thromboembolism by 54% (adjusted relative risk, 1.54; 95% CI, 1.29 to 1.85), and there was a graded, increased risk of thromboembolism associated with lower level of estimated glomerular filtration rate. Compared with glomerular filtration rate ≥60 mL · min−1 · 1.73 m−2, the adjusted relative risk for thromboembolism was 1.16 (95% CI, 0.95 to 1.40) for 45 to 59 mL · min−1 · 1.73 m−2 and 1.39 (95% CI, 1.13 to 1.71) for <45 mL · min−1 · 1.73 m−2 (P=0.0082 for trend). Chronic kidney disease increases the risk of thromboembolism in atrial fibrillation independently of other known risk factors. Clinicians should consider ascertaining information about the level of estimated glomerular filtration rate and the presence of proteinuria in patients with atrial fibrillation, which may improve risk stratification for decision making about the use of antithrombotic therapy for stroke prevention. See p 1363.
Effects of Regional Dysfunction and Late Gadolinium Enhancement on Global Right Ventricular Function and Exercise Capacity in Patients With Repaired Tetralogy of Fallot
It has long been known that right ventricular (RV) dysfunction often complicates the clinical course of patients with repaired tetralogy of Fallot and is associated with increased morbidity and mortality. For many years, investigators have suspected that scar tissue or patch material in the RV outflow tract can adversely affect RV mechanics after tetralogy of Fallot repair, but the degree to which regional abnormalities can affect global RV function has remained largely unknown. In addition, it is unclear whether regional abnormalities adversely affect exercise capacity, ventricular arrhythmia, and heart failure independent of global RV dysfunction. This article reports the use of newly developed cardiac MRI–based quantitative methods to analyze the effects of regional RV wall-motion abnormalities and late gadolinium enhancement on global RV systolic function and clinical status in 62 patients with repaired tetralogy of Fallot. In addition to showing that regional RV abnormalities contribute to RV dysfunction independent of RV size, degree of pulmonary regurgitation, and other confounding factors, the study also demonstrates that quantitative measures of regional dysfunction are associated with decreased exercise capacity, sustained ventricular tachycardia, and symptoms of heart failure. Furthermore, the study found that fibrosis and dyskinesis often extend beyond the superior aspect of the RV outflow tract (the site of pulmonary valve implantation) into adjacent segments. These observations suggest that in patients with substantial areas of patch and scar tissue associated with regional wall-motion abnormalities of the RV outflow tract and adjacent areas, pulmonary valve insertion alone, with or without local patch resection, may be insufficient and that extensive remodeling of the RV might be necessary for optimal functional recovery. See p 1370.
Diagnostic Ultrasound Combined With Glycoprotein IIb/IIIa–Targeted Microbubbles Improves Microvascular Recovery After Acute Coronary Thrombotic Occlusions
Coronary thrombosis on a ruptured coronary plaque is the main pathophysiological event that leads to acute coronary syndromes. Although current pharmacological therapies and interventional techniques have improved the prognosis of patients with acute coronary syndromes, each of these therapeutic interventions has significant limitations. In the present study, we demonstrate that diagnostic ultrasound and intravenous microbubbles can improve both microcirculatory and epicardial recanalization rates in acute coronary thromboses. After acute left anterior descending thrombotic occlusions, intravenous platelet-targeted microbubbles combined with brief high–mechanical index diagnostic transthoracic ultrasound transducer guided by a low–mechanical index pulse sequence scheme improved microvascular flow to the risk area and increased epicardial recanalization rates. The improvement in microvascular flow was observed even when epicardial recanalization did not occur and correlated with improvements in wall thickening within the risk area. The addition of ultrasound and microbubbles may permit lower doses of fibrinolytic agents to be administered while still achieving an equivalent pharmacological effect. Furthermore, the enhanced thrombolytic effects would be targeted to just the region being insonified, which would reduce the risk of bleeding at remote locations. Because the ultrasound pressures and frequencies used in this study are already within Food and Drug Administration limits, this supplemental treatment regimen could be tested in ST-segment elevation myocardial infarction to determine whether guided diagnostic ultrasound and intravenous microbubbles will result in improved regional function and better clinical outcomes compared with treatment regimens focused on just recanalizing the epicardial vessel. See p 1378.
Divergent Tumor Necrosis Factor Receptor–Related Remodeling Responses in Heart Failure: Role of Nuclear Factor-κB and Inflammatory Activation
Despite the seminal observation that tumor necrosis factor-α (TNF) is an important mediator of pathological left ventricular remodeling in heart failure (HF), this discovery has not resulted in the development of new, effective treatments. On the contrary, the unexpected failure of clinical trials of global TNF blockade casts doubt on the precise roles of inflammatory activation in general and of TNF in particular in the progression of chronic HF. Because there are 2 cell-surface receptors for TNF (TNFR1 and TNFR2), we evaluated the remodeling responses specifically referable to each TNFR in chronic ischemic HF in vivo using TNFR1- and TNFR2-null mice. Our results indicate that TNF induces dichotomous effects in HF such that TNFR1 aggravated, whereas TNFR2 ameliorated, chamber remodeling and hypertrophy. Moreover, these effects occurred, at least in part, because of divergent effects on the activation of the downstream signaling mediator nuclear factor-κB, the regulation of inflammatory cytokines, and the induction of apoptosis: TNFR1 exacerbated, whereas TNFR2 ameliorated, these events. These results suggest that the overall balance between these opposing receptor-specific responses determines the ultimate impact of TNF on the HF phenotype and that analogous TNFR-specific effects in human HF should be considered when anti-TNF therapies are developed. Dichotomous TNFR-specific effects may also provide an explanation for the failure of the anti-TNF clinical trials. Selective targeting of the individual TNFRs (TNFR1 blockade and/or TNFR2 augmentation) may represent a better therapeutic approach in HF. See p 1386.
Resolution of Established Cardiac Hypertrophy and Fibrosis and Prevention of Systolic Dysfunction in a Transgenic Rabbit Model of Human Cardiomyopathy Through Thiol-Sensitive Mechanisms
Hypertrophic cardiomyopathy (HCM) is a genetic disease characterized by primary cardiac hypertrophy. Cardiac hypertrophic and accompanying fibrosis are major determinants of clinical outcomes, including the risk of sudden cardiac death, not only in patients with HCM but also in patients with various cardiovascular diseases. Current pharmacological agents are not known to reverse established cardiac hypertrophy and fibrosis in patients with HCM. We and others have proposed that cardiac hypertrophy and fibrosis in HCM are secondary to activation of various stress-responsive signaling and trophic molecules, including oxidative stress-responsive molecules. Hence, cardiac hypertrophy and fibrosis are potentially reversible. We show in a transgenic rabbit model of human HCM that long-term treatment with N-acetylcysteine (NAC), a precursor of glutathione, the largest intracellular thiol pool against oxidative stress in the body, reverses established cardiac hypertrophy and fibrosis. We show that treatment with NAC also prevents deterioration of cardiac systolic function and reduces susceptibility to arrhythmias. We document the beneficial effects of NAC at molecular, cellular, and whole organ levels and illustrated putative molecular mechanisms. The findings suggest the potential utility of NAC in treatment of patients with HCM, a major cause of sudden cardiac death in the young and an important determinant of morbidity in the elderly. Because cardiac hypertrophy, fibrosis, and systolic dysfunction are common to various cardiovascular diseases, the findings could have broader clinical implications. Clinical studies are needed to determine the potential beneficial effects of NAC in prevention and treatment of HCM and heart failure in humans. See p 1398.
Frequency of Myocardial Bridges and Dynamic Compression of Epicardial Coronary Arteries: A Comparison Between Computed Tomography and Invasive Coronary Angiography
Myocardial bridging is clinically significant when associated with regional hemodynamic alterations, and studies have shown that such instances of myocardial bridging are linked to clinical complications that include ischemia, acute coronary syndrome, coronary spasm, arrhythmia, and sudden death, although in the vast majority of cases, myocardial bridging remains clinically silent. The wide discrepancy in the reported prevalence of myocardial bridging between autopsy findings and those of conventional angiography has been attributed to instances of myocardial bridging that do not cause dynamic compression. Recently, CT angiography has been suggested as a tool in the diagnosis of myocardial bridging, with an average depiction rate between that of autopsy and conventional angiography but with a wide variation among authors. In the present study, the frequency of myocardial bridging by CT angiography was 58%, and conventional angiography revealed dynamic compression in 13.3% of all cases. The correlation between CT and conventional angiography revealed that dynamic compression occurred almost exclusively (97.5%) in cases with full encasement of the left anterior descending coronary artery, regardless of the measurable presence of overlying muscle in CT. This finding is useful for more accurately detecting instances of myocardial bridging that are likely to produce dynamic compression. Entrapment within the interventricular gorge, a new hypothesis for the mechanism of dynamic compression, along with other factors suggested by earlier researchers, appears to play a pivotal role in producing dynamic compression, and this observation may pave the way for further research into myocardial bridging. See p 1408.
Predictors of Cerebral Arteriopathy in Children With Arterial Ischemic Stroke: Results of the International Pediatric Stroke Study
Cerebral arteriopathy has been increasingly recognized as a prevalent cause of pediatric acute ischemic stroke. However, the pathophysiology of cerebral arteriopathy in childhood is not well understood. Estimates of prevalence range from 18% to 64% and likely reflect differences in imaging modalities and classification. In addition, although sickle cell disease and varicella zoster virus are well associated with vasculopathy, the cause of cerebral vasculopathy in childhood is often unknown. Within a large international series of children with arterial ischemic stroke, we found that over half had cerebral arteriopathy. Focal cerebral arteriopathy was the most common subtype of arteriopathy observed. Sickle cell disease, early school age, and recent upper respiratory infection were predictors of arteriopathy in general, and recent upper respiratory infection was a predictor of focal cerebral arteriopathy. Because recent data suggest that arteriopathy is the strongest predictor of recurrent childhood stroke, this report underscores the importance of careful cerebrovascular imaging. It also emphasizes that understanding of the infectious and inflammatory mediators of vascular injury is critical to the development of secondary stroke prevention strategies in childhood arterial ischemic stroke. See p 1417.
Interleukin-17 and Interferon-γ Are Produced Concomitantly by Human Coronary Artery–Infiltrating T Cells and Act Synergistically on Vascular Smooth Muscle Cells
Coronary atherosclerosis is considered an inflammatory disease in which T cells play a key role. Different lineages of T cells are characterized by the production of specific cytokines. Interferon-γ, the signature cytokine of Th1 cells, is detected in clinical specimens of coronary atherosclerosis and has a proarteriosclerotic effect in experimental models. More recently, a new lineage of interleukin (IL)-17–producing Th17 cells has been described. There is currently a great deal of interest in defining the pathogenetic consequences of IL-17 in diverse inflammatory disease processes, although the role of IL-17 in atherosclerosis remains unknown. We investigated the production and effects of IL-17 in patient studies and experimental models of human coronary atherosclerosis. Although we anticipated that IL-17 production would be minimal owing to the described antagonism between Th1 and Th17 cells, we unexpectedly found a positive correlation between IL-17 and interferon-γ plasma levels. A distinct population of coronary artery–infiltrating CD4+ T helper cells produced both IL-17 and interferon-γ that differed from classic Th1 and Th17 cells. Finally, we observed a synergy between IL-17 and interferon-γ proinflammatory effects on vascular smooth muscle cells. Our findings underscore the interactions between a network of cytokines present in coronary atherosclerosis and may be of relevance regarding proposals for anticytokine biological therapy. See p 1424.
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