- High-Density Substrate Mapping in Brugada Syndrome: Combined Role of Conduction and Repolarization Heterogeneities in Arrhythmogenesis
- Preoperative Hemoglobin Level as a Predictor of Survival After Coronary Artery Bypass Grafting: A Comparison With the Matched General Population
- Psychosocial Modulators of Angina Response to Myocardial Ischemia
- Elevated Depression Symptoms Predict Long-Term Cardiovascular Mortality in Patients With Atrial Fibrillation and Heart Failure
- Comparison of Inflammatory Response After Implantation of Sirolimus- and Paclitaxel-Eluting Stents in Porcine Coronary Arteries
- Diabetes Mellitus Activates Signal Transduction Pathways Resulting in Vascular Endothelial Growth Factor Resistance of Human Monocytes
- Lecithin: Cholesterol Acyltransferase Expression Has Minimal Effects on Macrophage Reverse Cholesterol Transport In Vivo
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High-Density Substrate Mapping in Brugada Syndrome: Combined Role of Conduction and Repolarization Heterogeneities in Arrhythmogenesis
Characterized by coved J-point elevation in leads V1 through V3 and ventricular arrhythmia in apparently structurally normal hearts, the risk stratification and treatment of Brugada syndrome remain areas of active research. There is some debate in the literature in regard to whether proarrhythmia is secondary to localized right ventricular conduction abnormalities or transmural differences in repolarization in the anterior right ventricular wall. A single Langendorff study of a perfused Brugada syndrome patient’s ex vivo heart published in this journal (Circulation. 2005;112:2769–2777) demonstrated conduction delay localized to the right ventricular outflow tract without significant transmural differences in repolarization time. There are no published in vivo high-density mapping studies of the Brugada right ventricle examining conduction-repolarization kinetics and arrhythmogenesis. We performed an endocardial mapping study of the right ventricle in Brugada syndrome patients and demonstrate that significant localized conduction delays exist in the right ventricular outflow tract of Brugada syndrome patients compared with controls. Furthermore, these sites coincide with the diastolic pathway of induced ventricular tachycardia. Significant endocardial repolarization heterogeneities exist in the Brugada ventricle, which could explain the propensity of ventricular tachycardia to degenerate into ventricular fibrillation in these patients. The recent observation that fragmented QRS complexes are a predictor of prognosis in Brugada syndrome (Circulation. 2008;118:1697–1704) supports the contention that these conduction abnormalities are an important contributor to the arrhythmogenic substrate in this disease. See p 106.
Preoperative Hemoglobin Level as a Predictor of Survival After Coronary Artery Bypass Grafting: A Comparison With the Matched General Population
This single-center observational study investigated the association between preoperative hemoglobin level and both early and late mortality in >10 000 coronary surgery patients. To the best of our knowledge, no data are available on preoperative hemoglobin level as a predictor of long-term outcome of patients undergoing coronary artery bypass grafting. The predictive value of preoperative hemoglobin level indicates the importance of better investigation and management of preoperative anemia in coronary surgery patients. An important finding of this study is that patients with a normal preoperative hemoglobin level had a better long-term survival than age- and sex-matched groups of the general Dutch population. Although this information has no significance in preoperative assessment and decision making, it gives patients a rough idea of their long-term prognosis. See p 118.
Psychosocial Modulators of Angina Response to Myocardial Ischemia
Although angina is often caused by atherosclerotic obstruction of the coronary arteries, prior studies have demonstrated little association between coronary anatomy and the severity of patients’ chest pain. Several psychosocial factors have been found to be associated with increased anginal chest pain, but much of this research has focused on chest pain in patients with normal coronary arteries. We hypothesized that psychosocial factors may modulate angina in patients with demonstrable myocardial ischemia. We therefore investigated the association of psychosocial factors with angina frequency in patients with inducible ischemia on single-photon emission CT stress perfusion imaging after adjusting for the degree of ischemia. We assessed 788 consecutive patients undergoing clinically indicated single-photon emission CT stress perfusion imaging for their frequency of angina over the previous 4 weeks and for a broad range of psychosocial characteristics. Among patients with inducible ischemia (n=191), a history of coronary revascularization, anxiety, and depressive symptoms were independently associated with more frequent angina, after adjustment for the amount of inducible ischemia. In univariate analyses, other psychosocial factors (alexithymia, neuroticism, and somatosensory amplification) were also associated with more frequent angina, but these associations did not remain significant after adjustment for anxiety and depressive symptoms. Our results suggest that psychosocial characteristics are associated with angina frequency, independent of the magnitude of myocardial ischemia, and support further study to determine the effectiveness of angina treatment strategies that aim to reduce psychosocial distress in conjunction with efforts to lessen myocardial ischemia. See p 126.
Elevated Depression Symptoms Predict Long-Term Cardiovascular Mortality in Patients With Atrial Fibrillation and Heart Failure
Atrial fibrillation (AF) is common in patients with congestive heart failure (CHF), but little is known about potentially treatable risk factors for mortality in this population. Depression predicts prognosis in many cardiac conditions but has not been studied in relation to survival in AF-CHF. The present study examined the predictive importance of depression for cardiovascular mortality over a mean follow-up of 39 months in 974 patients enrolled in the multinational randomized AF-CHF trial of rhythm- versus rate-control treatment strategies. The 312 patients with elevated scores on the baseline self-report Beck Depression Inventory experienced a significant increase in risk for cardiovascular mortality. After adjustment for other prognostic factors (including age, marital status, cause of CHF, creatinine level, left ventricular ejection fraction, paroxysmal AF, previous AF hospitalization, previous electrical conversion, and baseline medications), the hazard ratio was 1.57 (95% confidence interval 1.20 to 2.07, P<0.001) for the depressed patients compared with the others. This was similar to the increase in risk associated with not taking oral anticoagulants. There is evidence that selective serotonin reuptake inhibitor antidepressant medications are safe and efficacious in patients with coronary artery disease, but no clinical trials have evaluated their use in CHF patients with AF. Furthermore, no studies have demonstrated that treating depression increases survival in any cardiac condition. We conclude that depression is at least a signal of increased risk in patients with AF and CHF. See p 134.
Comparison of Inflammatory Response After Implantation of Sirolimus- and Paclitaxel-Eluting Stents in Porcine Coronary Arteries
The present study compares sirolimus (CYPHER) and paclitaxel (TAXUS) drug-eluting stents implanted in noninjured coronary arteries in domestic swine for 30, 90, and 180 days. There was a much higher prevalence of a diffusely severe inflammatory response with granuloma formation and numerous eosinophils in the CYPHER-stented vessels compared with TAXUS. This distinctive inflammatory pattern, present diffusely through the stented arterial segment and seen repeatedly in the porcine model, has been identified in a small proportion of human autopsy cases involving CYPHER stents in which the diffuse granulomatous inflammation was associated with aneurysmal dilation and thrombosis of the stented coronary artery but to date has been reported in just 1 TAXUS stent with only focal involvement of a few struts. In the porcine coronary artery model, both CYPHER and TAXUS stents were associated with greater para-strut fibrin deposition than their bare metal controls at 30 days, but TAXUS stents showed greater fibrin deposition than CYPHER stents at 30 days persisting through 180 days. As a result of strut deployment in normal arteries combined with rapid smooth muscle cell proliferation and endothelialization in the pig, fibrin deposits were sequestered with the developing neointima and not exposed to flow in both drug-eluting stents. This characteristic of the porcine model limits its translation to the clinical issue of delayed thrombosis with drug-eluting stents. The porcine model does produce the severe, granulomatous inflammatory response seen in humans, but the true prevalence of this response in humans is unknown at this time. See p 141.
Diabetes Mellitus Activates Signal Transduction Pathways Resulting in Vascular Endothelial Growth Factor Resistance of Human Monocytes
This article describes a functionally relevant molecular defect in monocytes from individuals with diabetes mellitus (DM). It is well established that monocytes play a crucial role in both arteriogenesis (ie, collateral growth) and atherogenesis. Moreover, there is evidence that DM-related monocyte dysfunction such as impaired monocyte chemotaxis toward vascular endothelial growth factor-A (VEGF) is associated with impaired collateral growth and accelerated atherogenesis. We now report that the functional monocyte defect in DM is based on VEGF resistance: Although VEGF can activate its specific receptor, the migratory response is blocked. On a molecular level, this blockade/resistance can be explained by activation of crucial VEGF signaling pathways, including the Akt and mitogen-activated protein kinase pathways. DM is associated with reduced activity of protein tyrosine phosphatases, which allows enhanced activation of related kinases and results in nonspecific preactivation of relevant signaling pathways. In fact, we can mimic this diabetic phenotype by experimental inhibition of protein tyrosine phosphatases, again resulting in preactivation of signaling molecules and impaired chemotaxis. Likewise, receptor for advanced glycation end products activation, also known to occur in DM, results in similar changes associated with VEGF resistance. The clinical perspective of this concept is to use VEGF resistance and its underlying molecular changes for diagnostic purposes and thereby predict the efficiency of VEGF action in cardiovascular repair and potentially in therapeutic angiogenesis. Moreover, the therapeutic prevention of VEGF resistance could represent a novel concept to attenuate the negative functional consequences of DM in the vasculature. See p 150.
Lecithin: Cholesterol Acyltransferase Expression Has Minimal Effects on Macrophage Reverse Cholesterol Transport In Vivo
Lecithin:cholesterol acyltransferase (LCAT) is a key enzyme in the metabolism of high-density lipoprotein (HDL). It converts “free” cholesterol (form effluxed from macrophages) to cholesteryl ester, permitting the formation and progressive enlargement of mature HDL particles. It has long been believed that LCAT is critical in facilitating the process of reverse cholesterol transport, leading to the concept that upregulation of LCAT activity is a therapeutic target for atherosclerosis, but this has never been experimentally proven. Using a validated assay of macrophage-specific reverse cholesterol transport in mice, we explored the effects of both LCAT overexpression (which raises HDL cholesterol [HDL-C] levels) and LCAT deficiency (which reduces HDL-C levels). Surprisingly, LCAT overexpression, despite markedly raising HDL-C, did not promote macrophage reverse cholesterol transport. Even coexpression of scavenger receptor BI or cholesteryl ester transfer protein, both of which transfer cholesterol ester out of HDL and facilitate its return to the liver, failed to convert LCAT overexpression into an intervention that promotes reverse cholesterol transport. Furthermore, complete LCAT deficiency, despite reducing HDL-C to <5% of normal levels, reduced reverse cholesterol transport by only ≈50%, and moderate LCAT deficiency, despite moderately reducing HDL-C levels, had no effect on reverse cholesterol transport. These studies challenge the long-held belief that LCAT is critical for macrophage reverse cholesterol transport and bring into question whether LCAT activation would necessarily be an atheroprotective intervention even though it raises HDL-C levels. The results are consistent with a growing trend focused on HDL quality and function rather than simply plasma HDL-C levels as a target for the development of new therapies. See p 160.
- Psychosocial Modulators of Angina Response to Myocardial Ischemia
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