High procedure and patient success rates, combined with a low event rate and improved procedural characteristics, support further use of the hybrid algorithm for a broad community of appropriately trained CTO operators.

. Collecting duct-specific knockout of the endothelin B receptor causes hypertension and sodium retention. Am J Physiol Renal Physiol 291: F1274 -F1280, 2006. First published July 25, 2006 doi:10.1152/ajprenal.00190.2006.-Collecting duct (CD)-derived endothelin-1 (ET-1) inhibits renal Na reabsorption and its deficiency increases blood pressure (BP). The role of CD endothelin B (ETB) receptors in mediating these effects is unknown. CD-specific knockout of the ETB receptor was achieved using an aquaporin-2 promoter-Cre recombinase transgene and the loxP-flanked ETB receptor gene (CD ETB KO). Systolic BP in mice with CD-specific knockout of the ETB receptor, ETA receptor (CD ETA KO) and ET-1 (CD ET-1 KO), and their respective controls were compared during normal-and high-salt diet. On a normal-sodium diet, CD ETB KO mice had elevated BP, which increased further during high salt feeding. However, the degree of hypertension in CD ETB KO mice and the further increase in BP during salt feeding were lower than that of CD ET-1 KO mice, whereas CD ETA KO mice were normotensive. CD ETB KO mice had impaired sodium excretion following acute sodium loading. Aldosterone and plasma renin activity were decreased in CD ETB KO mice on normal-and high-sodium diets, while plasma and urinary ET-1 levels did not differ from controls. In conclusion, the CD ETB receptor partially mediates the antihypertensive and natriuretic effects of ET-1. CD ETA and ETB receptors do not fully account for the antihypertensive and natriuretic effects of CD-derived ET-1, suggesting paracrine effects of this peptide. blood pressure; urinary sodium excretion; cell-specific gene targeting NUMEROUS LINES OF EVIDENCE indicate that collecting duct (CD)-derived endothelin-1 (ET-1) is an important regulator of renal Na reabsorption and systemic blood pressure (BP). First, the CD is the major renal site of ET-1 production (8,25,41,48,49), synthesizing more of the peptide than any other cell type (24). Second, the distribution of ET receptors in the kidney closely corresponds to the sites of ET production. Binding and RT-PCR studies using microdissected nephron segments indicate that endothelin receptors are primarily expressed by the inner medullary CD, moderately expressed by outer medullary CD and cortical CD, with much lower expression by other nephron segments (43,45). Third, cultured inner medullary CD cells secrete ET-1 from, and bind ET-1 to, the same (basolateral) side (27). Fourth, in vitro studies indicate that ET-1 inhibits CD Na transport. ET-1 decreases Na reabsorption by the isolated CD, an effect that may be mediated by inhibition of amiloride-sensitive sodium channel activity (14,31,32,46) and/or Na-K-ATPase activity (53). Perhaps the most compelling evidence implicating CD-derived ET-1 in the regulation of renal Na excretion and BP comes from gene targeting studies. Mice with CD-specific knockout of the ET-1 gene (CD ET-1 KO) are hypertensive on a normal-Na diet and this is exacerbated by high Na intake, with systolic BP increasing by almost 40...

There is considerable evidence that the potent vasoconstrictor endothelin-1 (ET-1) contributes to the pathogenesis of a variety of cardiovascular diseases. As such, pharmacological manipulation of the ET system might represent a promising therapeutic goal. Many clinical trials have assessed the potential of ET receptor antagonists in cardiovascular disease, the most positive of which have resulted in the licensing of the mixed ET receptor antagonist bosentan, and the selective ET A receptor antagonists, sitaxsentan and ambrisentan, for the treatment of pulmonary arterial hypertension (PAH). In contrast, despite encouraging data from in vitro and animal studies, outcomes in human heart failure have been disappointing, perhaps illustrating the risk of extrapolating preclinical work to man. Many further potential applications of these compounds, including resistant hypertension, chronic kidney disease, connective tissue disease and sub-arachnoid haemorrhage are currently being investigated in the clinic. Furthermore, experience from previous studies should enable improved trial design and scope remains for development of improved compounds and alternative therapeutic strategies. Although ET-converting enzyme inhibitors may represent one such alternative, there have been relatively few suitable compounds developed, and consequently, clinical experience with these agents remains extremely limited. Recent advances, together with an increased understanding of the biology of the ET system provided by improved experimental tools (including cell-specific transgenic deletion of ET receptors), should allow further targeting of clinical trials to diseases in which ET is involved and allow the therapeutic potential for targeting the ET system in cardiovascular disease to be fully realized.

ResultsLymphopenia after PPCI predicts long-term mortality. First, we wanted to determine whether lymphopenia predicted outcome in a well-defined population of STEMI patients undergoing PPCI. We retrospectively analyzed the lymphocyte counts of 1,377 consecu-BACKGROUND. Lymphocytes contribute to ischemia/reperfusion (I/R) injury in several organ systems, but their relevance in ST elevation myocardial infarction (STEMI) is unknown. Our goal was to characterize lymphocyte dynamics in individuals after primary percutaneous coronary intervention (PPCI), assess the prognostic relevance of these cells, and explore mechanisms of lymphocyte-associated injury. METHODS.Lymphocyte counts were retrospectively analyzed in 1,377 STEMI patients, and the prognostic relevance of post-PPCI lymphopenia was assessed by Cox proportional hazards regression. Blood from 59 prospectively recruited STEMI patients undergoing PPCI was sampled, and leukocyte subpopulations were quantified. Microvascular obstruction (MVO), a component of I/R injury, was assessed using MRI. RESULTS.In the retrospective cohort, lymphopenia was associated with a lower rate of survival at 3 years (82.8% vs. 96.3%, lowest vs. highest tertile; hazard ratio 2.42). In the prospective cohort, lymphocyte counts fell 90 minutes after reperfusion, primarily due to loss of T cells. CD8 + T cells decreased more than CD4 + T cells, and effector subsets exhibited the largest decline. The early decrease in effector T cell levels was greater in individuals that developed substantial MVO. The drop in T cell subsets correlated with expression of the fractalkine receptor CX3CR1 (r 2 = 0.99, P = 0.006). Serum fractalkine concentration peaked at 90 minutes after reperfusion, coinciding with the T cell count nadir. CONCLUSIONS.Lymphopenia following PPCI is associated with poor prognosis. Our data suggest that fractalkine contributes to lymphocyte shifts, which may influence development of MVO through the action of effector T cells.

Hybrid-trained operators can achieve overall success rates of 90% in real world practice with acceptable MACE. Use of dissection re-entry and investment procedures maintains high success rates in complex lesions. The hybrid approach represents a significant advance in CTO treatment.

After 2 decades of development and use in interventional cardiology research, optical coherence tomography (OCT) has now become a core intravascular imaging modality in clinical practice. Its unprecedented spatial resolution allows visualization of the key components of the atherosclerotic plaque that appear to confer "vulnerability" to rupture-namely the thickness of the fibrous cap, size of the necrotic core, and the presence of macrophages. The utility of OCT in the evaluation of plaque composition can provide insights into the pathophysiology of acute coronary syndrome and the healing that occurs thereafter. A brief summary of the principles of OCT technology and a comparison with other intravascular imaging modalities is presented. The review focuses on the current evidence for the use of OCT in identifying vulnerable plaques in acute coronary syndrome and its limitations.

Abstract-Endothelin B receptors in different tissues regulate diverse physiological responses including vasoconstriction, vasodilatation, clearance of endothelin-1, and renal tubular sodium reabsorption. To examine the role of endothelial cell endothelin B receptors in these processes, we generated endothelial cell-specific endothelin B receptor knockout mice using a Cre-loxP approach. We have demonstrated loss of endothelial cell endothelin B receptor expression and function and preservation of nonendothelial endothelin B receptor-mediated responses through binding and functional assays. Ablation of endothelin B receptors exclusively from endothelial cells produces endothelial dysfunction in the absence of hypertension, with evidence of decreased endogenous release of NO and increased plasma endothelin-1. In contrast to models of total endothelin B receptor ablation, the blood pressure response to a high-salt diet is unchanged in endothelial cell-specific endothelin B receptor knockouts compared with control floxed mice. These findings suggest that the endothelial cell endothelin B receptor mediates a tonic vasodilator effect and that nonendothelial cell endothelin B receptors are important for the regulation of blood pressure. Key Words: endothelin Ⅲ mice Ⅲ endothelium Ⅲ receptors, endothelin Ⅲ vasodilation E ndothelin-1 (ET-1) was initially described as a potent vasoconstrictor and potential mediator of hypertension. 1,2 More recently, attention has focused on how ET-1 generated within the kidney may promote natriuresis and diuresis 3 and thus contribute to a lowering of blood pressure (BP). ET-1 acts through 2 types of receptors, endothelin receptor type A (ET A ) and endothelin receptor type B (ET B ). 4,5 Activation of ET A and ET B on vascular smooth muscle cells results in vasoconstriction. 6 In contrast, vascular endothelial cells (ECs) exclusively express the ET B subtype and mediate vasodilatation. 7 ET B has been proposed as the target receptor through which collecting duct (CD)-derived ET-1 regulates natriuresis and diuresis. 3,8,9 However, ET B may also influence BP through regulation of peripheral vascular tone, 6,7 renal hemodynamics, 10,11 and clearance of circulating ET-1. 12 The autocrine/paracrine nature of ET-1 signaling, the close interdependence between renal tubular function and intrarenal blood flow, and the modulation of peripheral vascular tone by ET-1 have made the precise mechanisms by which ET B on different cell types contribute to the regulation of BP and natriuresis difficult to define, although EC ET B may be central to each of these pathways. 13 We hypothesized that CD-derived ET-1 acted in a paracrine manner on medullary vasa recta EC ET B to regulate natriuresis 11,13 and that deletion of these receptors would result in salt-sensitive hypertension. We, thus, adopted a Cre-loxP approach that permitted specific ablation of EC ET B while preserving CD ET B expression to test this hypothesis. MethodsThe general approach to producing cell type-specific knockout (KO) of ET B throug...

Despite temporal increases in invasive management of NSTE-ACS, patients with kidney dysfunction are more commonly treated conservatively, with an associated worse outcome. In-hospital revascularization was independently associated with improved survival, irrespective of eGFR. Randomized controlled trials involving patients with kidney dysfunction are needed to confirm whether more aggressive treatment will improve their poor outcome.