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Background: A single-nucleotide polymorphism on chromosome 9p21, rs10757274 (9p21 allele), has been shown to predict coronary heart disease (CHD) in whites. We evaluated whether adding the 9p21 allele to traditional risk factors (RFs) improved CHD risk prediction in whites from the Atherosclerosis Risk in Communities study and whether changes in risk prediction would modify lipid therapy recommendations., Methods and Results: Whites (n=9998) in the Atherosclerosis Risk in Communities study for whom the 9p21 genotype and traditional RF information was available were included. Using Cox proportional hazards models, the Atherosclerosis Risk in Communities Cardiovascular Risk Score, which is based on traditional RFs, was determined. A total of 1349 individuals (13.5%) developed incident CHD events during a period of 14.6 years. Adding the 9p21 allele to traditional RFs was associated with a hazard ratio of incident CHD of 1.2 per allele (P<0.000003) and a significant increase in the area under the curve of the receiver operating characteristic from 0.782 to 0.786 (95% CI, 0.001, 0.007). The 9p21 allele's greatest influence to the Atherosclerosis Risk in Communities Cardiovascular Risk Score was observed in the intermediate-low (>5% to 10% to 100 mg/dL., Conclusions: Adding the 9p21 allele to traditional RFs in whites in the Atherosclerosis Risk in Communities study modestly improved CHD risk prediction in the intermediate categories.

Information on differences in platelet function between patients with peripheral arterial disease (PAD) and patients with coronary artery disease (CAD) is limited. We sought to examine the differences in the platelets response to shear stress in patients with PAD compared to those with CAD. Men with symptomatic PAD (ankle brachial index [ABI] < 0.9; n = 29) were compared with similarly aged men with CAD (post coronary artery bypass grafting; n = 40) but without PAD. All participants were on aspirin, and none were on clopidogrel. We measured changes in shear-induced platelet aggregation (SIPA) and shear-induced P-selectin expression (SIPE) under fluid shear rates of 5000 and 10,000 s(-1)which are typically found in arterioles and stenosed arteries, respectively. Aggregation was also induced by a combined stimulation of collagen, fluid shear stress, and adenosine diphosphate (ADP) or epinephrine using a platelet function analyzer (PFA-100) as well as optical aggregometry (arachidonic acid, collagen and epinephrine). Analyses of covariance adjusted for age, aspirin dose, and statin use were used to estimate differences between the groups. Values of SIPA at fluid shear rates of 5000 and 10,000 s(-1) were significantly higher in the PAD group, while there were no differences between the PAD and CAD groups in SIPE at both fluid shear rates. However, baseline shear-induced P-selectin expression was higher in patients with PAD than CAD (mean fluorescence intensity [MFI] = 2.93 +/- 1.37 vs.1.94 +/- 0.67; p = 0.01), while the percentage increases in SIPA and SIPE at fluid shear rates of 5000 and 10,000 s(-1) were significantly higher in patients with CAD when compared to PAD (p < 0.001 for all comparisons). Although there were several similarities in platelet function between men with PAD and men with CAD, significant differences in platelet responses to shear stress were observed in men with PAD when compared to those with CAD. Although the mechanism for these observed differences are not clear, we hypothesize that in vivo platelet activation in PAD patients may contribute to the differences and will need to be further investigated.

Managing dyslipidemia is an important part of the primary and secondary prevention of coronary heart disease. Low-density lipoprotein cholesterol reduction remains the primary lipid goal. Patients who have experienced an acute coronary syndrome (ACS) are at very high risk of recurrent adverse cardiovascular events. A growing body of literature supports the concept that early and intensive treatment with statins after an ACS event decreases recurrent adverse cardiovascular events. We review available evidence pertaining to lipid alterations in ACS.

Background and Purpose: Inflammation plays a critical role in the development of vascular disease, and increased levels of the inflammatory biomarkers, lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), and high-sensitivity C-reactive protein (hs-CRP) have been shown to be associated with an increased risk for ischemic stroke., Methods: In a prospective case-cohort (n=949) study in 12 762 apparently healthy, middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study, we first examined whether Lp-PLA(2) and hs-CRP levels improved the area under the receiver operator characteristic curve (AUC) for 5-year ischemic stroke risk. We then examined how Lp-PLA(2) and hs-CRP levels altered classification of individuals into low-, intermediate-, or high-risk categories compared with traditional risk factors., Results: In a model using traditional risk factors alone, the AUC adjusted for optimism was 0.732, whereas adding hs-CRP improved the AUC to 0.743, and adding Lp-PLA(2) significantly improved the AUC to 0.752. Addition of hs-CRP and Lp-PLA(2) together in the model improved the AUC to 0.761, and the addition of the interaction between Lp-PLA(2) and hs-CRP further significantly improved the AUC to 0.774. With the use of traditional risk factors to assess 5-year risk for ischemic stroke, 86% of participants were categorized as low risk (<2%); 11%, intermediate risk (2% to 5%); and 3%, high risk (>5%). The addition of hs-CRP, Lp-PLA(2), and their interaction to the model reclassified 4%, 39%, and 34% of the low-, intermediate- and high-risk categories, respectively., Conclusions: Lp-PLA(2) and hs-CRP may be useful in individuals classified as intermediate risk for ischemic stroke by traditional risk factors.

We sought to determine, retrospectively, whether obesity was associated with adverse renal outcomes in 17,630 patients who underwent cardiac surgery from January 1995 through December 2006. Obesity was defined as a body mass index > or = 30 kg/m2. The primary outcome was any episode of postoperative renal insufficiency (requiring or not requiring dialysis) before hospital discharge. Outcomes were evaluated in the entire cohort and in subgroups undergoing isolated coronary artery bypass grafting (CABG), isolated valve surgery, and combined CABG and valve surgery. The final analysis included 16,429 patients, 5,124 (31%) of whom were obese. In the entire cohort, obesity was associated both with increased risk of any postoperative renal insufficiency (odds ratio [OR], 1.37; 95% confidence interval [CI], 1.21-1.55) and with increased risk of renal insufficiency not requiring dialysis (OR, 1.41; 95% CI, 1.23-1.62). Obesity was associated with an increased risk of postoperative renal insufficiency in patients undergoing isolated CABG (OR, 1.38; 95% CI, 1.18-1.61), isolated valve surgeries (OR, 1.39; 95% CI, 1.05-1.85), and combined CABG and valve surgeries (OR, 1.35; 95% CI, 0.99-1.83; statistically nonsignificant). Development of postoperative renal insufficiency was associated with a significantly higher mortality rate (P <0.0001) and with a significantly longer hospital stay (23 vs 10.5 days; P <0.0001). We conclude that obesity is associated with a significant increase in postoperative renal insufficiency in cardiac surgery patients, an effect that we attribute to an increase in postoperative renal failure that does not require dialysis.

High-throughput screening of the GSK compound collection against the P2Y(1) receptor identified a novel series of tetrahydro-4-quinolinamine antagonists. Optimal substitution around the piperidine group was pivotal for ensuring activity. An exemplar analog from this series was shown to inhibit platelet aggregation.

Preoperative statins have been associated with decreased mortality after coronary artery bypass grafting. Data are limited on whether these benefits extend to patients undergoing cardiac valve surgery. We examined whether preoperative statins decrease morbidity and mortality in patients undergoing isolated cardiac valve surgery. In a retrospective cohort analysis of consecutive patients who underwent surgical valve repair or replacement (excluding concomitant coronary artery bypass grafting, aortic root replacement, or ventricular assist device placement) at St. Luke's Episcopal Hospital, the primary outcome was 30-day mortality. Secondary outcomes included 30-day major adverse events (composite of early mortality, postoperative myocardial infarction, or stroke). Of 825 patients, 31% received preoperative statins (n = 255). Logistic regression analysis revealed that age >65 years (p = 0.02), history of congestive heart failure (p = 0.001), and total bypass time >80 minutes (p = 0.01) were independent predictors of increased 30-day mortality. Preoperative statin therapy was not associated with decreased 30-day mortality (odds ratio 0.89, 95% confidence interval 0.38 to 2.03), major adverse events (odds ratio 1.09, 95% confidence interval 0.61 to 1.96), postoperative myocardial infarction (p = 0.70), or stroke (p = 0.57). At a mean follow-up of 1.57 years, preoperative statin therapy was not associated with decreased mortality (p = 0.81). In the analysis using propensity score matching (354 propensity-matched patients, 177 in each group), preoperative statin was not associated with improved primary or secondary outcomes. In conclusion, preoperative statin therapy was not associated with a decrease in morbidity or mortality in patients undergoing isolated cardiac valve surgery.

Lead compound 1 was successfully redesigned to provide compounds with improved pharmacokinetic profiles for this series of human urotensin-II antagonists. Replacement of the 2-pyrrolidinylmethyl-3-phenyl-piperidine core of 1 with a substituted N-methyl-2-(1-pyrrolidinyl)ethanamine core as in compound 7 resulted in compounds with improved oral bioavailability in rats. The relationship between stereochemistry and selectivity for hUT over the kappa-opioid receptor was also explored.

Managing dyslipidemia is an important part of the primary and secondary prevention of coronary heart disease. Low-density lipoprotein cholesterol reduction remains the primary lipid goal. Patients who have experienced an acute coronary syndrome (ACS) are at very high risk of recurrent adverse cardiovascular events. A growing body of literature supports the concept that early and intensive treatment with statins after an ACS event decreases recurrent adverse cardiovascular events. We review available evidence pertaining to lipid alterations in ACS.

This work describes the development of potent and selective human Urotensin-II receptor antagonists starting from lead compound 1, (3,4-dichlorophenyl)methyl{2-oxo-2-[3-phenyl-2-(1-pyrrolidinylmethyl)-1-piperidinyl]ethyl}amine. Several problems relating to oral bioavailability, cytochrome P450 inhibition, and off-target activity at the kappa opioid receptor and cardiac sodium channel were addressed during lead development. hUT binding affinity relative to compound 1 was improved by more than 40-fold in some analogs, and a structural modification was identified which significantly attenuated both off-target activities.

Inflammation plays a key role in the pathogenesis of atherosclerosis. Understanding the process of inflammation as it pertains to atherosclerosis has provided researchers with multiple opportunities to identify novel markers for use in cardiovascular disease management. This article discusses the inflammatory cascade as it pertains to atherosclerosis and some of the well-studied markers of inflammation. It also discusses the limitations of current risk stratification models and characteristics of a good biomarker.

Background: Atrial fibrillation (AF) after cardiac surgery is associated with significant morbidity. We investigated whether preoperative statin therapy was associated with decreased incidence of postoperative AF in patients undergoing cardiac surgery, including isolated valve surgery and patients with low ejection fraction (EF)., Methods: A retrospective study of consecutive patients without history of AF (n = 4044) who underwent cardiac surgeries at St. Luke's Episcopal Hospital (Houston, TX), from January 1, 2003, through April 30, 2006, was conducted. Postoperative AF was assessed by continuous telemetry monitoring during hospitalization for cardiac surgery., Results: A total of 2096 patients (52%) received preoperative statins. Atrial fibrillation occurred in 1270 patients (31.4% in both the statin and nonstatin groups). In multivariate regression analysis, age >65 years, history of valvular heart disease, rheumatic disease, pulmonary disease, and New York Heart Association class III/IV were independent predictors of increased risk, whereas female sex was associated with decreased risk. Preoperative statin therapy was not associated with decreased risk in the entire cohort (odds ratio [OR] 1.13, 95% confidence interval [CI] 0.98-1.31) or in subgroups undergoing isolated coronary artery bypass grafting (OR 1.16, 95% CI 0.97-1.43), isolated valve surgery (OR 1.09, 95% CI 0.81-1.46), or both (OR 1.09, 95% CI 0.72-1.65), or the subgroup with EF <35% (OR 1.23, 95% CI 0.84-1.82). After propensity score analysis (n = 867 patients in each group), preoperative statin therapy was not associated with decreased AF incidence (OR 1.14, 95% CI 0.92-1.41)., Conclusions: Preoperative statin therapy was not associated with decreased incidence of postoperative AF in patients undergoing cardiac surgery, including patients with low EF.

A 62-year-old woman with a history of heart failure, hypertension and stroke presented to hospital with dyspnea. Transthoracic echocardiography revealed significant left ventricular dysfunction; with contrast-enhanced 2- and 3-dimensional echocardiography, extensive hypetrabeculation of the left ventricular myocardium was visualized, leading to a diagnosis of noncompaction cardiomyopathy. Apical thrombi were excluded with contrast imaging; however, the patient was systemically anticoagulated owing to the presence of noncompaction cardiomyopathy in the setting of prior stroke. This case report demonstrates remarkable imaging of the left ventricular myocardium achieved with contrast-enhanced 3-dimensional echocardiography in the setting of noncompaction cardiomyopathy.

Matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) are thought to be associated with coronary artery disease. The association of these markers with incident coronary artery disease has not been well described. Using a case-cohort design, we selected 216 individuals who had incident coronary artery disease (case group) and 225 individuals from a cohort random sample (comparison group) from participants enrolled in the Atherosclerosis Risk in Communities study. We measured plasma levels of MMP-1 and TIMP-1, traditional risk factors, and other markers of inflammation. We found no significant difference in TIMP-1 levels between the case group (827.8 +/- 23.8 ng/mL) and the comparison group (819.31 +/- 16.1 ng/mL) (P=0.77), and no significant difference in the frequency of MMP-1 levels that were dichotomized at the minimum detectable value of 1.7 ng/mL (P=0.49). In models adjusted for age, sex, race, body mass index, hypertension, diabetes, total cholesterol, high-density lipoprotein cholesterol, triglycerides, fibrinogen, von Willebrand factor, and white blood cell count, the hazard-rate ratio for incident coronary artery disease was 1.14 (95% confidence interval, 0.63-2.04; P=0.67) for individuals whose TIMP-1 levels were above, versus at or below the mean, and 1.17 (95% confidence interval, 0.63-2.19; P=0.62) for individuals whose MMP-1 levels were above 1.7 ng/mL. We conclude that TIMP-1 and MMP-1 levels in plasma were not predictive of incident coronary artery disease in a case-cohort random sample of the Atherosclerosis Risk in Communities study, a population study of asymptomatic middle-aged adults who had no prevalent atherosclerosis upon enrollment.

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme that belongs to the superfamily of phospholipase A2 enzymes. Although initial studies showed that Lp-PLA2 might be protective against atherosclerosis, emerging data seem to suggest that Lp-PLA2 may be proatherogenic, which is an effect thought to be mediated by lysophosphatidylcholine and oxidized nonesterified fatty acids, two mediators generated by Lp-PLA2. This article reviews the potential mechanisms by which Lp-PLA2 may participate in the pathogenesis of atherosclerosis and its clinical manifestations, namely, coronary artery disease and stroke.

Background: The use of biomarkers has been among the advances that have helped in the better medical management of patients. Biomarkers such as total cholesterol, low-density lipoprotein cholesterol, and hemoglobin A1c are used routinely. Advances in technologies, proteomics, and genomics and the resultant improved understanding of the pathophysiology of vascular diseases have led to the identification of several promising biomarkers. These biomarkers may be used to identify specific populations that may benefit from therapies, as surrogate markers of clinical efficacy, or as targets of therapy.

Atherosclerosis accounts for most peripheral arterial occlusive disease (PAD). Although many of the risk factors for atherosclerotic coronary artery disease (CAD) such as hyperlipidemia have been identified as risk factors for peripheral arterial disease, strong evidence is lacking that risk factor modification is effective in halting progression or improving outcomes. A better understanding is needed regarding the clinical and pathophysiologic responses to risk factor modification. This review describes current advances in the medical management for PAD including lipid modification antiplatelet therapy, angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, exercise, and endovascular intervention. In addition, we discuss our active ELIMIT Trial (Effect of Lipid Modification on Peripheral Arterial Disease after Endovascular Intervention). We test the hypothesis that an aggressive regimen of serum lipid modification will inhibit the progression of atherosclerosis in femoral arteries and reduce the incidence of restenosis of femoral arteries following endovascular stenting by decreasing thrombosis and inflammation. This study will provide a novel strategy for retarding or preventing progression of atherosclerosis and re-stenosis of peripheral arterial disease following arterial revascularization procedures. Importantly, our magnetic resonance imaging studies will provide quantitative data on the vascular lesions in PAD. These studies will advance our understanding of the molecular mechanisms of inflammation and thrombosis associated with aggressive lipid modification.

Lipoprotein-associated phospholipase A(2 )(Lp-PLA(2)), a member of the phospholipase superfamily, circulates primarily bound to low-density lipoprotein and has been associated with cardiovascular disease risk in epidemiologic studies. However, it has not been established whether Lp-PLA(2) is a risk marker or a risk factor. Identification of individuals with elevated Lp-PLA(2) may improve risk assessment, and Lp-PLA(2) may also provide an additional target of therapy. Statin therapy has been shown to reduce Lp-PLA(2), and selective inhibitors of Lp-PLA(2) are under development. Additional research is needed to further determine the role of Lp-PLA(2) in atherogenesis and atherothrombotic events.

Combined dyslipidemia is the concurrent presence of multiple abnormalities in various lipid subfractions, including elevated concentrations of low-density lipoprotein (LDL) cholesterol and triglycerides (TGs), as well as decreased concentrations of high-density lipoprotein (HDL) cholesterol. The Adult Treatment Panel III (ATP III) guidelines of the US National Cholesterol Education Program (NCEP) lowered the cut points for classification of TG levels, established non-HDL cholesterol levels as a secondary target of therapy in patients with TGs of >or=2.26 mmol/L (200 mg/dL), and defined the metabolic syndrome as a secondary target of therapy. Although 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are first-line therapy for most patients with elevated LDL cholesterol, statin monotherapy may not be sufficient to achieve recommended non-HDL cholesterol goals, and statins have only modest effects on reducing TG levels. Similarly, patients whose TG levels remain elevated despite treatment with a TG-lowering agent may require the addition of a statin to provide further TG reduction. In addition, statin therapy may be needed to offset the secondary increase in levels of LDL cholesterol that frequently results from treatment with a TG-lowering agent in patients with marked hypertriglyceridemia. In a number of small studies, the combination of statins and omega-3 fatty acids has been consistently shown to be an effective, safe, and well-tolerated treatment for combined dyslipidemia. Patients with recent myocardial infarction may also benefit from this combination. When considering risks and benefits of adding a second agent to statins for treatment of combined dyslipidemia, omega-3 fatty acids provide additional lipid improvements without requiring additional laboratory tests and do not increase risk for adverse muscle or liver effects.

Urotensin-II (U-II), a ligand for the G-protein-coupled receptor UT, has been characterized as the most potent mammalian vasoconstrictor identified to date. Although circulating levels of U-II are altered in lower species (e.g., fish) upon exposure to hypo-osmotic stress, little is known about the actions of this cyclic undecapeptide within the kidney, an organ that plays a pivotal role in the control of cardiovascular homeostasis, influencing both cardiac preload (plasma volume) and after load (peripheral resistance). The present study reports the identification of specific, high affinity [125I]hU-II binding sites in Sprague-Dawley rat kidney outer medulla by autoradiography and also through membrane radioligand binding (Kd 1.9 +/- 0.9 nM and Bmax 408 +/- 47 amol mm(-2) and Kd 1.4 +/- 0.3 nM and Bmax 51.3 +/- 7.8 fmol mg(-1) protein, respectively). Differences were observed in the binding characteristics within rat strains. Compared to the Sprague-Dawley, Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rat kidney outer medulla displayed low density < 20 fmol mg(-1) protein and low affinity (> 1 microM) [125I]hU-II binding sites. Thus, the relative contribution of specific U-II binding sites to the physiological actions of U-II in the control of cardiorenal homeostasis is worthy of further investigation.

Several peptidic urotensin-II (UT) receptor antagonists exert 'paradoxical' agonist activity in recombinant cell- and tissue-based bioassay systems, likely the result of differential urotensin-II receptor (UT receptor) signal transduction/coupling efficiency between assays. The present study has examined this phenomenon in mammalian arteries and recombinant UT-HEK (human embryonic kidney) cells.BacMam-mediated recombinant UT receptor upregulation in HEK cells augmented agonist activity for all four peptidic UT ligands studied. The nominal rank order of relative intrinsic efficacy was U-II>urantide ([Pen(5)-DTrp(7)-Orn(8)]hU-II(4-11))>SB-710411 (Cpa-c[DCys-Pal-DTrp-Lys-Val-Cys]-Cpa-amide)>>GSK248451 (Cin-c[DCys-Pal-DTrp-Orn-Val-Cys]-His-amide) (the relative coupling efficiency of recombinant HEK cells was cat>human>>rat UT receptor). The present study further demonstrated that the use of high signal transduction/coupling efficiency isolated blood vessel assays (primate>cat arteries) is required in order to characterize UT receptor antagonism thoroughly. This cannot be attained simply by using the rat isolated aorta, an artery with low signal transduction/coupling efficiency in which low-efficacy agonists appear to function as antagonists. In contrast to the 'low-efficacy agonists' urantide and SB-710411, GSK248451 functioned as a potent UT receptor antagonist in all native isolated tissues studied (UT receptor selectivity was confirmed in the rat aorta). Further, GSK248451 exhibited an extremely low level of relative intrinsic activity in recombinant HEK cells (4-5-fold less than seen with urantide). Since GSK248451 (1 mg kg(-1), i.v.) blocked the systemic pressor actions of exogenous U-II in the anaesthetized cat, it represents a suitable peptidic tool antagonist for delineating the role of U-II in the aetiology of mammalian cardiometabolic diseases.

Seven patients with obstructive hypertrophic cardiomyopathy and single-vessel coronary artery disease underwent percutaneous revascularization of the coronary lesion in addition to alcohol septal ablation therapy for dynamic outflow tract obstruction. One year later, there was a significant reduction of dynamic left ventricular outflow tract obstruction and no clinical evidence of restenosis.

1. SB-706375 potently inhibited [(125)I]hU-II binding to both mammalian recombinant and 'native' UT receptors (K(i) 4.7+/-1.5 to 20.7+/-3.6 nM at rodent, feline and primate recombinant UT receptors and K(i) 5.4+/-0.4 nM at the endogenous UT receptor in SJRH30 cells). 2. Prior exposure to SB-706375 (1 microM, 30 min) did not alter [(125)I]hU-II binding affinity or density in recombinant cells (K(D) 3.1+/-0.4 vs 5.8+/-0.9 nM and B(max) 3.1+/-1.0 vs 2.8+/-0.8 pmol mg(-1)) consistent with a reversible mode of action. 3. The novel, nonpeptidic radioligand [(3)H]SB-657510, a close analogue of SB-706375, bound to the monkey UT receptor (K(D) 2.6+/-0.4 nM, B(max) 0.86+/-0.12 pmol mg(-1)) in a manner that was inhibited by both U-II isopeptides and SB-706375 (K(i) 4.6+/-1.4 to 17.6+/-5.4 nM) consistent with the sulphonamides and native U-II ligands sharing a common UT receptor binding domain. 4. SB-706375 was a potent, competitive hU-II antagonist across species with pK(b) 7.29-8.00 in HEK293-UT receptor cells (inhibition of [Ca(2+)](i)-mobilization) and pK(b) 7.47 in rat isolated aorta (inhibition of contraction). SB-706375 also reversed tone established in the rat aorta by prior exposure to hU-II (K(app) approximately 20 nM). 5. SB-706375 was a selective U-II antagonist with >/=100-fold selectivity for the human UT receptor compared to 86 distinct receptors, ion channels, enzymes, transporters and nuclear hormones (K(i)/IC(50)>1 microM). Accordingly, the contractile responses induced in isolated aortae by KCl, phenylephrine, angiotensin II and endothelin-1 were unaltered by SB-706375 (1 microM). 6. In summary, SB-706375 is a high-affinity, surmountable, reversible and selective nonpeptide UT receptor antagonist with cross-species activity that will assist in delineating the pathophysiological actions of U-II in mammals.

Urotensin-II is purported to influence pulmonary function by modulating smooth muscle tone/growth. In the present study, Northern blot and reverse transcription polymerase chain reaction (RT-PCR) analysis indicated the presence of UT receptor mRNA in cat trachea, bronchi and lung parenchyma. Urotensin-II contracted cat isolated trachea and bronchi with similar potencies (pEC(50)s 8.61+/-0.07-8.81+/-0.10). Contractile efficacies ranged from 19+/-9% to 63+/-11% KCl in the primary and secondary bronchi. The peptidic UT receptor antagonists BIM-23127, SB-710411 and GSK248451 (7.18+/-0.12, 7.52+/-0.08 and 9.05+/-0.16 cat recombinant UT pK(i)s) inhibited urotensin-II-induced contraction of cat isolated trachea with pK(b)s 6.36+/-0.11, 6.74+/-0.07 and 9.27+/-0.12, respectively. As such, feline lung contains significant amounts of UT mRNA and this receptor appears to be functionally coupled to bronchoconstriction (the peptidic tool compound GSK248451 representing a sub-nanomolar inhibitor of such effects). These findings suggest that the cat represents a suitable species for future studies designed to assess the effects of the urotensin-II receptor on pulmonary (patho)physiology.

Inflammation plays an important role in the initiation and progression of atherosclerosis and the development of atherosclerotic events. Understanding the molecular basis of inflammation has led to the identification of markers that may also serve as new targets of therapy in the management of atherothrombotic disease. Inflammatory markers, such as C-reactive protein (CRP), have been shown to predict future cardiovascular events in individuals with and without established cardiovascular disease (CVD). Statins substantially reduce cardiovascular morbidity and mortality, and recently their anti-inflammatory properties have been investigated. In this paper, we discuss biomarkers implicated in the inflammatory process leading to atherothrombosis, including CRP, adiponectin, monocyte chemoattractant protein 1 (MCP-1), CD40 ligand and lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), and the effect of statins on these markers and their potential relationship to cardiovascular events.

The mechanisms of atheroma formation and their ensuing complications and methods by which these can be detected have been the focus of several in vitro, in vivo, and clinical studies. Myeloperoxidase (MPO) is a microbicidal hemoprotein that serves as a part of the neutrophils' armory in host defense. However, the oxidation products generated by MPO have now been shown to be related to various stages of atheroma development. MPO and its oxidant products have been shown to be capable of modifying low-density lipoprotein cholesterol and to be enriched in human atheromas and rupture-prone plaques. Clinical studies have suggested an association between levels of MPO and the presence of coronary artery disease and endothelial dysfunction, and have shown a possible additional role to troponin in patients with chest pain.

High-sensitivity C-reactive protein (CRP), a nonspecific marker of inflammation, is a newly available biomarker for predicting the risk of cardiovascular events. CRP has been shown to predict risk of cardiovascular events independent of traditional risk factors and in the setting of low levels of low-density lipoprotein cholesterol. Statins have been shown to decrease CRP, and studies are now under way to evaluate if targeting patients with high CRP and low low-density lipoprotein cholesterol will have any impact on future cardiovascular events and survival and whether changes in CRP correlate to event reduction. The utility of CRP as a target of therapy remains to be proved, and these ongoing studies will likely provide us with guidance.

The challenge of medical practice today is to identify individuals who are at risk of developing disease, determine the severity of the disease and distinguish the responders from the nonresponders to therapy (individualized medicine). Advances in molecular genetics and biology have shifted the paradigm for identification of markers from large-scale epidemiologic studies to studies on genomic- and proteomic-based techniques. Consequently, a large number of biologic markers, referred to as biomarkers, are being identified and validated to serve for risk stratification, prognostication and individualization of therapy. Identification of biomarkers for cardiovascular diseases could also provide insight into the pathogenesis of the phenotype, which is fundamental for the development of specific therapies. The list of biomarkers for cardiovascular disease is expanding rapidly. Nonetheless, the field is in the early stages of evolution and large-scale clinical studies are required to validate the utility of newly identified biomarkers in diagnosis, risk stratification and treatment of cardiovascular diseases. Selected biomarkers for coronary atherosclerosis, acute coronary syndromes and heart failure are discussed in this review.

Although each revision of the US National Cholesterol Education Program guidelines has made increasing provision for the use of global risk assessment in determining need for and intensity of therapy, the guidelines' continued focus on low-density lipoprotein (LDL) cholesterol may result in inadequate or no treatment for individuals at high risk for coronary artery disease (CAD) who do not have substantially elevated LDL cholesterol. However, recent clinical trial evidence has shown that high-risk patients benefit from lipid-regulating therapy regardless of LDL cholesterol level. In the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm, high-risk hypertensive patients had reductions in clinical events despite not having substantially elevated LDL cholesterol at baseline. These results suggest that all hypertensive patients with additional risk factors should receive lipid-regulating statin therapy to prevent CAD events.

1 In an effort to identify endogenous, native mammalian urotensin-II (U-II) receptors (UT), a diverse range of human, primate and rodent cell lines (49 in total) were screened for the presence of detectable [125I]hU-II binding sites. 2 UT mRNA (Northern blot, PCR) and protein (immunocytochemistry) were evident in human skeletal muscle tissue and cells. 3 [(125)I]hU-II bound to a homogenous population of high-affinity, saturable (Kd 67.0+/-11.8 pm, Bmax 9687+/-843 sites cell(-1)) receptors in the skeletal muscle (rhabdomyosarcoma) cell line SJRH30. Radiolabel was characteristically slow to dissociate (< or =15% dissociation 90 min). A lower density of high-affinity U-II binding sites was also evident in the rhabdomyosarcoma cell line TE671 (1667+/-165 sites cell(-1), Kd 74+/-8 pm). 4 Consistent with the profile recorded in human recombinant UT-HEK293 cells, [125I]hU-II binding to SJRH30 cells was selectively displaced by both mammalian and fish U-II isopeptides (Kis 0.5+/-0.1-1.2+/-0.3 nm) and related analogues (hU-II[4-11]>[Cys(5,10)]Acm hU-II; Kis 0.4+/-0.1 and 864+/-193 nm, respectively). 5 U-II receptor activation was functionally coupled to phospholipase C-mediated [Ca2+]i mobilization (EC50 6.9+/-2.2 nm) in SJRH30 cells. 6 The present study is the first to identify the presence of 'endogenous' U-II receptors in SJRH30 and TE671 cells. SJRH30 cells, in particular, might prove to be of utility for (a) investigating the pharmacological properties of hU-II and related small molecule antagonists at native human UT and (b) delineating the role of this neuropeptide in the (patho)physiological regulation of mammalian neuromuscular function.

SB-710411 (Cpa-c[d-Cys-Pal-d-Trp-Lys-Val-Cys]-Cpa-amide) inhibited [(125)I]urotensin-II rat and monkey UT receptor binding (pK(i)s 7.50+/-0.07 and 6.82+/-0.06). However, whereas SB-710411 antagonized urotensin-II-induced inositol phosphate formation at the rat UT receptor (pK(b) 6.54+/-0.05), this ligand functioned as an agonist at the monkey UT receptor (pEC(50) 6.56+/-0.35, E(max) 5.27+/-0.65-fold over basal). Indeed, in contrast to the rat UT receptor (and rat isolated arteries), SB-710411 exhibited intrinsic activity in monkey arteries acting as an efficacious vasoconstrictor (pEC(50)s 5.03+/-0.18 to 5.71+/-0.21, E(max)s 101+/-4 to 218+/-58% KCl). These data demonstrate that caution must be taken when extrapolating the pharmacology of a specific ligand(s) between the rodent and primate UT receptors.

The goal of a therapeutic intervention should be to positively impact a meaningful patient outcome. Too often, though, efficacy of a treatment is based on a surrogate endpoint. Thrombolytic therapy for venous thromboembolic disease is an example of a treatment whose success is primarily based on radiographic or echocardiographic endpoints and not endpoints such as symptom relief, functional capacity, quality of life, thrombosis recurrence, and survival. Thrombolysis for lower-extremity deep venous thrombosis does not reduce the incidence of pulmonary embolism, has unclear impact on the rates of post-thrombotic syndrome, and is associated with increased rates of major hemorrhage compared to conventional anticoagulation. Reserving thrombolysis for limb-threatening thrombosis especially in the young seems prudent. Currently available evidence does not support the routine use of thrombolytic therapy in patients with hemodynamically stable pulmonary embolism regardless of right ventricular function status. Risks, benefits, and alternative therapies must always be considered, and therapy must be guided by individual case circumstances and the best available scientific evidence.

We report the production and characterization of four monoclonal antibodies (MAbs) against human urotensin-II (hU-II). The antibodies were raised against human hU-II, which contains the C-terminus cyclic ring (CFWKYC) that is conserved across species. Multiple selection assays were applied to ensure antibody potency and reactivity against the ring structure. The MAbs reacted via ELISA with hU-II bound to plastic, immunoprecipitated [(125)I-Y(9)] hU-II, bound to biotinylated hU-II in BIAcore analysis and, by Western analysis, recognized the full-length human preprourotensin-II expressed in transfected HEK293 cells. All four MAbs cross-reacted with porcine A, porcine B, rat, mouse, and goby U-II in ELISA. By competitive RIA, hU-II(5-11) (identical to the C-terminus of goby U-II) reacted equivalently to hU-II and goby U-II. The IC(50)s were 0.8 nM for one MAb and 1.6 nM for the others. All four MAbs reacted 15-fold less potently with hU-II(5-10) and 50-fold less potently with hU-II(5-10) amide. Thus, the ring structure and terminal Val/Ile comprise the binding site for this group of MAbs. This panel of antibodies could be useful tools to help delineate the biology and pharmacology of U-II. They may also be of diagnostic value in monitoring hU-II in body fluids.

Background: Inflammation is linked to adverse outcomes in acute coronary syndromes. Myeloperoxidase, an abundant leukocyte enzyme, is elevated in culprit lesions that have fissured or ruptured in patients with sudden death from cardiac causes. Numerous lines of evidence suggest mechanistic links between myeloperoxidase and both inflammation and cardiovascular disease., Methods: We assessed the value of plasma levels of myeloperoxidase as a predictor of the risk of cardiovascular events in 604 sequential patients presenting to the emergency department with chest pain., Results: Initial plasma myeloperoxidase levels predicted the risk of myocardial infarction, even in patients who are negative for troponin T (<0.1 ng per milliliter) at base line (P<0.001). Myeloperoxidase levels at presentation also predicted the risk of major adverse cardiac events (myocardial infarction, the need for revascularization, or death) within 30 days and 6 months after presentation (P<0.001). In patients without evidence of myocardial necrosis (defined as those who were negative for troponin T), the base-line myeloperoxidase levels independently predicted the risk of major adverse coronary events at 30 days (unadjusted 2nd, 3rd, and 4th quartile odds ratios, 2.2 [95 percent confidence interval, 1.1 to 4.6], 4.2 [95 percent confidence interval, 2.1 to 8.4], and 4.1 [95 percent confidence interval, 2.0 to 8.4], respectively) and at 6 months., Conclusions: A single initial measurement of plasma myeloperoxidase independently predicts the early risk of myocardial infarction, as well as the risk of major adverse cardiac events in the ensuing 30-day and 6-month periods. Myeloperoxidase levels, in contrast to troponin T, creatine kinase MB isoform, and C-reactive protein levels, identified patients at risk for cardiac events in the absence of myocardial necrosis, highlighting its potential usefulness for risk stratification among patients who present with chest pain., (Copyright 2003 Massachusetts Medical Society)

This study tested the hypothesis that prolonged QRS duration independently predicts long-term mortality in patients who underwent risk stratification and treatment for ventricular arrhythmias. Patients who underwent risk stratification by electrophysiologic study were identified. Electrophysiologic study results were defined as positive if sustained monomorphic ventricular tachycardia was induced. Mortality was the primary end point. Of 915 patients studied, mean left ventricular (LV) ejection fraction (EF) was 35.3 +/- 15.7%, 608 (66.4%) had coronary artery disease, 233 (25.5%) had positive electrophysiologic study findings, 298 (32.6%) received implantable cardioverter-defibrillators, and 174 (19%) died (mean follow-up 35.0 +/- 15.0 months). Cox regression analysis identified older age, coronary artery disease, digoxin use, absence of beta blockers, lower LVEF, and prolonged QRS duration to be independent predictors of mortality. QRS duration > or =130 ms, present in 33.6% of patients, was associated with a twofold increase in mortality (hazard ratio 2.1, 95% confidence interval 1.5 to 2.8; p <0.0001). For every 10 ms increase in QRS duration, mortality rate increased 10%. In a subgroup of patients with coronary artery disease and LVEF < or =30%, prolonged QRS duration remained an independent predictor of mortality (hazard ratio 2.6, 95% confidence interval 1.6 to 4.2; p <0.0001). Thus, prolonged QRS duration is a strong independent marker of long-term mortality in patients who undergo risk stratification for ventricular arrhythmias. Whether QRS duration represents only a marker for mortality or if modification of this factor using resynchronization therapies will impact mortality merits further study.

Background: Statins have become a mainstay in the treatment of hyperlipidemia, based on their potency and favorable side-effect profile. Drug choice is presumed to be guided by the estimated degree of low-density lipoprotein (LDL) cholesterol lowering required in a particular patient and the projected efficacy of any drug-dose combination, as contained in the package inserts for each medication. We investigated whether these expectations were met in a clinical practice., Methods: Data were analyzed for 367 hyperlipidemic patients in a preventive cardiology practice who were not taking statins at entry, who were given a standard statin dose at their first visit, and who had at least one follow-up visit on the same drug/dose. Expected LDL cholesterol reductions were calculated for each patient based on guidelines in the package inserts for each drug., Results: The mean (+/-SD) observed LDL cholesterol reduction of 26% +/- 20% was significantly less than expected (34% +/- 7%, P < 0.001). The ratio of observed to expected reduction was not different for the three statins used (atorvastatin, 0.79 +/- 0.48; simvastatin, 0.88 +/- 0.61; pravastatin, 0.75 +/- 0.69; P = 0.39)., Conclusions: The use of statins in a clinical practice led to observed reductions in LDL cholesterol level that were significantly less than those projected by package insert guidelines. We believe this gap reflects the reduced patient compliance frequently observed in clinical practice settings, rather than any inherent difference in statin responsiveness of a practice versus a trial population. Physicians should be aware of this disparity when using statins in the clinical setting.

The National Cholesterol Education Program recognizes the importance of the metabolic syndrome and has published guidelines for its diagnosis. Weight loss, physical activity, and treatment of the individual risk factors constitute the main strategies for treatment. For now, the goals and methods of treating hypertension and dyslipidemia are the same in people with the metabolic syndrome as in the general population. Thiazolidinedione drugs increase insulin sensitivity, but their use in the metabolic syndrome is only speculative at present. We recommend they be used only as indicated to treat diabetes mellitus.

Urotensin-II (U-II) and its receptor (UT) represent novel therapeutic targets for management of a variety of cardiovascular diseases. To test such hypothesis, it will be necessary to develop experimental animal models for the manipulation of U-II/UT receptor system. The goal of this study was to clone mouse and primate preproU-II and UT for pharmacological profiling. Monkey and mouse preproU-II genes were identified to encode 123 and 125 amino acids. Monkey and mouse UT receptors were 389, and 386 amino acids, respectively. Genomic organization of mouse genes showed that the preproU-II has four exons, while the UT receptor has one exon. Although initially viewed by many exclusively as cardiovascular targets, the present study demonstrates expression of mouse and monkey U-II/UT receptor mRNA in extra-vascular tissue including lung, pancreas, skeletal muscle, kidney and liver. Ligand binding studies showed that [125I]h U-II bound to a single sites to the cloned receptors in a saturable/high affinity manner (Kd 654+/-154 and 214+/-65 pM and Bmax of 1011+/-125 and 497+/-68 fmol mg-1 for mouse and monkey UT receptors, respectively). Competition binding analysis demonstrated equipotent, high affinity binding of numerous mammalian, amphibian and piscine U-II isopeptides to these receptors (Ki=0.8 - 3 nM). Fluorescein isothiocyanate (FITC) labelled U-II, bound specifically to HEK-293 cells expressing mouse or monkey UT receptor, confirming cell surface expression of recombinant UT receptor. Exposure of these cells to human U-II resulted in an increase in intracellular [Ca2+] concentrations (EC50 3.2+/-0.8 and 1.1+/-0.3 nM for mouse and monkey UT receptors, respectively) and inositol phosphate (Ip) formation (EC50 7.2+/-1.8 and 0.9+/-0.2 nM for mouse and monkey UT receptors, respectively) consistent with the primary signalling pathway for UT receptor involving phospholipase C activation.