Alan Bagnall

The endothelin system as a therapeutic target in cardiovascular disease: great expectations or bleak house?

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 ETA 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.

The endothelin system as a therapeutic target in cardiovascular disease

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 ETA 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.

Deletion of Endothelial Cell Endothelin B Receptors Does Not Affect Blood Pressure or Sensitivity to Salt

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.

Temporal management patterns and outcomes of non-ST elevation acute coronary syndromes in patients with kidney dysfunction.

AIMS To examine: (i) the temporal changes in the management pattern; (ii) the reasons for any treatment disparities; (iii) the relationship between invasive treatment and outcome, among acute coronary syndrome (ACS) patients with vs. without kidney dysfunction. METHODS AND RESULTS Canadian ACS I, ACS II registries and Global Registry of Acute Coronary Events (GRACE) were prospective, multi-centre, observational studies of patients with ACS. From 1999 to 2007, non-ST elevation (NSTE) ACS patients were recruited in ACS I (n = 3295; 1999-2001), ACS II (n = 1956; 2002-2003), and GRACE (n = 6491; 2004-2007) in Canada. Using the four-variable Modified Diet in Renal Disease equation, we stratified the study population (n = 11,377) into three groups based on their estimated glomerular filtration rate (eGFR), and examined their treatment and outcome. While in-hospital use of coronary angiography and revascularization increased over time in all groups (P < 0.001), patients with kidney dysfunction were less likely to undergo invasive management (P < 0.001). Unadjusted 1 year mortality was lower among patients receiving in-hospital coronary angiography within all eGFR categories (> or =60 mL/min/1.73 m(2): 2.5 vs. 7.6%, P < 0.001; 30-59 mL/min/1.73 m(2): 8.0 vs. 14.6%, P < 0.001; <30 mL/min/1.73 m(2): 27.5 vs. 41.5%, P = 0.043). In-hospital revascularization was independently associated with lower 1-year mortality (adjusted OR = 0.52, 95% CI 0.36-0.77, P = 0.001), irrespective of eGFR (P for heterogeneity = 0.39). Underestimation of patient risk was the most common barrier to an invasive treatment strategy. CONCLUSION 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.

Influence of Age on Use of Cardiac Catheterization and Associated Outcomes in Patients With Non-ST-Elevation Acute Coronary Syndromes

Randomized controlled trials support the use of an early invasive strategy in high-risk patients with non-ST-segment elevation (NSTE) acute coronary syndromes (ACS). Although risk increases with age, limited data are available to support this strategy in older patients. The aims of this study were to examine temporal trends in the management and outcomes of NSTE ACS in elderly patients and to explore reasons for the lower use of early angiography in the aged population. Data from 11,732 patients with NSTE ACS were collected from 3 consecutive Canadian registries (ACS I, ACS II, and Global Registry of Acute Coronary Events [GRACE]/GRACE2) from 1999 to 2007. Rates of in-hospital cardiac catheterization, revascularization, infarction or reinfarction, and death were stratified by age (<65, 65 to 74, and > or = 75 years). Although overall, rates of in-hospital catheterization and revascularization increased over time (p <0.001), the largest increase occurred in patients aged <65 years. The strongest independent negative predictor of the use of cardiac catheterization was age > or = 75 years (adjusted odds ratio 0.45, 95% confidence interval 0.37 to 0.56, p <0.001). Use of an early invasive approach was associated with a reduction in 1-year mortality across all age groups, but the absolute difference was greatest in patients aged > or = 75 years. The underestimation of risk by physicians (ascertained in ACS II) was the most common reason for choosing a conservative strategy. In conclusion, despite an overall increased use of an early invasive strategy, elderly patients with NSTE ACS remain significantly less likely to undergo cardiac catheterization and revascularization and are often erroneously perceived to be at low risk by their physicians. Future studies should determine whether more aggressive treatment of these high-risk elderly patients improves outcomes.

Endothelial cell-specific ETB receptor knockout: autoradiographic and histological characterisation and crucial role in the clearance of endothelin-1

Inactivation of endothelin B receptors (ETB), either through selective pharmacological antagonism or genetic mutation, increases the circulating concentration of endothelin-1 (ET-1), suggesting ETB plays an important role in clearance of this peptide. However, the cellular site of ETB-mediated clearance has not yet been determined. We have used a novel mouse model of endothelial cell-specific knockout (KO) of ETB (EC ETB(-/-)) to evaluate the relative contribution of EC-ETB to the clearance of ET-1. Phenotypic evidence of EC-specific ETB KO was confirmed by immunocytochemistry and autoradiography. Binding of the radiolabelled selective ETB ligand BQ3020 was significantly and selectively decreased in EC-rich tissues of EC ETB(-/-) mice, including the lung, liver, and kidney. By contrast, ETA binding was unaltered. RT-PCR confirmed equal expression of ET-1 in tissue from EC ETB(-/-) mice and controls, despite increased concentration of plasma ET-1 in EC ETB(-/-). Clearance of an intravenous bolus of [(125)I]ET-1 was impaired in EC ETB(-/-) mice. Pretreatment with the selective ETB antagonist A192621 impaired [(125)I]ET-1 clearance in control animals to a similar extent, but did not further impair clearance in EC ETB(-/-) mice. These studies suggest that EC-ETB are largely responsible for the clearance of ET-1 from the circulation.

Impact of thrombus aspiration during primary percutaneous coronary intervention on mortality in ST-segment elevation myocardial infarction

AIMS To assess the impact of thrombus aspiration during primary percutaneous coronary intervention (PPCI) on the mortality of patients with ST-elevation myocardial infarction (STEMI) patients. METHODS AND RESULTS Retrospective analysis of prospectively collected data on 2567 consecutive PPCI-treated STEMI patients between 2008 and 2011. Cox proportional hazard models and multiple logistic regression analysis were used to adjust for known covariates. Thrombectomy was performed in 1095 patients (42.7%). Post-PPCI thrombolysis in myocardial infarction 3 flow was more frequently achieved in the thrombectomy group [adjusted odds ratio (OR); 1.92, 95% confidence interval (CI): 1.34-2.76, P = 0.0004]. Overall in-hospital and longer term (mean follow-up 9.9 months) mortality rates were 4.5 and 9.0%, respectively. Thrombectomy was associated with a significant reduction in in-hospital (adjusted OR: 0.51, 95% CI: 0.29-0.93, P = 0.027) and longer term mortality [adjusted hazard ratio (HR): 0.69, 95% CI: 0.48-0.96, P = 0.028]. With propensity weighting, the adjusted HR for longer term mortality for thrombectomy was 0.43 (95% CI: 0.19-0.97; P = 0.042). The association between thrombectomy and reduced longer term mortality was only significant in those with a total ischaemic time ≤180min (P = 0.001) but not in patients with a total ischaemic time >180min (P = 0.99). CONCLUSION This study of real-world, unselected STEMI patients demonstrates that thrombus aspiration during PPCI is associated with a significant reduction in mortality, especially in those with a short total ischaemic time. These findings support the use of thrombectomy during PPCI in this group of patients.

Optimal Medical Therapy for Non–ST-Segment–Elevation Acute Coronary Syndromes Exploring Why Physicians Do Not Prescribe Evidence-Based Treatment and Why Patients Discontinue Medications After Discharge

Background—Acute coronary syndrome (ACS) patients in the highest risk categories are least likely to receive evidence-based treatments (EBTs). We sought to determine why physicians do not prescribe EBTs for patients with non–ST-segment–elevation ACSs and the factors determining use of these treatments after 1 year. Methods and Results—One thousand nine hundred fifty-six non–ST-segment-elevation ACS patients were enrolled in the prospective, multicenter Canadian ACS registry II between October 2002 and December 2003. Each patients physician gave reasons why guideline-indicated medication(s) was not prescribed during hospitalization. Medication use and reason(s) for discontinuation after 1 year were obtained by telephone interview of the patients. The commonest reason for not prescribing EBTs was “not high-enough risk” or “no evidence/guidelines to support use.” However, Global Registry of Acute Coronary Events scores of patients not treated for this reason were often similar to or higher than those of patients prescribed such treatment. After 1 year, 77% of patients not on optimal ACS treatment at discharge remained without optimal treatment, and overall antiplatelet, &bgr;-blocker, and angiotensin-converting enzyme inhibitor use declined. Approximately one third of patients not taking EBTs had stopped their medication without instruction from their doctor. Conclusions—Nonprovision of EBTs may be due to subjective underestimation of patient risk and hence, likely treatment benefit. Oversights in care delivery were also apparent. Objective risk stratification, combined with efforts to ensure provision and adherence to EBTs, should be encouraged.

T lymphocytes and fractalkine contribute to myocardial ischemia/reperfusion injury in patients

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 (r2 = 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. TRIAL REGISTRATION Not applicable. FUNDING British Heart Foundation (FS/12/31/29533) and National Institute of Health Research (NIHR) Newcastle Biomedical Research Centre.

Mortality outcome of out-of-hours primary percutaneous coronary intervention in the current era

AIMS To assess the impact of the time of primary percutaneous coronary intervention (PPCI) on in-hospital and long-term all-cause mortality in ST-segment elevation myocardial infarction (STEMI). METHODS AND RESULTS The study retrospectively analyses the prospectively collected data on 2571 consecutive PPCI-treated STEMI patients between March 2008 and June 2011. Of these, 1036 patients (40.3%) underwent PPCI during a weekday between 08:00 and 18:00 (routine-hours group) and 1535 patients (59.7%) underwent PPCI on a weekday between 18:00 and 08:00 or a weekend (out-of-hours group). Compared with the routine-hours group, the out-of-hours group had a lower mean age, fewer patients with previous angina, longer call-to-hospital time, and fewer multivessel PCI. The overall in-hospital mortality rate was 4.5% with no significant difference [0.2%, 95% confidence interval (CI): -1.4 to 1.9%] between the routine-hours group (4.3%) and the out-of-hours group (4.6%) (adjusted odds ratio: 1.33, 95% CI: 0.73-2.40, P = 0.35). During a mean follow-up period of 560 days, 295 patients (11.5%) died, 12.2% in the routine-hours group and 11.0% in the out-of-hours group (difference of -0.1%, 95% CI: -0.4 to 0.2%). In the multiple Cox proportional hazards model, there was no difference in mortality between the two groups (adjusted hazard ratio: 1.09, 95% CI: 0.82-1.46, P = 0.57). Similarly, no increase in mortality was seen in patients who underwent PPCI later at night (22:00-06:00). CONCLUSION This study of real-world, unselected STEMI patients demonstrates that in a large, well-staffed centre, PPCI outside routine-working hours is safe with no difference in outcome of in-hospital and long-term mortality compared with PPCI during routine-working hours.