Validation of NICE diagnostic guidance for rule out of myocardial infarction using high-sensitivity troponin tests.

OBJECTIVE: To validate the National Institute for Health and Care Excellence (NICE) recommended algorithms for high-sensitivity troponin (hsTn) assays in adults presenting with chest pain. METHODS: International post hoc analysis of three prospective, observational studies from tertiary hospital emergency departments. The primary endpoint was cardiac death or acute myocardial infarction (AMI) within 24 hours of presentation, and the secondary endpoint was major adverse cardiac events (MACE) at 30 days. RESULTS: 15% of patients were diagnosed with non-ST elevation myocardial infarction (MI) on admission. The hsTnI algorithm classified 2506/3128 (80.1%) of patients as 'ruled out' with 50 (2.0%) missed MI. 943/3128 (30.1%) of patients had a troponin I level below the limit of detection on admission with 2 (0.2%) missed MI. For the hsTnT algorithm, 1794/3374 (53.1%) of patients were 'ruled out' with 7 (0.4%) missed MI. 490/3374 (14.5%) of patients had a troponin T below the limit of blank on admission with no MI. MACE at 30 days occurred in 10.7% and 8.5% of patients 'ruled out' defined by the hsTnI and hsTnT algorithms, respectively. CONCLUSIONS: The NICE algorithms could identify patients with low probability of AMI within 2 hours; however, neither strategy performed as predicted by the NICE diagnostic guidance model. Additionally, the rate of MACE at 30 days was sufficiently high that the algorithms should only be used as one component of a more extensive model of risk stratification. TRIAL REGISTRATION NUMBER: ACTRN12611001069943, NCT00470587; post-results.

Human heart beta-adrenoceptors: beta1-adrenoceptor diversification through 'affinity states' and polymorphism.

1. In atrium and ventricle from failing and non-failing human hearts, activation of beta(1)- or beta(2)-adrenoceptors causes increases in contractile force, hastening of relaxation, protein kinase A-catalysed phosphorylation of proteins implicated in the hastening of relaxation, phospholamban, troponin I and C-protein, consistent with coupling of both beta(1)- and beta(2)-adrenoceptors to stimulatory G(salpha)-protein but not inhibitory G(ialpha)-protein. 2. Two 'affinity states', namely beta(1H) and beta(1L), of the beta(1)-adrenoceptor exist. In human heart, noradrenaline elicits powerful increases in contractile force and hastening of relaxation. These effects are blocked with high affinity by beta-adenoceptor antagonists, including propranolol, (-)-pindolol, (-)-CGP 12177 and carvedilol. Some beta-blockers, typified by (-)-pindolol and (-)-CGP 12177, not only block the receptor, but also activate it, albeit at much higher concentrations (approximately 2 log units) than those required to antagonize the effects of catecholamines. In human heart, both (-)-CGP 12177 and (-)-pindolol increase contractile force and hasten relaxation. However, the involvement of the beta(1)-adrenoceptor was not immediately obvious because (-)-pindolol- and (-)-CGP 12177-evoked responses were relatively resistant to blockade by (-)-propranolol. Abrogation of cardiostimulant effects of (-)-CGP 12177 in beta(1)-/beta(2)-adrenoceptor double-knockout mice, but not beta(2)-adrenoceptor-knockout mice, revealed an obligatory role of the beta(1)-adrenoceptor. On the basis of these results, two 'affinity states' have been designated, the beta(1H)- and beta(1L)-adrenoceptor, where the beta(1H)-adrenoceptor is activated by noradrenaline and blocked with high affinity by beta-blockers and the beta(1L)-adrenoceptor is activated by drugs such as (-)-CGP 12177 and (-)-pindolol and blocked with low affinity by beta-blockers such as (-)-propranolol. The beta(1H)- and beta(1L)-adrenoceptor states are consistent with high- and low-affinity binding sites for (-)-[(3)H]-CGP 12177 radioligand binding found in cardiac muscle and recombinant beta(1)-adrenoceptors. 3. There are two common polymorphic locations of the beta(1)-adrenoceptor, at amino acids 49 (Ser/Gly) and 389 (Arg/Gly). Their existence has raised several questions, including their role in determining the effectiveness of heart failure treatment with beta-blockers. We have investigated the effect of long-term maximally tolerated carvedilol administration (> 1 year) on left ventricular ejection fraction (LVEF) in patients with non-ischaemic cardiomyopathy (mean left ventricular ejection fraction 23 +/- 7%; n = 135 patients). The administration of carvedilol improved LVEF to 37 +/- 13% (P < 0.005); however, the improvement was variable, with 32% of patients showing pound 5% improvement. Upon segregation of patients into Arg389Gly-beta(1)-adrenoceptors, it was found that carvedilol caused a greater increase in left ventricular ejection faction in patients carrying the Arg389 allele with Arg389Arg > Arg389Gly > Gly389Gly.

Beneficial haemodynamic effects of insulin in chronic heart failure.

OBJECTIVE: To characterise the central and regional haemodynamic effects of insulin in patients with chronic heart failure. DESIGN: Single blind, placebo controlled study. SETTING: University teaching hospital. PATIENTS: Ten patients with stable chronic heart failure. INTERVENTIONS: Hyperinsulinaemic euglycaemic clamp and non-invasive haemodynamic measurements. MAIN OUTCOME MEASURES: Change in resting heart rate, blood pressure, cardiac output, and regional splanchnic and skeletal muscle blood flow. RESULTS: Insulin infusion led to a dose dependent increase in skeletal muscle blood flow of 0.36 (0.13) and 0.73 (0.14) ml/dl/min during low and high dose insulin infusions (p < 0.05 and p < 0.005 v placebo, respectively). Low and high dose insulin infusions led to a fall in heart rate of 4.6 (1.4) and 5.1 (1.3) beats/min (p < 0.05 and p < 0.005 v placebo, respectively) and a modest increase in cardiac output. There was no significant change in superior mesenteric artery blood flow. CONCLUSION: In patients with chronic heart failure insulin is a selective skeletal muscle vasodilator that leads to increased muscle perfusion primarily through redistribution of regional blood flow rather than by increased cardiac output. These results provide a rational haemodynamic explanation for the apparent beneficial effects of insulin infusion in the setting of heart failure.