Elevated baseline cardiac troponin levels in the elderly - another variable to consider?

AIMS: This study aimed to determine the frequency of baseline high-sensitivity troponin T (hs-TnT) elevation in different age groups presenting to the Emergency Department without acute coronary syndromes (ACS) or other acute illnesses known to cause to troponin elevation. We additionally sought to determine whether the relationship between age and hs-TnT was independent of co-morbidities. METHODS: We retrospectively analysed data on all patients presenting to the Emergency Department (ED) between November 2010 and June 2011 in whom hs-TnT was measured. Patients presenting with acute coronary syndromes (ACS) or other acute illness known to elevate hs-TnT levels were excluded. Demographics, clinical characteristics and diagnosis were recorded, together with hs-TnT assay results. RESULTS: Of 3219 patients with hs-TnT testing in the ED during the study period, 526 with proven/suspected ACS and 1376 with other acute medical conditions known to elevate troponin concentrations were excluded. The percentage of patients with hs-TnT concentrations elevated above the upper reference limit (>14ng/L) increased with age: <50 years (1.8%), 50-69 years (7.3%), ≥70 years (41.5%), p=0.001. Multivariate analysis identified age over 70 years (p<0.001) as the strongest independent predictor of elevated hs-TnT. Other independent predictors included atrial fibrillation (p<0.001), age 50-69 years (p<0.001) male gender (p<0.001), previous heart failure (p<0.007) and previous ischaemic heart disease (p<0.04). CONCLUSIONS: Hs-TnT elevations (>14ng/L) are common in elderly patients presenting to the ED without ACS or other acute illnesses known to cause to troponin elevation. This finding appears to be independent of the higher burden of co-morbidities in this age group.

Myocardial stress remodelling after regional infarction is independent of glycogen synthase kinase-3 inactivation.

Phosphorylation and inactivation of glycogen synthase kinase 3 (GSK-3) is observed in the failing heart induced by chronic pharmacological stress and aortic banding. Constitutive kinase activity attenuates pathological remodelling, suggesting an obligatory role in stress signalling. However, this has been challenged by recent data whereby conditional GSK-3ß deletion has been shown to protect against post-infarct remodelling. Here, we set out to determine the chronic remodelling response to infarction in hearts of GSK-3α/ß(Ala21/9) knockin (KI) mice encoding constitutively active GSK-3 isoforms. At 4 weeks after infarction there were significant increases in normalised heart weight and left ventricular (LV) muscle volume compared to sham in both KI and wild type animals. This was associated with an increase in LV cavity dimensions and remote LV wall thickness. Hypertrophy in both genotypes resulted in marked contractile impairment on both invasive and non-invasive interrogation. Increased phosphorylation of GSK-3ß, but not GSK-3α, was demonstrated at 1 week after infarction and remained elevated at 4 weeks compared to sham-treated hearts. In conclusion, GSK-3ß phosphorylation and inactivation occurs with, but is not an obligatory signalling event in, chronic post-infarct remodelling in the mouse heart. This highlights the heterogeneity of pathological hypertrophy and the divergent role of GSK-3 signalling in chronic myocardial stress.

Glycogen synthase kinase-3 inactivation is not required for ischemic preconditioning or postconditioning in the mouse.

The inactivation of glycogen synthase kinase-3beta (GSK-3beta) is proposed as the event integrating protective pathways initiated by preconditioning and other interventions. The inactivation of GSK-3 is thought to decrease the probability of opening of the mitochondrial permeability transition pore. The aim of this study was to verify the role of GSK-3 using a targeted mouse line lacking the critical N-terminal serine within GSK-3beta (Ser9) and the highly homologous GSK-3alpha (Ser21), which when phosphorylated results in kinase inactivation. Postconditioning with 10 cycles of 5 seconds of reperfusion/5 seconds of ischemia and preconditioning with 6 cycles of 4 minutes of ischemia/6 minutes of reperfusion, similarly reduced infarction of the isolated perfused mouse heart in response to 30 minutes of global ischemia and 120 minutes of reperfusion. Preconditioning caused noticeable inactivating phosphorylation of GSK-3. However, both preconditioning and postconditioning still protected hearts of homozygous GSK-3 double knockin mice. Moreover, direct pharmacological inhibition of GSK-3 catalytic activity with structurally diverse inhibitors before or after ischemia failed to recapitulate conditioning protection. Nonetheless, cyclosporin A, a direct mitochondrial permeability transition pore inhibitor, reduced infarction in hearts from both wild-type and homozygous GSK-3 double knockin mice. Furthermore, in adult cardiac myocytes from GSK-3 double knockin mice, insulin exposure was still as effective as cyclosporin A in delaying mitochondrial permeability transition pore opening. Our results, which include a novel genetic approach, suggest that the inhibition of GSK-3 is unlikely to be the key determinant of cardioprotective signaling in either preconditioning or postconditioning in the mouse.

Constitutive glycogen synthase kinase-3alpha/beta activity protects against chronic beta-adrenergic remodelling of the heart.

AIMS: Glycogen synthase kinase 3 (GSK-3) signalling is implicated in the growth of the heart during development and in response to stress. However, its precise role remains unclear. We set out to characterize developmental growth and response to chronic isoproterenol (ISO) stress in knockin (KI) mice lacking the critical N-terminal serines, 21 of GSK-3alpha and 9 of GSK-3beta respectively, required for inactivation by upstream kinases. METHODS AND RESULTS: Between 5 and 15 weeks, KI mice grew more rapidly, but normalized heart weight and contractile performance were similar to wild-type (WT) mice. Isolated hearts of both genotypes responded comparably to acute ISO infusion with increases in heart rate and contractility. In WT mice, chronic subcutaneous ISO infusion over 14 days resulted in cardiac hypertrophy, interstitial fibrosis, and impaired contractility, accompanied by foetal gene reactivation. These effects were all significantly attenuated in KI mice. Indeed, ISO-treated KI hearts demonstrated reversible physiological remodelling traits with increased stroke volume and a preserved contractile response to acute adrenergic stimulation. Furthermore, simultaneous pharmacological inhibition of GSK-3 in KI mice treated with chronic subcutaneous ISO recapitulated the adverse remodelling phenotype seen in WT hearts. CONCLUSION: Expression of inactivation-resistant GSK-3alpha/beta does not affect eutrophic myocardial growth but protects against pathological hypertrophy induced by chronic adrenergic stimulation, maintaining cardiac function and attenuating interstitial fibrosis. Accordingly, strategies to prevent phosphorylation of Ser-21/9, and consequent inactivation of GSK-3alpha/beta, may enable a sustained cardiac response to chronic beta-agonist stimulation while preventing pathological remodelling.