The association between early ventricular arrhythmias, renin-angiotensin-aldosterone system antagonism, and mortality in patients with ST-segment-elevation myocardial infarction: Insights from Global Use of Strategies to Open coronary arteries (GUSTO) V.

BACKGROUND: The long-term prognostic significance of early (<48 hours) ventricular fibrillation (VF) or sustained ventricular tachycardia (VT) in patients with an acute myocardial infarction remains controversial. Emerging data suggest that some of the benefit of renin-angiotensin-aldosterone system (RAAS) antagonism may be derived from a reduction in the incidence of these arrhythmias in the setting of acute myocardial infarction. METHODS: We assessed the relationship between early VF/VT (defined as within 48 hours after admission) and mortality in 16,588 patients from global use of strategies to open coronary arteries (GUSTO) V trial. Furthermore, we examined the relationship between baseline use of angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB), early VF/VT, and mortality. RESULTS: Early VF or VT occurred in 732 (4.4%) patients. Compared to patients without VF/VT, those experiencing early VF or VT had a significant increase in 30-day mortality (22% vs 5%, P < .001). Baseline use of an ACEI/ARB was associated with a decreased incidence of early VF/VT (odds ratio 0.65, 0.47-0.89, P = .008). A lower 30-day mortality was seen in patients with early VF/VT on baseline ACEI/ARB compared with patients with early VF/VT not receiving an ACEI/ARB at baseline (17.7% vs 24.2%, respectively, P = .04). The association between baseline RAAS antagonism and mortality persisted after adjustment for multiple confounders. CONCLUSIONS: In patients presenting with acute myocardial infarction, early VF/VT identifies those at increased risk for 30-day mortality. Baseline use of RAAS antagonists is associated with a reduced incidence of malignant arrhythmias. Identifying how this association impacts short-term mortality in this patient population requires further prospective evaluation.

High molecular weight neurofilament proteins are physiological substrates of adduction by the lipid peroxidation product hydroxynonenal.

Protein adducts of the lipid peroxidation product trans-4-hydroxy-2-nonenal (HNE) are features of oxidative damage in neuronal cell bodies in Alzheimer's disease but are also seen in axons of normal as well as diseased individuals. In this study, focusing on the axons of the mouse sciatic nerve, we found that HNE adducts characterize axons of mice from birth to senility. Immunoblots of axonal proteins showed that HNE adducts are only detected in neurofilament heavy subunit (NFH) and, to a lesser extent, neurofilament medium subunit (NFM), both lysine-rich proteins, consistent with the adducts being limited to lysine residues. In vitro, HNE treatment of permeabilized sciatic nerve showed the same specificity, i.e. NFH and NFM are the only proteins that reacted with HNE, providing they are phosphorylated. Quantitative immunoblot analysis of two strains of mice ages 1-33 months showed that the levels of HNE adducts on NFH are consistent throughout life. Additionally, mice transgenic for human superoxide dismutase-1 with G85R mutation show no difference in HNE adduction to NFH compared with controls. Taken together, these studies indicate that HNE adduction to NFH is physiological, and its constancy from birth to senility as well as its dependence on phosphorylation argues that NFH and NFM modification may play a role in protecting the membrane-rich axon from toxic aldehydes resulting from oxidative damage.