Arginine Vasopressin Plays a Role in Microvascular Dysfunction After ST-Elevation Myocardial Infarction

Abstract

Background Coronary microvascular dysfunction (CMD) predicts mortality after ST-elevation-myocardial infarction (STEMI). Arginine vasopressin (AVP) may be implicated, but data in humans are lacking, and no study has investigated the link between arginine vasopressin and invasive measures of CMD. Methods and Results We invasively assessed CMD in 55 patients with STEMI treated with primary percutaneous coronary intervention (PPCI), by measuring the index of microcirculatory resistance after PPCI. In a separate group of 45 patients with STEMI/PPCI, recruited for a clinical trial, we measured infarct size and microvascular obstruction with cardiac magnetic resonance (CMR) imaging at 1 week and 12 weeks post-STEMI. Serum copeptin was measured at 4 time points before and after PPCI in all patients with STEMI. Plasma copeptin levels fell from 92.5 pmol/L before reperfusion to 6.4 pmol/L at 24 hours. Copeptin inversely correlated with diastolic, but not systolic, blood pressure (r=-0.431, P=0.001), suggesting it is released in response to myocardial ischemia. Persistently raised copeptin at 24 hours was correlated with higher index of microcirculatory resistance (r=0.372, P=0.011). Patients with microvascular obstruction on early CMR imaging showed a trend toward higher admission copeptin, which was not statistically significant. Copeptin levels were not associated with infarct size on either early or late CMR. Conclusions Patients with CMD after STEMI have persistently elevated copeptin at 24 hours, suggesting arginine vasopressin may contribute to microvascular dysfunction. Arginine vasopressin receptor antagonists may represent a novel therapeutic option in patients with STEMI and CMD.

Keywords: acute myocardial infarction; copeptin; microvascular dysfunction; microvascular obstruction.

Figure 1. Plasma concentration of five hormones and copeptin from pre‐reperfusion to 24 hours post‐reperfusion.

A, Median plasma concentrations of 5 hormones during acute ST‐segment–elevation myocardial infarction (STEMI) and reperfusion (n=13). B, Median plasma concentration of copeptin during STEMI and reperfusion in two cohorts (n=100 for 0 minutes, 30 minutes, and 24 hours; n=45 for 90 minutes; n=55 for 180 minutes). 0 minutes represents the value immediately before reperfusion with primary percutaneous coronary intervention, other time points are after reperfusion. ACTH indicates adrenocorticotropic hormone; ANP, atrial natriuretic peptide; AVP, arginine vasopressin; and CRH, corticotropin‐releasing hormone. Values at 0 minutes and 24 hours compared using the Wilcoxon matched‐pairs signed rank test. Error bars represent interquartile range.

Figure 2. Variables associated with admission copeptin value.

A, Relationship between admission copeptin concentration and admission serum troponin T and onset‐to‐reperfusion time (n=100). Both showed a negative correlation with admission copeptin concentration. B, Relationship between admission copeptin concentration and blood pressure (n=55). Only patients in the IMR cohort had admission blood pressure data available. Diastolic, but not systolic, blood pressure showed a significant negative correlation with admission copeptin concentration. Correlations determined with Spearman's rho. P<0.05 considered significant. IMR indicates index of microcirculatory resistance.

Figure 3. Copeptin concentration and objective measures of coronary microvascular dysfunction.

A, Trend of copeptin before and after reperfusion in patients with STEMI, comparing those with evidence of coronary microvascular dysfunction (CMD) on invasive testing (IMR >40, n=22; CFR <2, n=23) with those without (IMR ≤40, n=33; CFR ≥2, n=31). Copeptin was significantly higher at 24 hours in patents with CMD. B, Trend of copeptin in similar patients, comparing those with microvascular obstruction (MVO) on cardiac magnetic resonance imaging (n=20) and those without (n=25). Hypothesis testing was with Mann–Whitney U test. P<0.05 was considered significant. CFR indicates coronary flow reserve; IMR, index of microcirculatory resistance; and STEMI, ST‐segment–elevation myocardial infarction.