A combination of increased Rho kinase activity and N-terminal pro-B-type natriuretic peptide predicts worse cardiovascular outcome in patients with acute coronary syndrome

Abstract

Background: Recent experimental evidence suggests that the Rho/Rho-kinase (ROCK) system may play an important role in the pathogenesis of acute coronary syndrome (ACS) but there are little clinical data. This study examined if ROCK activity is increased in patients with acute coronary syndrome and if ROCK activity predicts long-term cardiovascular event.

Method: Blood samples were collected from 188 patients within 12h after admission for ACS (53% men; aged 70 ± 13) and from 61 control subject. The main outcome measures were all cause mortality, readmission with ACS or congestive heart failure (CHF) from presentation within around 2 years (mean:14.4 ± 7.2 months; range: 0.5 to 26 months).

Results: ROCK activity increased in ST elevation myocardial infarction (STEMI, n=90) (3.33 ± 0.93), non-STEMI (NSTEMI, n=68) (3.37 ± 1.04) and unstable angina (UA, n=30) (2.53 ± 0.59) groups when compared with disease controls (n=31) (2.06 ± 0.38, all p<0.001) and healthy controls (n=30) (1.54 ± 0.43, all p<0.001). There were 24 deaths, 34 readmissions with ACS and 15 admissions with CHF within 2 years. Patients with a high N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high ROCK activity on admission had a five-fold risk of a cardiovascular event (RR: 5.156; 95% CI: 2.180-12.191) when compared to those with low NT-proBNP and low ROCK activity.

Conclusion: ROCK activity was increased in patients with ACS, particularly in those with myocardial infarction. The combined usage of both ROCK activity and NT-proBNP might identify a subset of ACS patients at particularly high risk.

Keywords: ACS; ANOVA; Acute coronary syndrome; BH; BMI; BW; Body height; Body mass index; Body weight; C-reactive protein; CHD; CHF; CIHD; CPK; CRP; CVA; Cardiac troponin T; Cardio vascular accidents; Congestive heart failure; Coronary heart disease; Coronary ischemic heart disease; Creatine phosphokinase; DBP; DM; Diabetes mellitus; Diastolic blood pressure; Estimated Glomerular Filtration Rate; GRACE; Global Registry of Acute Coronary Events; HDL-C; HR; Heart rate; High-density lipoprotein cholesterol; LDL-C; LVEF; Left ventricular ejection fraction; Low-density lipoprotein cholesterol; N-terminal pro-B-type natriuretic peptide; NSTEMI; NT-proBNP; Non-ST elevation myocardial infarction; One-way analysis of variance; PCI; Percutaneous coronary intervention; ROCK; ROCK activity; Rho kinase; Rho kinase activity; SBP; ST elevation myocardial infarction; STEMI; Systolic blood pressure; TC; TG; Total cholesterol; Triglycerides; UA; Unstable angina; WBC; White blood cells; cTnT; eGFR.

Fig. 1

Comparison of ROCK activity in different ACS groups, disease and normal control groups.

Fig. 2

Expression of ROCK1 and ROCK2 protein levels in different groups. ROCK1/actin and ROCK2/actin in STEMI and NSTEMI were significantly higher than that in UA, disease and normal controls (all p<0.001). ROCK1/actin and ROCK2/actin in UA were significantly higher than that in disease and normal controls (all p<0.001). However, no significant difference of ROCK1 and ROCK2 between STEMI and NSTEMI, similarly between disease and normal controls.

Fig. 3

Kaplan–Meier survival curves for cardiovascular events. High NT-proBNP defined as 1986 pg/ml (sensitivity is 63.8% and specificity is 67.3%) and high ROCK activity defined as 3.03 (sensitivity is 56.5% and specificity is 56.7%). High NT-proBNP-high ROCK activity group has higher risk (RR: 5.156; 95% CI: 2.180 to 12.191) to low NT-proBNP-low ROCK activity group. Similarly, high NT-proBNP-high ROCK activity group has higher risk (RR: 2.624; 95% CI: 1.035 to 6.651) to high NT-proBNP-low ROCK activity group. Log rank=20, p<0.001.